Evolving Approaches to Improve Outcomes & Minimize Txicities in Radiation Therapy (2002)

Evolving Approaches to Improve Outcomes and Minimize Toxicities in Radiation TherapySan Francisco, Calif., USA, November 4, 2001

24 figures and 17 tables, 1999

Guest Editor

Gillian M. Thomas, Toronto, Canada

Basel � Freiburg � Paris � London � New York �

Bangalore � Bangkok � Singapore � Tokyo � Sydney

Supported by an educational grant from Ortho Biotech Products L.P.

S. KargerMedical and Scientific PublishersBasel � Freiburg � Paris � LondonNew York � Bangalore � BangkokSingapore � Tokyo � Sydney

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Vol. 63, Suppl. 2, 2002

1 Foreword

Thomas, G.M. (Toronto)

2 Radioprotectants: Current Status and New Directions

Grdina, D.J.; Murley, J.S.; Kataoka, Y. (Chicago, Ill.)

11 Prevalence of Anemia in Cancer Patients Undergoing Radiotherapy:

Prognostic Significance and Treatment

Harrison, L.B.; Shasha, D.; Homel, P. (New York, N.Y.)

19 Raising Hemoglobin: An Opportunity for Increasing Survival?

Thomas, G.M. (Toronto)

29 New Chemotherapeutic Agents: Update of Major Chemoradiation Trials

in Solid Tumors

Curran, W.J. (Philadelphia, Pa.)

Contents

© 2002 S. Karger AG, Basel

Fax + 41 61 306 12 34 Access to full text and tables of contents,E-Mail [email protected] including tentative ones for forthcoming issues:www.karger.com www.karger.com/ocl_issues

Oncology 2002;63(suppl 2):1DOI: 10.1159/00067144

Foreword

Gillian M. ThomasRadiation Oncology, Obstetrics & GynecologyUniversity of TorontoToronto-Sunnybrook Regional Cancer CentreToronto, Onta. (Canada)

ABCFax + 41 61 306 12 34E-Mail [email protected]

© 2002 S. Karger AG, Basel0030–2414/02/0636–0001$18.50/0

Accessible online at:www.karger.com/ocl

A variety of techniques are now available to radiationoncologists to optimize treatment of cancers, includingaltered fractionation schedules, enhanced image guidance,intensity modulation allowing radiation dose escalationand improved brachytherapy techniques. In recent years,there has been increasing interest in the concurrent orsequential use of chemotherapeutic agents with radiosensi-tizing ability to enhance the effectiveness of radiotherapy.These agents include cisplatin, 5-fluorouracil, taxanes, to-potecan, gemcitabine, vinorelbine, and tirapazamine. Incertain malignancies (e.g., non-small-cell lung cancer, headand neck cancers, esophageal cancer and cervical cancer),concurrent chemotherapy and radiotherapy protocols haveresulted in better tumor control and/or patient survivalthan with radiotherapy alone. The review by Dr. Curran inthis supplement provides an update of recent clinical trialsin this area, and emphasizes that while much has beenachieved in the quest for new combined modality regimenscapable of improving the outcomes for patients with can-cer, important questions concerning the selection of pa-tients, and the optimal dosages and timing of sequentialtherapies remain to be answered in future studies.

Other evolving approaches to optimizing radiotherapyinclude the use of radioprotectants to reduce radio-therapy-induced toxicity without affecting its antitumorefficacy, cytotoxic agents such as mitomycin C to specifi-cally target hypoxic tumor cells, and strategies to counteranemia such as treatment with epoetin alfa (recombinanthuman erythropoietin). It is postulated that anemia incancer patients may result in a poor treatment outcomebecause of an increased resistance to radiation or chemo-therapy. Radioprotectants currently under investigationinclude amifostine (WR-1065), which has been shown inexperimental studies to prevent both radiation-inducedcell death and radiation-induced mutagenesis. Moreover,this agent reduced the incidence of early and late radio-therapy-induced xerostomia in a multicenter clinical

study of patients with head and neck cancers. Otherpotential applications of amifostine are reviewed in thearticle by Dr. Grdina and colleagues, along with recentadvances in the development of newer cytoprotectants toreduce the acute and chronic toxicities associated withhigh-dose treatment strategies and aggressive combinedmodality protocols.

The occurrence of anemia in cancer patients is an oftenoverlooked complicating factor that is associated withpoorer outcome possibly by decreasing the response toradiotherapy, presumably via lowering the oxygen-carry-ing capacity of the blood and thus exacerbating intratu-moral hypoxia. In addition, anemia has an adverse effecton the quality of life of cancer patients, as evidenced bythe increased fatigue that has been associated with lowhemoglobin levels. Studies in various types of cancershave indicated that a high proportion of patients areanemic prior to or during radiotherapy, and that lowhemoglobin levels are associated with poor clinical out-comes with radiotherapy. As emphasized in other articlesin this supplement, these findings underline the impor-tance of early detection and treatment of anemia in cancerpatients. Administration of epoetin alfa to correct anemiahas been reported to enhance locoregional response ratesto chemoradiation therapy in patients with certain typesof cancers (e.g., oropharyngeal squamous cell carcinomas)and to improve quality of life. Whether epoetin alfa thera-py will also increase long-term survival is currently beinginvestigated. Other ongoing studies are investigatingwhether epoetin alfa may also be effective in protectingagainst radiotherapy-induced neurotoxicity.

The challenge for the future is to utilize our presentknowledge to optimize the management of cancer pa-tients undergoing radiotherapy or combined modalityprotocols with the objective of improving both the out-come of treatment and quality of life.

Gillian M. Thomas

Oncology 2002;63(suppl 2):2–10DOI: 10.1159/000067146

Radioprotectants: Current Status andNew Directions

David J. Grdina Jeffrey S. Murley Yasushi Kataoka

Department of Radiation and Cellular Oncology, The University of Chicago, Chicago, Ill., USA

David J. GrdinaDepartment of Radiation and Cellular OncologyUniversity of Chicago Medical Center, MC 11055841 S. Maryland Avenue, Chicago, IL 60637 (USA)Tel. +1 773 702 5250, Fax +1 773 702 5940, E-Mail [email protected]


© 2002 S. Karger AG, Basel0030–2414/02/0636–0002$18.50/0


Key WordsCytoprotection W Radiotherapy W Radiation-inducedtoxicity W Mutagenesis W Amifostine W Thiol compounds

AbstractThe ability to prevent radiotherapy-induced toxicity with-out affecting antitumor efficacy has the potential toenhance the therapeutic benefit for cancer patients with-out increasing their risk of serious adverse effects.Among the currently available cytoprotective agents ca-pable of protecting normal tissue against damagecaused by either chemo- or radiotherapy, only amifos-tine has been shown in clinical trials to reduce radiation-induced toxicity. Most notably, it reduces the incidenceof xerostomia, which is a clinically significant long-termtoxicity arising in patients undergoing irradiation of headand neck cancers. In vitro studies with the active metabo-lite of amifostine (WR-1065) have shown it to preventboth radiation-induced cell death and radiation-inducedmutagenesis. The potential of this agent to prevent sec-ondary tumors, as well as other radiation-induced toxici-ties is now the focus of ongoing research. Among othernovel approaches to radioprotection being explored aremethods to increase levels of the antioxidant mito-chondrial enzyme manganese superoxide dismutase

(MnSOD). In addition, the use of epoetin alfa, alone or incombination with cytoprotectants (e.g., amifostine), totreat radiation-induced anemia is also being investi-gated. The objective of developing newer cytoprotectivetherapies is to improve the therapeutic ratio by reducingthe acute and chronic toxicities associated with moreintensive and more effective anticancer therapies.

Copyright © 2002 S. Karger AG, Basel

Introduction

Radiotherapy is toxic not only toward cancer cells butalso to healthy cells, particularly those with a high rate ofproliferation, which may result in serious adverse effectsfor patients. The risk of cell toxicity is increased with theapplication of more intensive radiotherapy techniquesintended to increase tumor cell kill. Radiation-inducedadverse effects commonly include mucositis and/or der-matitis, and are usually managed symptomatically as theymanifest. However, preventing these complications isclearly more desirable, and various approaches to reduc-ing radiation-induced toxicities while maintaining antitu-mor efficacy have been investigated. These include al-tered radiation dose fractionation, the use of physicalshielding or intensity modulated radiation therapy to

Prevention of Radiation-Induced Toxicity Oncology 2002;63(suppl 2):2–10 3

reduce the volume of exposure, and pharmacologic ap-proaches. The latter can be divided into radiosensitizerswhich ideally differentially enhance the sensitivity oftumors rather than normal tissue, and radioprotectants toreduce the detrimental effects of radiation on normal tis-sue while maintaining tumor sensitivity [1, 2]. This articlereviews the current status of radioprotectants in cancertherapy and provides an insight into some of the newdirections that research in this area is taking.

Typical response curves illustrating the probability oftumor control and normal tissue damage at varying radia-tion doses are shown in figure 1. The objective of radio-protection is to shift the response curve for normal tissueas far as possible to the right to achieve the highest proba-bility of tumor control with the least amount of damage tonormal tissue. The ideal radioprotectant is one that pro-tects normal tissue while preserving antitumor effective-ness, and is itself without moderate or severe toxicity.

Pharmacologic Strategies for Cytoprotectionof Normal Cells

In recent years, a number of cytoprotective agentscapable of protecting normal tissue against damagecaused by either chemo- or radiotherapy have been devel-oped. As a result of studies implicating toxic metabolitesof chemotherapeutic agents and/or the generation of high-ly reactive species or free radicals in the etiology of DNAdamage [3–5], a number of different strategies have beenproposed for cytoprotection of normal cells, including:E preventing the generation of toxic metabolites of che-

motherapeutic agents;E enhancing the elimination of toxic metabolites of che-

motherapeutic agents;E neutralizing DNA adduct-forming metabolites;E detoxifying free radicals.

A number of compounds have been investigated withthe objective of providing site-specific protection for nor-mal tissues without compromising the antitumor efficacyof chemotherapeutic agents and/or radiotherapy, includ-ing amifostine (WR-2721), dexrazoxane, mesna, gluta-thione, and N-acetylcysteine. Among these, amifostine,dexrazoxane and mesna have FDA approval for use incytoprotection.

AmifostineAmifostine (WR-2721) is a nucleophilic sulfur prodrug

that is dephosphorylated in vivo by membrane-boundalkaline phosphatase to the active, free thiol metabolite

Fig. 1. Tumor and normal tissue response curves to radiotherapy,illustrating the probability of tumor control and normal tissue dam-age at varying radiation doses (reproduced with permission fromHall [12]).

100

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orm

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WR-1065. This metabolite is then oxidized to the disul-fide form WR-33278 [4–6]. Numerous preclinical studieshave shown that amifostine protects normal cells againstthe adverse effects of both radiation and chemotherapeut-ic agents (e.g., alkylating agents, platinum compounds,anthracyclines and taxanes) without attenuating their cy-totoxic effects on large solid tumors. This selective protec-tion is due, in part, to the more efficient conversion anduptake of the active metabolite WR-1065 in normal tissuein comparison with neoplastic tissue, as a result of thehigher alkaline phosphatase activity, greater vasculariza-tion, and higher pH of normal tissue [4–6].

Following intravenous administration, amifostine israpidly and extensively taken up by normal tissue. Ani-mal studies have indicated that maximal concentrationsof the active metabolite WR-1065 occur 5–15 min afteradministration [7]. Uptake of WR-1065 in normal tissueis not uniform, and appears to be greatest in the kidney,salivary glands, intestinal mucosa, liver and lung [6].Once inside the cell, WR-1065 protects against chemo-therapy- and radiotherapy-induced DNA damage by (1)binding to and neutralizing the reactive species of organo-platinum and alkylating agents, thus preventing forma-tion of adducts with DNA, and (2) scavenging free radi-cals [5–7].

4 Oncology 2002;63(suppl 2):2–10 Grdina/Murley/Kataoka

Table 1. Net charges of thiol compounds with putative cytoprotec-tive activity

Compound Net charge

WR-33278 (disulfide metabolite of amifostine) +4WR-1065 (free thiol metabolite of amifostine) +2Cystamine +2Cysteamine +1Captopril 0Dithiothreitol (DTT) 02-Mercaptoethanol (2-ME) 0N-Acetyl-L-cysteine (L-NAC) –1N-Acetyl-D-cysteine (D-NAC) –1Mesna –1Glutathione, reduced (GSH) –1Glutathione, oxidized (GSSG) –2

The efficacy of amifostine in protecting cancer patientsagainst radiotherapy-induced toxicity is discussed below.Currently, amifostine has FDA approval to reduce theincidence of xerostomia in patients undergoing radiationtreatment for head and neck cancers. It is also approved toreduce cumulative renal toxicity associated with cisplatintreatment in patients with ovarian cancer or non-small-cell lung cancer.

DexrazoxaneDexrazoxane (ICRF-187) is a cyclic derivative of the

metal-chelating agent ethylenediamine-tetraacetic acid(EDTA) that provides protection against the cardiotoxici-ty of anthracycline-based chemotherapeutic agents, suchas doxorubicin. Although the risk of cardiotoxicity ap-pears to be reduced with newer formulations, such aspeglyated liposomal doxorubicin [8], cardiotoxicity is awell-recognized, serious, treatment-limiting adverse ef-fect of these compounds. It occurs via the generation ofreactive oxygen species, which are highly toxic to cardiactissues, by the stable complexes formed between anthra-cycline drugs and iron [9]. The cardioprotective effect ofdexrazoxane is believed to result from its intracellularmetabolism to a ring-opened hydrolysis product (ICRF-198), which is a strong chelator of free and bound intracel-lular iron in the myocardium. As a consequence, theamount of iron available to form complexes with anthra-cyclines is reduced and formation of the reactive oxygenspecies is blocked. Importantly, the protective effect ofdexrazoxane against the cardiotoxicity of anthracyclinedrugs occurs without affecting their antitumor activity.This may be due, in part, to differences in the intracellular

metabolism of dexrazoxane and/or differences in its uptakebetween normal cardiac cells and tumor cells [5, 9–11].

Currently, dexrazoxane has FDA approval to reducethe incidence and severity of cardiomyopathy associatedwith doxorubicin administration in women with meta-static breast cancer who have received cumulative doses1300 mg/m2.

MesnaMesna (sodium 2-mercaptoethane sulfonate) was de-

veloped as a specific chemoprotectant against the toxicityof acrolein, a urotoxic metabolite of oxazaphosphorine-based alkylating agents (e.g., ifosfamide and cyclophos-phamide), which produces hemorrhagic cystitis followingits excretion into the urinary bladder. Following intrave-nous administration, mesna is converted into an inactivedisulfide form in the blood and is then metabolized backto mesna in the urinary tract where its free sulfhydrylgroups bind to and inactivate acrolein, forming a stable,non-toxic thioether that is rapidly excreted in the urine.Mesna also inhibits the further formation of acrolein inthe bladder. Because its activity is restricted to the urinarytract, the systemic activity and non-urologic toxicity ofoxazaphosphorine drugs are not affected [4, 5].

Currently, mesna has FDA approval for the prophylax-is of ifosfamide-induced hemorrhagic cystitis.

Relationship Between the Net Charge of ThiolCompounds and Their Ability to ProtectAgainst Radiation-Induced DNA Damage

The mechanism by which radiation induces DNAdamage is slightly different to that of chemotherapeuticagents. Radiation-induced damage is introduced into agenome by either a direct action, where the energy isdeposited directly on the genome, or indirectly via the for-mation of free radicals which are responsible for the resul-tant cell killing, mutagenesis, transformation, and carci-nogenesis. The latter mechanism, which accounts forabout 75% of radiation-induced DNA damage by pho-tons, can be abrogated with free radical scavengerspresent in the local microenvironment at the time the freeradicals are formed. However, in the case of direct dam-age, there are no known radioprotectants as this processoccurs too rapidly to be prevented by a pharmacologicagent [12].

Studies performed several years ago by Fahey et al.have shown that the net charge of thiol compounds withputative cytoprotective activity (table 1) markedly in-


Fig. 2. Response to varying doses of 60Co Á-radiation of V79 Chinesehamster lung fibroblast cells in the absence or presence of WR-10654 mmol/l added to cell cultures 30 min before irradiation and allowedto remain until 3 h after irradiation. a Surviving fraction of cells.b Mutation induction at the HPRT (hypoxanthine-guanine phospho-ribosyl transferase) locus among surviving cells that were grown in anon-selective medium for 6 days and then exposed to 6-thioguanine5 Ìg/ml in ·-MEM-10 medium (containing hypoxanthine, aminop-terin and thymidine) for 7 days and stained with 0.5% methyleneblue. Bars indicate the standard errors of the mean of two or morereplicate experiments (reproduced with permission from Grdina etal. [15]).

0 2 4 6 8 10 1260

Co � dose (Gy)

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Fig. 3. Response to varying doses of 60Co Á-radiation of V79 Chinesehamster lung fibroblast cells exposed immediately after irradiation toWR-1065 4 mmol/l added to cell cultures and allowed to remain for3 h. a Surviving fraction of cells. b Mutation induction at the HPRT(hypoxanthine-guanine phosphoribosyl transferase) locus among sur-viving cells (assessed as described in fig. 2). The broken lines repre-sent the radiation-only curves and are presented for comparison.Bars represent the standard errors of the mean of two or more repli-cate experiments (reproduced with permission from Grdina et al.[15]).

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fluences the degree of protection that they provide againstthe DNA-damaging effects of radiation [13, 14]. BecauseWR-1065 has a net charge of +2, it will be attracted toDNA (which is negatively charged) and is therefore morelikely to exert a protective effect against radiation-induced damage than a compound with a net charge of 0or a negative net charge. Evidence in support of thishypothesis has come from studies with WR-1065, capto-pril, and N-acetylcysteine in Chinese hamster lung fibro-blast and ovary cells.

Protective Effect of WR-1065 (Amifostine Metabolite)Studies in our institution using V79 Chinese hamster

lung fibroblast cells have shown that WR-1065 in a con-centration of 4 mmol/l protects against radiation-inducedcell death when added to cell cultures 30 min before var-ious doses of 60Co Á-radiation, but not when it is addedimmediately after irradiation (fig. 2a, 3a). This treatment-schedule dependence in the protective effect of WR-1065is to be expected if it is acting as a free radical scavenger,since protection could only be expected to occur when thecompound is present during irradiation [15].


Fig. 4. Surviving fractions of Chinese hamster ovary (CHO)-AA8cells exposed to varying doses of 60Co Á-radiation in the absence orpresence of captopril 1 mmol/l added to the cell cultures 30 min priorto irradiation (Grdina DJ, unpubl. data).

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Fig. 5. Surviving fractions of Chinese hamster ovary (CHO)-AA8cells exposed to varying doses of 60Co Á-radiation in the absence orpresence of N-acetylcysteine 0.04 mmol/l and 4 mmol/l added to thecell cultures 30 min prior to irradiation (Grdina DJ, unpubl. data).

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Radiation + 0.04 mmol/l N-acetylcysteine

As well as increasing the surviving fraction of cellswhen administered before irradiation, WR-1065 has alsobeen shown to reduce the degree of radiation-inducedmutagenesis in V79 Chinese hamster lung fibroblast cells(expressed as the HPRT mutant frequency per 106 survi-vors exposed to 6-thioguanine 5 Ìg/ml) (fig. 2b). In con-trast to the treatment-schedule dependence for the protec-tive effect against cell killing, the antimutagenic effect ofWR-1065 is also observed when it is administered afterirradiation (fig. 3b), indicating that its post-irradiationaction can effectively alter mutation induction in surviv-ing cells [16].

Lack of Protective Effect of Captopril andN-AcetylcysteineBecause the net charges of captopril and N-acetylcys-

teine are 0 and –1, respectively, these thiol compoundswould not be expected to concentrate within the nega-tively charged nucleus or the microenvironment of DNAto the same extent as those with positive net charges.Studies using Chinese hamster ovary (CHO)-AA8 cellsexposed to various doses of 60Co Á-radiation in theabsence or presence of captopril 1 mmol/l and N-acetyl-cysteine 0.04 mmol/l or 4 mmol/l have shown no evidence

of a protective effect against radiation-induced cell killingwith either drug (fig. 4, 5) [Grdina DJ, unpubl. data].

Thus, key factors governing the radioprotective effica-cy of a drug acting as free radical scavenger are: (1) anability to concentrate within the nucleus or microenviron-ment of DNA (dependent on its net charge), and (2) thepresence of the protectant at the radiation target at thetime it is irradiated (important for prevention of celldeath). No clinical advantage is achieved if the protectordoes not differentially protect normal tissues compared totumor.

Dose-Response Considerations withAmifostine: Prevention of Cell Death vsPrevention of Mutagenesis

The protection factor achievable with a radioprotec-tant is defined as the ratio of surviving cell fraction fortreated cells as compared with untreated cells followingradiation exposure. The clinical potential of a putativeradioprotectant depends on the tolerability of the drug ata dosage required to achieve a particular protection fac-tor. In studies conducted at our institution using CHO-


AA8 cells, the protection factor for cell survival with theamifostine metabolite WR-1065 (i.e., the ratio of cell sur-viving fractions for WR-1065-treated versus untreatedcells) was determined at various concentrations of WR-1065 added to the incubation medium 30 minutes priorto exposure to a radiation dose of 750 cGy from a 60CoÁ-ray source. As shown in figure 6, the protection factorfell sharply from 16 to around 3 as the concentration ofWR-1065 was decreased from 4 to 1 mmol/l, and thendeclined further to essentially no protection at lower con-centrations of 0.01–0.1 mmol/l. In contrast, the protec-tion against mutagenesis (expressed as the HPRT mutantfrequency per 106 survivors exposed to 6-thioguanine 5Ìg/ml) remained largely constant over the same WR-1065concentration range (0.01–4 mmol/l). This suggests thatthe mechanism by which WR-1065 provides protectionagainst mutagenesis differs from that for protectionagainst cell killing, and that the antimutagenic effectcan be achieved at lower concentrations (as low as0.01 mmol/l) [16].

Viewed in relation to therapeutic use of amifostine, theconcentrations of WR-1065 achieved with dosages of am-ifostine used clinically are in the range 1.5–3.85 mmol/l[17], which suggests that the degree of cytoprotection pro-vided at antimutagenic dosages are insufficient to in-crease survival of either normal or neoplastic cells. How-ever, its effect in reducing the risk of radiation-inducedmutagenesis, carcinogenesis, and secondary tumors is ofconsiderable interest and this area is now an importantfocus for ongoing research into the protective effects ofamifostine, particularly in view of increasing evidencethat the risk of secondary tumors is increased as cancertherapies become more effective and, coincidentally,more damaging to normal tissues.

Clinical Studies of Amifostine as aRadioprotectant

Clinical trials of the radioprotective effect of amifos-tine have been undertaken in patients receiving radiother-apy for head and neck, pelvic, and thoracic cancers [6].Thus far, most studies have involved relatively smallnumbers of patients but have generally demonstrated sig-nificant reductions in the incidence of radiation-inducedlocal toxicities. In the largest trial conducted to date, theefficacy of amifostine in ameliorating the adverse effectsof radiotherapy and its influence on the clinical effective-ness of radiotherapy were evaluated in patients with pre-viously untreated head and neck squamous cell carcino-

Fig. 6. Protection factor for survival of Chinese hamster ovary(CHO)-AA8 cells (i.e., the ratio of cell surviving fractions for WR-1065-treated to untreated cells) at varying concentrations of WR-1065 added to the incubation medium 30 min prior to exposure to aradiation dose of 750 cGy from a 60Co Á-ray source. All plot pointsare the average of three separate experiments and the bars representthe standard errors of the mean (reproduced with permission fromGrdina et al. [16]).

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mas [18]. Patients in this multicenter study (n = 303)received radiotherapy in a dose of 1.8 to 2.0 Gy/day for 30to 35 fractions (total dose 50–70 Gy), approximately halfof whom (n = 153) were randomized to receive amifostine(200 mg/m2 intravenously over 3 min) 15 to 30 min be-fore irradiation and half to receive radiotherapy alone(n = 150). As shown in table 2, amifostine significantlyreduced the incidence of both early xerostomia within thefirst 90 days (as well as the cumulative radiotherapy doserequired to cause this adverse effect) and late xerostomiaat 1 year after initiation of radiotherapy, although it didnot significantly reduce the incidence of acute mucositis.Patients who received amifostine were also found to pro-duce more saliva than those treated with radiotherapyalone (median saliva production 0.26 vs 0.10 g; p = 0.04).When overall survival data for the two groups of patientswere compared, there was a slight advantage for thosereceiving amifostine (fig. 7), but the difference was notstatistically significant. Nor was there any significant dif-


Fig. 7. Percentages of survivors over a peri-od of 27 months among patients with pre-viously untreated head and neck squamouscell carcinomas who were randomized toreceive either amifostine (200 mg/m2 i.v.over 3 min) 15–30 min before radiotherapydoses of 1.8–2 Gy/day for 30 to 35 fractions(total 54–70 Gy) or similar doses of radio-therapy alone. The numbers of patients atrisk at 12 and 18 months are indicated inparentheses (reproduced with permissionfrom Brizel et al. [18]).

0

10

20

30

40

50

60

70

80

90

100

0 3 6 9 12 15 18 21 24 27

Months

Per

cen

t su

rviv

al

(119)

(98)

(104)

(124)

Amifostine + radiotherapy 34 153

Radiotherapy alone

Log-rank: p = 0.184

Hazard ratio: 1.351 (95% Cl 0.865 - 2.109)

45 180

Events

Total No.

of patients

Table 2. Incidence of acute and latexerostomia 6grade 2 (RTOG acute/latemorbidity scoring criteria) in patients withhead and neck squamous cell carcinomaswho received radiotherapy with or withoutamifostine (200 mg/m2 i.v. 15–30 minprior to irradiation) [18]

Complication Amifostine plusradiotherapy(n = 153)

Radiotherapyalone(n = 150)

p value

Acute xerostomiaa

Incidence (% of patients) 51% 78% !0.0001Cumulative radiotherapy

dose to onset 60 Gy 42 Gy !0.0001

Late xerostomiab

Incidence (% of patients) 34% 57% !0.002

RTOG = Radiation Therapy Oncology Group.a Within 90 days of initiation of radiotherapy.b At 1 year after initiation of radiotherapy.

ference between the two groups in locoregional tumorcontrol rates. Thus, amifostine significantly reduced acuteand chronic xerostomia in these patients without com-promising the antitumor effectiveness of radiotherapy[18].

Potential Future Applications of Amifostine

Other potential roles for amifostine that are beingexplored include reducing renal toxicity associated withcisplatin treatment in ovarian cancer and non-small-cell

lung cancer and reduction of toxicities associated withdoxorubicin- and paclitaxel-containing regimens, high-dose chemotherapies, and multimodality chemotherapyand radiotherapy for a variety of solid tumors. Possibleprevention of secondary tumors (see above), is also beingexplored. In addition, the observation that amifostinemay stimulate bone marrow progenitor cells has led tostudies of its use as a potential treatment for patients withmyelodysplastic syndrome. As yet, however, clinical dataare limited and its value in this setting remains to be clari-fied [6].


New Advances in Cytoprotection

A number of newer potential radioprotectants are cur-rently undergoing preclinical research, including: (1) Theamifostine analog S-[2-(3-methylaminopropyl) aminoe-thyl] phosphorothioate acid, which is orally bioavailableand less toxic than amifostine; (2) thiolamine compoundswith thioglycoside-protecting groups; (3) covalent conju-gates of thioamines and antioxidant vitamins, and (4) sel-enazolidine prodrugs.

In addition, other approaches to radioprotection arealso being explored. These include altering endogenouslevels of antioxidant enzymes (specifically the mitochon-drial enzyme manganese superoxide dismutase [MnSOD]which protects against oxidative stress induced by variousagents including irradiation), and enhancement of eryth-ropoiesis to treat the anemia that commonly occurs dur-ing irradiation (see review by Harrison in this supple-ment). Novel approaches that are currently being investi-gated include:E The use of MnSOD plasmid/liposome complex gene

therapy to protect against radiation-induced esophagi-tis. Improved tolerance of the esophageal epithelium tofractionated radiation has recently been demonstratedwith this approach in a mouse model [19, 20].

E The use of nonprotein thiol-containing compounds toactivate MnSOD gene expression, e.g., the amifostine

metabolites WR-1065 and WR-33278, N-acetylcys-teine, mesna, captopril, oltipraz, and dithiothreitol[21–23]. In human microvascular endothelial cells,exposure to WR-1065 0.04 mmol/l for 30 min has beenshown to cause an increase in MnSOD gene expressionthat begins about 12 h after exposure to WR-1065,peaks at 16 to 18 h, and ends after about 22 h [21].

E The use of epoetin alfa (recombinant human erythro-poietin; r-HuEPO) alone or in combination with cyto-protectants (e.g., amifostine) to treat radiation-inducedanemia. The interaction of amifostine with epoetinalfa may produce a synergy in gene activation/expres-sion (e.g., of the c-myb gene thereby leading to anincrease in hematopoietic progenitor cells), as well asan increase in myeloproliferation and a reduction ofgenomic instability [24–26].The objective of developing newer cytoprotective ther-

apies is to be able to reduce the acute and cumulative toxi-cities associated with more intensive and more effectivetherapeutic anticancer regimens now being introducedinto clinical practice, whether delivered as radiotherapy,chemotherapy, or combined modality regimens. Themerging of these technologies will, it is hoped, enhancethe therapeutic benefit for cancer patients without in-creasing their risk of serious adverse effects, and thusimproving both their quality and duration of life.

References

1 Curran WJ: Radiation-induced toxicities: therole of radioprotectants. Semin Radiat Oncol1998;8(4 suppl 1):2–4.

2 Brizel DM: Future directions in toxicity pre-vention. Semin Radiat Oncol 1998;8(4 suppl1):17–20.

3 Schuchter LM: Current role of protectiveagents in cancer treatment. Oncology (Hun-tingt) 1997;11:505–512, 515–518.

4 Hoekman K, van der Vijgh WJF, VermorkenJB: Clinical and preclinical modulation of che-motherapy-induced toxicity in patients withcancer. Drugs 1999;57:133–155.

5 Links M, Lewis C: Chemoprotectants: A re-view of their clinical pharmacology and thera-peutic efficacy. Drugs 1999;57:293–308.

6 Culy CR, Spencer CM: Amifostine: an updateon its clinical status as a cytoprotectant inpatients with cancer receiving chemotherapy orradiotherapy and its potential therapeutic ap-plication in myelodysplastic syndrome. Drugs2001;61:641–684.

7 Schuchter LM: Guidelines for the administra-tion of amifostine. Semin Oncol 1996;23(4suppl 8):40–43.

8 Safra T, Muggia F, Jeffers S, Tsao-Wei DD,Groshen S, Lyass O, Henderson R, Berry G,Gabizon A: Pegylated liposomal doxorubicin(doxil): reduced clinical cardiotoxicity in pa-tients reaching or exceeding cumulative dosesof 500 mg/m2. Ann Oncol 2000;11:1029–1033.

9 Wiseman LR, Spencer CM: Dexrazoxane: areview of its use as a cardioprotective agent inpatients receiving anthracycline-based chemo-therapy. Drugs 1998;56:385–403.

10 Hasinoff BB: The iron(III) and copper(II) com-plexes of adriamycin promote the hydrolysis ofthe cardioprotective agent ICRF-187 ((+)-1,2-bis(3,5-dioxopiperazinyl-1-yl)propane). AgentsActions 1990;29:374–381.

11 Koning J, Palmer P, Franks CR, Mulder DE,Speyer JL, Green MD, Hellmann K: Cardio-xane – ICRF-187 towards anticancer drugspecificity through selective toxicity reduction.Cancer Treat Rev 1991;18:1–19.

12 Hall EJ: Radiobiology for the radiologist, ed 5.Philadelphia, Lippincott Williams & Wilkins,2000.

13 Zheng S, Newton GL, Gonick G, Fahey RC,Ward JF: Radioprotection of DNA by thiols:relationship between the net charge on a thioland its ability to protect DNA. Radiat Res1988;114:11–27.

14 Zheng S, Newton GL, Ward JF, Fahey RC:Aerobic radioprotection of pBR322 by thiols:effect of thiol net charge upon scavenging ofhydroxyl radicals and repair of DNA radicals.Radiat Res 1992;130:183–193.

15 Grdina DJ, Nagy B, Hill CK, Wells RL, Perai-no C: The radioprotector WR1065 reduces ra-diation-induced mutations at the hypoxan-thine-guanine phosphoribosyl transferase locusin V79 cells. Carcinogenesis 1985;6:929–931.

16 Grdina DJ, Shigematsu N, Dale P, NewtonGL, Aguilera JA, Fahey RC: Thiol and disul-fide metabolites of the radiation protector andpotential chemopreventive agent WR-2721 arelinked to both its anti-cytotoxic and anti-muta-genic mechanisms of action. Carcinogenesis1995;16:767–774.


17 Shaw LM, Bonner HS, Schuchter L, Schiller J,Lieberman R: Pharmacokinetics of amifostine:effects of dose and method of administration.Semin Oncol 1999;26(2 suppl 7):34–36.

18 Brizel DM, Wasserman TH, Henke M, StrnadV, Rudat V, Monnier A, Eschwege F, Zhang J,Russell L, Oster W, Sauer R: Phase III random-ized trial of amifostine as a radioprotector inhead and neck cancer. J Clin Oncol 2000;18:3339–3345.

19 Epperly MW, Gretton JA, DeFilippi SJ, Green-berger JS, Sikora CA, Liggitt D, Koe G: Modu-lation of radiation-induced cytokine elevationassociated with esophagitis and esophagealstricture by manganese superoxide dismutase-plasmid/liposome (SOD2-PL) gene therapy.Radiat Res 2001;155:2–14.

20 Epperly MW, Kagan VE, Sikora CA, GrettonJE, Defilippi SJ, Bar-Sagi D, Greenberger JS:Manganese superoxide dismutase-plasmid/li-posome (MnSOD-PL) administration protectsmice from esophagitis associated with fraction-ated radiation. Int J Cancer 2001;96:221–231.

21 Murley JS, Kataoka Y, Hallahan DE, RobertsJC, Grdina DJ: Activation of NFkappaB andMnSOD gene expression by free radical scav-engers in human microvascular endothelialcells. Free Radic Biol Med 2001;30:1426–1439.

22 Das KC, Lewis-Molock Y, White CW: Activa-tion of NF-kappa B and elevation of MnSODgene expression by thiol-reducing agents inlung adenocarcinoma (A549) cells. Am J Physi-ol 1995;269(5 Pt 1):L588–L602.

23 Antras-Ferry J, Maheo K, Chevanne M, DubosMP, Morel F, Guillouzo A, Cillard P, Cillard J:Oltipraz stimulates the transcription of themanganese superoxide dismutase gene in rathepatocytes. Carcinogenesis 1997;18:2113–2117.

24 List AF: Use of amifostine in hematologic ma-lignancies, myelodysplastic syndrome, andacute leukemia. Semin Oncol 1999;26(2 suppl7):61–65.

25 Jongen-Lavrencic M, Peeters HR, VreugdenhilG, Swaak AJ: Interaction of inflammatory cy-tokines and erythropoietin in iron metabolismand erythropoiesis in anaemia of chronic dis-ease. Clin Rheumatol 1995;14:519–525.

26 Zhu J, Heyworth CM, Glasow A, Huang QH,Petrie K, Lanotte M, Benoit G, Gallagher R,Waxman S, Enver T, Zelent A: Lineage restric-tion of the RARalpha gene expression in my-eloid differentiation. Blood 2001;98:2563–2567.


Prevalence of Anemia in Cancer PatientsUndergoing Radiotherapy:Prognostic Significance and Treatment

Louis B. Harrisona Daniel Shashaa Peter Homelb

aDepartment of Radiation Oncology, Beth Israel Medical Center/St Luke’s-Roosevelt Hospital Center;bDepartment of Grants and Research, Beth Israel Medical Center, New York, N.Y., USA

Louis B. Harrison, MDDepartment of Radiation Oncology, Beth Israel Medical Center10 Union Square East, New York, NY 10003 (USA)Tel. +1 212 844-8087, Fax +1 212 844-8086E-Mail [email protected]


© 2002 S. Karger AG, Basel0030–2414/02/0636–0011$18.50/0


Key WordsRadiotherapy W Anemia W Hypoxia W Radiation-inducedtoxicity W Epoetin alfa W Quality of life

AbstractAs the antitumor activity of radiation is mediated via itsinteraction with oxygen to form labile free radicals, theintratumoral oxygen level has an important influence onthe ability of radiation therapy to kill malignant cells. Bydecreasing the oxygen-carrying capacity of the blood,anemia may result in tumor hypoxia and may have anegative influence on the outcome of radiotherapy forvarious malignancies, even for small tumors not normal-ly assumed to be hypoxic. In addition, anemia also has anegative effect on the quality of life of cancer patients, asevidenced by worsening fatigue. As a high proportion(about 50%) of cancer patients undergoing radiotherapyare anemic prior to or during treatment, strategies to cor-rect anemia and/or the resultant tumor hypoxia areincreasingly being considered an important componentof treatment. In particular, epoetin alfa (recombinanthuman erythropoietin), which has proved an effectiveand well-tolerated means of raising hemoglobin levels inanemic patients receiving radiotherapy, potentiallycould reverse the negative prognostic influence of a low

hemoglobin in patients with certain malignancies. Radia-tion oncologists need to be aware of the possibility ofanemia in cancer patients undergoing radiotherapy sothat timely intervention can be instituted whenever ane-mia is diagnosed.


Introduction

The objective of radiotherapy in cancer treatment is tomaximize locoregional tumor control and patient surviv-al. As the antitumor activity of radiation is known to bemediated via its interaction with oxygen to form labilefree radicals, the intratumoral oxygen level has an impor-tant influence on the number of free radicals producedwithin a tumor and thus on the ability of radiation thera-py to induce DNA damage in malignant cells. Conse-quently, the presence of acute or chronic anemia, whichmay decrease the oxygen-carrying capacity of the bloodand results in tumor hypoxia, lowers the propensity ofradiotherapy to produce DNA damage and is an obstacleto achieving maximal locoregional tumor control [1–3]. Ithas been estimated that the dose of radiation required tokill tumor cells under hypoxic conditions is 2 to 3 times

12 Oncology 2002;63(suppl 2):11–18 Harrison/Shasha/Homel

Fig. 1. Enhancement of radiation resistance by hypoxia. The oxygenenhancement ratio (OER) is the ratio of the radiation dose requiredto kill a given fraction of malignant cells in a hypoxic environment inrelation to that in a normoxic environment.

0.001

0.01

0.1

1

Frac

tio

no

fsu

rviv

ng

cells

0 200 400 600 800 1,000 1,200 1,400 1,600 1,800 2,000

Radiation dose (cGy)

OER = 1,750 700= 2.5

�

HypoxicNormoxic

the dose required in a normoxic environment (fig. 1).Hypoxia has also been found to produce mutations of thep53 suppressor gene, which results in an increase in angio-genesis and an increased tendency for the development ofdistant metastases. Thus, overcoming hypoxia may havepositive effects on not only locoregional tumor control butalso on decreasing the risk of developing metastatic dis-ease [1, 3].

Hypoxia is a common characteristic of solid tumors.Athough the number and size of their hypoxic regions var-ies substantially [1], hypoxia may be present in even smalltumors at an early stage of development. In the past, theprevalence of anemia and tumor hypoxia in cancer pa-tients receiving radiotherapy has been an underappre-ciated problem that has frequently led to undertreatment.This article reviews the prevalence of anemia in patientsundergoing radiotherapy, and emphasizes that effectivereversal of anemia can be achieved. Until recently, littleattention has been paid to hemoglobin levels in cancerpatients.

Prognostic Significance of Anemia in CancerPatients

Relationships between low hemoglobin levels and in-tratumoral hypoxia, and between intratumoral hypoxiaand a less favorable prognosis in various cancers havebeen identified in studies in which oxygen partial pres-sures (pO2) were measured in tumor tissue [4–7]. In

patients with head and neck cancers, a pretreatmenthemoglobin level !11.0 g/dl was found to be a strongerpredictor of poor tumor oxygenation than other factorssuch as tumor stage, tumor volume and smoking status[4]. Even prostate tumors, which are generally not con-sidered to be hypoxic, have been reported to be associat-ed with significantly lower pO2 levels in comparisonwith pathologically normal prostate tissue and muscles,particularly in patients with more advanced (T2/T3)prostatic tumors and in older individuals (662 years ofage) [5].

Effect on Locoregional Tumor Control and SurvivalRecent studies have demonstrated an important rela-

tionship between anemia on locoregional tumor controland patient survival, principally in head and neck can-cers. In patients with early stage glottic cancers, which areamongst the smallest tumors treated by oncologists, aclear relationship has been demonstrated between the pre-treatment hemoglobin level and the hazard ratio for localrelapse following radiotherapy (50 Gy in 20 fractions over4 weeks) during a median follow-up period of 6.8 years[8]. Similarly, studies in patients with squamous cell car-cinomas of the glottic larynx and head/neck who weretreated with radiotherapy have noted significantly better2-year locoregional tumor control rates and 2-year surviv-al rates in those who presented with normal hemoglobinlevels in comparison with those who presented withbelow-normal hemoglobin levels (!13 g/dl) (table 1) [9,10]. In the patients with head/neck cancers, 5-year locore-gional control and survival rates were also significantlybetter in those with normal hemoglobin levels (p ! 0.001and p ! 0.01, respectively; table 1) [10].

Other studies have shown a relationship between thepost-radiotherapy hemoglobin level and the outcome oftreatment. Among patients with squamous cell carcino-mas of either the glottic or supraglottic regions whoreceived primary radiotherapy in doses ranging from 60to 70 Gy over 6 to 7 weeks, disease-free survival rateswere significantly better in those who had normal hemo-globin levels (defined as 12–16 g/dl in women, 13.7–18 g/dl in men) at day 35 of treatment in comparison withthose who had below-normal hemoglobin levels at thistime (p = 0.0012 for glottic carcinoma; p = 0.05 for supra-glottic carcinoma) (fig. 2) [11].

Effect on FatigueIn addition to locoregional tumor control and survival,

other outcomes in patients undergoing radiotherapy mayalso be influenced by the presence of anemia. Fatigue is

Prevalence and Treatment ofRadiotherapy-Associated Anemia

Oncology 2002;63(suppl 2):11–18 13

Fig. 2. Disease-free survival among patients with squamous cell car-cinoma of the glottic and supraglottic regions treated with primaryradiotherapy (60–70 Gy in 30–35 fractions over 6–7 weeks) in rela-tion to their hemoglobin (Hb) levels at day 35 of treatment. p Valuesindicate differences between disease-free survival in each group forpatients with normal vs below normal Hb levels. Normal Hb valueswere defined as 13.7–18 g/dl (8.5–11.0 mmol/l) for men and 12–16 g/dl (7.5–10.0 mmol/l) for women (reproduced with permissionfrom van Acht et al. [11]).

Fig. 3. Percentages of prostate cancer patients with fatigue ratingsgreater than 5 (on a scale of 0–10) before, during and after radiother-apy in relation to whether they were anemic (Hb level !12 g/dl) ornot anemic at the time (Harrison LB, unpublished data). * Statistical-ly significant versus non-anemic patients (p = 0.015).

0Pre-radiotherapy During radiotherapy Post-radiotherapy

4%

29%

14%

37%

28%�

10

20

30

40

Per

cen

tag

eo

fpat

ien

tsw

ith

afa

tig

ue

rati

ng

>5

Time relative to radiotherapy

Not anemic

Anemic

Table 1. Influence of anemia on locoregional tumor control rates and survival rates in two studies in patients withsquamous cell carcinomas of the glottic larynx (n = 109) or head/neck region (n = 504) [9, 10]

Patient group Locoregional control rates, %

2-year 5-year

Survival rates, %

2-year 5-year

Glottic squamous cell carcinomas [9]Normal hemoglobin levels 95* NR 88** NRAnemiaa 66 NR 46 NR

Head/neck squamous cell carcinomas [10]Normal hemoglobin levels 52** 48** 51* 36*Anemiab 34 32 37 22

a Hemoglobin !13 g/dl.b Hemoglobin !13 g/dl (women) or !14.5 g/dl (men).

* p ! 0.01 vs anemic patients; ** p ! 0.001 vs anemic patients; NR = not reported.

one such outcome that has been strongly associated withanemia [12–14]. In a group of patients with prostate can-cer treated with radiotherapy at our institution, the per-centage with a fatigue rating 15 (on a scale of 0–10) fol-lowing radiotherapy was found to be significantly higher

in those who were anemic (hemoglobin !12 g/dl) than inthose who were not anemic (fig. 3). This finding is ofinterest because fatigue is generally not considered a prob-lem in prostate cancer patients receiving radiotherapyalone.


Fig. 4. The prevalence of anemia (Hb !12g/dl) before and during radiotherapy in pa-tients with different types of cancer treatedat the Department of Radiation Oncology,Beth Israel Medical Center/St Luke’s-Roo-sevelt Hospital Center, New York betweenDecember 1996 and June 1999. Baselinewas defined as within 4 weeks prior to thefirst radiation dose. During therapy was de-fined as within 3 to 5 weeks of the first radia-tion dose.

0Breastcancer(n = 81)

44% 45%

Pat

ien

tsw

ith

anem

ia(%

)

20

40

60

80

100

Colorectalcancer(n = 64)

Lung/bronchus

cancer(n = 64)

Prostatecancer(n = 90)

Uterine/cervicalcancer(n = 53)

Head/neck

cancer(n = 68)

44%

55%

9%

75%

16%

63%

77%

26%

79%

32%

Baseline

During radiotherapy

Fig. 5. Mean decreases in hemoglobin (Hb) levels during radiothera-py versus preradiotherapy in patients treated at the Department ofRadiation Oncology, Beth Israel Medical Center/St Luke’s-RooseveltHospital Center, New York between December 1996 and June 1999.Data shown are for patients whose Hb levels decreased during treat-ment. * Statistically significant difference versus baseline (p !

0.001).

0Breastcancer(n = 71)

�

Mea

nd

ecre

ase

inh

emo

glo

bin

du

rin

gra

dio

ther

apy

(g/d

l)

0.2

0.4

0.6

0.8

1.0

1.2

1.4

1.6

1.8

2.0

Colorectalcancer(n = 48)

Lungcancer

(n = 101)

Prostatecancer(n = 78)

Cervicalcancer(n = 48)

Head/neck

cancer(n = 86)

�

�

�

Prevalence of Anemia in Patients UndergoingRadiotherapy for Various Cancers

Studies of patients presenting for radiotherapy at ourinstitution between December 1996 and June 1999 (n =574) have revealed a high prevalence of anemia (hemoglo-bin !12 g/dl) both before and during irradiation. Overall,

41% of patients were found to be anemic at baseline(within 4 weeks prior to radiotherapy) and 54% wereanemic within 3 to 5 weeks after receiving the first dose ofradiation [15]. The prevalence of anemia was higher inwomen than in men (54 vs 28% at baseline; 63 vs 43%during radiotherapy), and was higher in patients with cer-tain types of cancer than others (fig. 4). In particular, highprevalences of anemia were noted in patients with colo-rectal, lung/bronchus and uterine/cervical cancers, andincreases in prevalence from baseline to end of therapywere most notable for those with colorectal and lung/bronchus cancers (fig. 4). Among patients who experi-enced a drop in their hemoglobin level during radiothera-py, the mean decreases ranged from 0.75 g/dl for thosewith breast cancer to 1.8 g/dl for those with head or neckcancers, and the decreases were statistically significant(p ! 0.001) in all groups except those with breast and cer-vical cancer (fig. 5).

When the prevalence of anemia for each cancer typewas stratified by the hemoglobin level measured at base-line and the lowest level recorded during radiotherapy,most patients in each group were found to have mild ane-mia (hemoglobin levels 610 g/dl), which should be easilycorrectable. These data, and the findings of studies re-viewed previously in this article indicating that the pres-ence of anemia is associated with poorer treatment out-comes, provide compelling evidence for employing strate-gies to correct anemia and/or the resultant tumor hypoxiain cancer patients undergoing radiotherapy.


Oncology 2002;63(suppl 2):11–18 15

0

20

40

60

80

100

Loca

lrel

apse

-fre

era

te(%

)

0 1 2 3 4 5

HBO4

Air

Years

Fig. 6. Local relapse-free survival over 5 years in patients with locallyadvanced squamous cell carcinomas of the head or neck who wererandomized to treatment with either radiotherapy under hyperbaricoxygen at 4 atmospheres (HBO4) delivered in two fractions of11.5 Gy over 21 days (n = 23), or radiotherapy delivered in air in twofractions of 12.65 Gy over 21 days (n = 25) (reproduced with permis-sion from Haffty et al. [17]).

Fig. 7. Influence of carbogen breathing on local control, cause-spe-cific survival and overall survival in patients with advanced head orneck cancers treated with a hyperfractionated chemoradiotherapyregimen. Patients received either carboplatin 5 mg/m2 administered45 min before radiotherapy (115 cGy) with carbogen breathed 4 minprior to and during irradiation twice per day on 5 days a week for 7weeks (n = 36), or the same chemoradiotherapy regimen without car-bogen breathing (comparison group; n = 36). Data at 3 years for thecarbogen breathing group are estimated probabilities [18].

0Local control

91% 91%

Pat

ien

ts(%

)

20

40

60

80

100

Carbogen patients at 18 months (n = 36)

Carbogen patients at 3 years (n = 36)[estimated probabilities]

69%

Noncarbogen patients at 18 months (n = 36)

Cause-specific survival Overall survival

75%

62%

75%

62%55%

50%

Strategies to Correct Anemia and/or TumorHypoxia

Strategies that have been proposed to correct anemiaand/or the resultant tumor hypoxia include the use of:E Hypoxic cell sensitizers (e.g., cytotoxic agents)E Fluosol infusionE Carbogen breathingE Hyperbaric oxygenE Blood transfusionsE Epoetin alfa (recombinant human erythropoietin;

r-HuEPO).

Hypoxic Cell SensitizersIn a study designed to evaluate the efficacy of the cyto-

toxic agent mitomycin C in sensitizing hypoxic tumorcells to the effects of radiotherapy, patients with squa-mous cell carcinomas of the head or neck were treatedwith either conventional fractionated radiotherapy(70 Gy/35 fractions/7 weeks) or continuous hyperfrac-tionated accelerated radiotherapy (55.3 Gy/17 consecu-tive days/33 fractions) with or without mitomycin C(20 mg/m2) given on day 5 of treatment [16]. Local tumorcontrol and survival rates over a median follow-up periodof 148 months were similar with the two radiotherapyregimens given alone; however, the addition of mitomy-cin C to the accelerated regimen significantly reducedboth the local tumor control rate and the overall survival

rate in comparison with the accelerated regimen alone (48vs 34% and 39 vs 28%, respectively), indicating that hyp-oxia can, in part, be overcome by mitomycin C adminis-tration. Mitomycin C did not influence the local toxicityof radiotherapy as neither the intensity nor the durationof radiotherapy-induced mucositis was altered by its ad-ministration [16].

Hyperbaric Oxygen and Carbogen BreathingThe use of hyperbaric oxygen to overcome tumor hyp-

oxia has been reported to produce an improved responseto hypofractionated radiotherapy in a randomized trial inpatients with advanced squamous cell carcinoma of thehead or neck. Patients who received radiotherapy underhyperbaric oxygen at 4 atmospheres showed a higher 5-year local relapse-free rate than those who received a simi-lar radiotherapy regimen delivered in air (29 vs 16%;fig. 6). However, there were no significant differencesbetween the two groups in 5-year survival, distant metas-tasis, or second primary tumors [17].

Similarly, carbogen breathing has also been shown toimprove the results of chemoradiotherapy (carboplatin5 mg/m2 given before radiation doses of 115 cGy twice


Table 2. Influence of the pretreatment hemoglobin level and epoetin alfa on the outcome of therapy in patientsundergoing chemoradiation plus surgical treatment for squamous cell carcinomas of the oral cavity or oropharynx[24]

Patient group Overall completeresponse, %a

2-year locoregionaltumor control, %

2-yearsurvival, %

Group 1: patients with Hb 614.5 g/dl not treatedwith epoetin alfa (n = 43) 65* 88** 81**

Group 2: patients with Hb !14.5 g/dl not treatedwith epoetin alfa (n = 87) 17 72 60

Group 3: patients with Hb !14.5 g/dl treatedwith epoetin alfab (n = 57) 61* 95* 88*

* p (0.001 compared with group 2; ** p ! 0.05 compared with group 2; Hb = hemoglobin; SC = subcutaneously.a Complete responses were determined by histopathologic analysis of the en bloc resection of the primary tumor andregional cervical lymphatics performed 5 to 6 weeks after the completion of chemoradiotherapy.b Dosage: 10,000 IU/kg SC 3 to 6 times per week until week of surgery.

daily on 5 days per week for 7 weeks) in patients withlocally advanced head or neck cancer. Anemic patientsalso received either blood transfusions or epoetin alfa tocorrect the anemia. Patients who breathed carbogen4 min before and during irradiation exhibited improvedlocal control, cause-specific survival, and overall survivalat 18 months in comparison with a similar number ofpatients who received the same chemoradiotherapy regi-men without carbogen breathing (fig. 7). The high re-sponse rates achieved in this study appeared to persist asthe estimated probabilities of local control, cause-specificsurvival, and overall survival at 3 years in the carbogenbreathing group were similar to the rates observed at 18months [18].

Epoetin Alfa (Recombinant Human Erythropoietin;r-HuEPO)The ability of epoetin alfa to correct anemia prior to

and during radiotherapy has been evaluated in cancerpatients to determine whether it produces clinicallymeaningful benefit. Studies in patients receiving radio-therapy for various malignancies have shown that theadministration of epoetin alfa, with or without oral iron,is effective in increasing hemoglobin levels and is well tol-erated [19–21]. A study in our institution in cancerpatients receiving a variety of different chemotherapy reg-imens with concomitant or sequential radiotherapy hasshown that weekly epoetin alfa administration improvedthe mean hemoglobin level by 1.8–3.4 g/dl [22] (fig. 5).Improvements of this magnitude are similar to or greaterthan the reductions in hemoglobin noted during radio-

therapy in our earlier study of the prevalence of anemia inpatients with various malignancies (fig. 5).

The effects of epoetin alfa on the outcomes of therapyhave been studied in anemic patients (Hb !14.5 g/dl)with squamous cell carcinomas of the oral cavity or oro-pharynx [23, 24]. All patients in this study received a regi-men consisting of mitomycin C (15 mg/m2 on day 1), 5-fluorouracil (750 mg/m2 on days 1–5) and radiotherapy(50 Gy in 25 fractions during weeks 1–5), followed by dis-section of the primary tumor bed and a neck dissection.Epoetin alfa (10,000 IU/kg subcutaneously 3 to 6 timesper week until the week of surgery) was administered to agroup of patients (n = 57) who had a pretreatment hemo-globin level !14.5 g/dl. The outcome in this group ofpatients was compared with the outcomes in two othergroups who did not receive epoetin alfa. One of these non-epoetin alfa groups had a pretreatment hemoglobin level!14.5 g/dl (n = 87) and the other had a pretreatmenthemoglobin level 614.5 g/dl (n = 43). The results aresummarized in table 2. In the two groups of patients whodid not receive epoetin alfa, those with a low pretreatmenthemoglobin level (!14.5 g/dl) (group 2) exhibited signifi-cantly lower complete response rates, 2-year locoregionalcontrol rates, and 2-year survival rates than those whohad normal hemoglobin levels (614.5 g/dl) (group 1).However, in the patients with a low pretreatment hemo-globin level who received epoetin alfa (group 3), the ratesof complete response, 2-year locoregional control and 2-year survival were equivalent to or higher than those inpatients with normal pretreatment hemoglobin levels(group 1) [24].


Oncology 2002;63(suppl 2):11–18 17

These findings suggest that epoetin alfa is an effectiveand well-tolerated means of achieving normal hemoglo-bin levels in patients undergoing radiotherapy, and mayreverse the negative prognostic influence of a low pre-treatment hemoglobin level. Improvements in quality-of-life parameters (linear analog scale assessment) have alsobeen noted with epoetin alfa therapy in groups of patientsreceiving a variety of different chemotherapy regimenswith concomitant or sequential radiotherapy [22].

Potential Benefit of Epoetin Alfa in ReducingRadiotherapy-Induced Neurotoxicity

In addition to studies of the efficacy of epoetin alfa inimproving the clinical outcome of radiotherapy in pa-tients with low hemoglobin levels, its potential to reduceradiation-induced neurotoxicity is also being investi-gated. Studies in experimental animals have revealed thatendogenous erythropoietin (EPO) possesses other biologi-cal activities in addition to erythropoietic effects, and thatmany cells besides erythroid progenitors express theerythropoietin receptor, including brain cells. As in theperiphery, erythropoietin production is known to be in-duced by hypoxia in the central nervous system (CNS),and it has been shown in animals to protect CNS neuronalcells from ischemic injury [25]. A recent study found thaterythropoietin receptors are abundantly expressed in cap-illaries of the brain-periphery interface, suggesting thatthis may provide a route for circulating erythropoietin toenter the brain [26]. In support of this hypothesis, a studyin mice showed that systemic administration of epoetinalfa (5,000 IU/kg intraperitoneally) 24 h before or up to6 h after controlled blunt trauma to the frontal cortex andthen continued once daily for 4 additional days (5 dosestotal) attenuated the resultant brain injury. Quantitativeanalysis of the cavitary injury volume showed that theconcussive injury in mice treated with epoetin alfa wassignificantly less than in those treated with saline. In addi-tion, epoetin alfa also ameliorated the damage caused byexperimentally-induced focal ischemic stroke in ratbrains, reduced the severity of experimental autoimmuneencephalitis in Lewis rats, and delayed and lessened sei-zures induced in mice by the glutamate analog kainicacid. These findings in different models of neurologicinjury suggest that epoetin alfa is able to cross the blood-brain barrier and may provide protection against CNSneurologic damage [26].

Further evidence in support of a protective effect oferythropoietin against neurologic damage is provided by

the results of studies in our institution in which visualevoked potentials (VEPs) were measured in animals re-ceiving radiotherapy in the presence and absence of r-HuEPO. Pretreatment of animals with epoetin alfa signif-icantly prolonged VEPs as compared with those notreceiving epoetin alfa, suggesting that it may protectvisual pathways against radiation-induced damage (A.Evans, unpublished data). If confirmed clinically, thisfinding may have substantial implications for the use ofradiotherapy in patients with malignancies of the head,paranasal sinuses and ocular regions because it suggeststhat epoetin alfa may provide biologic protection of theoptic nerve against radiation-induced damage.

Conclusions

Anemia may result in tumor hypoxia by decreasing theoxygen-carrying capacity of the blood, resulting in radia-tion and, in some instances, chemotherapy resistance.Anemia is associated with a poorer prognosis in a varietyof malignancies. It may be an important obstacle toachieving maximal locoregional tumor control and sur-vival with radiotherapy, even for small tumors not nor-mally assumed to be hypoxic. In addition, anemia nega-tively affects the quality of life of cancer patients, as evi-denced by worsening fatigue. In view of the high preva-lence of anemia recorded in cancer patients receivingradiotherapy (about 50% at our institution), it is evidentthat measures to reverse anemia and tumor hypoxiashould be considered an important component of treat-ment for such patients. Indeed, a number of strategies,notably the administration of epoetin alfa, have beenfound to attenuate the negative prognostic influence of alow hemoglobin level in patients receiving radiotherapywith or without chemotherapy.

These findings indicate the need for radiation oncolog-ists to be aware of the possibility of anemia in cancerpatients undergoing radiotherapy so that timely interven-tion with strategies to improve the outcome of treatmentcan be instituted whenever anemia is diagnosed. In viewof the potential benefits of treating anemia, it is hopedthat this aspect of cancer management will receive moreattention in the future.


References

1 Shasha D: The negative impact of anemia onradiotherapy and chemoradiation outcomes.Semin Hematol 2001;38(3 suppl 7):8–15.

2 Kumar P: Tumor hypoxia and anemia: impacton the efficacy of radiation therapy. SeminHematol 2000;37(4 suppl 6):4–8.

3 Dunst J: Hemoglobin level and anemia in ra-diation oncology: prognostic impact and thera-peutic implications. Semin Oncol 2000;27(2suppl 4):4–8, 16–17.

4 Becker A, Stadler P, Lavey RS, Hansgen G,Kuhnt T, Lautenschlager C, Feldmann HJ,Molls M, Dunst J: Severe anemia is associatedwith poor tumor oxygenation in head and necksquamous cell carcinomas. Int J Radiat OncolBiol Phys 2000;46:459–466.

5 Movsas B, Chapman JD, Greenberg RE, Hor-witz EM, Pinover WH, Hanlon AL, Stobbe C,Hanks GE: Increasing levels of hypoxia in hu-man prostate carcinoma correlate significantlywith increasing clinical stage and age: an Ep-pendorf pO2 study. Int J Radiat Oncol BiolPhys 1999;45(3 suppl):202.

6 Brizel DM, Dodge RK, Clough RW, DewhirstMW: Oxygenation of head and neck cancer:changes during radiotherapy and impact ontreatment outcome. Radiother Oncol 1999;53:113–117.

7 Höckel M, Vorndran B, Schlenger K, Bauss-mann E, Knapstein PG: Tumor oxygenation: anew predictive parameter in locally advancedcancer of the uterine cervix. Gynecol Oncol1993;51:141–149.

8 Warde P, O’Sullivan B, Bristow RG, Panzarel-la T, Keane TJ, Gullane PJ, Witterick IP,Payne D, Liu FF, McLean M, Waldron J, Cum-mings BJ: T1/T2 glottic cancer managed byexternal beam radiotherapy: the influence ofpretreatment hemoglobin on local control. Int JRadiat Oncol Biol Phys 1998;41:347–353.

9 Fein DA, Lee WR, Hanlon AL, Ridge JA, Lan-ger CJ, Curran WJ Jr, Coia LR: Pretreatmenthemoglobin level influences local control andsurvival of T1–T2 squamous cell carcinomas ofthe glottic larynx. J Clin Oncol 1995;13:2077–2083.

10 Lee WR, Berkey B, Marcial V, Fu KK, CooperJS, Vikram B, Coia LR, Rotman M, Ortiz H:Anemia is associated with decreased survivaland increased locoregional failure in patientswith locally advanced head and neck carcino-ma: a secondary analysis of RTOG 85-27. Int JRadiat Oncol Biol Phys 1998;42:1069–1075.

11 van Acht MJ, Hermans J, Boks DE, Leer JW:The prognostic value of hemoglobin and a de-crease in hemoglobin during radiotherapy inlaryngeal carcinoma. Radiother Oncol 1992;23:229–235.

12 Groopman JE: Fatigue in cancer and HIV/AIDS. Oncology (Huntingt) 1998;12:335–344.

13 Sabbatini P: Contribution of anemia to fatiguein the cancer patient. Oncology (Huntingt)2000;14(11A):69–71.

14 Sobrero A, Puglisi F, Guglielmi A, BelvedereO, Aprile G, Ramello M, Grossi F: Fatigue: amain component of anemia symptomatology.Semin Oncol 2001;28(2 suppl 8):15–18.

15 Harrison LB, Shasha D, Shiaova L, et al: Preva-lence of anemia in cancer patients undergoingradiotherapy (abstract). Proc Am Soc Clin On-col 2000;19:471a.

16 Dobrowsky WH, Naudé J, Widder J, Dobrow-sky E: Continuous hyperfractionated acceler-ated radiotherapy and mitomycin C in headand neck cancer. Int J Radiat Oncol Biol Phys1999;45(3 suppl):148.

17 Haffty BG, Hurley R, Peters LJ: Radiationtherapy with hyperbaric oxygen at 4 atmo-spheres pressure in the management of squa-mous cell carcinoma of the head and neck:results of a randomized clinical trial. Cancer JSci Am 1999;5:341–347.

18 Martinez A, Cabezon M, Fuentes C, EspiñeiraM, Perez M, Serdio J, Artazkoz J, Gil J, BorqueC, Villar A: Hyperfractionated chemoradio-therapy with carbogen breathing for advancedcancer of the head and neck. Int J Radiat OncolBiol Phys 1999;45(3 suppl):377.

19 Lavey RS, Dempsey WH: Erythropoietin in-creases hemoglobin in cancer patients duringradiation therapy. Int J Radiat Oncol Biol Phys1993;27:1147–1152.

20 Dusenbery KE, McGuire WA, Holt PJ, CarsonLF, Fowler JM, Twiggs LB, Potish RA: Eryth-ropoietin increases hemoglobin during radia-tion therapy for cervical cancer. Int J RadiatOncol Biol Phys 1994;29:1079–1084.

21 Sweeney PJ, Nicolae D, Ignacio L, Chen L,Roach M 3rd, Wara W, Marcus KC, Vijayaku-mar S: Effect of subcutaneous recombinant hu-man erythropoietin in cancer patients receivingradiotherapy: final report of a randomised,open-labelled, phase II trial. Br J Cancer 1998;77:1996–2002.

22 Shasha D, George M, Harrison LB: Once-weekly dosing of epoetin alfa increases hemo-globin and improves quality of life in anemiccancer patients receiving radiation therapyeither concurrently or sequentially with chemo-therapy. Presented at the 42nd Annual Meetingof the American Society of Hematology, SanFrancisco, CA, Dec 2000.

23 Glaser CM, Millesi W, Kornek GV, Lang S,Schüll B, Klug K, F, Wanschitz F, Lavey RS:Impact of hemoglobin (Hgb) level and use ofrecombinant human erythropoietin (r-HuEPO)on response to neoadjuvant chemoradiationtherapy, tumor control, and survival in patientswith oral or oropharyngeal squamous cell carci-noma (SCCA). Int J Radiat Oncol Biol Phys1999;45(3 suppl):149.

24 Glaser CM, Millesi W, Kornek GV, Lang S,Schüll B, Watzinger F, Selzer E, Lavey RS:Impact of hemoglobin level and use of recom-binant erythropoietin on efficacy of preopera-tive chemoradiation therapy for squamous cellcarcinoma of the oral cavity and oropharynx.Int J Radiat Oncol Biol Phys 2001;50:705–715.

25 Sakanaka M, Wen TC, Matsuda S, Masuda S,Morishita E, Nagao M, Sasaki R: In vivo evi-dence that erythropoietin protects neuronsfrom ischemic damage. Proc Natl Acad SciUSA 1998;95:4635–4640.

26 Brines ML, Ghezzi P, Keenan S, Agnello D, deLanerolle NC, Cerami C, Itri LM, Cerami A:Erythropoietin crosses the blood-brain barrierto protect against experimental brain injury.Proc Natl Acad Sci USA 2000;97:10526–10531.


Raising Hemoglobin: An Opportunity forIncreasing Survival?

Gillian M. Thomas

Department of Radiation Oncology, Obstetrics & Gynecology, University of Toronto,Toronto-Sunnybrook Regional Cancer Centre, Toronto, Canada

Gillian M. Thomas, BSc, MD, FRCPCGlaxoSmithKline, 7333 Mississauge Road NorthMississauge, Ont. L5N 8L4 (Canada)Tel. +1 905 814 2256, Fax +1 905 814 2100E-Mail [email protected]


© 2002 S. Karger AG, Basel0030–2414/02/0636–0019$18.50/0


Key WordsAnemia W Hemoglobin W Hypoxia W Angiogenesis W

Cancer W Radiotherapy W Chemotherapy W Surgery W

Prognostic factor W Epoetin alfa

AbstractAlthough the association between low hemoglobin lev-els and poorer outcomes in radiation oncology has longbeen recognized, anemia is often overlooked and un-treated. However, a growing body of clinical evidencenow indicates that low hemoglobin levels during radia-tion treatment are associated with decreased responseand survival following radiotherapy. For example, alarge Canadian retrospective study in patients receivingradical radiotherapy for cervical cancer showed that the5-year survival rate was 19% higher in those whosehemoglobin during radiation treatment was =12 g/dlcompared to those with levels !12 g/dl. The data suggestthat clinical trials need to be performed to determinewhether increasing hemoglobin levels leads to improvedlocal control and survival. The mechanism by which lowhemoglobin levels could cause poorer outcomes is notwell understood and needs further elucidation. It is pos-tulated that lower hemoglobin levels resulting in de-

creased oxygen carrying capacity may lead to increasedtumor hypoxia, radiation resistance and increased tumorangiogenesis. The interrelationship of low hemoglobinlevels, hypoxia, tumor angiogenesis and survival is ex-plored in this article.


Introduction

In radiation oncology, it is widely accepted that tumorhypoxia causes radiation resistance. Anemia is also asso-ciated with poorer outcomes to radiation. It has beeninferred that there is a causal relationship between lowhemoglobin levels, the resulting hypoxia and a poor out-come of radiotherapy in patients with cancer.

Even though hemoglobin levels are monitored at mostradiation oncology centers, anemia is often overlooked byradiation oncologists and is frequently only treated ifsevere. It has been suggested that oncologists do not rou-tinely treat mild-to-moderate anemia as it is perceived tobe clinically unimportant [1] and that patients are oftennot transfused unless hemoglobin levels fell below 10 g/dlor even 8 g/dl [1, 2]. For example, a US study in 1987showed approximately two-thirds of academic radiation

20 Oncology 2002;63(suppl 2):19–28 Thomas

Table 1. Summary of studies which examined the relationshipbetween anemia and outcome (local control B survival) of radiother-apy B chemotherapy in patients with cancer

Tumor site Number ofstudies

Effect of anemia on outcome,number of studies

Adverse None

Bladder 6 6 0Bronchus 5 4 1Cervix 22 19 3Glioma 1 0 1Head and neck 17 11 6Prostate 1 0 1Total 52 (100%) 40 (76.9%) 12 (23.1%)

oncology departments transfusedpatients only if their he-moglobin levels were = 10 g/dl [3]. This reluctance to cor-rect anemia was further increased in Canada in the late1980s when the risk of contracting HIV or hepatitis fromcontaminated blood was first recognized.

Although views are changing, there is still much uncer-tainty among radiation oncologists about the clinical im-portance of radiotherapy-associated anemia and the exactbenefits of increasing hemoglobin levels. However, agrowing body of clinical data is gathering in the medicalliterature which examines the relationship between hemo-globin levels and response to radiotherapy in patientswith cancer. The present article reviews these data andalso seeks to explore some of the downstream mecha-nisms, namely tumor hypoxia and angiogenesis, that maylink low hemoglobin levels with clinical outcome in pa-tients with cancer. It also poses questions for future studythat may help to clarify treatment options for this patientgroup.

Effect of Hemoglobin Levels on TreatmentOutcome

Historic DataMore than 50 studies have investigated the effect of

low hemoglobin levels at the start of radiotherapy B che-motherapy on outcomes in patients with various cancers[mostly of the cervix (42%) or head and neck (33%)]mainly using univariate analysis. A summary of thesestudies is provided in table 1. It should be noted that,although the term ‘anemia’ was used in all studies, there

was no consistency in how it was defined (i.e., cut-offhemoglobin levels ranged from 10 to 12.5 g/dl). Neverthe-less, 40 of the 52 (76.9%) studies showed that low hemo-globin levels were adversely related to local control and/orsurvival after radical adverse radiotherapy (table 1).

There are two possible explanations, not mutuallyexclusive, for the observed relationship between low he-moglobin levels and impaired outcomes with radiothera-py. First, low hemoglobin levels may be a tumor-relatedmarker for an aggressive cancer. In this scenario, it isunlikely that raising hemoglobin levels will improve theoutcome of radiotherapy. The second, and more tradi-tional, explanation is that there is a causal relationshipbetween low hemoglobin levels and poor outcome of ther-apy. With a causal relationship, raising hemoglobin levelsmight therefore improve outcome following radiotherapy[4].

Until recently, clinical evidence to support a causalrelationship between low hemoglobin levels and poor out-come was relatively limited. A single prospective, ran-domized trial, conducted over 30 years ago, was inter-preted as demonstrating some benefit after correctinganemia during radiotherapy in patients with cervical can-cer [5]. Pelvic recurrence occurred in 11 of 67 patients(16.4%) who received transfusions and maintained hemo-globin levels 112 g/dl compared with 21 of 68 patients(30.9%) who were given transfusions only if their hemo-globin levels dropped to !10 g/dl. No differences in sur-vival were noted between the two treatment groups [5].Although this study is widely quoted in the medical litera-ture as proof that correcting hemoglobin levels improvesoutcomes following radiotherapy, the study was under-powered and had an inconclusive univariate analysiswhich did not assess the possible effect of other prognosticfactors on patient outcome.

Studies in Patients with Cervical Cancer

Radiotherapy AloneTo examine the relationship between anemia and

treatment outcome more rigorously, a large retrospectivestudy using data from seven Canadian radiation oncologycenters between 1989 and 1992 was performed [4]. Theaim of the study was to examine the prevalence of anemia,its time course, and the effect of anemia and blood trans-fusions on the treatment outcome in 605 patients who hadradical radiotherapy for cervical cancer.

At presentation, approximately one-third of patientshad hemoglobin levels of =12 g/dl (i.e., below the lower

Hemoglobin Levels and Outcome in CancerPatients

Oncology 2002;63(suppl 2):19–28 21

Table 2. Significance of prognostic factors on outcome of radiothera-py in 605 patients with cervical cancer: results of a multivariate anal-ysis (with permission from Grogan et al. [4])

Prognostic factor p value

SignificantStage 0.0001Average weekly nadir hemoglobin level 0.0001Intracavitary treatment 0.0004Squamous histology 0.0446

NonsignificantAgePresenting hemoglobin levelRadiation doseCenterTransfusionTransfusion yearTreatment volumeTreatment timeChemotherapy

limit of the normal range for women). Despite this, only25% of patients received blood transfusions because clini-cians were more likely to transfuse patients with nadirhemoglobin levels of !10 g/dl. This is demonstrated bythe fact that most patients with hemoglobin levels of!9 g/dl (90%) and !10 g/dl (77%) were transfused, where-as much fewer patients (3–41%) with hemoglobin levelsbetween 10 and 12 g/dl received transfusions. In all, fourof the seven centers had policies for blood transfusionoften not followed: two recommended transfusions forpatients with hemoglobin levels of !10 g/dl, and one eachfor patients with hemoglobin levels of !11 and !12 g/dl[4].

The Canadian study showed that hemoglobin levels atbaseline correlated with patient survival (fig. 1). This isconsistent with earlier data indicating a correlation be-tween anemia and poor prognosis in patients receivingradiotherapy B chemotherapy (table 1). Using a cut-offvalue for hemoglobin levels of 12 g/dl, the Canadian studyreported a 12% greater 5-year survival rate in patientswith baseline hemoglobin levels of 612 g/dl than in thosewith baseline levels of 612 g/dl (p ! 0.003; fig. 1). Hemo-globin levels at baseline also had a significant effect ondisease-free survival (p = 0.005) and control of local pelvicdisease (p = 0.002) according to univariate analysis [4].

Of note, however, are the results of the multivariateanalysis from this study which considered patient-, tu-mor- and treatment-related factors, as well as hemoglobin

Fig. 1. Survival in patients with carcinoma of the cervix receivingradiotherapy stratified according to hemoglobin level (Hb) at presen-tation (reproduced with permission from Grogan et al. [4]).

= 172)

= 337)dl (

dl (

12.0 g/

12.0 g/

=<

Hb

Hb- - -

—–

p <0.003

0 1 3 4 5 62

1.0

0.8

0.6

0.4

0.2

0.0

va

li

Su

rv

n

n

YearYear

Fig. 2. Survival in patients withcarcinoma of the cervix according tohemoglobin levels at baseline and during radiotherapy, where L indi-cates hemoglobin levels of !12 g/dl and H indicates hemoglobin lev-els of 612 g/dl. Results are adjusted for disease stage and for the useof intracavitary irradiation (reproduced with permission from Gro-gan et al. [4]).

= 228)

40)

2)

= 25)

= 1

= 8

H (n

H (n

L (n

L (n

–

–

–

–

L

H

L

H

0 1 3 4 5 62

p <0.0002

1.0

0.8

0.6

0.4

0.2

0.0

Su

rviv

al

—

—

—

—

YearYear

levels (table 2). The multivariate analysis showed thathemoglobin levels during radiotherapy, rather than at pre-sentation, were predictive of outcome of radiotherapy interms of overall survival (p = 0.0001; table 2) [4] second inimportance only to tumor stage. Average weekly hemoglo-bin nadir, which was calculated by averaging the weeklynadir hemoglobin levels for each patient, was taken as anestimate of hemoglobin levels during radiotherapy. Othersignificant prognostic factors for outcome were diseasestage, intracavitary treatment, and squamous histology


Fig. 3. Survival in patients with carcinomaof the cervix according to transfusion statusand average weekly nadir hemoglobin levels(Hb) during radiotherapy, where T = trans-fused and NT = not transfused (reproducedwith permission from Grogan et al. [4]).

<11.0 g/dl

11.0–11.9 g/dl

12.0 g/dl

Hb

NT

T

NT

T

NT

Tp <0.0001

0 1 3 4 5 62

1.0

0.8

0.6

0.4

0.2

0.0

Su

rviv

al

YearYear

(table 2). Initial hemoglobin levels were not significantsuggesting that the effect of low presenting hemoglobinlevels could be overcome by raising the level during treat-ment.

To further examine the differential impact of lowhemoglobin levels during treatment versus those at pre-sentation, the survival data were reanalyzed according tohemoglobin levels both at baseline and during radiothera-py (fig. 2; n = 475). The analysis showed that patients whohad low hemoglobin levels during radiotherapy, regard-less of their baseline hemoglobin levels, had a significantlypoorer rate of survival than those whose hemoglobin lev-els were maintained greater than 12 g/dl during radiother-apy (fig. 2). The 5-year survival rates for those with lowhemoglobin levels during radiotherapy were 51% or lesscompared with rates of at least 70% in patients who hadhigh hemoglobin levels during radiotherapy (fig. 2). Therelapse rates in patients with low hemoglobin levels dur-ing radiotherapy (56 and 60%) were almost double thoseof patients with high hemoglobin levels during therapy(32 and 33%). Interestingly, patients with high hemoglo-bin levels during radiotherapy also showed significantreductions in both pelvic (p ! 0.0001) and extrapelvic fail-ure rates (p ! 0.0006) [4].

Finally, the study examined whether raising hemoglo-bin levels with blood transfusions influenced the outcomeof radiotherapy (fig. 3). A significant stepwise increase inoverall survival was observed with increasing hemoglobinlevels during radiotherapy (fig. 3; p ! 0.0001). Survivalrates were not significantly different between patientswho attained a given hemoglobin level spontaneously andthose who received blood transfusions (fig. 3). These data

show that it is the hemoglobin level attained, rather thanthe use of blood transfusions, that influenced outcome inthese patients. It also confirmed the prognostic signifi-cance of hemoglobin levels during radiotherapy [4].

It was concluded from the Canadian study that thehemoglobin level during radiotherapy is an importantprognostic factor, second only to disease stage, in patientswith cervical cancer. The survival data from this studygenerate the hypothesis that maintaining hemoglobin lev-els above 12 g/dl in patients with cervical cancer canimprove the response to radiotherapy. The study furthershowed that the mechanism by which hemoglobin levelsare maintained (i.e., transfusion) is not important, butrather the hemoglobin level that is attained during radio-therapy.

Concurrent Radiotherapy and ChemotherapySince the study by Grogan et al. [4] was completed,

concurrent cisplatin-based chemotherapy and radiothera-py has emerged as the treatment of choice for patientswith advanced cancer of the cervix [6] as for many otherepithelial cancers.

A recent study by Pearcey et al. [7], however, showedno benefit for the addition of concurrent cisplatin toradiation. Contrary to the previous trials in patients withcervical cancer, which demonstrated a survival benefit forchemoradiotherapy versus radiotherapy alone [8–12],Pearcey et al. [7] observed similar 3- and 5-year survivalrates with concurrent cisplatin and radiotherapy versusradiotherapy alone in patients with advanced cervical car-cinoma. While there are many possible explanations forthe lack of benefit observed with chemoradiotherapy in


Oncology 2002;63(suppl 2):19–28 23

Fig. 4. Distribution of patients with ad-vanced cervical cancer according to decreasein hemoglobin levels (Hb) during therapy.Patients were randomized to receive pelvicradiotherapy alone (n = 126) or radiotherapyplus cisplatin 40 mg/m2 weekly (n = 127) (re-produced with permission from Pearcey etal. [7]).

this trial, one reason may have been a differential drop inhemoglobin levels during therapy (fig. 4) between treat-ment groups. As would be expected, decreases in hemo-globin levels were found to be significantly greater inpatients receiving chemotherapy plus radiotherapy versusthose receiving radiotherapy alone (fig. 4). Thus, is it pos-sible that the decreases in hemoglobin levels during thera-py abrogated the beneficial effects of chemotherapy inthis study.

Studies in Patients with Head and Neck Cancer

Several studies have looked at the impact of anemiaon clinical outcome following radiotherapy in patientswith head and neck cancer (for review see Kumar 2001)[13]. As an example, van Acht et al. [14] observed thatthe 10-year rate of disease-free survival was significantlylower in patients with laryngeal cancer (n = 306) whosehemoglobin levels were below normal (!8.5 mmol/l inmen and !7.5 mmol/l in women) after radiotherapythan in those with normal hemoglobin levels. Patientswith glottic carcinoma and hemoglobin levels below nor-mal at the start and/or the end of radiotherapy had sig-nificantly reduced 10-year disease-free survival rates(p = 0.009 and 0.0012, respectively), whereas below-nor-mal hemoglobin levels at the end of therapy only werepredictive of disease-free survival in those with supra-glottic cancers (p = 0.05) [14].

These data are of interest because they confirm thenegative association between low hemoglobin levels at theend of treatment and survival following definitive radio-

therapy in a cancer type other than cervical cancer. Somehave postulated that the poor results in anemic patientsare a result of the association between anemia and largetumor volumes and development of distant metastases.Since laryngeal cancer does not have these characteristics,these data add weight to the suggestion that the relation-ship between anemia and outcome is not solely tumor-related; the hypothesis generated is that some decrementin response to therapy may occur if the hemoglobin levelis low during treatment.

Effect of Hypoxia on Treatment Outcome

Hypoxia is a characteristic feature of solid tumorswhich is thought to occur when tumor growth exceeds theability of the local microvasculature to supply oxygen. It isthought that approximately 60% of locally advancedsquamous cell cervical carcinomas contain hypoxic and/or anoxic areas of tissue [15]. Resistance to treatment andaccelerated tumor growth and progression occur as aresult of hypoxia. Hypoxia causes resistance to bothradiotherapy and chemotherapy.

It is now well established that intratumoral hypoxiahas a negative effect on locoregional control in patientsreceiving definitive radiotherapy for head and neck orcervical cancer. Table 3 provides a summary of studiesthat measured tumor oxygenation levels directly and cor-related tumor oxygenation status with locoregional con-trol following radiotherapy [16–21]. Although the defini-tions assigned to hypoxia differed between studies, four ofsix studies showed a significant increase in local failure


Table 3. Summary of studies investigatinglocoregional control following radiotherapyaccording to tumor oxygenation status inpatients with cervical or head and neckcancer

Study Tumor site Local failure rate (patients)

nonhypoxictumors

hypoxictumors

p value

Fyles et al. [16] Cervix 4/21 6/10 0.03Höckel et al. [17] Cervix 4/19 10/23 0.13Kolstad [18] Cervix 4/21 6/10 0.03Brizel et al. [19] Head and neck 3/10 11/17 0.09Gatenby et al. [20] Head and neck 1/19 11/12 !0.001Nordsmark et al. [21] Head and neck 5/18 11/17 0.03

Table 4. Molecular events linking hypoxia and angiogenesis [25]

Hypoxia-regulated genes (e.g., VEGF, EPO, LDHA, Glut-1)HIF-1· mediates transcriptional response by binding to the hypoxia

responsive elements of genesHIF-1· induces VEGF and increases expression and half-life of

mRNAHypoxia leads to loss of p53, increases VEGF and decreases TSP-1H-ras and V-src (oncoproteins) amplify response to hypoxia and

lead to increased VEGF and decreased TSP-1

EPO = erythropoietin; HIF-1a = hypoxia-inducible factor 1a;LDHA = lactate dehydrogenase A; TSP-1 = thrombospondin-1;VEGF = vascular endothelial growth factor.

rate in patients who had hypoxic tumors compared withthose whose tumors were oxygenated (table 3).

It has long been recognized that hypoxia adverselyaffects the sensitivity of tumor cells to many chemothera-peutic agents. Although the precise mechanisms are un-known, oxygen is a radiosensitizer and impairs the abilityto repair DNA damage caused by radiation-induced freeradicals.

More recently, attention has focused on the ability oftumor hypoxia to enhance malignant progression. This isbased on the findings of Höckel et al. [17] who showedthat, following tumor resection in 47 patients with cervi-cal cancer, hypoxic tumors had larger extensions, morefrequent parametrial spread and lymph-vascular involve-ment compared with oxygenated tumors. It is thoughtthat hypoxia may drive disease progression through clonalselection and genome changes (for review see Höckel &Vaupel 2001) [22], which in turn produces a growthadvantage for tumor cells that are resistant to apoptosis.Hypoxic tumors may overexpress the suppressor genep53, a phenotype with a high malignant potential [23].

Hypoxia may also induce changes within the tumorcells for the expression of oxygen-dependent proteins,such as vascular endothelial growth factor (VEGF), whichstimulate angiogenesis and increase the potential for tu-mor growth and metastases [24].

Effect of Angiogenesis on Treatment Outcome

Angiogenesis, the growth of new capillary vessels sup-porting tumor growth and progression, is stimulated byhypoxia. A summary of molecular events linking angio-genesis with intratumoral hypoxia is provided in table 4[25]. Like hypoxia, angiogenesis has also been shown toinfluence outcome to surgery in patients with cancer,

although the available data are limited. Obermair et al.[26] used microvessel density count as a measure of angio-genesis in patients with stage IB cervical cancer whounderwent surgery. They found that the 5-year overallsurvival rate was significantly better in patients with amicrovessel density of 20/field (n = 102) than in thosewith higher microvessel densities (n = 64) (80.7 versus63.0%; p ! 0.0001).

More recently, Birner et al. [27] showed that theexpression of hypoxia-inducible factor 1a (HIF-1a), atranscriptional factor that promotes angiogenesis and reg-ulates genes involved in the response to hypoxia, in-fluenced prognosis in 91 surgically-treated patients withstage I cancer of the cervix. Once again, patients withstrong expression of HIF-1a had a significantly pooreroverall survival (p = 0.03) and disease-free survival (p !0.0001) compared with those with moderate or no expres-sion of HIF-1a.


Oncology 2002;63(suppl 2):19–28 25

Fig. 5. Possible management options to overcome the problems of anemia and hypoxia during radiotherapy. HCRS =Hypoxic cell radiation sensitizers; HT = hyperthermia; HBO = hyperbaric oxygen.

Anemia, Hypoxia and Angiogenesis: Are TheyLinked?

While there is evidence to suggest a direct associationbetween hypoxia and angiogenesis, less is known abouthow anemia is linked to hypoxia and angiogenesis (fig. 5).Anemia may exacerbate intratumoral hypoxia by lower-ing the oxygen carrying capacity of the blood, although thelink between the two and its relevance in the clinical set-ting remain controversial [1]. Nordsmark et al. [28] inDenmark recently showed that there was no relationshipbetween hemoglobin levels and pretreatment tumor oxy-gen partial pressure in 263 patients with head and neckcarcinoma. However, both hemoglobin levels and tumoroxygenation status (pO2 fraction !2.5 mm Hg) were inde-pendent prognostic factors for overall survival. LikewiseBrizel et al. [29] noted only a weak association betweenlow hemoglobin levels and poor tumor oxygenation statusin patients with head and neck cancer receiving primaryradiotherapy; many patients with higher hemoglobin lev-els (= 13 g/dl) also had hypoxic tumors. These data suggestthat low hemoglobin levels and tumor hypoxia may belinked in a complex fashion but other factors, tumor

type and individual patient physiology, may also be in-volved.

The relationship between anemia and angiogenesisremains poorly understood and data are sparse. A Ger-man group [30] showed that there was a trend towardshigher serum VEGF levels in cancer patients with lowhemoglobin levels undergoing radiotherapy, suggestingthat anemia may stimulate angiogenesis via hypoxia. Pa-tients had previously untreated, non-metastatic gyneco-logic cancer (n = 22), head and neck cancer (n = 14), gas-trointestinal cancer (n = 13), lung cancer (n = 4) and pros-tate cancer (n = 1). In 26 patients with hemoglobin levelsof !13 g/dl, mean serum VEGF levels were 805,656 pg/mlcompared with levels of 438,360 pg/ml in 28 patients withhemoglobin levels of 113 g/dl (p = 0.016) [30].

Correcting Hemoglobin Levels

There are several potentially reversible causes of ane-mia (such as nutritional deficiencies, chronic blood loss,and subclinical disseminated intravascular coagulopa-thy), which should be sought and, if possible, corrected in


patients presenting with anemia. A summary of manage-ment options for the prevention and treatment of hypoxiaand anemia in patients with cancer in the radiation onco-logy setting, some of which are in the early stages of devel-opment, are summarized in figure 5.

Transfusion of red blood cells is one readily availablemanagement option for patients with anemia (fig. 5),although it carries risks of unwanted transfusion reac-tions, infectious disease transmission, and possibly im-munomodulation. Concerns about the risks of homolo-gous blood transfusion, uncertainty about the benefitsand inconvenience, mean that anemia is often under-treated in patients undergoing radiotherapy unless theyare clearly symptomatic or have very low hemoglobin lev-els (!10 g/dl) [2].

Recombinant human erythropoietin is an alternativeoption that avoids the risks associated with transfusions.While several trials have already demonstrated that epoe-tin alfa (Procrit®; Ortho Biotech Products, LP, Bridgewat-er, NJ; Eprex®/Erypo®; Janssen-Cilag and Ortho Biotechoutside the US) effectively corrects anemia and improvesquality of life in patients with cancer receiving chemo-therapy [31–35], it is only more recently that its use hasbeen examined in patients receiving radiotherapy or com-bined chemoradiotherapy [36–42].

For example, a prospective, multicenter trial per-formed in Austria [40] showed that 84% of 143 patientswith anemia responded to epoetin alfa, which was ini-tiated approximately 10 days prior to radiotherapy or che-moradiotherapy. Hemoglobin levels increased at a me-dian rate of 0.37 g/dl/week with epoetin alfa. These dataare consistent with previous studies, which demonstratedthe efficacy of epoetin alfa in cancer patients [36–39, 41,42]. Furthermore, there are now data to support the use ofepoetin alfa administered once weekly [41, 42], ratherthan the less convenient 3-times weekly regimen that iscurrently approved for use in anemic cancer patientsreceiving chemotherapy.

In a multicenter study performed in the US, Shasha etal. [42] showed that overall patient quality of life, andenergy and activity levels were significantly improved(p ! 0.05 versus baseline) after subcutaneous epoetin alfa40,000 units was administered once weekly for 16 weeks.The size of effect observed with epoetin alfa (0.5–0.7) wasjudged to be representative of a medium to large improve-ment in patient quality of life [42].

Future Research

Examining the impact of raising hemoglobin levels incancer patients and finding ways of overcoming tumorhypoxia will be important areas of research over the nextdecade. The specific questions that need to be addressedinclude:E Does raising hemoglobin levels improve patient sur-

vival?E If so, by what mechanisms (i.e., does it improve the

effectiveness of radiotherapy or chemotherapy or doesit actually switch off the molecular events that lead totumor growth, progression and metastases)?

E What constitutes the ‘optimal’ hemoglobin level inpatients with cancer? This may depend not only ontumor- and patient-related factors but also on the func-tional endpoint being studied.In an attempt to answer some of these questions, the

Gynecologic Oncology Group (GOG) has initiated aninternational randomized trial in patients with stage IIB–IVA cervical cancer and hemoglobin levels of !13 g/dl.Patients will receive standard combination therapy ofweekly cisplatin and radiotherapy with or without subcu-taneous epoetin alfa 40,000 units administered onceweekly. Blood transfusions are permitted in the controlgroup if hemoglobin levels fall to !10 g/dl and in the epoe-tin alfa group if hemoglobin levels drop precipitously orare too low to raise to 112 g/dl before chemoradiotherapybegins. As well as survival, patient quality of life and eco-nomic outcomes will be evaluated in this trial.

Ancillary studies will also be performed in an attemptto elucidate the underlying molecular mechanisms. Theseinclude monitoring cell markers of hypoxia (EF5 or 2-(2-nitro-1-H-imidazol-I-yl)-N-(2,2,3,3,3-pentafluoropropyl)acetamide) and angiogenesis [VEGF, thrombospondin-1and platelet/endothelial cell adhesion molecule-1 (PE-CAM-1 or CD31)]. There will also be an assessment of theprognostic value of DNA-cisplatin adducts taken frombuckle smears.

Conclusions

A growing body of literature now shows that there is arelationship between low hemoglobin levels and low ratesof disease control and survival in the radiation oncologysetting. Data suggest that correcting anemia with epoetinalfa improves quality of life, and we postulate, mayimprove response and thus impact survival followingradiotherapy with or without concurrent chemotherapy.


Oncology 2002;63(suppl 2):19–28 27

Although the long-term implications of correcting anemiahave yet to be definitively established, collectively, thesedata suggest that it may be important to maintain adequatehemoglobin levels in patients receiving radiotherapy.

At present, radiation oncologists are focused on wheth-er or not it is possible to improve the control of local dis-ease and survival, but it is important to consider patient

quality of life also. This is particularly relevant given theaggressive combined modality and high-dose treatmentstrategies commonly used in oncology today. Therefore,the challenge for the future will be to devise a unifiedapproach to the management of anemia in patients withcancer, with the aim of improving both disease outcomeand patient quality of life.

References

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20 Gatenby RA, Kessler HB, Rosenblum JS, CoiaLR, Moldofsky PJ, Hartz WH, Broder GJ: Ox-ygen distribution in squamous cell carcinomametastases and its relationship to outcome ofradiation therapy. Int J Radiat Oncol Biol Phys1988;14:831–838.

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24 Brown LF, Berse B, Jackman RW, Tognazzi K,Manseau EJ, Dvorak HF, Senger DR: In-creased expression of vascular permeabilityfactor (vascular endothelial growth factor) andits receptors in kidney and bladder carcinomas.Am J Pathol 1993;143:1255–1262.

25 Blancher C, Harris AL: The molecular basis ofthe hypoxia response pathway: tumour hypoxiaas a therapy target. Cancer Metastasis Rev1998;17(2):187–194.

26 Obermair A, Wanner C, Bilgi S, Speiser P,Kaider A, Reinthaller A, Leodolter S, Gitsch G:Tumor angiogenesis in stage IB cervical cancer:correlation of microvessel density with surviv-al. Am J Obstet Gynecol 1998;178:314–319.

27 Birner P, Schindl M, Obermair A, Plank C,Breitenecker G, Oberhuber G: Overexpressionof hypoxia-inducible factor 1alpha is a markerfor an unfavorable prognosis in early-stage in-vasive cervical cancer. Cancer Res 2000;60:4693–4696.

28 Nordsmark M, Rudat V, Lartigau E, Stadler P,Becker A, Adam M, Molls M, Dunst J, TerrisD, Overgaard J: Hypoxia and hemoglobin asprognostic markers of survival in head & neckcarcinoma after primary radiation therapy. Aninternational multi-center study (abstract 125).Eur J Cancer 2001;37(suppl 6):37.

29 Brizel DM, Dodge RK, Clough RW, DewhirstMW: Oxygenation of head and neck cancer:changes during radiotherapy and impact ontreatment outcome. Radiother Oncol 1999;53:113–117.

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31 Littlewood TJ, Bajetta E, Nortier JWR, Ver-cammen E, Rapoport B: Effects of epoetin alfaon hematologic parameters and quality of lifein cancer patients receiving nonplatinum che-motherapy: results of a randomized, double-blind, placebo-controlled trial. J Clin Oncol2001;19:2865–2874.

32 Dammacco F, Silvestris F, Castoldi GL, GrassiB, Bernasconi C, Nadali G, Perona G, De Laur-enzi A, Torelli U, Ascari E, Rossi Ferrini PL,Caligaris-Cappio F, Pileri A, Resegotti L: Theeffectiveness and tolerability of epoetin alfa inpatients with multiple myeloma refractory tochemotherapy. Int J Clin Lab Res 1998;28:127–134.

33 Garton JP, Gertz MA, Witzig TE, Greipp PR,Lust JA, Schroeder G, Kyle RA: Epoetin alfafor the treatment of the anemia of multiplemyeloma. A prospective, randomized, placebo-controlled, double-blind trial. Arch Intern Med1995;155:2069–2074.

34 Demetri GD, Kris J, Wade J, Degas L, Celia D:Quality-of-life benefit in chemotherapy pa-tients treated with epoetin alfa is independentof disease response or tumor type: results froma prospective community oncology study. JClin Oncol 1998;16:3412–3425.

35 Glaspy J, Bukowski R, Steinberg D, Taylor C,Tchekmedyian S, Vadhan-Raj S: Impact oftherapy with epoetin alfa on clinical outcomesin patients with nonmyeloid malignancies dur-ing cancer chemotherapy in community onco-logy practice. J Clin Oncol 1997;15:1218–1234.

36 Lavey RS: Clinical trial experience using eryth-ropoietin during radiation therapy. Strahlen-ther Onkol 1998;174(suppl 4):24–30.

37 Dusenbery KE, McGuire WA, Holt PJ, et al:Erythropoietin increases hemoglobin duringradiation therapy for cervical cancer. Int J Ra-diat Oncol Biol Phys 1994;29:1079–1084.

38 Antonadou D, Cardamakis E, Sarris G, et al:Effect of the administration of recombinanthuman erythropoietin in patients with pelvicmalignancies during radiotherapy. RadiotherOnol 1998;48:S122.

39 Glaser CM, Millesi W, Kornek GV, Lang S,Schull B, Watzinger F, Selzer E, Lavey RS:Impact of hemoglobin level and use of recom-binant erythropoietin on efficacy of preopera-tive chemoradiation therapy for squamous cellcarcinoma of the oral cavity and oropharynx.Int J Radiat Oncol Biol Phys 2001;50(3):705–715.

40 Hawliczek R, Oismüller R: The effect of sys-tematic rHu-erythropoietin (Epoietin alpha[sic]) treatment before and during radiotherapy(radio-chemotherapy) in unselected anemiccancer patients: results of an Austrian multi-center observation study (abstract 1465). Eur JCancer Clin Oncol 1999;35(suppl 4):S361.

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42 Shasha D, George MJ, Harrison LB: Once-weekly dosing of epoetin alfa increases hemo-globin and improves quality of life in anemiccancer patients receiving radiation therapyeither concomitantly or sequentially with che-motherapy (poster). Presented at the AmericanSociety of Hematology (ASH), 3 Dec 2000, SanFrancisco (CA).


New Chemotherapeutic Agents:Update of Major Chemoradiation Trialsin Solid Tumors

Walter J. Curran

Department of Radiation Oncology, Jefferson Medical College, Philadelphia, Pa., USA

Walter J. Curran, Jr., MDDepartment of Radiation Oncology, Jefferson Medical College111 S. 11th St.Philadelphia, PA 19107-5097 (USA)Tel. +1 215 955 6700, Fax +1 215 955 0412, E-Mail [email protected]


© 2002 S. Karger AG, Basel0030–2414/02/0636–0029$18.50/0


Key WordsRadiotherapy W Chemoradiation W Solid tumors W

Locoregional control W Combined modality therapy

AbstractThe institution of combined modality therapy for unre-sected solid tumors has resulted in significant improve-ments in tumor control and survival benefit comparedwith radiotherapy (RT) alone. A number of chemothera-py agents that can enhance the effectiveness of RT, suchas cisplatin and 5-fluorouracil, are now considered stan-dard treatment for patients with a number of cancertypes. There is growing interest in a number of addition-al agents that have also been found to have radiosensi-tizing ability. These include paclitaxel, docetaxel, irinote-can, gemcitabine, and vinorelbine, as well as biologicagents. Other agents may be of value because they act tocounter dose-limiting toxicities associated with RT. Thisarticle provides an update of some important, recentlycompleted and ongoing clinical trials evaluating novelchemoradiation protocols, with examples taken primari-ly from studies conducted by the Radiation TherapyOncology Group (RTOG). Theoretical approaches to thedevelopment of new agents and combined modality reg-imens are also discussed.


Introduction

Combined modality therapy has been instituted for thetreatment of several types of unresectable solid tumors,with various chemotherapeutic agents used either sequen-tially or concurrently with radiation. Some of these com-bination therapies have resulted in significant improve-ments in tumor control and survival benefit comparedwith radiotherapy (RT) alone. For example, Cancer andLeukemia Group B (CALGB) 8433 was the first majorchemoradiotherapy trial to demonstrate a significant sur-vival advantage with sequential chemotherapy and radia-tion in patients with inoperable stage III non-small-celllung cancer (NSCLC) [1]. These results were subsequentlyconfirmed in the same patient population in a phase IIIstudy carried out by the Radiation Therapy OncologyGroup (RTOG) [2].

A number of chemotherapy agents, including radiosen-sitizing agents such as cisplatin and 5-fluorouracil (5-FU),that can be used in conjunction with RT have been identi-fied and found to be effective in enhancing tumor controland/or improving survival rates in clinical trials. Therehas since been growing interest in a number of agents thathave also been found to have radiosensitizing ability,including paclitaxel, docetaxel, irinotecan, gemcitabine,and vinorelbine, as well as agents with other antitumoractivities, including the antiangiogenesis drugs [3–5].Other agents, such as recombinant human erythropoietin

30 Oncology 2002;63(suppl 2):29–38 Curran

(rHuEPO, epoetin alfa), are of potential value becausethey may counter dose-limiting toxicities associated withRT [6–9], and they may potentially increase tumor oxy-genation, and, therefore, the efficacy of RT.

This article provides an update of some importantrecently completed and ongoing trials evaluating novelchemoradiation protocols. It also highlights methodologicchanges in the way new agents and combined modalityregimens are being developed.

Optimization of Radiotherapy Delivery

The quality and the mode of delivery of RT are of cen-tral importance to the success of combined modality ther-apy. An important hypothesis that underlies the develop-ment of new and more effective RT protocols is thatimprovement of radiotherapy delivery will reduce locore-gional tumor failures. Consequently, this should lead todecreased mortality, and/or decreased treatment-relatedmorbidity.

Radiotherapy can be optimized in a number of ways.These include technical improvements in patient selec-tion and staging, which involves the use of ever-improv-ing imaging techniques, radiotherapy sequencing andfractionation, image guidance during RT procedures, bra-chytherapy, the provision of high radiation doses directlyto a tumor through the implantation of small radioactiveseeds or sources, radiation intensity modulation, andradiation dose escalation.

Until 2000, standard treatment for stage III unresectednon-small-cell lung cancer has been sequential chemo-therapy and radiation. An example of this is the treatmentprotocol that was evaluated in the CALGB and RTOGstudies in NSCLC mentioned previously [1, 2]. The com-bination regimen evaluated in both studies involved ad-ministration of cisplatin, 100 mg/m2 intravenously ondays 1 and 29, and vinblastine, 5 mg/m2 on days 1, 8, 15,22, and 29, followed by RT beginning on day 50 (60 Gy).This was compared with RT alone. Median survival timesfor patients treated with this regimen in the CALGB andRTOG studies were 13.7 and 13.2 months, respectively,versus 9.6 and 11.4 months for patients treated with RTalone. It was concluded by the authors of the CALGBstudy that the use of sequential chemoradiotherapy in-creases the projected proportion of 5-year survivors by afactor of 2.8 compared with standard RT [1]. Even withthis improvement, however, approximately 80–85% ofpatients treated with sequential chemoradiotherapy willbe expected to die within 5 years [1]. Therefore, there is a

need for further improvements in the treatment of locallyor regionally advanced unresectable tumors.

Results from several, recent, prospective phase IIItrials provide convincing evidence that further optimiza-tion of RT delivery in the context of combined modalitytherapy, beyond that evaluated in the CALGB and RTOGtrials, can result in better tumor control and/or patientsurvival. These studies are described below.

Lung CancerRTOG 9410 is a phase III study of 611 patients with

unresected NSCLC, which compared a standard sequen-tial protocol (chemotherapy followed by 60 Gy RT/7weeks given once daily, initiated at day 50) with two con-current chemoradiation protocols (RT initiated on day 1of chemotherapy) [10]. Concurrent RT was administeredeither once daily (60 Gy RT/7 weeks) or as hyperfraction-ated RT (69.9 Gy/6 weeks, twice daily). Preliminary me-dian survival times at a median follow-up time of 40months for sequential, concurrent RT once daily, and con-current hyperfractionated RT were 14.6, 17.1, and 15.6months, respectively, from each patient’s registration. Theconcurrent RT/cisplatin/vinblastine arm had significantlybetter survival than the sequential arm with the sameagents, with a p-value of 0.038. The rates of grade 3–4 non-hematologic toxicity were higher with concurrent vs. se-quential chemotherapy, but late toxicity rates were similarand no differences in grade 5 toxicity rates were noted.

A randomized intergroup study (RTOG 8815) carriedout by Turrisi et al. [11] was aimed at optimizing RTdelivery in patients (n = 417) with small-cell lung cancer(SCLC). After a follow-up of almost 8 years, patients whowere given 45 Gy RT, concurrently with cisplatin and eto-poside, twice daily for 3 weeks, had significantly im-proved median survival rates versus those who received45 Gy RT given concurrently only once daily over 5 weeks(23 months vs. 19 months for patients receiving once-dai-ly vs. twice-daily RT, respectively, p = 0.04). Survivalrates at 5 years were 26 and 16% for patients receivingconcurrent twice-daily or once-daily RT, respectively.However, patients receiving twice-daily RT experiencedgrade 3 esophagitis significantly more frequently thanthose receiving once-daily concurrent RT (27 vs. 11%, p !0.001).

Head and Neck CancerThe randomized phase III trial RTOG 9111 compared

concurrent chemoradiation (RT initiated on day 1 of che-motherapy) versus sequential chemoradiation (RT ini-tiated on day 63 after chemotherapy) vs. RT alone, in 547

Update on Chemoradiation Trials in SolidTumors

Oncology 2002;63(suppl 2):29–38 31

patients with stage 3–4 potentially resectable cancer of thelarynx [12]. The total RT dose was 70 Gy in 7 weeks(2 Gy/fraction), administered in the same regimen, for allof the study arms. The results showed that over a 2-yearfollow-up period, concurrent chemoradiation was statisti-cally significantly better for laryngectomy-free survivaltime compared with RT alone (66 vs. 52%, respectively,p = 0.02). Similarly, concurrent chemoradiotherapy wasstatistically significantly better than sequential chemora-diation and RT alone for time to laryngectomy (p =0.0094 and 0.00035 vs. sequential chemoradiation andRT alone, respectively) over the same follow-up period.

In another phase III trial (RTOG 9003), Fu et al. [13]tested the efficacy of hyperfractionation in patients withlocally advanced head and neck cancer, comparing twotypes of accelerated fractionation therapy with standardfractionated RT. A total of 1,113 patients were random-ized into one of four treatment groups: (1) RT deliveredwith standard fractionation at 2 Gy/fraction/day, 5 days/week, to 70 Gy/35 fractions/7 weeks; (2) hyperfractiona-tion at 1.2 Gy/fraction, twice daily, 5 days/week, to 81.6Gy/68 fractions/7 weeks; (3) accelerated fractionationwith split at 1.6 Gy/fraction, twice daily, 5 days/week, to67.2 Gy/42 fractions/6 weeks including a 2-week rest after38.4 Gy; or (4) accelerated fractionation with concomi-tant boost at 1.8 Gy/fraction/day, 5 days/week and 1.5Gy/fraction/day to a boost field as a second daily treat-ment for the last 12 treatment days to 72 Gy/42 fractions/6 weeks. At a median follow-up time of 23 months for allassessable patients (n = 1,073), those treated with hyper-fractionation (treatment 2) or accelerated fractionationwith concomitant boost (treatment 4) had significantlybetter locoregional tumor control than those treated withstandard fractionation (treatment 1) (54.4 and 54.5% fortreatments 2 and 4, respectively, vs. 46.0% for treatment1, p = 0.045 and 0.050, respectively) (fig. 1). A trendtoward improved disease-free survival was also noted forthe same comparisons (37.6 and 39.3% for treatments 2and 4, respectively, vs. 31.7% for treatment 1), althoughthese differences failed to achieve significance (p = 0.067and 0.054, respectively). All three altered fractionationgroups (treatments 2, 3, and 4) had increased grade 3 orworse acute adverse effects in skin, mucous membranes,pharynx/esophagus, and larynx compared with the stan-dard RT group (treatment 1), but there was no differencein late toxicity (190 days after start of RT).

The results of these studies clearly demonstrate thatthe quality of RT can be modified to improve tumor con-trol and survival. In patients with NSCLC or laryngealcancer, concurrent RT provided a clear benefit over

Fig. 1. RTOG 9003: Phase III trial comparing hyperfractionated RTor accelerated fractionation RT with concomitant boost vs. standardRT in patients with advanced head and neck cancer. a Twice-daily(fractionated) RT resulted in significantly better locoregional controlthan did standard RT (p = 0.05). b Accelerated fractionation resultedin significantly better locoregional control than did standard, twice-daily fractionation (p = 0.05). Follow-up was from the time patientswere randomized into the study (reproduced with permission fromFu et al. [13]).

sequential therapy, and in patients with SCLC, RT twicedaily significantly improved survival rates vs. once-dailytreatment. Clearly, it is important to keep in mind the val-ue of modifying RT delivery when attempting to optimizeestablished chemoradiation combinations, and when test-ing new systemic agents for use in combined modality reg-imens.


Integration of New Systemic Therapies withOptimized Locoregional Therapy

A second important hypothesis that forms the basis forthe development of novel combined modality therapies isthe notion that the integration of new systemic therapieswith optimized locoregional RT will decrease cancer-related mortality. A number of recent trials were designedto compare the efficacy of RT with or without systemictherapy in patients with prostate cancer (RTOG 8531,8610, 9202), stage III NSCLC (RTOG 8808), laryngealcancer (RTOG 9111), esophageal cancer (RTOG 8501),and cervical cancer (RTOG 9001). Overall, the resultsfrom these trials, described in the following sections, indi-cate a significant clinical benefit from the addition of oneor more systemic agents to RT regimens.

Prostate CancerThe benefits of combined modality chemoradiotherapy

were illustrated in the results of three phase III RTOGstudies that evaluated the combination of RT with hor-monal therapy for treatment of prostate cancer (RTOG8531, RTOG 8610, RTOG 9202) [14–16]. A total of 977patients with locally advanced prostate cancer (RTOG8531) [14] were followed for a median period of 5.6 years.Results indicated that long-term administration of adju-vant goserelin (initiated at relapse and continued through-out the follow-up period) to induce androgen suppression,in addition to standard external-beam RT (n = 477 analyz-able patients), significantly improved local tumor control(p ! 0.0001), freedom from distant metastases, and bothabsolute (p = 0.036) and cause-specific (p = 0.019) survival,as compared with patients who received standard external-beam RT alone (n = 468 assessable patients).

Another randomized, phase III trial (RTOG 8610) [15]investigated the effects of androgen ablation with gosere-lin before and during RT for patients with locally ad-vanced prostate cancer vs. RT alone (n = 471). The resultsat an 8-year follow-up demonstrated that combined mo-dality therapy was associated with a significant improve-ment in local tumor control (30 vs. 42% local failure rate;p = 0.016), reduction in disease progression (34 vs. 45%distant metastasis; p = 0.04), and improvement in surviv-al (33 vs. 21% disease-free survival; p = 0.004) comparedwith RT alone. A subset analysis of patients with a Glea-son score of 2 to 6 (indicating relatively less aggressivetumors) showed a highly significant improvement in allendpoints, including overall survival (p = 0.015) in pa-tients treated with combined modality therapy comparedwith those treated with RT alone.

In a prospective, randomized study conducted byHanks et al. [16], a total of 1,554 patients with locallyadvanced prostate cancer received androgen suppressiontherapy (goserelin and flutamide) 2 months before andduring RT. Patients were then randomized to either nofurther therapy or 24 months of additional goserelinalone; the groups were well matched for stratification andother baseline variables considered. The investigatorsfound that disease-free survival (54 vs. 34%), local pro-gression (6 vs. 13%), and reduction in distant metastasis(11 vs. 17%) were significantly better in patients receivingthe longer-duration hormonal therapy compared withthose receiving no further hormonal therapy after radia-tion. Patients with a Gleason score of 8–10 (more aggres-sive tumors) also showed a statistically significant advan-tage in overall survival compared with the same subset ofpatients who did not receive long-term hormone therapy(p = 0.017). It should be noted that long-term androgenablation has hematologic toxicity, which may be detri-mental to locoregional control with RT [17]. Given thispossibility, these patients may benefit from additionalsystemic agents, such as epoetin alfa, to counter treat-ment-related anemias. The potential benefit of epoetinalfa for enhancing locoregional tumor control as well asimproving patient quality of life has received supportfrom recent clinical trials [6–9] and is currently underinvestigation in an RTOG phase III trial (9903).

Stage III NSCLCThe final results of an important randomized phase III

trial involving 458 patients with unresectable NSCLCwere published in 2000 (RTOG 88-08) [2]. This studycompared sequential chemoradiation with either hyper-fractionated or standard RT. Sause et al. evaluated theefficacy of three regimens: (1) chemoradiation, consistingof 2 months of cisplatin and vinblastine therapy, followedby either 60 Gy of radiation at 2.0 Gy per fraction ofradiation delivered once daily (n = 152), (2) hyperfrac-tionated RT, consisting of 1.2 Gy per fraction of radiationdelivered twice daily to a total dose of 69.6 Gy (n = 152),and (3) standard RT alone (n = 154). Results indicatedthat overall survival was statistically significantly betterin patients receiving chemoradiotherapy compared withthe RT regimens (median survival of 13.2, 12, and 11.4months for concurrent chemoradiotherapy, hyperfrac-tionated RT, and standard RT, respectively, p = 0.04 forchemoradiotherapy vs. the RT regimens); the investiga-tors did not find a statistically significant difference insurvival between the two RT arms (standard vs. hyper-fractionated) in this study.


Oncology 2002;63(suppl 2):29–38 33

Laryngeal CancerThe objective of RTOG 9111, a randomized, phase III

study described previously, was to compare the ability ofsequential chemoradiation (cisplatin 100 mg/m2 plus 5-FU 1,000 mg/m2/day ! 120 h for 3 cycles, followed byRT in responding patients) or concurrent chemoradiation(cisplatin 100 mg/m2 plus 5-FU on days 1, 22, 43 plus RT)with that of RT alone, to promote laryngectomy-free sur-vival in patients with cancer of the larynx (n = 547) [12].Although the study failed to establish a significant differ-ence in survival between sequential chemoradiation andstandard RT alone, concurrent chemoradiation resultedin significantly better survival than RT alone (66 vs. 52%after 2 years, respectively, p = 0.02). Moreover, concur-rent chemoradiation was also significantly better thansequential chemoradiation (p = 0.0094) and RT alone (p =0.00035) with regard to time to laryngectomy. Theseresults not only demonstrate the benefit of concurrentchemoradiation over standard RT for treatment of laryn-geal cancer, as assessed by either survival or time to laryn-gectomy, but also highlight the importance of optimizingRT delivery in the context of the specific combinedmodality therapy and the form of cancer involved.

Esophageal CancerLong-term follow-up results (of at least 5 years) from a

randomized, controlled trial conducted from 1985 to1990 (RTOG 8501) demonstrated that concurrent che-moradiotherapy (50 Gy/5 weeks plus cisplatin and 5-FUat weeks 1, 5, 8, and 11; n = 134) statistically significantlyincreased the survival of patients with squamous cell can-cer or adenocarcinoma of the esophagus compared withRT alone (64 Gy/6.4 weeks; n = 62). The overall survivalrate with combined therapy was 26% compared with 0%for RT alone [18].

Cervical CancerRTOG 9001 was a randomized trial that examined the

effects of adding chemotherapy with 5-FU and cisplatinto treatment with external beam and intracavitary radia-tion in women with locally advanced cervical cancer [19].Of 403 patients followed for a mean duration of 43months, estimated cumulative rates of overall survivalwere 73% among patients receiving combined modalitytherapy, compared with 58% for patients receiving RTalone (p = 0.004). Rates of disease-free survival at 5 yearswere also significantly higher among patients receivingchemoradiation (67 vs. 40%; p ! 0.001), and rates of dis-tant metastases (14 vs. 33%) and locoregional recurrences(19 vs. 35%) were significantly lower in these patients (p !

0.001 for both parameters). These impressive results ofdisease-free survival and local control were corroboratedin three important trials involving women with bulkystage IB cervical cancer [20] or locally advanced cervicalcancer [21, 22], carried out by the Gynecologic OncologyGroup. In both of these studies, chemoradiation regimensincluding cisplatin resulted in significantly improved sur-vival and reduced risk of disease recurrence as comparedwith RT alone.

Unique Approaches to Testing Novel SystemicTherapies With Radiotherapy

A review of trials evaluating combined modality thera-pies illustrates some of the ways in which the approach totesting combined modality chemoradiation protocolsmay differ from traditional drug development strategies.It should always be kept in mind that the latest reports ofnew systemic agents undergoing testing, or the mostrecent modifications in RT delivery, may prove quitevaluable for formulating novel combined modality regi-mens. It is possible that agents that exhibit only minimalefficacy when used alone may prove useful when com-bined with RT. Because of this, many new agents shouldbe tested concurrently with RT after their safety has beenestablished, rather than postpone concurrent testing untiltheir efficacy when used alone has been demonstrated. Inaddition, because of the increasing numbers of potentiallyuseful systemic agents, and the resultant exponentialgrowth in the numbers of possible therapeutic drug com-binations, the results of preclinical studies will likely playan increasing role in decisions on which new agentsshould be tested, and in what types of combinations.

It is important to note that the maximum tolerateddose (MTD) of a systemic agent, or of a RT protocol, maybe defined quite differently when these modalities arecombined because of the potential interactions betweenthe two forms of therapy. There may be quantitative dif-ferences, such as the dosages at which toxicity is seen, orthere may be qualitative differences, such as in the typesof adverse effects that occur. For example, the MTD mayrelate to organ-specific side effects, such as esophagitis,pneumonitis, or proctitis, rather than to hematologic pa-rameters, when combined modality therapy is adminis-tered. Moreover, interactions between the treatment mo-dalities render it likely that optimization of RT deliverywill result in changes in optimal drug schedules, and viceversa.


Optimization of Combined Modality RegimensThe results of a phase I trial reported by Fossella et al.

[23], aimed at identifying the MTD of gemcitabine inpatients with NSCLC undergoing thoracic RT, provide anexcellent illustration of how the optimization of RT deliv-ery can play an important role when devising a combinedmodality regimen. These investigators found that dose-limiting toxicity of gemcitabine occurred at 125 mg/m2

when used with a conventional RT regimen, whereas theMTD was 190 mg/m2 when gemcitabine was combinedwith 3-dimensional conformal RT. Thus, optimization ofthe RT protocol with reduction in the radiation volumeallowed for the delivery of a substantially higher dose ofchemotherapy.

RTOG L-0017 is an ongoing phase I trial evaluatinggemcitabine, paclitaxel, and RT vs. gemcitabine, carbo-platin and RT in patients with NSCLC. The study designis an example of a technique that is being used within theRTOG to test more efficiently integrated treatment mo-dalities. The design includes a first schema that involvesadministration of escalating doses of gemcitabine concur-rently with a constant carboplatin dose, with the combi-nation at each dose level of gemcitabine given to a groupof 6 patients. A second schema involves an escalation ofgemcitabine while also escalating paclitaxel in an alternat-ing stepwise fashion, such that the dose of only one of thedrugs is escalated at a time. In both schemata, chemother-apy is accompanied by adjuvant thoracic RT at a totaldose of 63 Gy in 34 fractions in 7 weeks to affected areas,commencing on the first day of chemotherapy. Using thisapproach, it should be possible to efficiently establish aMTD for gemcitabine that is specific for its combinationwith either carboplatin or paclitaxel.

Novel Systemic Agents Undergoing Testing inChemoradiotherapy Regimens

Substantial gains have been made over the past severalyears in the induction of remissions with the use of che-moradiation therapy. Despite these advances, patient sur-vival rates are still unacceptably low and new treatmentstrategies are needed. Several promising, novel systemicagents are currently undergoing evaluation for use in con-junction with RT.

Cyclooxygenase-2 InhibitorsCyclooxygenase (COX) catalyzes the synthesis of pros-

taglandins from arachidonic acid. One form of the en-zyme, COX-2, is overexpressed in a variety of different

tumors, including colon, pancreatic, prostate, lung, andhead and neck cancers, and is also observed in tumorneovasculature [24]. These and other data suggest thatCOX-2-mediated angiogenesis plays a major role in tu-mor growth. These findings have stimulated initiation ofa number of trials evaluating COX-2 inhibitors used inconjunction with RT.

A phase I/II RTOG trial (C-0128) is underway to deter-mine treatment-related toxicity rates in patients withlocally advanced carcinoma of the cervix who are beingtreated with a combination of celecoxib, cisplatin, and 5-FU with concurrent pelvic radiation therapy. In addition,this study is designed to evaluate whether this regimencan improve locoregional control rates, distant control,and/or survival.

Vascular Endothelial Growth Factor (VEGF) BlockadeVEGF is thought to play an important role in tumor

angiogenesis. Blockade of its function is, therefore, con-sidered a treatment target for a number of tumor types,and is likely to be tested in conjunction with combinedmodality therapy.

Sugen (SU) 5416SU 5416 is a small molecule that exhibits potent inhi-

bition of the fetal liver kinase (flk) receptor tyrosinekinase, which is the receptor for VEGF. Expression of flkis limited to endothelial cells and it appears to play a criti-cal role in angiogenesis [25]. RTOG S-0120 and S-0121are two ongoing phase I/II studies aimed at evaluating SU5416 as part of a chemoradiotherapy protocol for treat-ment of low-to-intermediate grade (S-0120) or high-risk,high-grade (S-0121) soft tissue sarcoma.

AngiostatinIn a recent phase I trial at Jefferson Medical College in

Philadelphia involving a small number of patients withadvanced cancer of the head and neck, prostate, breast,and lung, it was determined that the combination ofangiostatin (an antiangiogenesis drug that has antitumoractivity) plus radiotherapy is well tolerated and partiallocal responses were observed. Studies are ongoing toevaluate longer-term treatment at higher doses [26].

Farnesyl Transferase InhibitorsFarnesyl transferase inhibitors target the protein en-

coded by the ras oncogene, blocking its membrane anchor-age, and thereby inhibiting its cell transforming ability [27].R11577 is a potent and selective farnesyl transferase inhib-itor that has shown antitumor activity in animal models,


Oncology 2002;63(suppl 2):29–38 35

and was found to have an acceptable tolerability profile inphase I trials (unpublished data). RTOG 0020 is an ongo-ing phase II trial in patients with locally advanced pan-creatic cancer designed to evaluate the one-year survivalrates of patients treated with paclitaxel, gemcitabine, andRT with or without farnesyl transferase inhibitorR115777.

The above represents only a small number of the clini-cal trials and the novel agents currently being evaluatedfor use in combined modality therapies. Given the rela-tively recent understanding of the potential value of com-bining chemotherapeutic and RT regimens for patientswith unresected solid tumors, this approach can be ex-pected to further improve outcomes for patients withunresectable solid tumors.

New Therapeutic Strategies Based on Analysesof RTOG Clinical and Tissue Databases

The structure of the RTOG and other groups that areinvolved in evaluating new combined modality therapiesencourages the development of such treatments from hy-potheses-based analyses of clinical and tissue databases.Over the past few years, there has been a large expansion ofknowledge concerning the biology of cancer. These ad-vances include new information on the control of cancercell growth and growth factor expression, regulation ofnecrotic and apoptotic cell death, regulation of angiogene-sis and cell-cell communication, the influence of environ-mental factors, such as hypoxia, on tumor growth, andidentification of markers that are over- or underexpressedon cancer cells. By maintaining centralized databases thatmake information on basic cancer biology widely availableit will be possible to reassess archived information and uti-lize proteomic analysis on banked tissue and tumor speci-mens and apply this knowledge to the formulation of newcombined modality clinical trials.

An example of this process involves evaluation of cellmarkers, such as epidermal growth factor receptor(EGFR), on stored tumor tissue that had been obtainedfrom patients with advanced head and neck cancertreated in study RTOG 9003. This was a phase III studythat compared hyperfractionation and standard RT pro-tocols [13]. Further analysis of the results of this trialrevealed that there was a statistically significant increasein locoregional failure in cases where the tumor over-expressed EGFR vs. those without EGFR, resulting in adifference in survival. Interestingly, there was no differ-ence in the development of distant metastases. This find-

ing, which was derived from archived material and infor-mation, suggests that the development of a strategy forEGFR blockade would be useful. Moreover, such a strate-gy would be most beneficial if used during radiotherapy,when locoregional failure can be targeted, rather thanafter radiotherapy, when attempts to influence distantmetastases would probably be less useful.

New Standards of Care

Although there is still much work to be done, com-pleted phase III trials carried out by the RTOG, GOG andother groups have made important contributions to defin-ing new standards of care in locally advanced cervicalcancer, stage III NSCLC, locally advanced head and neckand prostate cancer, localized prostate cancer, central ner-vous system lymphoma, and operable laryngeal cancer.Some of the RTOG studies are listed in table 1.

A number of RTOG studies, also shown in table 1,have recently completed accrual, and should be providingdata within the next few years. These trials include much-needed prospective evaluations of radiosurgery. The re-sults of two major phase III trials will be presented at the2002 American Society for Therapeutic Radiology andOncology (ASTRO) meeting.

Concurrent Chemoradiotherapy Now the StandardThe adoption of concurrent rather than sequential che-

motherapy exemplifies how a meaningful improvementin outcome resulted from relatively subtle changes in ther-apy, including changes in the technique for delivering che-moradiotherapy. Using progress that has been made inthe treatment of stage III NSCLC as an example, the sur-vival of good performance status patients with unresectedtumors progressively improved in a number of studiesconducted over approximately 11 years (table 2) [12, 28].This degree of improvement cannot be explained by stagemigration alone (i.e., changes in staging due to a discrep-ancy between clinical and pathologic staging or other fac-tors). As shown in table 3, the administration of concur-rent rather than sequential chemoradiation, in a random-ized RTOG study (9410) of patients with NSCLC, re-sulted in more than a 20% increase in median survivaltime, a statistically significant improvement [10]. A simi-lar result was seen in a Japanese study reported by Furuseet al. [29]. These results support the positioning of concur-rent chemoradiotherapy as the current standard of care.Although the ability to obtain positive results with consis-tency across studies is encouraging, it is important to note


Table 1. Summary of some recently completed and ongoing major chemoradiation trials

Study Treatment evaluated

Completed phase III RTOG studies9001 Concurrent chemoradiation for locally advanced cervical cancer9410 Sequential vs concurrent chemoradiotherapy for stage III NSCLC9003 Hyperfractionated and accelerated fractionated RT vs standard RT for locally

advanced head and neck cancer9202, 8610 Long- vs short-term adjuvant hormone therapy for locally advanced prostate cancer8531 Adjuvant hormone therapy plus RT for localized prostate cancer9111 Sequential or concurrent chemoradiotherapy vs RT alone for operable laryngeal

cancer

Phase III studies with completed accrual9305, 9508 Radiosurgery for glioma and brain metastases9501 Chemotherapy for resected head and neck cancer9408 Androgen ablation for localized prostate cancer9413 Large-field RT for advanced prostate cancer9802 Chemotherapy for low-grade glioma

Unreported/active phase III trials for stage III NSCLC (RTOG and other groups)RTOG 9801 Amifostine as radioprotectantECOG 2597 Role of 3 times daily RTCALGB 39801 Evaluation of induction chemotherapyR 9309/Intergroup Role of surgery in N2 diseaseECOG Role of thalidomideSWOG/Intergroup Role of EGFR blockade

CALGB = Cancer and Leukemia Group B; ECOG = Eastern Cooperative Oncology Group; EGFR = Epidermalgrowth factor receptor; N2 = mediastinal lymph node metastasis; NSCLC = non-small-cell lung cancer; RT = radio-therapy; RTOG = Radiation Therapy Oncology Group; SWOG = Southwest Oncology Group.

Table 2. Evidence for improvement over time in the treatment ofunresected NSCLC

Cooperative Group Trial Median survivaltime (months)

3-yearsurvival

CALGB 8433 RT [1] 9.6 10%CALGB 8433 sequential CRT [1] 13.7 24%RTOG 9104 concurrent CRT 19.6 40%RTOG 9410 sequential CRT [2] 14.6 31%RTOG 9410 concurrent CRT [2] 17.0 37%SWOG 9504 concurrent CRT [28] 27 140%

CALGB = Cancer and Leukemia Group B; RT = radiotherapy;CRT = chemoradiotherapy; NSCLC = non-small-cell lung cancer;RTOG = Radiation Therapy Oncology Group; SWOG = Southwest-ern Oncology Group.

Table 3. Concurrent vs. sequential chemoradiotherapy for NSCLC –impact on median survival time

Study Median survival time (months)

concurrent sequential p value

Curran et al. [10] 17.1 14.6 0.03998Furuse et al. [29] 16.5 13.3 0.038

NSCLC = Non-small-cell lung cancer.

that there is much room for further improvement in out-comes. Moreover, with the concurrent protocols, there issubstantially greater acute toxicity; work on the develop-ment of systemic agents to counter this is ongoing.

Achieving Further Improvement UsingCombined Modality Regimens

Based on the results of the most recent phase III trialsin patients with stage III NSCLC treated with concurrentchemoradiation, there appears to be a plateau in mediansurvival time of approximately a year and a half. It is like-ly that continued optimization of patient selection and thecontinued development, selection, and implementation


Oncology 2002;63(suppl 2):29–38 37

of combined therapies will play important roles in anyfurther improvements in survival times.

One area of research that is contributing to improve-ments in both patient staging and treatment planninginvolves new uses of computed tomography (CT) andrelated techniques to provide more detailed informationon target structures. For example, the use of metabolicimaging by means of F-18 fluorodeoxyglucose positronemission tomography (FDG-PET) can improve tumordefinition. This helps the clinician to delineate tumorextent and determine the areas that will require high-dosetherapy, and to monitor the therapeutic response [30].Recent work has also indicated that the use of FDG-PETstaging for NSCLC, for example, is a powerful predictorof survival, and it should prove to be a valuable resourcein treatment planning [31].

Continued improvements in radiotherapy delivery, in-cluding dose escalation, intensity modulation, develop-ment of fractionation techniques, enhanced image guid-ance, and exploitation of brachytherapy technology willbe crucial to achieving further success; likewise, the ongo-ing search for novel systemic agents without heavy depen-dence on drugs that have undergone extensive testingwithout RT. Because of the possibility of unique interac-tions between agents with regard to both efficacy and tox-icity profiles, aggressive concurrent testing, as alreadydescribed, should also play a major role.

The use of chemotherapy ‘doublets’ or ‘triplets’, inwhich novel interactions between chemotherapy agentsand RT might be exploited, or in which novel biologicagents may be combined with other chemotherapy agents,is another promising area of research. For example, workcarried out by Ang and others demonstrated that the com-bination of EGFR blockade using monoclonal antibodyC225, radiosensitization with docetaxel, and RT resultedin a significantly greater delay in tumor growth than didany one or combination of two therapies (unpublisheddata). It is likely that in the next several years, what mightbe referred to as new trimodality therapy will be devel-oped for a number of locally advanced malignancies.

Conclusions

Based on the studies described in this review, it is clearthat much has been achieved in the quest for new com-bined modality regimens that improve outcomes in pa-tients with cancer. One major problem, however, is thelong duration of patient accrual, which sometimes resultsin trials that are inadequately powered. Moreover, there isvery little information available from controlled trialsinvolving low-performance status patients (based on theECOG Performance Status Scale) [32]. Staging of patientshas been variable across studies, which can lead to anuneven assessment of outcomes. Importantly, there hasbeen too much reliance on the stage IV drug pipeline,rather than expending sufficient effort on developingdrugs that might be of specific value when used in con-junction with RT. This last point relates to differencesbetween the strategy for developing combined modalityregimens testing concurrent regimens early in drug devel-opment rather than the approach used in standard drugdevelopment where single agent efficacy is the first pro-cess.

Many factors will contribute to improving outcomesfor patients with locally advanced lung cancer, as well asother solid tumors. Testing novel systemic agents with RTis critical, and should pave the way to substantial im-provements in outcomes. Conducting large explanatory,proof of principle trials that address a single question,such as to determine the role of surgery or the optimumtiming of sequential therapies, may prove more valuablethan complicated studies that mask important principles.Clearly, improving radiation standards and quality assu-rance is also critical in this context. All of these ap-proaches combined will slowly but surely contribute to-wards improving the survival of many patients with local-ly advanced solid tumors.

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Evolving Approaches to Improve Outcomes & Minimize Txicities in Radiation Therapy (2002)