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Split-course radiation therapy of carcinoma of the base of the tongue: Results of a prospective national collaborative clinical trial conducted by the radiation therapy oncology group
hr. J. Radiation Onco/ogv Biol. Phys.. Vol. Printed in the U.S.A. All rights reserved.
036(r3016/83/040437~7S03.00/0 Copyright 8 1983 Pergamon Press Ltd.
9. pp. 437-443
??Original Contribution SPLIT-COURSE RADIATION THERAPY OF CARCINOMA OF THE BASE OF THE TONGUE: RESULTS OF A PROSPECTIVE NATIONAL COLLABORATIVE CLINICAL TRIAL CONDUCTED BY THE RADIATION THERAPY ONCOLOGY GROUP V.A. MARCIAL, Professor
and Head, Radiation
Oncology
J.A. Statistician,
RTOG Statistical F.
Professor
and Head, Department
Professor,
Radiation
Radiology, ORTIZ,
San Juan, PR
PH.D.
HENDRICKSON,
of Therapeutic
Oncology
HANLEY,
of P. R. School of Medicine,
Center, Sidney Farber Cancer
H. Assistant
M.D.
Division, University
Institute,
Boston, MA
M.D. Rush-Presbyterian-St.
Luke’s Hospital,
Chicago,
IL
M.D.
Division, University
of P. R. School of Medicine,
San Juan, PR
One hundred forty-one patients with carcinoma of the base of tongue were randomized to receive either continuous course radiotherapy (6600 rad in 30/33 fractions over 7-8 weeks) or split course therapy (3000 rad in 10 fractions over 2 weeks, a three-week rest, 3000 rad in 10 fractions over 2 weeks). Both treatment groups tolerated the treatment well, but the continuous course group required more treatment modifications. The results of therapy, as judged by control of primary tumor, control of metastatic lymph nodes, time to failure and overall survival were comparable in the two treatment groups. Split-course
radiotherapy,
Base of tongue carcinoma,
Dose fractionation.
INTRODUCTION
Split-course
irradiation
consists
of the introduction
of
This report deals with 141 patients with carcinoma of the base of the tongue who were randomly assigned to receive either continuous or split-course irradiation.5 This study forms part of a larger Radiation Therapy Oncology Group (RTOG) study, begun in 197 1, in which these two treatment approaches are being compared. The other cancers being studied are cancers of the tonsillar fossa and nasopharynx and of the urinary bladder and uterine cervix. Since accrual recently terminated for the two other head and neck regions, the results in these two regions, and in all three head and neck regions combined, have been or will be reported on separately.3x4.6.7
one or more planned
rest periods during the radiation therapy course. The rationale for this technique and the details of this study have been published.2 The potential advantages justifying the technique were: Better patient tolerance of large volume therapy; the use of larger fraction doses was permitted; tumor reduction observed during the rest period resulted in psychological benefits to the patient and usually allowed a reduction in the field size for the second part of therapy; and the theoretical better oxygenation of the tumor in the second part could improve curability. In addition, the tested split-course therapy plan implied a shorter hospital stay for hospital-
This work was supported in part by NC1 grant #l RIO CA-12258-06. RTOG Headquarters grant RCA-21661 and PR Cancer Center grant #5 R18 CA-16598-07. Reprint requests to: Dr. V.A. Marcial, Radiation Oncology Division, Puerto Rico, Cancer Center, G.P.O. Box 5067, San Juan, PR 00936. Acknowledgements-The authors want to thank Dr. David Amato, Mr. Morris Gold, for their collaboration in the analysis
of the statistical data. We also want to thank Ms. Liz Hassler for her help and Ms. Raquel Santos who typed the manuscript. Participating Institutions-University of Puerto Rico, RushPresbyterian Medical School, University of Pennsylvania, Hahnemann Medical College, Medical Center Hospital of Vermont, New York Medical College, Maryland University, Other (institutions with less than 5 patients). Accepted for publication 23 November 1982.
437
438
Radiation Oncology 0 Biology 0 Physics
ized patients, a smaller number of treatment visits for the ambulatory patients, and less burden on the radiotherapy facilities. METHOD
AND MATERIALS
Procedure Registration and eligibility. The details of registration and eligibility have been published.2.4 Patients were stratified on the basis of institution, T stage, N stage and set and assignments were balanced in sets of four. RTOG Headquarters returned a written confirmation to the principal investigator containing the name, site and study number of the case and a schedule for the submission of reports. Patients with all stages of untreated carcinoma of the base of the tongue registered in the collaborating radiotherapy departments qualified for the study. Excluded were: patients over 80 years of age, patients with adenocarcinoma or other cancer (previous or present) except skin carcinoma, patients with distant metastases, or whose medical condition made treatment completion unlikely, and patients for whom the prospects of follow-up were uncertain. Staging. Tumors were classified at the primary and neck levels according to a particular staging classification introduced by the Committee for Radiation Therapy Studies and accepted by the RTOG at the time of this study, as follows: T,-up to 2 cm in diameter; T,+ver 2 cm but not larger than 4 cm and not extending beyond the base of the tongue; T,-larger than 4 cm and/or minimal extension to surrounding structures; and T,-massive extension to surrounding structures; N,-no clinical evidence of lymph node metastases; N,-an ipsilateral clinically positive movable node up to 3 cm in size; N,-a single ipsilateral movable node larger than 3 cm or multiple ipsilateral movable nodes of any size; N,-fixed, bilateral or contralateral clinically positive nodes. Pre-treatment studies and special management. All patients were required to have a complete history and physical examination, diagram of the lesion on a standard form, chest PA and lateral radiographs, CBC, urinalysis, fasting blood sugar, urea nitrogen, serum alkaline phosphatase, and lateral soft tissue radiograph of pharynx. Carious teeth were to be removed prior to radiotherapy. Teeth in the path of the beam were to be managed in accordance with institutional policies applicable to both therapeutic groups. Gums were to be sutured after postextraction alveolectomy had been performed. An interval
April 1983, Volume 9, Number 4
of one and a half to two weeks was advised before starting radiotherapy after tooth extraction. Radiotherapy. Patients were to be treated with 1 MEV or higher, with a minimal source skin distance of 75 cm. The collaborating center was free to use its own treatment techniques regarding choice and size of fields, provided that the corresponding treatment plan achieved an adequate dose distribution in the stated primary tumor and metastatic node irradiation volume. The possibilities were: lateral parallel opposing fields, two lateral and an anterior field, single field for half of the course and lateral parallel opposing fields for the other half, lateral and anterior field wedged arrangement and rotational field. The field size had to be adequate to cover the primary disease, the direct extensions and the involved nodes with at least 2 cm margin around the clinically apparent tumor. Palpable nodes required extension of the fields, at least on the involved side, down to the clavicle. Well differentiated tumors with N, status did not require irradiation of the lower neck. The size of the field could be reduced in the second part of therapy to conform to significant tumor size reduction. The schedule of fraction doses, total doses and total time, for the two radiotherapy regimes is shown in Table 1. It was suggested that week-end rest periods should not exceed three days. Early in the study, some institutions complained that the fraction dose for continuous irradiation of 220 rad was too severe; because of this the Steering Committee allowed the choice of 200 rad fractions with total doses of 6000 to 6600 rad in 6 to 7 weeks. Spinal cord protection was required after a dose of 5000 rad for continuous therapy or in the second part for split-course irradiation. Most patients had cord protection after attaining a dose of 4600 rad or less. No supplementary radiological or non-radiological treatment was allowable unless the patient was considered a failure of therapy after a reasonable length of time had elapsed following protocol irradiation. Study endpoints. The main endpoints pursued by this study were immediate and late normal tissue tolerance, control of tumor in the irradiated volume, and survival. Secondary endpoints were reduction of irradiated volume, time of tumor disappearance, change in weight during therapy, time from end of therapy to appearance of recurrences, frequency of distant metastases, and tolerance and results of surgery for persistent or recurrent tumor in the irradiated volume. Study forms. The study required the submission of the
Table 1. Treatment options Total dose Technique
Split
Continuous
Fraction dose
No. of fractions
(rad)
NSD
TDF
1st part 300 rad
I O/2 wks.
3000
2010
118
3 wks. rest 2nd part 300 rad 220 rad
IO/2 wks. 3016 wks.
3000 6600
1940
115
439
Split radiotherapy for base of tongue Ca 0 V.A. MARCIALet al.
following forms: Initial Evaluation-shortly after registration; Treatment Data-at the end of irradiation; Tumor and Normal Tissue Reaction-at the end of irradiation; Follow-up-every three months in the first two years and every four months thereafter; and Death Report. Statistical considerations. Calculations of tumor control and survival rates up to 5 years were made using the Kaplan-Meier estimations.’
concentration of older patients is noted in the split course group with 69% being 60 years or older versus only 45% in the continuous course group. Both treatment groups contain equal numbers of females. The majority (89%) of the tumors were classed as T, or T,. Three-quarters of the patients had regional adenopathy with a full one-half presenting with N, (fixed, bilateral or contralateral) disease. This late stage N, disease was more common in the Puerto Rico patients (60%) than in patients from mainland institutions (39%).
RESULTS Registration and patient characteristics A total of 142 patients were randomized to this study between February, 1971 and June 1976. We have information on 141 of the 142 patients randomized. The remaining patient could not be followed as the name of the institution that entered the patient was not recorded. The patient accession by institution was as follows: University of Puerto Ric-63 patients, Rush-Presbyterian Medical School-14, and University of Pennsylvania-10 patients. There were other institutions with an average of 6-7 patients per institution (Hahnemann Medical College, Medical Center Hospital of Vermont, New York Medical College, and Maryland University26 patients). Another 1.5 institutions had less than 5 patients each-28 patients. These 141 patients were distributed to 68 in the continuous arm and 73 in split therapy. This slightly uneven distribution was because of the randomization by institution. The distribution by age, sex, T stage and N stage of the 141 patients analyzed is shown in Table 2. A slight
Treatment tolerance The tolerance of treatment, as judged by the number of patients completing therapy, is shown in Table 3. Only 4% of the patients did not complete therapy. Four of the five who did not complete therapy withdrew from therapy against the wishes of their physicians at or before 4200 rad; the fifth, a split-course patient, could not come back for the twentieth fraction and received only 5700 rad. Generally, split-course therapy was more often completed as planned than continuous-course therapy. Forty-six patients began the continuous-course treatment at 220 rad per fraction, and 22 began at the lower fraction size of 200 rad. If anything, the larger fraction size was better tolerated, if one judges from the fact that the reactions prevented therapy from being completed as planned in only six of 46 (13%) patients of those treated with the larger, as opposed to five of 22 (23%) treated with the smaller fraction size. (Admittedly the larger fractions were given primarily at Puerto Rico and the smaller fractions at other institutions.) In addition, the
Table 2. Patient characteristics Treatment Continuous Age*
Split-course
Total
No.
%
No.
%
10 27 20 II
I5 40 29 I6
9 14 27 21
I3 20 38 31
19 41 47 32
I4 30 34 23
56 12
82 I8
61 I2
84 I6
II7 24
83 I7
T-Stage T, T* T, T,
2 5 29 32
3 7 43 47
3 5 40 25
4 7 55 34
5 IO 69 57
4 7 49 40
N-Stage N, N, N* N, Total
I9 IO 4 35 68
28 IS 6 51
I7 20 2 34 73
23 27 3 47
36 30 6 69 I41
26 21 4 50
Sex Male Female
*Age could not be determined
Continuous
Split
Total
68
73
I41
66 (97%)
70 (96%)
I36 (96%)
51 (75%)
61 (86%)
I I2 (79%)
Began therapy
%
250 50-59 60-69 270
of therapy
group
No.
-
Table 3. Completion
in two split-course
patients.
Completed therapy Completed as planned Completed but with interruptions* Completed but with reduced dose per fraction* Completed but with interruption(s) and reduced doses* Did not complete therapy *Reasons for modification Excessive reactions Other (social, personal, holidays)
I3
5
I8
I
4
5
I 2 (3%1)
I 3 (4%)
5 (4%)
II
5
I6
4
4
8
Radiation Oncology 0 Biology 0 Physics
440
April 1983, Volume 9, Number
4
Table 4. Severe normal tissue reactions Continuous course (% of 68 pts.) Reaction Pain in irradiated area Pain in swallowing Difficulty swallowing Edema of mucosa Edema of neck tissue Mucositis Necrosis Skin reaction Difficulty breathing
Split-course (% of 73 pts.)
Combined (% of 141 pts.)
44 53 52 16 8 41 6 8
% 5 32 24 32 7
40 47 50 IO 6 38 6 9
reaction
13
48 58 55 22 IO 44 7 7 3 5
Overall severity None Moderate Severe-no medication required Severe-medication required Severe-hospitalization required
% 7 33 24 27 9
% 2 30 25 37 6
Laryngeal
frequency of no completion of therapy at all, and of modifications in dose and/or interruptions because of excessive reactions, was very similar in both subgroups. The signs of tissue effect, the treatment related interruptions of therapy, the loss of weight during therapy, and the late tissue changes were not statistically different in the two subgroups. The 14 interruptions of continuous-course therapy noted in Table 3 ranged from 5 to 28 days; 4 were not longer than a week, six were one to two weeks, and four were of longer than two weeks duration. The 5 interruptions of split-course therapy were of six, seven, seven, eleven and 18 days duration respectively. Hospitalization for more than half of the treatment period was reported in 21% of patients in the continuouscourse group and 14% of the split-course group. Hospitalization required because of treatment reactions was reported in 9% of continuous and 6% of split-course patients (Table 4). The normal tissue reactions to radiotherapy were slightly but consistently more numerous with split-course therapy than with continuous therapy, as shown in Table 4. Pain in the irradiated area, pain on swallowing, and difficulty swallowing were the most commonly encountered symptoms. Laryngeal reaction was more commonly reported in the continuous group. Follow-up One hundred-sixteen patients are known to have died and another 4 are presumed dead; they had persistent or recurrent disease at last contact and could not be located for further follow-up (2 of these were treated with continuous, and 2 with split-course irradiation). Twenty-one patients are considered to be alive for the purposes of this analysis; the length of time each one has been followed is as follows: 11 (7%) patients, 6 continuous-5 split, 5
I 9
years; 4 (3%), 1 cont.-3 split, 4 years; 4 (3%), 3 cont.-l split, 3 years; 1 (l%), 1 split, 2 years; 1 (l%), 1 split, 1 year. Immediate results As can be seen from Table 5, 66 (47% of the 141) patients became free of their primary tumors. The likelihood of becoming free of local tumor varied considerably by the extent of the primary (all 5 T,.,; 70% T,.,; 57% of T,.,; and only 21% of T4.\ became clear), but did not seem to depend on which treatment regimen was used. Nor does a treatment differential emerge if one estimates the probability of primary tumor clearance as a function of treatment and actual tumor diameter. Similarly, in judging how often lymph node metastases become undetectable after therapy (Table 6), one fails to see any treatment differential that could not have been Table 5. RTOG-7 I -02-Base Primary
Without further treatment 7‘1 T2 T, T, All
of tongue. Initial tumor control: tumor (T)
Treatment ~ Continuous course 212 415 16129 6132 28168 (41%)
group Combined Split course
No.
%
313 315 23140 6125 35173 (48%)
515 7110 39169 I2157 631141 (45%)
IO0 70 57 21
Persistant primary tumors cleared by surgery
3 (T,Y4)
Overall control rate
28168 (41%)
38173 (52%)
661141 (47%)
Split radiotherapy for base of tongue Ca 0 V.A.
Table 6. RTOG-71-02-Base of tongue. Initial tumor control: Regional lymph node metastases (N) Treatment
group Combined
Without further treatment
Continuous course
N, N, N, All N + combined
Split course
5110
14120
314 14135 22149 (45%)
II2 12134 27156 (48%)
No.
%
19/30 416 49169 491105 (47%)
63 67 38
Persistent lymph node metastases cleared by surgery
5 (N ,.,.,1.r)
Overall control rate _
22149 (45%)
32156 (57%)
541105 (51%)
produced by random variation. The worst lymph node metastases (i.e. N,-bilateral or fixed lesions) were slightly more likely to be controlled than the worst (T4) primaries; the success rates were 38% of N,,, controlled versus 21% of T.,., controlled. When one considered the ability of treatment to control both local and regional tumor (Table 7), results are more dismal. Only 24% of the 88 patients who presented with T, or N, lesions (or only 38% of all 141) became clear of all loco-regional tumor. An additional 6 patients, all in the split-course group, did achieve T,N, status through surgery for persistent disease. Whether these latter 6 patients are counted as successes or as failures, the observed treatment variations are not statistically significant. First evidence of failure The patterns of failure in the two treatment groups show that there were 1 IO (57 cont.-53 split) failures in all: 82 with persistent disease plus 15 loco-regional recur-
441
MARCIAL et al.
rences, plus 13 where distant metastases occurred while the primary and nodes remained controlled. Ninety-seven or 88% of the 110 failures were loco-regional, and the most important determinants of the length of time until failure are the (raw) tumor size and whether the regional lymph nodes were involved. The observed treatment differences are slight (84% of continuous course patients have failed, and 73% of splitcourse have failed). If one adjusts for any imbalances in the composition of the two treatment groups, the groups are not statistically different with respect to either frequency of loco-regional failure, patterns of failure, or time to failure (with both groups combined, the estimated percentages of patients free of tumor at 1, 2, and 3 years post randomization are 35%, 27% and 22%, respectively). (These figures are calculated counting patients whose persistent or recurrent disease was successfully removed by surgery as ‘free of tumor’.) Considered another way, this says that an estimated 65% of patients fail in the first year, 8% in the second, 5% in the third and the remainder in the fourth and subsequent years. Ultimate results The current reported status of all 141 patients reveals that 21 or 15% are alive and 120 or 85% are dead. The excess of 9:l in the number of patients who died without apparent disease in the two treatment groups is less impressive when one notes that the 9 died at 7, 8, 8, 14, 17, 19, 25, 27, and 30 months post-randomization and that on the basis of the results in the other comparable patients, as many as 5 of them might have been expected to fail at a later time if they had lived. There were five second primaries in all in this study (4 in the continuous-course group and 1 in the split); they were either successfully controlled or occurred in patients who already had active disease. The actuarial 5-year survival from date of randomization for the entire group of 141 patients is 15% (Table 8). Just under half of all patients died within one year of entering the study. There are marked differences in
Table 7. RTOG-7 I-02-Base of tongue. Initial tumor control: T and N Table 8. Survival: Post-randomization Treatment
group Continuous
Combined Without further treatment T, z, N, , TIN, z or T, 3NZ T, any N or N, and T All Persistent primary or regional tumor cleared by surgery Overall clearance rate
*TIN,. TIN,, T,N,, T,N,,
Continuous course 314 IO/l8 12146 25168 (37%)
25168 (37%) T,N,, T,N,.
course
Split course
No.
%
214 17127 9142 28173 (38%)
518 27145 21/88 531141 (38%)
63 60 24
6*
6
34173 (47%)
591141 (42%)
Patients treated Estimated percentage alive at 1 Year* 2 Yearst 3 Years 4 Years 5 Years Median survival
Split course
68
73
54 29 21 19 15 1.1 years
61 26 18 16 14 1.2 years
Combined 141
58 28 19 18 15
* 1 patient died of intercurrent disease 4 mos. after completion of treatment. t3 patients died of intercurrent disease before 2 yrs. after completion of treatment.
442
Radiation
4
T-CONTROL BASE
Oncology
??Biology 0 Physics
April 1983, Volume 9, Number 4 Table 9. Late effects
BY TREATMENT
OF TONGUE
8L
12
TREATMENT CONTINUOUS -SPLIT
t%T”S
CNSRO 3:
36
46
60
FAIL0 46 43
TOTAL 66 73
HEOIAC. 0.0 II .5
Continuous course %
Split course %
12 3 0 3 40 32 9 0 3 34 I9
14 8 3 I 50 43 4
Necrosis* Soft tissue Bone Cartilage Skin Edemaf Fibrosist Fistmat Myelitis Other neuropathy Persistent weight loss Other
Total %
13 6
I 5 45 38 6
1
I
4 36 13
4 35 16
*All cases were related to active tumor (the majority of patients), or previous surgery, or both (I patient). One case of bone necrosis was related to dental caries. tAny degree-Any time, disregarding the duration. fAll cases were related to previous surgery (more than half), or active tumor, or both (I patient).
I
Fig. 1. Primary tumor control by treatment-Up
to 5 yrs.
survival depending on the size of the primary tumor and whether regional nodes were initially involved. No differences could be ascribed to treatment. Fig. 1 and 2 present the primary tumor and node control up to 5 years. Late effects of therapy Table 9 shows the late reactions reported at any time during follow-up. Generally the reactions are somewhat A.
N-CONTROL BASE
OF
BY
TREATMENT
TONGUE
1 .O .9 F
.a. m <
b E
..--_
.4.
DISCUSSION 12
-
more frequent with split-course radiotherapy, especially with respect to edema, any degree in the treated area, and fibrosis. There were no significant differences in the frequencies of any of these effects for the two treatment groups (Fisher-Exact test); nevertheless, the total number of patients with some type of necrosis is higher in the split technique. It should be clarified, however, that all the patients with fistula and/or necrosis clearly had active tumor at the moment of reporting these complications and, sometimes, had had previous surgery. The patient with myelitis had NSD-TDF over the 5% permissible variation, and active tumor associated with this complication. One patient with neuropathy had laryngeal nerve paralysis because of a fibrotic metastatic mass in the neck; another patient had neuropathy with transient Lermitte’s sign. Even though the seriousness of these late tissue reactions was not scored, it may vary in different institutions; in the Puerto Rico patients, no complications were considered disabling; one post-surgery skin necrosis healed spontaneously and a pin-point size orocutaneous fistula, following a combined surgical procedure, was corrected by surgery.
TREATMENT CONTINUOUS -SPLIT
“%T”S
CNSRO 36 40
36
48
60
FAIL0 32 33
TOTAL 68 73
MEOIAN 18.6 49.8
Fig. 2. Node control by treatment-Up
to 5 yrs.
AND
CONCLUSIONS
While the results described in this paper do not show any therapeutic advantage to split-course therapy over conventional fractionation, they do suggest that the split technique, involving four weeks of therapy rather than six to seven, provides comparable therapeutic results in a more efficient manner. They suggest that there are savings in physician time, in use of facilities and in cost to the patient. The only reservations about these conclusions are: 1) the patients studied had such a poor prognosis (only 15% 5-year survival) that split-course therapy did not have a
Split radiotherapy for base of tongue Ca 0 V.A. MARCIAL etal.
good opportunity to demonstrate an improvement and 2) with the number of patients studied, there was only a 50% chance of detecting a treatment difference of 10% in the cure rate (e.g. 15% versus 25%) if indeed one existed, and that the true (long-run) difference would have to have been as large as 20% (e.g. 15% versus 35%) if we were to be virtually assured of calling the observed results statistically significant. However, both these shortcomings must be balanced by the fact that a comparable equivalence pattern is emerging in the other two head and neck regions being studied (tonsillar fossa and nasopharynx). When the data from
443
these other two regions mature a little more, the publication of the results seen in all three sites should be more convincing. Also, if one calculates the posterior distributions for the “cure” rates with the two treatments on the base of the tongue patients, the probability that the treatments produce cure rates which are more than 5% different from each other is less than 1 in 3. Concerning the variations introduced in some of the protocol cases (staging, treatment schedule, institutional variations, etc.), it is felt that they did not influence the results; this aspect will be analyzed with more detail in a future paper.
REFERENCES 1. Kaplan,
E., Meier, P.: Non-parametric estimation from incomplete observations. J. Am. Stat. Assoc. 53: 457-48 1, 1958. 2. Marcial, V.A., M.D.: Split-Course Radiation Therapy Project. Cancer 29: 6, 1463-1467, 1972. 3. Mar&al, V.A., M.D., Amato, D., MS., Chang, C.H., M.D., Figueroa, N.R., M.D.: Pattern of failure after radiotherapy of cervical node metastases in carcinoma of the base of the tongue, tonsillar fossa, and nasopharynx. Presented at the Annual Meeting of the American Radium Society, March 14-l 8, 1982, San Antonio, Texas. 4. Marcial, V.A., M.D., Hanley, J.A., Ph.D., Chang, C., M.D., Davis, L.W., M.D., Moscol, J., M.D.: Split-course radiation therapy of carcinoma of the nasopharynx: Results of a National Collaborative Clinical Trial of the Radiation Therapy Oncology Group. Int. J. Radiat. Oncol. Biol. Phys. 6: 409-414, 1980.
5. Marcial, V.A., Hanley, J.A., Hendrickson, F., Ortiz, H.G.: Split-course radiation therapy of carcinoma of the base of the tongue: Results of a Prospective National Collaborative Clinical Trial of the Radiation Therapy Oncology Group Int. J. Radiat. Oncol. Biol. Phys. 2 (Suppl. 1): (Abstract). 40, 1977. 6.
Marcial, V.A., Hanley, J.A., Rotman, M.: Split-course radiation therapy of carcinoma of the tonsil!ar fossa: Results of a prospective National Collaborative Clinical Trial of the Radiation Therapy Oncology Group (Abstract). Int. J. Radiat. Oncol. Biof. Phys. 4 (Suppl. 1): 17-18, 1978.
7. Marcial, V.A., M.D., Hanley, J.A., Ph.D., Ydrach, A., M.D., Vallecillo, L.A., M.D.: Tolerance of surgery after radical radiotherapy of carcinoma of the oropharynx. Cancer 46: 9,191&1912,1980.
036(r3016/83/040437~7S03.00/0 Copyright 8 1983 Pergamon Press Ltd.
9. pp. 437-443
??Original Contribution SPLIT-COURSE RADIATION THERAPY OF CARCINOMA OF THE BASE OF THE TONGUE: RESULTS OF A PROSPECTIVE NATIONAL COLLABORATIVE CLINICAL TRIAL CONDUCTED BY THE RADIATION THERAPY ONCOLOGY GROUP V.A. MARCIAL, Professor
and Head, Radiation
Oncology
J.A. Statistician,
RTOG Statistical F.
Professor
and Head, Department
Professor,
Radiation
Radiology, ORTIZ,
San Juan, PR
PH.D.
HENDRICKSON,
of Therapeutic
Oncology
HANLEY,
of P. R. School of Medicine,
Center, Sidney Farber Cancer
H. Assistant
M.D.
Division, University
Institute,
Boston, MA
M.D. Rush-Presbyterian-St.
Luke’s Hospital,
Chicago,
IL
M.D.
Division, University
of P. R. School of Medicine,
San Juan, PR
One hundred forty-one patients with carcinoma of the base of tongue were randomized to receive either continuous course radiotherapy (6600 rad in 30/33 fractions over 7-8 weeks) or split course therapy (3000 rad in 10 fractions over 2 weeks, a three-week rest, 3000 rad in 10 fractions over 2 weeks). Both treatment groups tolerated the treatment well, but the continuous course group required more treatment modifications. The results of therapy, as judged by control of primary tumor, control of metastatic lymph nodes, time to failure and overall survival were comparable in the two treatment groups. Split-course
radiotherapy,
Base of tongue carcinoma,
Dose fractionation.
INTRODUCTION
Split-course
irradiation
consists
of the introduction
of
This report deals with 141 patients with carcinoma of the base of the tongue who were randomly assigned to receive either continuous or split-course irradiation.5 This study forms part of a larger Radiation Therapy Oncology Group (RTOG) study, begun in 197 1, in which these two treatment approaches are being compared. The other cancers being studied are cancers of the tonsillar fossa and nasopharynx and of the urinary bladder and uterine cervix. Since accrual recently terminated for the two other head and neck regions, the results in these two regions, and in all three head and neck regions combined, have been or will be reported on separately.3x4.6.7
one or more planned
rest periods during the radiation therapy course. The rationale for this technique and the details of this study have been published.2 The potential advantages justifying the technique were: Better patient tolerance of large volume therapy; the use of larger fraction doses was permitted; tumor reduction observed during the rest period resulted in psychological benefits to the patient and usually allowed a reduction in the field size for the second part of therapy; and the theoretical better oxygenation of the tumor in the second part could improve curability. In addition, the tested split-course therapy plan implied a shorter hospital stay for hospital-
This work was supported in part by NC1 grant #l RIO CA-12258-06. RTOG Headquarters grant RCA-21661 and PR Cancer Center grant #5 R18 CA-16598-07. Reprint requests to: Dr. V.A. Marcial, Radiation Oncology Division, Puerto Rico, Cancer Center, G.P.O. Box 5067, San Juan, PR 00936. Acknowledgements-The authors want to thank Dr. David Amato, Mr. Morris Gold, for their collaboration in the analysis
of the statistical data. We also want to thank Ms. Liz Hassler for her help and Ms. Raquel Santos who typed the manuscript. Participating Institutions-University of Puerto Rico, RushPresbyterian Medical School, University of Pennsylvania, Hahnemann Medical College, Medical Center Hospital of Vermont, New York Medical College, Maryland University, Other (institutions with less than 5 patients). Accepted for publication 23 November 1982.
437
438
Radiation Oncology 0 Biology 0 Physics
ized patients, a smaller number of treatment visits for the ambulatory patients, and less burden on the radiotherapy facilities. METHOD
AND MATERIALS
Procedure Registration and eligibility. The details of registration and eligibility have been published.2.4 Patients were stratified on the basis of institution, T stage, N stage and set and assignments were balanced in sets of four. RTOG Headquarters returned a written confirmation to the principal investigator containing the name, site and study number of the case and a schedule for the submission of reports. Patients with all stages of untreated carcinoma of the base of the tongue registered in the collaborating radiotherapy departments qualified for the study. Excluded were: patients over 80 years of age, patients with adenocarcinoma or other cancer (previous or present) except skin carcinoma, patients with distant metastases, or whose medical condition made treatment completion unlikely, and patients for whom the prospects of follow-up were uncertain. Staging. Tumors were classified at the primary and neck levels according to a particular staging classification introduced by the Committee for Radiation Therapy Studies and accepted by the RTOG at the time of this study, as follows: T,-up to 2 cm in diameter; T,+ver 2 cm but not larger than 4 cm and not extending beyond the base of the tongue; T,-larger than 4 cm and/or minimal extension to surrounding structures; and T,-massive extension to surrounding structures; N,-no clinical evidence of lymph node metastases; N,-an ipsilateral clinically positive movable node up to 3 cm in size; N,-a single ipsilateral movable node larger than 3 cm or multiple ipsilateral movable nodes of any size; N,-fixed, bilateral or contralateral clinically positive nodes. Pre-treatment studies and special management. All patients were required to have a complete history and physical examination, diagram of the lesion on a standard form, chest PA and lateral radiographs, CBC, urinalysis, fasting blood sugar, urea nitrogen, serum alkaline phosphatase, and lateral soft tissue radiograph of pharynx. Carious teeth were to be removed prior to radiotherapy. Teeth in the path of the beam were to be managed in accordance with institutional policies applicable to both therapeutic groups. Gums were to be sutured after postextraction alveolectomy had been performed. An interval
April 1983, Volume 9, Number 4
of one and a half to two weeks was advised before starting radiotherapy after tooth extraction. Radiotherapy. Patients were to be treated with 1 MEV or higher, with a minimal source skin distance of 75 cm. The collaborating center was free to use its own treatment techniques regarding choice and size of fields, provided that the corresponding treatment plan achieved an adequate dose distribution in the stated primary tumor and metastatic node irradiation volume. The possibilities were: lateral parallel opposing fields, two lateral and an anterior field, single field for half of the course and lateral parallel opposing fields for the other half, lateral and anterior field wedged arrangement and rotational field. The field size had to be adequate to cover the primary disease, the direct extensions and the involved nodes with at least 2 cm margin around the clinically apparent tumor. Palpable nodes required extension of the fields, at least on the involved side, down to the clavicle. Well differentiated tumors with N, status did not require irradiation of the lower neck. The size of the field could be reduced in the second part of therapy to conform to significant tumor size reduction. The schedule of fraction doses, total doses and total time, for the two radiotherapy regimes is shown in Table 1. It was suggested that week-end rest periods should not exceed three days. Early in the study, some institutions complained that the fraction dose for continuous irradiation of 220 rad was too severe; because of this the Steering Committee allowed the choice of 200 rad fractions with total doses of 6000 to 6600 rad in 6 to 7 weeks. Spinal cord protection was required after a dose of 5000 rad for continuous therapy or in the second part for split-course irradiation. Most patients had cord protection after attaining a dose of 4600 rad or less. No supplementary radiological or non-radiological treatment was allowable unless the patient was considered a failure of therapy after a reasonable length of time had elapsed following protocol irradiation. Study endpoints. The main endpoints pursued by this study were immediate and late normal tissue tolerance, control of tumor in the irradiated volume, and survival. Secondary endpoints were reduction of irradiated volume, time of tumor disappearance, change in weight during therapy, time from end of therapy to appearance of recurrences, frequency of distant metastases, and tolerance and results of surgery for persistent or recurrent tumor in the irradiated volume. Study forms. The study required the submission of the
Table 1. Treatment options Total dose Technique
Split
Continuous
Fraction dose
No. of fractions
(rad)
NSD
TDF
1st part 300 rad
I O/2 wks.
3000
2010
118
3 wks. rest 2nd part 300 rad 220 rad
IO/2 wks. 3016 wks.
3000 6600
1940
115
439
Split radiotherapy for base of tongue Ca 0 V.A. MARCIALet al.
following forms: Initial Evaluation-shortly after registration; Treatment Data-at the end of irradiation; Tumor and Normal Tissue Reaction-at the end of irradiation; Follow-up-every three months in the first two years and every four months thereafter; and Death Report. Statistical considerations. Calculations of tumor control and survival rates up to 5 years were made using the Kaplan-Meier estimations.’
concentration of older patients is noted in the split course group with 69% being 60 years or older versus only 45% in the continuous course group. Both treatment groups contain equal numbers of females. The majority (89%) of the tumors were classed as T, or T,. Three-quarters of the patients had regional adenopathy with a full one-half presenting with N, (fixed, bilateral or contralateral) disease. This late stage N, disease was more common in the Puerto Rico patients (60%) than in patients from mainland institutions (39%).
RESULTS Registration and patient characteristics A total of 142 patients were randomized to this study between February, 1971 and June 1976. We have information on 141 of the 142 patients randomized. The remaining patient could not be followed as the name of the institution that entered the patient was not recorded. The patient accession by institution was as follows: University of Puerto Ric-63 patients, Rush-Presbyterian Medical School-14, and University of Pennsylvania-10 patients. There were other institutions with an average of 6-7 patients per institution (Hahnemann Medical College, Medical Center Hospital of Vermont, New York Medical College, and Maryland University26 patients). Another 1.5 institutions had less than 5 patients each-28 patients. These 141 patients were distributed to 68 in the continuous arm and 73 in split therapy. This slightly uneven distribution was because of the randomization by institution. The distribution by age, sex, T stage and N stage of the 141 patients analyzed is shown in Table 2. A slight
Treatment tolerance The tolerance of treatment, as judged by the number of patients completing therapy, is shown in Table 3. Only 4% of the patients did not complete therapy. Four of the five who did not complete therapy withdrew from therapy against the wishes of their physicians at or before 4200 rad; the fifth, a split-course patient, could not come back for the twentieth fraction and received only 5700 rad. Generally, split-course therapy was more often completed as planned than continuous-course therapy. Forty-six patients began the continuous-course treatment at 220 rad per fraction, and 22 began at the lower fraction size of 200 rad. If anything, the larger fraction size was better tolerated, if one judges from the fact that the reactions prevented therapy from being completed as planned in only six of 46 (13%) patients of those treated with the larger, as opposed to five of 22 (23%) treated with the smaller fraction size. (Admittedly the larger fractions were given primarily at Puerto Rico and the smaller fractions at other institutions.) In addition, the
Table 2. Patient characteristics Treatment Continuous Age*
Split-course
Total
No.
%
No.
%
10 27 20 II
I5 40 29 I6
9 14 27 21
I3 20 38 31
19 41 47 32
I4 30 34 23
56 12
82 I8
61 I2
84 I6
II7 24
83 I7
T-Stage T, T* T, T,
2 5 29 32
3 7 43 47
3 5 40 25
4 7 55 34
5 IO 69 57
4 7 49 40
N-Stage N, N, N* N, Total
I9 IO 4 35 68
28 IS 6 51
I7 20 2 34 73
23 27 3 47
36 30 6 69 I41
26 21 4 50
Sex Male Female
*Age could not be determined
Continuous
Split
Total
68
73
I41
66 (97%)
70 (96%)
I36 (96%)
51 (75%)
61 (86%)
I I2 (79%)
Began therapy
%
250 50-59 60-69 270
of therapy
group
No.
-
Table 3. Completion
in two split-course
patients.
Completed therapy Completed as planned Completed but with interruptions* Completed but with reduced dose per fraction* Completed but with interruption(s) and reduced doses* Did not complete therapy *Reasons for modification Excessive reactions Other (social, personal, holidays)
I3
5
I8
I
4
5
I 2 (3%1)
I 3 (4%)
5 (4%)
II
5
I6
4
4
8
Radiation Oncology 0 Biology 0 Physics
440
April 1983, Volume 9, Number
4
Table 4. Severe normal tissue reactions Continuous course (% of 68 pts.) Reaction Pain in irradiated area Pain in swallowing Difficulty swallowing Edema of mucosa Edema of neck tissue Mucositis Necrosis Skin reaction Difficulty breathing
Split-course (% of 73 pts.)
Combined (% of 141 pts.)
44 53 52 16 8 41 6 8
% 5 32 24 32 7
40 47 50 IO 6 38 6 9
reaction
13
48 58 55 22 IO 44 7 7 3 5
Overall severity None Moderate Severe-no medication required Severe-medication required Severe-hospitalization required
% 7 33 24 27 9
% 2 30 25 37 6
Laryngeal
frequency of no completion of therapy at all, and of modifications in dose and/or interruptions because of excessive reactions, was very similar in both subgroups. The signs of tissue effect, the treatment related interruptions of therapy, the loss of weight during therapy, and the late tissue changes were not statistically different in the two subgroups. The 14 interruptions of continuous-course therapy noted in Table 3 ranged from 5 to 28 days; 4 were not longer than a week, six were one to two weeks, and four were of longer than two weeks duration. The 5 interruptions of split-course therapy were of six, seven, seven, eleven and 18 days duration respectively. Hospitalization for more than half of the treatment period was reported in 21% of patients in the continuouscourse group and 14% of the split-course group. Hospitalization required because of treatment reactions was reported in 9% of continuous and 6% of split-course patients (Table 4). The normal tissue reactions to radiotherapy were slightly but consistently more numerous with split-course therapy than with continuous therapy, as shown in Table 4. Pain in the irradiated area, pain on swallowing, and difficulty swallowing were the most commonly encountered symptoms. Laryngeal reaction was more commonly reported in the continuous group. Follow-up One hundred-sixteen patients are known to have died and another 4 are presumed dead; they had persistent or recurrent disease at last contact and could not be located for further follow-up (2 of these were treated with continuous, and 2 with split-course irradiation). Twenty-one patients are considered to be alive for the purposes of this analysis; the length of time each one has been followed is as follows: 11 (7%) patients, 6 continuous-5 split, 5
I 9
years; 4 (3%), 1 cont.-3 split, 4 years; 4 (3%), 3 cont.-l split, 3 years; 1 (l%), 1 split, 2 years; 1 (l%), 1 split, 1 year. Immediate results As can be seen from Table 5, 66 (47% of the 141) patients became free of their primary tumors. The likelihood of becoming free of local tumor varied considerably by the extent of the primary (all 5 T,.,; 70% T,.,; 57% of T,.,; and only 21% of T4.\ became clear), but did not seem to depend on which treatment regimen was used. Nor does a treatment differential emerge if one estimates the probability of primary tumor clearance as a function of treatment and actual tumor diameter. Similarly, in judging how often lymph node metastases become undetectable after therapy (Table 6), one fails to see any treatment differential that could not have been Table 5. RTOG-7 I -02-Base Primary
Without further treatment 7‘1 T2 T, T, All
of tongue. Initial tumor control: tumor (T)
Treatment ~ Continuous course 212 415 16129 6132 28168 (41%)
group Combined Split course
No.
%
313 315 23140 6125 35173 (48%)
515 7110 39169 I2157 631141 (45%)
IO0 70 57 21
Persistant primary tumors cleared by surgery
3 (T,Y4)
Overall control rate
28168 (41%)
38173 (52%)
661141 (47%)
Split radiotherapy for base of tongue Ca 0 V.A.
Table 6. RTOG-71-02-Base of tongue. Initial tumor control: Regional lymph node metastases (N) Treatment
group Combined
Without further treatment
Continuous course
N, N, N, All N + combined
Split course
5110
14120
314 14135 22149 (45%)
II2 12134 27156 (48%)
No.
%
19/30 416 49169 491105 (47%)
63 67 38
Persistent lymph node metastases cleared by surgery
5 (N ,.,.,1.r)
Overall control rate _
22149 (45%)
32156 (57%)
541105 (51%)
produced by random variation. The worst lymph node metastases (i.e. N,-bilateral or fixed lesions) were slightly more likely to be controlled than the worst (T4) primaries; the success rates were 38% of N,,, controlled versus 21% of T.,., controlled. When one considered the ability of treatment to control both local and regional tumor (Table 7), results are more dismal. Only 24% of the 88 patients who presented with T, or N, lesions (or only 38% of all 141) became clear of all loco-regional tumor. An additional 6 patients, all in the split-course group, did achieve T,N, status through surgery for persistent disease. Whether these latter 6 patients are counted as successes or as failures, the observed treatment variations are not statistically significant. First evidence of failure The patterns of failure in the two treatment groups show that there were 1 IO (57 cont.-53 split) failures in all: 82 with persistent disease plus 15 loco-regional recur-
441
MARCIAL et al.
rences, plus 13 where distant metastases occurred while the primary and nodes remained controlled. Ninety-seven or 88% of the 110 failures were loco-regional, and the most important determinants of the length of time until failure are the (raw) tumor size and whether the regional lymph nodes were involved. The observed treatment differences are slight (84% of continuous course patients have failed, and 73% of splitcourse have failed). If one adjusts for any imbalances in the composition of the two treatment groups, the groups are not statistically different with respect to either frequency of loco-regional failure, patterns of failure, or time to failure (with both groups combined, the estimated percentages of patients free of tumor at 1, 2, and 3 years post randomization are 35%, 27% and 22%, respectively). (These figures are calculated counting patients whose persistent or recurrent disease was successfully removed by surgery as ‘free of tumor’.) Considered another way, this says that an estimated 65% of patients fail in the first year, 8% in the second, 5% in the third and the remainder in the fourth and subsequent years. Ultimate results The current reported status of all 141 patients reveals that 21 or 15% are alive and 120 or 85% are dead. The excess of 9:l in the number of patients who died without apparent disease in the two treatment groups is less impressive when one notes that the 9 died at 7, 8, 8, 14, 17, 19, 25, 27, and 30 months post-randomization and that on the basis of the results in the other comparable patients, as many as 5 of them might have been expected to fail at a later time if they had lived. There were five second primaries in all in this study (4 in the continuous-course group and 1 in the split); they were either successfully controlled or occurred in patients who already had active disease. The actuarial 5-year survival from date of randomization for the entire group of 141 patients is 15% (Table 8). Just under half of all patients died within one year of entering the study. There are marked differences in
Table 7. RTOG-7 I-02-Base of tongue. Initial tumor control: T and N Table 8. Survival: Post-randomization Treatment
group Continuous
Combined Without further treatment T, z, N, , TIN, z or T, 3NZ T, any N or N, and T All Persistent primary or regional tumor cleared by surgery Overall clearance rate
*TIN,. TIN,, T,N,, T,N,,
Continuous course 314 IO/l8 12146 25168 (37%)
25168 (37%) T,N,, T,N,.
course
Split course
No.
%
214 17127 9142 28173 (38%)
518 27145 21/88 531141 (38%)
63 60 24
6*
6
34173 (47%)
591141 (42%)
Patients treated Estimated percentage alive at 1 Year* 2 Yearst 3 Years 4 Years 5 Years Median survival
Split course
68
73
54 29 21 19 15 1.1 years
61 26 18 16 14 1.2 years
Combined 141
58 28 19 18 15
* 1 patient died of intercurrent disease 4 mos. after completion of treatment. t3 patients died of intercurrent disease before 2 yrs. after completion of treatment.
442
Radiation
4
T-CONTROL BASE
Oncology
??Biology 0 Physics
April 1983, Volume 9, Number 4 Table 9. Late effects
BY TREATMENT
OF TONGUE
8L
12
TREATMENT CONTINUOUS -SPLIT
t%T”S
CNSRO 3:
36
46
60
FAIL0 46 43
TOTAL 66 73
HEOIAC. 0.0 II .5
Continuous course %
Split course %
12 3 0 3 40 32 9 0 3 34 I9
14 8 3 I 50 43 4
Necrosis* Soft tissue Bone Cartilage Skin Edemaf Fibrosist Fistmat Myelitis Other neuropathy Persistent weight loss Other
Total %
13 6
I 5 45 38 6
1
I
4 36 13
4 35 16
*All cases were related to active tumor (the majority of patients), or previous surgery, or both (I patient). One case of bone necrosis was related to dental caries. tAny degree-Any time, disregarding the duration. fAll cases were related to previous surgery (more than half), or active tumor, or both (I patient).
I
Fig. 1. Primary tumor control by treatment-Up
to 5 yrs.
survival depending on the size of the primary tumor and whether regional nodes were initially involved. No differences could be ascribed to treatment. Fig. 1 and 2 present the primary tumor and node control up to 5 years. Late effects of therapy Table 9 shows the late reactions reported at any time during follow-up. Generally the reactions are somewhat A.
N-CONTROL BASE
OF
BY
TREATMENT
TONGUE
1 .O .9 F
.a. m <
b E
..--_
.4.
DISCUSSION 12
-
more frequent with split-course radiotherapy, especially with respect to edema, any degree in the treated area, and fibrosis. There were no significant differences in the frequencies of any of these effects for the two treatment groups (Fisher-Exact test); nevertheless, the total number of patients with some type of necrosis is higher in the split technique. It should be clarified, however, that all the patients with fistula and/or necrosis clearly had active tumor at the moment of reporting these complications and, sometimes, had had previous surgery. The patient with myelitis had NSD-TDF over the 5% permissible variation, and active tumor associated with this complication. One patient with neuropathy had laryngeal nerve paralysis because of a fibrotic metastatic mass in the neck; another patient had neuropathy with transient Lermitte’s sign. Even though the seriousness of these late tissue reactions was not scored, it may vary in different institutions; in the Puerto Rico patients, no complications were considered disabling; one post-surgery skin necrosis healed spontaneously and a pin-point size orocutaneous fistula, following a combined surgical procedure, was corrected by surgery.
TREATMENT CONTINUOUS -SPLIT
“%T”S
CNSRO 36 40
36
48
60
FAIL0 32 33
TOTAL 68 73
MEOIAN 18.6 49.8
Fig. 2. Node control by treatment-Up
to 5 yrs.
AND
CONCLUSIONS
While the results described in this paper do not show any therapeutic advantage to split-course therapy over conventional fractionation, they do suggest that the split technique, involving four weeks of therapy rather than six to seven, provides comparable therapeutic results in a more efficient manner. They suggest that there are savings in physician time, in use of facilities and in cost to the patient. The only reservations about these conclusions are: 1) the patients studied had such a poor prognosis (only 15% 5-year survival) that split-course therapy did not have a
Split radiotherapy for base of tongue Ca 0 V.A. MARCIAL etal.
good opportunity to demonstrate an improvement and 2) with the number of patients studied, there was only a 50% chance of detecting a treatment difference of 10% in the cure rate (e.g. 15% versus 25%) if indeed one existed, and that the true (long-run) difference would have to have been as large as 20% (e.g. 15% versus 35%) if we were to be virtually assured of calling the observed results statistically significant. However, both these shortcomings must be balanced by the fact that a comparable equivalence pattern is emerging in the other two head and neck regions being studied (tonsillar fossa and nasopharynx). When the data from
443
these other two regions mature a little more, the publication of the results seen in all three sites should be more convincing. Also, if one calculates the posterior distributions for the “cure” rates with the two treatments on the base of the tongue patients, the probability that the treatments produce cure rates which are more than 5% different from each other is less than 1 in 3. Concerning the variations introduced in some of the protocol cases (staging, treatment schedule, institutional variations, etc.), it is felt that they did not influence the results; this aspect will be analyzed with more detail in a future paper.
REFERENCES 1. Kaplan,
E., Meier, P.: Non-parametric estimation from incomplete observations. J. Am. Stat. Assoc. 53: 457-48 1, 1958. 2. Marcial, V.A., M.D.: Split-Course Radiation Therapy Project. Cancer 29: 6, 1463-1467, 1972. 3. Mar&al, V.A., M.D., Amato, D., MS., Chang, C.H., M.D., Figueroa, N.R., M.D.: Pattern of failure after radiotherapy of cervical node metastases in carcinoma of the base of the tongue, tonsillar fossa, and nasopharynx. Presented at the Annual Meeting of the American Radium Society, March 14-l 8, 1982, San Antonio, Texas. 4. Marcial, V.A., M.D., Hanley, J.A., Ph.D., Chang, C., M.D., Davis, L.W., M.D., Moscol, J., M.D.: Split-course radiation therapy of carcinoma of the nasopharynx: Results of a National Collaborative Clinical Trial of the Radiation Therapy Oncology Group. Int. J. Radiat. Oncol. Biol. Phys. 6: 409-414, 1980.
5. Marcial, V.A., Hanley, J.A., Hendrickson, F., Ortiz, H.G.: Split-course radiation therapy of carcinoma of the base of the tongue: Results of a Prospective National Collaborative Clinical Trial of the Radiation Therapy Oncology Group Int. J. Radiat. Oncol. Biol. Phys. 2 (Suppl. 1): (Abstract). 40, 1977. 6.
Marcial, V.A., Hanley, J.A., Rotman, M.: Split-course radiation therapy of carcinoma of the tonsil!ar fossa: Results of a prospective National Collaborative Clinical Trial of the Radiation Therapy Oncology Group (Abstract). Int. J. Radiat. Oncol. Biof. Phys. 4 (Suppl. 1): 17-18, 1978.
7. Marcial, V.A., M.D., Hanley, J.A., Ph.D., Ydrach, A., M.D., Vallecillo, L.A., M.D.: Tolerance of surgery after radical radiotherapy of carcinoma of the oropharynx. Cancer 46: 9,191&1912,1980.