115

Radical Chemoradiotherapy for Elderly Patients withBladder Carcinoma Invading Muscle

BACKGROUND. Chemoradiotherapy is becoming an alternative to radical cystec-Fernando Arias, M.D.

tomy among patients with bladder carcinoma invading muscle. In 1988, the authorsMayte Duenas, M.D.began a protocol with methotrexate, vinblastine, doxorubicin, and cisplatin (M-Enrique MartıBnez, M.D.VAC regimen) and radiotherapy for these patients. Traditionally, age has beenMiguel Angel DomıBnguez, M.D.considered a determinant factor thereby excluding the older patients from theJose Juan Illarramendi, Ph.D.oncologic protocols that are considered to be more aggressive. The authors ana-Elena Villafranca, M.D.lyzed 20 patients (age ú 70 years) who were treated during this period with theMartıBn Tejedor, M.D.same protocol as the authors’ other patients.Francisco Molina, M.D.METHODS. The study included 20 patients (age range, 70–78 years; median age,

Rosa Meirino, M.D.74 years) including 4 patients with T2 disease, 9 with T3 disease, and 7 with T4

Juan Jose Valerdi, M.D.disease. All patients had a Karnofsky performance status ofú 60. Treatment proto-

col included cytoreductive transurethral resection, 2 cycles of M-VAC chemother-Service of Oncology, Hospital of Navarre, Pam- apy, and radiotherapy (45 grays [Gy] on pelvic volume) with concurrent cisplatinplona, Spain.

(20 mg/m2 on Days 1–5. Response was determined by cystoscopic evaluation. If

there was a complete response, radiotherapy continued until a total dose of 65

Gy; if there was not a complete response, cystectomy was performed.

RESULTS. Tumor response after a dose of 45 Gy included 11 complete responses

(55%), 5 partial responses (25%), and 4 nonresponses (20%). Overall survival was

75%, 34%, and 27% in the 2nd, 3rd, and 5th years of follow-up, respectively. Cause

specific survival was 79%, 54%, and 38%, respectively. Survival for patients with

complete response was 100%, 60%, and 48%, respectively. Severe toxicity was

uncommon, with the most frequent toxicities being leukopenia and cystitis. No

treatment-related death occurred with either treatment protocol.

CONCLUSIONS. The age of the individual must not become a strict exclusion crite-

rion for the radical treatment of old patients with invasive bladder carcinoma.

Cancer 1997;80:115–20. q 1997 American Cancer Society.

KEYWORDS: elderly patients, chemoradiotherapy, bladder carcinoma, tumor re-sponse.

Over the last decade, multimodality organ-sparing treatment hasbecome the standard of care for many common malignancies.

However, bladder carcinoma is an exception, with most patients withmuscle-invading disease receiving radical cystectomy without thequestion of organ preservation ever being raised. Nevertheless, inCanada and Europe, definitive radiotherapy with or without chemo-therapy is still the principal mode of treatment for bladder carcinoma.Several groups of investigators have recently explored the use of com-

Address for reprints: Fernando Arias, M.D., Ser- bined chemoradiotherapy in an attempt to improve the results ofvice of Oncology, Hospital of Navarre, Irunlarrea radiotherapy alone. The incorporation of systemic chemotherapy intoRd., 31008 Pamplona, Spain. the primary management of bladder carcinoma invading muscle is an

attractive strategy for several reasons. The risk of distant metastases isReceived November 4, 1996; revision receivedFebruary 4, 1997; accepted March 19, 1997. high, and local treatment modalities cannot reduce that risk. Preclini-

q 1997 American Cancer Society

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116 CANCER July 1, 1997 / Volume 80 / Number 1

cal studies with animal tumor models and humanbladder carcinoma cell lines have demonstrated syner-gistic cytotoxicity when cisplatin is combined withconcurrent radiotherapy.1,2 In several Phase II andPhase III clinical trials, the concomitant use of cis-platin with radiotherapy has been associated withhigher rates of local responses.3–6 Multiagent chemo-therapy has also been reported to result in significantresponses in both the primary tumor and distant fail-ure. This combination of neoadjuvant chemotherapy(generally methotrexate, vinblastine, doxorubicin, andcisplatin [M-VAC] or methotrexate, vinblastine, andcisplatin) followed by radiotherapy with or withoutconcomitant cisplatin has been investigated by severalauthors.7–12 In all of these studies, this combinationapproach showed that bladder preservation could beachieved in the majority of patients, and that overallsurvival was at least similar to that reported with ag- FIGURE 1. Treatment schedule for patients with invasive bladder carci-gressive surgical approaches. noma at the Hospital of Navarre. TUR: transurethral resection; M-VAC:

Elderly patients form a significant proportion of methotrexate, vinblastine, doxorubicin, and cisplatin; Gy: grays.those developing bladder carcinoma. Traditionally,age has been considered a determinant factor for ex-cluding elderly patients from radical oncology proto- examinations were optional. Transitional cell histology

was present in all patients.cols that are considered more aggressive. Althoughmost series of chemoradiotherapy treatment for blad- Exclusion criteria for aggressive treatment were:

Karnofsky performance status õ 60%, previous pelvicder carcinoma included some elderly patients, untilnow, to the authors’ knowledge, there has not been radiotherapy, metastatic lymph nodes above of the

bifurcation of the common iliac vessels, a plateletany serious study of the real impact of this aggressivetreatment in elderly patients. In 1988, the authors be- count õ 100,000/mm3, a leukocyte count õ 4000/

mm3, and creatinine clearance õ 50 mL/minute. Thegan a protocol with neoadjuvant chemoradiotherapyfor the treatment of patients with muscle-invading minimum follow-up of the series was 30 months

(range, 30–93 months), with a median follow-up of 60bladder carcinoma. They analyzed 20 patients age õ70 years who were treated during this period with the months.

The treatment protocol is shown in Figure 1. Aftersame protocol as the rest of the patients, focusing onthe tumor response, toxicity, and survival. the maximum transurethral resection (7 patients had a

complete visible tumor resection), all patients receivedintravenous methotrexate, 30 mg/m2 on Days 1, 15,PATIENTS AND METHODS

There were 20 patients (17 males and 3 females), all and 22; cisplatin, 70 mg/m2 on Day 2; doxorubicin, 70mg/m2 on Day 2; and vinblastine, 3 mg/m2 on Daysage ú 70 years (median age, 75 years). Using the 4th

edition of the TNM International Union Against Can- 2, 15, and 22. This treatment cycle was repeated oncebeginning on Day 29. Patients then received inductioncer staging classification, published in 1987, there

were: 4 T2 classified tumors (20%), 9 T3 classified tu- chemoradiotherapy. The irradiation dose was 1.80grays (Gy) daily, up to 45 Gy in 5 weeks. All patientsmors (45%), and 7 T4 classified tumors (35%). Only

one patient had radiologically positive regional lymph received concurrent cisplatin, 20 mg/m2/day in con-tinuous perfusion, over the first 5 days of irradiation.nodes. According to histologic grade, two tumors were

Grade 2, ten were Grade 3, and eight were Grade 4. After 45 Gy of pelvic irradiation, restaging was per-formed that included examination under anesthesia,All patients presented with hematuria as the primary

symptom, and 40% of patients had unilateral or bilat- cystoscopy with tumor site biopsy, and urinary cytol-ogy. Patients were considered to have achieved a com-eral hydronephrosis. Staging was determined clini-

cally; all patients underwent examination under anes- plete response if there was no evidence of tumor inall of the above studies. Complete responders werethesia, using cystoscopic resection to determine depth

of invasion, chest X-ray, blood chemistry studies, in- treated with consolidation radiotherapy, 2 Gy daily,up to 20 Gy in 2 weeks. After consolidation, patientstravenous pyelogram, and computed tomography

scan of pelvis and abdomen. Bone scan and others were evaluated every 6 months with cystoscopy. Pa-

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Bladder Carcinoma in Elderly Patients/Arias et al. 117

tients who did not achieve a complete response after45 Gy of irradiation were assigned to undergo cystec-tomy. One patient refused cystectomy and receivedradiotherapy to 65 Gy, plus an additional course ofconcomitant cisplatin.

The target volume for induction radiotherapy in-cluded the bladder and pelvic lymphatics. Planningcystograms were used for this phase of irradiation. Thefield borders were the S1–S2 interspace cephalad, atleast 1 cm beyond the bony pelvis laterally, and theinferior border of the obturator foramen caudally. Thetarget volume for consolidation patients included the FIGURE 2. Survival curves for all 20 evaluable patients. OS: overallwhole bladder or, when possible, only the tumor with survival; CSS: cause specific survival.a margin. Multiple fields were used for both radiationcourses; generally, a four-field technique was used.Photons of 6–15 megavolts, proceeding from a linearaccelerator, were used to administer the prescheduleddose of irradiation. CT scans were used for planningthe target volume.

Acute and delayed toxicities of radiotherapy werereported according to standard Radiation Therapy On-cology Group (RTOG) criteria.13 Toxicities of chemo-therapy were reported according to World Health Or-ganization (WHO)criteria.14

Statistical AnalysisFIGURE 3. Overall survival according to the tumor response evaluationSurvival was estimated using the Kaplan-Meierafter neoadjuvant methotrexate, vinblastine, doxorubicin, and cisplatin andmethod.13 Potential prognostic factors were evaluatedcisplatin/radiotherapy (45 grays). CR: complete response.using logistic regression for the endpoint of complete

responses. Levels of significance were represented byP values derived from two-sided tests.

tumor) at last follow-up. By univariate analysis, prog-nostic factors for complete response were T2 diseaseRESULTS

Of the 20 patients, 11 had a complete response (55%), (Põ 0.001) and absence of hydronephrosis (Põ 0.05).The survival curve for all 20 patients is shown in5 had a partial response (evident tumor response but

no complete response) (25%), and 4 patients had no Figure 2. At last follow-up, the 3- and 5-year actuarialsurvival rates were 34% and 27%, respectively. The 3-response (20%). Of nine patients who did not achieve

complete response evaluation, five were treated by and 5-year cause specific survival rates, important forthis group of elderly patients, were 54% and 43%, re-cystectomy (three with pT3 disease, one with pT1 dis-

ease, and one with pT0 disease) one was judged unre- spectively. Figure 3 shows the survival according toresponses after the 2 cycles of chemotherapy and 45sectable at laparotomy, one refused surgery and was

assigned to receive consolidation radiotherapy, one Gy of pelvic irradiation and concomitant cisplatin. Itis interesting to note the high rate of survival at 3 andreceived intravesical chemotherapy, and one devel-

oped tumor progression during the course of the treat- 5 years for the patients with complete responses (61%and 49%, respectively), whereas all the noncompletement and died soon after. All five surgical patients

died of disease, three with local recurrence and two responding patients died within the first 3 years of thetreatment.with metastases. Only one patient who underwent cys-

tectomy due to hematuria (pT0 disease at pathologic The percentage of patients who developed variousacute toxicities during treatment is listed in Table 1.examination) was alive without carcinoma at 72

months’ follow-up. Severe and life-threatening toxicity was uncommon.The severe acute toxicity reactions (Grade 3 or 4 basedOf the 11 patients who achieved a complete re-

sponse, 5 were alive without disease (at 32, 52, 81, 83, on WHO or RTOG criteria) included leukopenia (10%),trombocytopenia (5%), severe cystitis (10%), emesisand 84 months, respectively),and 6 had died (3 with

local recurrence, 1 with lung metastases, and 2 without (10%), and diarrhea (5%). Curiously, no patient had

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118 CANCER July 1, 1997 / Volume 80 / Number 1

TABLE 3TABLE 1Toxicities Associated with Neoadjuvant M-VAC Patients with Free of Invasive Tumor

Age T Local DistantGrade of toxicity(yrs) classification Response recurrence recurrence Outcome a

Toxicity 0 1 2 3 478 T3 PR b — — Alive (80 yrs)73 T3 CR — Bone Died (76 yrs)Anemia 17 2 1 0 0

Leukopenia 10 5 3 2 0 78 T4 CR T1 — Died (83 yrs)73 T2 CR — — Died (76 yrs)Thrombocytopenia 17 2 0 1 0

Nausea/emesis 8 6 4 1 1 72 T2 CR — — Alive (79 yrs)73 T2 CR T1 — Alive (78 yrs)Alopecia 2 4 10 4 0

Mucositis 17 2 1 0 0 73 T4 PR c — Bone Died (76 yrs)70 T2 CR — — Alive (74 yrs)Renal 15 4 1 0 072 T3 CR T1 — Died (75 yrs)78 T3 CR — — Died (81 yrs)M-VAC: methotrexate, vinblastine, doxorubicin, and cisplatin.

76 T4 CR — — Alive (78 yrs)

PR: partial response; CR: complete response.a Age in parentheses indicates age at last follow-up or death.

TABLE 2 b Classified as T1. No surgery was performed due to presence of Alzheimer’s disease.Toxicities Associated with Concomitant Cisplatin/Radiotherapy c Complete response obtained after 65 grays of radiation.

Grade of toxicity

Toxicity 0 1 2 3 4tion of cisplatin with other drugs (doxorubicin,methotrexate, and vinblastine) elevates their re-Anemia 16 4 0 0 0

Leukopenia 10 5 5 0 0 sponse rates to 60% in patients with advanced blad-Thrombocytopenia 18 1 1 0 0 der carcinoma. Nephrotoxicity is an acute dose-lim-Diarrhea 4 13 3 0 0 iting toxicity of cisplatin. Acute nephrotoxicity isNausea/emesis 10 6 4 0 0

common in the absence of hyperhydration but hyp-Bladder 3 12 3 2 0erhydration reduces this incidence to approximatelyRenal 14 4 2 0 05%. Little information is available regarding the in-fluence of age in cisplatin toxicity. Hrushesky et al.17 investigated the reduction in creatinine clearanceafter at least 4 cycles of chemotherapy that includedrenal toxicityú Grade 1. One patient required delayed

cystectomy because of severe hemorrhagic cystitis. No cisplatin at a dose of 60 mg/m2 in patients age 29 –77 years. In their study, the creatinine clearance de-treatment-related deaths occurred with either treat-

ment protocol. For comparison, this toxicity was simi- creased 30 mL/minute in patients age õ 50 yearsand 21 mL/minute in patients age ú 60 years. Thelar to the toxicity observed in the group of the younger

patients treated at the study institution with the same renal toxicity of cisplatin does not appear to increasewith age; on the contrary, age may confer a benefit.protocol during the same period, and also to that re-

ported in other series with similar protocols. Other authors also have investigated the nephrotox-icity of cisplatin in patients age ú 70 years.16,18 – 20At last follow-up, 11 patients had died, 5 with local

recurrence or progression, 3 with metastases without These authors concluded that cisplatin can be usedwithout any increased toxicity and with an efficacylocal recurrence, 1 with both local and distant disease,

2 because of myocardial infarction, 1 with intestinal comparable to that observed in younger patients.Several hypothesis have been advanced to explainischemia, 1 with gastrointestinal sepsis, and 1 died of

an unknown cause. Of all 20 patients, 60% remained this relative protection against nephrotoxicity ob-served in very elderly patients. The first explanationfree of tumor during follow-up or until death (Ta-

ble 3). is simply the reduced urinary concentration of cis-platin in elderly patients due to the overall decreasein renal concentration capacity.21 A second hypothe-DISCUSSION

Today it is known that cisplatin at moderate doses sis is hyperfiltration by the remaining nephrons.22 Athird hypothesis is based on the widely recognized( 60 to 100 mg/m2) can be reasonably administered

to patients ú 80 years who may benefit from anti- relative preservation of the renal cortex duringaging.23 Nevertheless, no experimental data exist toneoplasic chemotherapy.16 Cisplatin is the most ac-

tive drug against bladder carcinoma. The combina- support that hypothesis at this time.

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Bladder Carcinoma in Elderly Patients/Arias et al. 119

The effect of radiation and cytotoxic platinum compoundsWith regard to the other cytostatic drugs includedon the growth of normal and tumor bladder explant cultures.in the M-VAC protocol (methotrexate, vinblastine, andActa Oncol 1990;29:179.

doxorubicin) at doses used and with dose modifica- 2. Soloway MS, Morris CR, Sudderth B. Radiation therapy andtions according to the toxicity, no data exist that sup- cisdiamminedichloroplatinum (II) in transplantable and pri-port a higher toxicity when these drugs are adminis- mary murine bladder cancer. Int J Radiat Oncol Biol Phys

1979;5:1355.tered to older patients with good performance status.3. Shipley WU, Prout GR, Einstein AB, Coombs LJ, WajsmanIn the authors’ experience, the acute toxicity due to

Z, Soloway MS, et al. Treatment of invasive bladder cancerthe M-VAC regimen was similar in both age groups (õby cisplatin and radiation in patients unsuited for surgery.

70 years and ú 70 years). JAMA 1987;258:931.With optimal technique and dosage, irradiation 4. Dunst J, Sauer R, Schott KM, Kuhn R, Wittekind C, Altendorf-

Hofman A. Organ-sparing treatment of advanced bladdercauses little morbidity. There are several factors thatcancer. A 10-year experience. Int J Radiat Oncol Biol Physpredispose patients to severe radiation reaction: previ-1994;30:261.ous surgical procedures (particularly multiple biopsies

5. Tester W, Porter A, Asbell S, Coughlin C, Heaney J, Krallperformed within 3 weeks of the beginning of radiation J, et al. Combined modality program with possible organtherapy), obstructive uropathy, bladder infection, and preservation for invasive bladder carcinoma: results of

RTOG protocol 85-12. Int J Radiat Oncol Biol Phys 1993;large ulcerative or necrotic tumor. Mild to severe cysti-25:783.tis or diarrhea are the more frequent complications in

6. Gospodarowicz MK, Rider WD, Keen CW, Connolly JG, Jewetpatients receiving pelvic irradiation. Preexisting dis-MA, Cummings BJ, et al. Bladder cancer: long-term follow-

eases such as diverticulosis predispose a patient to up results of patients treated with radical radiation. Clinsevere complications. Rectal ulcers also can develop Oncol (R Coll Radiol) 1991;3:155.because of improper technique or when the anterior 7. Zietman A, Shipley WU, Kaufman DS. The combination of

cisplatin based chemotherapy and radiation in the treat-rectal wall is included in the treatment port to encom-ment of muscle-invading transitional cell cancer of the blad-pass tumor extension. Nevertheless, age per se is notder. Int J Radiat Oncol Biol Phys 1993;27:161.

a predisposing factor for acute toxicity to radiotherapy.8. Tester W, Caplan R, Venner P, Wittington R, Byhardt R, True

Indeed, elderly patients with bladder carcinoma con- L, et al. Neoadjuvant combined modality program with se-sidered not suitable for cystectomy are being given lective organ preservation for invasive bladder cancer: re-

sults of Radiation Therapy Oncology Group Phase II Trialradical or palliative radiotherapy, and they have simi-8802. J Clin Oncol 1996;14:119.lar toxicity to that observed in younger patients. In a

9. Vogelzang N, Moormeier JA, Awan AR, Weichselbaum RR,review of 135 patients with muscle-invading bladderFarah R, Straus FH, et al. Methotrexate, vinblastine, doxoru-

carcinoma treated with external beam radiotherapy bicin and cisplatin followed by radiotherapy or surgery forat the M. D. Anderson Cancer Center, Pollak et al.23

muscle invasive bladder cancer: the University of Chicagoexperience. J Urol 1993;149:753.reported a similar rate of severe complication in the

10. Einstein AB, Wolf M, Halliday KR, Miller GJ, Hafermann M,patients age ú 65 years ( N Å 85) and in patients ageLowe BA, et al. Combination transurethral resection, sys-õ 65 years (N Å 50). In all series, patients undergoingtemic chemotherapy, and pelvic radiotherapy for invasivefour-field radiation technique or those receiving high(T2–T4) bladder cancer unsuitable for cystectomy: a phase

energy radiation or õ 70 Gy of irradiation had a sig- I/II Southwestern Oncology Group Study. Urology 1996;nificantly lower actuarial severe complications rate. A 47:652.

11. Cox JD, Stetz J, Pajak TF. Toxicity criteria of the RadiationCox proportional hazards analysis revealed this tech-Therapy Oncology Group (RTOG) and the European Organi-nique to be the only independent significant factorzation for Research and Treatment of Cancer (EORTC). Intpredictive of severe complications (P Å 0.0001).J Radiat Oncol Biol Phys 1995;31:1341.

The acute toxicity and cause specific survival 12. Miller AB, Hoogstraten B, Staquet M, Winkler A. Reportingfound in the current series are similar to those re- results of cancer treatment: evaluation of toxicity: clinicalported by other authors and to the authors’ own expe- issues. Cancer 1981;47:207.

13. Kaplan EL, Meier P. Nonparametric estimation from incom-rience with younger patients with bladder carcinoma.plete observations. J Am Stat Assoc 1958;53:457.The authors conclude that patient age must not be-

14. Thys A, Saudes L, Otto J, Creison A, Gaspard MH, Dassonvillecome a strict exclusion criterion for radical treatmentO, et al. Renal tolerance of cisplatin in patients more than

in patients with invasive bladder carcinoma. Only 80 years old. J Clin Oncol 1994;12:2121.those patients with T4 tumors who do not undergo 15. Hrushesky WJ, Shimp W, Kennedy BJ. Lack of age-depen-cytoreductive transurethral resection or those with dent cisplatin nephrotoxicity. Am J Med 1984;76:579.

16. Becouarn Y, Bui BN, Brunet R, Ravaud A. Cancer and che-Grade 3/4 hydronephrosis or low performance statusmotherapy in the elderly: a series of 51 patients aged ú70should be ineligible for radical chemoradiotherapyyears. Cancer Chemother Pharmacol 1992;29.159.and considered for palliative treatment.

17. Sella A, Logothetis J, Drexfus FH, Amato R, Finn L, Fitz K.Cisplatin combination chemotherapy for elderly patientsREFERENCES

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