CLINICAL EVALUATION OF T H E TREATMENT OF ADVANCED HEAD AND NECK CANCERS

WITH HIGH-ENERGY ELECTRON BEAMS HAROLD PERRY, MD," FLORENCE C. H. CHU, MD, TOSHIO KITAGAWA, MD,+

ARVIN S. GLICKSMAN, M D , ~ AND JAMES J. NICKSON, MDS

T w o hundred ten cases of head and neck carcinoma have been reviewed fol- lowing treatment with high-energy electrons, 6 mev to 24 mev. T h e ease of altering the electron beam energy allows for a rapid replanning of treatment when tumor size diminishes. T h e primary aim of treatment in most cases was palliation. Doses greater than 5,500 rads in 5 weeks were necessary for control of the primary and recurrent tumors as well as the metastatic nodes. T h e inter- vening normal tissue tolerated the dosage schedules quite well. In the material reported here the number of complete regressions was modest and the duration of continued control was short. T h e obvious reason for this finding is that the material was advanced or recurrent in 90% of cases. Other factors may account in par t for the failures. T h e RBE of electrons is still uncertain. Consideration of tissue heterogeneity which was not done with these cases may produce different dose distributions. T h e authors conclude that high-energy electrons are a safe and convenient source of ionization for the treatment of head and neck cancers.

IGH-ENERGY ELECTRON BEAMS IN THE RANGE H of 6 to 24 mev have been used at the Memorial Center for the past 10 years. Two main groups of patients have been treated with high-energy electrons. These are patients

From the Department of Radiation Therapy, Me- morial Hospital for Cancer and Allied Diseases, James Ewing Hospital, and the Section of Radiobiology, Sloan-Kettering Institute, New York, N.Y.

Supported in part by the Kress Foundation. Presented in part at the Eighth International Cancer

Congress, Moscow, U.S.S.R., July 1962. * Present Address: Department of Radiology, Divi-

sion of Radiotherapy, Sinai Hospital of Detroit, De- troit, Mich. Formerly Kress Fellow in Radiation Ther- apy, Memorial Center and Division of Biophysics, Sloan-Kettering Institute, New York, N.Y.

t Morris Fund Fellow, Division of Experimental Radiobiology, Sloan-Kettering Institute (1959). Present address: National Institute of Radiological Sciences, 250, Kurosnna-cho, Chiba-Shi, Japan.

Z Present address: Department of Radiotherapy, Michael Reese Hospital, Chicago, Ill.

Address for reprints: Florence C. H. Chu, MD, 444 East 68th Street, New York, N.Y. 10021.

The authors express their appreciation to the mem- bers of the Head and Neck service, Department of Surgery, for permission to treat the majority of the patients reported here. They are also grateful to mem- bers of the Department of Medical Physics for the preparation of isodoses on these patients.

Received for publication November 15, 1965.

with cancer of the breast and cancer of the head and neck regions. The former group has been previously reported.3~ 4 The purpose of this paper is to report the clinical experience obtained in the treatment of head and neck cancers with high-energy electrons. For the most part, only advanced or recurrent cases were treated with electrons. Initially, these cases were chosen to permit the development of treatment techniques and for the evalua- tion of early and late normal tissue reactions and tumor responses. Latterly, the number of early cases did not increase.

MATERIAL

From June 29, 1955 to December 31, 1960 more than 300 patients with cancers of the head and neck region were treated with high- energy electrons. Sixty-one with epidermoid carcinomas received preoperative radiation to the neck, followed immediately by surgical removal of the primary and radical neck dis- section. These have been reported elsewhere.5 Fifty-five were treated for various other malig- nancies, such as malignant lymphoma, soft part sarcomas, sarcomas of the bone, brain

1081

1082 CANCER August 1966 Vol. 19

TABLE 1. Distribution of Cases According to the Primary Sites

Site

Oral Cavity Hard palate Buccal mucosa Inferior gingiva Floor of mouth Anterior 2/3 tongue

Oropharynx Tonsil Base of tongue Soft palate

Laryngopharynx Epiglottis Pharyngeal walls Hypopharynx True vocal cord

Nasopharynx Others

Maxillary antrum Parotid Cervical nodes

No.

40 1 4 7

15 13

19 34 15

3 17 25 9

68

54

22 26

10 9 2

Primary unknown Ear 1 External auditory canal 1 Middle ear 1

2 Lip - TOTAL 210

tumors and tumors of other primary sites metastatic to the head and neck region. These 2 groups will not be evaluated in this paper. T h e remaining 210 patients with head and neck cancers compose the material for this report.

The distribution of these cases according to the sites of primaries is presented in Table 1. Essentially all of the neoplasms were epi- dermoid carcinomas (squamous cell carci- noma) except for a small number who had other histologic types such as adenocarcinoma (4 cases), adenocystic carcinoma (5 cases), mu- coepidermoid carcinoma (4 cases), lymphoepi- thelioma (3 cases), salivary gland tumors (3 cases) and basal cell carcinoma (one case).

Of the patients in this series 90% had an advanced stage of disease. Many had bulky primary tumors, often with large and/or bi- lateral metastatic cervical lymph nodes: some had distant metastases. As can be seen in Ta - ble 2, 98 cases were previously untreated while 112 were recurrent following prior sur- gery, radiotherapy, chemotherapy or com- bined treatment.

Clinical staging according to the system of the International Union Against Cancer was possible in 96 of the previously untreated cases and is presented in Table 3. I t is ap- parent that the majority of cases were stages

T,N,, and T,N,. Thus the primary aim of treatment in most cases was palliation.

TREATMENT TECHNIQUES AND DOSAGE

The principles underlying the utilization of electron beams for the treatment of head and neck cancers previously have been described.l.8 The physical characteristics of high energy electrons makes for ease of treatment planning resulting in a dose distribution suitable for each patient’s situation. The treatment tech- niques employed varied with the size and location of the primary tumor and the pres- ence or absence of cervical lymph node metas- tases. Most patients were treated 5 days a week. Treatment was generally given at 180 to 190 rads tumor dose daily, with a total tumor dose of 6,000 to 7,000 rads in 6 to 8 weeks being achieved in most patients. In those patients who completed a prescribed course of treatment the dose range was 2,100 rads in 2 weeks to 8,800 rads in 11 weeks. Isodose curves were plotted for each patient under the supervision of the Department of Clinical Physics.

EVALUATION

.A11 patients have had a minimum follow-up of 3% years with a maximum follow-up of

TABLE 2. Distribution of Cases According to

Cases No.

Prcviously untreated 98

Previously Untreated and Recurrent Tumors

Primaries with or without nodes Nodes only, epidermoid carcinoma,

Recurrence in primary with or

Nodes only, primary site negative

96

primary undetermined 2

without nodes 93 19

TOTAL 2 10

Recurrent 112

-

TABLE 3. Distribution of Previously Untreated Cases According to Clinical Stages

T* 2 2 1 2 7 T* 11 2 3 11 27 T3 4 3 0 17 24 T4 5 4 3 26 38

TOTAL 22 11 7 56 96 - - - - -

No. 8 CANCER TREATMENT WITH HIGH-ENERGY ELECTRON BEAMS Perry et al. 1083

TABLE 4. Response of Primary Tumors to Electron Irradiation-Previously Untreated T I T ~ ( N o . NIN2)

Response of primary Response of lymph nodes Total __ --

Field Dose Site Stage size (rads/wk.) Result

Inferior gingiva

Floor of mouth

Ant. 2/3 tongue

Base of tongue

Tonsil

Epiglottis

HYPO- pharynx

Pharyngeal walls

Intrinsic larynx

TzNn 8 x 1 5 6,500/6 Control

T16a 4 x 5 3.450/31 Control

TINO 6 x 4 7.600/8 Control f8,OOO R Rn

+2.000 R Ra TnNa 6 x 8 3.250/3

f6.100/6 ~ 9 2

TzNo 6 x 6 6,600/8)

TzNi 8 x 1 0 2,OSO/Z

TiNi 6 x 8 6,200/61 TzNo 9 x 1 0 3.700/5) TzNo 6 x 8 4.200/33

then Rx stopped 8 x 8 for surg.

TzNo 6 x 4 7,050/7 4 x 5

TiNi 6 x 8 5,800/7

TzNn 6 x 8 7.450/8: TINS 7 x 1 0 7,1001’7

9 x 1 5 8 x 2 0 +wax

TzNo 6 x 1 0 7.000/7

TzNo 8 x 1 0 7.450/6

TzNi 6 x 1 0 7.70018 6 X 5

6 X 9

TzNo 4 x 1 0 7,500/71

TzNo 6 x 8 8.800/11

TzNo 6 x 1 0 5.650/4

TiNo 2 x 4 6,200/6

TINO 4 x 5 5,850/54 4 x5

Partial

Control

Failure

Control Partial Failure

had com- mando

Control

Duration Field Dose Duration surv. (mo.) size (raddwk.) Result (mo.) Status (mo.)

16

23

7

2 then surg.

30

-

60 f 1

-

10 then rec. then

surg.

Control 60 then

Control 23 Control 4 then

surg.

surg.

Control 60f

Control 11

Control 9 then surg.

Control 604-

Control 5 then surg.

Partial 8

Control 96+

Control 65f

Partial

-

-

-

-

Failure

Control -

-

-

Control

Control Partial

-

Control

-

-

-

-

-

-

Died (node)

NED Died I D Died P

Alive NED

NED Died I D Died 1. PN 2. DM ca esoph.

Alive NED Died I D with P Alive NED

Alive NED

Died ID

Died ID Died PN DM

Alive NED

Died I D

Died postop. carotid hemorrhage Alive with 2nd P Alive NED after surg Died N E D 2nd P NED alive

20 then LTV 24 24 23

LTV 10

33

1

60 f 1

30 + 36 f

69

25 17

60 f

11

11

60 4-

36 f

9

96 f

NED alive 654-

Abbreviations: P-primary; N-nodes; DM-distant metastasis; ID-intercurrent disease; NED-no evidence of disease; LTV-lost to view.

approximately 9 years. Since most patients were treated for palliation, this allows ade- quate time for evaluation of acute and chronic normal tissue reactions as well as of tumor response.

Tumor Response

The response of tumors was evaluated in terms of control, partial control, failure and the duration of response. Control denoted

regression of the tumor with no clinical evi- dence of residual neoplasm. Partial control indicated reduction in the size of the neo- plasm with residual tumor remaining. The duration of response was the time from the first sign of shrinkage of the tumor to the time of the first sign of reappearance or en- largement of the tumor, or to the patient’s last evaluation due to death, surgical re- moval of the tumor or loss of the patient to follow-up. Tumors which did not reduce in

I084 CANCER August 1966 Vol. 19

TABLE 5 . Response of Primary Tumors to Electron Irradiation-Previously Untreated Cases, TINS, T ~ N I

Control Partial control Failure _--__ -

Duration Duration N O . (ma.) No. (mo.) N O .

Total of Dose - of Dose of Dose Location* cases cases (rads/wk.) Mean Ranne cases (raddwk.1 Mean Ranne cases ( raddwk. )

Oro-

Laryngo-

Naso-

pharynx 4 1 8.250/8; 10 2 7,500/9: 3 2,3 1 1.300,’lf

pharynx 7 3 6.000/9-7,25018 19 4-36 4 3.300‘3-7.950/11 8 2-21 0 -

pharynx 2 2 4,050/5-5,750/71 6 1‘-10 - - - - - - - - - - -

TOTAL 13 6 13 1-36 6 6 2-21 1

* No statistics on oral cavity. ’ Hemorrhage from liver metastasis.

size or which increased in size during treat- ment, those not completing the planned course of treatment and those lost to view were considered failures.

Primary tumor: Electron-beam irradiation was used on 189 primary tumors (96 pre- viously untreated and 93 recurrent) (Table 2). Statistical evaluation of the response of the individual primary sites is not possible due to the small number of cases.

Previously untreated cases-Response of the previously untreated primary tumors is presented in Tables 4, 5 and 6. As would be expected, control was obtained more frequently in patients with small primaries (TIT2) and small or no meta- static cervical nodes (NoN,N2) (Table 4). In these patients, control was achieved with doses greater than 5,500 rads in 5 weeks. With more advanced disease there were many patients who obtained only

partial control with doses in excess of 7,000 rads in 7 to 8 weeks (Tables 5 and 6).

Recurrent cases-For recurrence at the primary site 93 patients received electron irradiation. T h e results are presented in Table 7. In 36 control was achieved for a mean duration of 17 months. Thirty- seven had partial control for a mean duration of 4 months. Twenty failed to respond. In most cases control was ob- tained with doses in the same range as in the previously untreated group although a few cases responded to less than 4,000 rads in 3% weeks. On the other hand, most failures occurred when doses under 4,500 rads in 5 weeks were given.

Metastatic lymph nodes: One hundred seventy-one groups of lymph nodes were treated either alone or at the time of treat-

TABLE 6. Response of Primary Tumors to Electron Irradiation Previously Untreated Cases, T~TI (NoNINcN~)

Control Partial control Failure

Duration Duration No. (mo.) No. (mod No.

Total of Dose of Dose of Dose Location cases cases (rads/wk.) Mean Range cases (rads/wk.) Mean Range cases (rads/wk.,

Oral

Oro-

Naso-

Laryngo-

cavity

pharynx

pharynx

pharynx

Miscel.

TOTAI

7 3 5.950/6-6,600/7$ 22 5-42 4 4,700/5:-7.650/8 2 1-2 0

31 16 6.000/11-7.800 8 10 3-54 15 3,950/5-8.300/9 4 1-10 0

6 2 5.750/5-6,000/5 6 3,s 4 3,350/9-7.350/81 5 2-6 0

14 4 6,000/7-6.650/81 19 5-54 7 5.750/&6.500/9 7 2-20 3 600 /h 4.750/5

4 1 7,450/8 11 1 5.550/5 * 8 2 1.400/2 - - - - - - 62 25 12 3-54 31 5 1-20 5

No. 8 CANCER TREATMENT WITH HIGH-ENERGY ELECTRON BEAMS - Perry et al. 1085

TABLE 7. Response of Primary Tumors to Electron Irradiation-Recurrent Cases

Control Partial control Failure _-____ _ _ _ ~ _ - ~ ~

Duration Duration NO. (ma.) No. (ma.) N O .

Total of Dose of Dose Of Dose Location cases cases (rads/wk.) Mean Range cases (raddwk.) Mean Range cases (rads/wk.)

Oral 21 5 3,850/4-7,400/9; 20 2-43 10 3.750/4-7,800/8 6 2-22 6 1,700/2- cavity 6,900/7

Oro- 26 11 2,800/3-6.900/7 12 1-60 12 4.050/4-6.400/7; 3 1-7 3 700/1- pharynx 4,100/4

HYPO- 18 i 4,500/5-6,700/7 16 5-52 9 3,800/3-7,150/8 3 1-7 2 2.100/6-

Naso- 12 7 3,800/4-6,950/6 12 1-18 2 3,800/3b-3.850/4 3 2.3 3 700/5- pharynx 4,550/6

Miscel. 16 6 4.000/3+-8.550/9 29 1-54 4 3.750/5b5,300/53 9 4-14 6 400/1- 6.700/8

pharynx 2,200/2 +

- - - - - -

TOTAI. 93 36 1 7 1-54 37 4 1-22 2 0

ment of the primary tumor. The results of treatment are presented in Table 8. Ninety- seven had no prior therapy. Of these, 44 showed control for a mean duration of 12 months; 47 had partial control for a mean duration of 5 months and 6 failed to respond. Seventy-four had received prior therapy. Of these, 16 groups were controlled for a mean duration of 11 months; 36 had partial control for a mean duration of 4 months and 22 failed to show response. As for the primary tumor, lymph node metastases required at least 5,500 rads in 5 weeks to achieve control.

Suroival: I t is not feasible to evaluate this group of patients in terms of a 5-year survival rate. Not only was the number of patients in each tumor category small but, for the most part, patients presented with advanced dis- ease. Palliation rather than cure was the pri-

mary aim of treatment. Only a small number of patients are living with no evidence of disease. I n this series of 210 patients 86% have died.

Normal tissue reactions

Skin: The treatment fields varied from a 3 cm circle to a 15x15 cm square. On average the dose delivered to the skin of each field was 800 rads* per week. Erythema appeared when the dose reached 1,500 to 2,000 rads. In the majority of cases the skin reaction con-

* The following correction factors were used by the Department of Clinical Physics to determine skin dose: (a) 16-22 mev-skin dose 90% of maximum dose; (b) 10-15 mev-skin dose 85% of maximum dose; (c) 7-9 mev-skin dose 80% of maximum dose; (a) 4-6 mev- skin dose 75y0 of maximum dose.

TABLE 8. Response of Metastatic Cervical Lymph Nodes to Electron Irradiation

Control Partial control

Duration Mean Duration Mean No. of Treatment No. (mo.) (range) NO. (mo.) (range) failures

Primary controlled Nodes previously

Nodes previously untreated 25 15 1-68 18 7 2-19 4

treated 16 11 1-39 19 6 1-12 11 Primary partially controlled

Nodes previously

Nodes previously

Nodes previously

Nodes previously

untreated 19 9 1-20 28 5 1-20 1

treated 0 - 17 3 1-7 5

untreated 0

treated

-

Primary failure

1

6

- 1 3 - -

- _ - - - - -

1086 CANCER August 1966 VOI. 19

sisted of a brisk or dusky erythema. Tanning and dry desquamation appeared with a skin dose of 4,500 to 6,000 rads delivered in 5 to 7 weeks. The skin often had a leathery appear- ance immediately after therapy was completed.

T o treat the 210 patients, 380 fields were used. There were 41 instances of moist de- squamation. In 22 prior radiotherapy and/or surgery had preceded electron-beam therapy. In 11 a moist reaction occurred due to hot spots at the anterior neck from lateral oppos- ing or oblique fields. Latterly these have been eliminated through use of polystyrene wedges. In those with moist reaction the skin dose was greater than 5,400 rads in 6 to 7 weeks except in 2 instances; in one of those a moist reaction occurred with a dose of 3,800 racls in 22 days to a 12x15 cm field. The second re- ceived a skin dose of 3,400 rads in 19 days to a 12x12 cm field. In both patients electron beam therapy had been preceded by surgery. Moist reactions usually healed without diffi- culty. Fewer patients developed moist reac- tions with small fields compared with those who had medium and large fields.

Subcutaneous fibrosis was observed in 8 fields. Most had prior surgery or radiother- apy. Moist reaction preceded the subcutane- ous fibrosis in only one instance. Skin necrosis occurred in one patient in a field over an area that had already received 6,000 r with inter- stitial radon therapy.

Mucosa: The mucosal reactions as a whole were limited, transient and well tolerated. In most patients the mucositis was patchy or punctate. In a few it became confluent. In the treatment of an eccentric lesion, mucositis was confined to the area of maximal absorbed dose. The limited mucosal reaction reduced the discomfort of the patients during therapy. In 14 patients severe confluent mucositis was observed after tumor doses of 3,800 rads in 3 weeks to 8,000 rads in 10 weeks. The former cases had received prior radiotherapy.

Dry mouth with marked thickening of saliva occurred in 13 patients. There was no correlation between this complication and the size of the fields. I n addition, one of these patients experienced a severe salty taste, which persisted until the patient's death, 11 months after completion of treatment.

Chronic ulceration occurred in 13 patients, 7 of whom had received prior treatment by surgery, irradiation or chemotherapy. The dose at which chronic ulcerations occurred was generally higher than 5,000 rads in 6

weeks. In one patient 4,000 rads in 4 weeks was combined with chlorambucil.

Bone: Bone damage was rare. Only one pa- tient developed necrosis of the mandible. This was precipitated by a tooth extraction 2 years after completion of radiotherapy. The low in- cidence of bone necrosis (one of 210 patients) is noteworthy.

DISCUSSION

Our experience indicates that the physical characteristics of high-energy electrons makes them suitable for the treatment of head and neck tumors and their cervical lymph node metastases. A satisfactory dose distribution niay be obtained throughout the volume to be treated, avoiding significant quantities of radiation to the adjacent normal structures. This is readily accomplished by the proper choice of treatment field or fields for adequate coverage of the tumor and choice of energy appropriate for the depth and size of the tu- mor. Wedges and polystyrene shields may be used to prevent overlap of energy deposition or compensate for anatomical irregularities. The ease of altering the electron beam energy and hence its depth of penetration allows for a rapid replanning of treatment when the size of the tumor decreases.

The number of complete regressions was modest and the duration of continued control was short. T h e obvious reason for this is that the material composing this series was ad- vanced or was recurrent in the majority of cases. Permanent control of the cancer was therefore unlikely. Other factors were in- volved; an example is RBE. The RBE of high energy electrons obtained by experimental and clinical work has been reported with values varying from 0.65 to 0.95.69 o, 11, 12 Al- though the exact RBE of electrons is still uncertain, it is less than unity and is probably about 0.9. Underdosage may account in part for the low rate of permanent control.

Bone shielding may have played a role. The presence of bone in the treatment volume results in decreased dose beyond the bone2.?,1* because there is higher absorption of elec- trons in bone due to its higher density. In the treatment of most of the cases in this series the absorbed dose as calculated did not take into consideration the presence of interposed bone. Thus, the actual absorbed dose in many tumors was lower than the calculated dose.

The importance of tissue inhomogeneity

No. 8 CANCER TREATMEKT WITH HIGH-ENERGY ELECTRON BEAMS - Perry et al. 1087

has been considered increasingly in treatment planning. Laughlin et al.7 recently have pre- sented the procedures used at Memorial Cen- ter to determine a general correction factor for the presence of inhomogeneities such as lung and bone. These were not used in treat- ment planning of the cases reported here. The group at M. D. Anderson Hospital, in their study of electron-beam irradiation of head and neck neoplasms2, 10 also have called attention to the bone-shielding effect; they suggest a method of correction similar to that reported by Laughlin et al.7

We believe that higher doses in a shorter time with suitable corrections for RBE and tissue heterogeneity may yield better results with electron-beam therapy. We suggest that curative tumor doses should be in the order of 5,000 to 6,000 rads in 4 to 5 weeks for small volumes and 6,500 to 7,000 rads in 6 to 7 weeks for medium and large volumes. Un- fortunately, the poor case material available for treatment in this series is reflected in this report. An orderly trial of these concepts requires patients with TIT2, NoN,N, Iesions.

REFERENCES

1. Bcattie, J. W., Tsien, K. C., Ovadia, J., and Laughlin, T. S.: Production and properties of high energy electrons for therapy. Am. 150, 1962.

Roentgen. 88235-

2. Boone, M. L. M., Crosby, H., and Shalek, R. J.: Skin reactions and tissue heterogeneity in electron beam therapy-11. In vivo dosimetry. Radiology 84:

3. Chu, F. C. H., Nisce, L., and Laughlin, J. S.: Treatment of breast cancer with high energy electrons produced by 24 mev betatron. Ibid. 81:871-879, 1963.

4. ~ , Scheer, A. C., and Gaspar-Landero, J.: Electron beam therapy in the management of carci- noma of the breast. Ibid. 75:378-385.

5. Henschke, U. K., Frazell, E. L., Hilaris, B. S., Nickson, J. J., Tollefsen, H. R., and Strong, E. W.: Local recurrences after radical neck dissection with and without preoperative x-ray therapy. Ibid. 82:331- 332, 1964.

6. Laughlin, J. S.: Physical Aspects of Betatron

817-822. 1965.

Therapy. Springfield, Ill., Charles C Thomas, 1954;

7. -, Lundy, B. S., Phillips, R., Sattar, A., and Chu, F. C. H.: Electron beam treatment planning in inhomogeneous tissue. Radiology 85:524-531, 1965.

8. Perry, H., Tsien, K. C., Nickson, J. J., and Laugh- lin, J. s.: Treatment planning in therapeutic applica- tion of high energy electrons to head and neck cases. Am. .I. Roentgen. 88:251-261, 1962.

9. Sinclair, W. K., and Kohn, H. I.: The relative biological effectiveness of high-energy photons and electrons. Radiology 82:800-815, 1964.

10. Tapley, N. du V., and Fletcher, G. H.: Skin reactions and tissue heterogeneity in electron beam therapy-I: Clinical experience. Ibid. 84:812-816, 1965.

11. Veraguth, P.: Clinical experiments with electron therapy up to 30 mev. Brit. J . Radiol. 34:152-154, 1961.

12. Zatz, L. M., van Essen, F. F., and Kaplan, H. S.: Radiation therapy with high energy electrons-11. Clinical experience, 10 to 40 mev. Radiology 77:928- 939, 1961.

p. 55.