Radiation Therapy Oncology Group (RTOG) studies in head and neck cancer.

Since its foundation in 1971, the RTOG has conducted a successful clinical research program in head and neck mucosal squamous cell carcinoma with 22 treatment protocols and one registry study which combined have accumulated data on over 5,500 patients. The RTOG was the first multicenter group to evaluate neoadjuvant chemotherapy before definitive radiation with its methotrexate study. Although the study was negative, RTOG has since conducted five pilot or phase II studies of neoinduction or concurrent chemotherapy with radiation therapy in patients with inoperable tumors. The last study showed that radiation concurrent with cisplatinum was tolerable with a suggestion of increased antitumor effect. In patients with potentially resectable tumors, RTOG has completed a pilot study of combination chemotherapy administered either before or after the surgery with radiotherapy. Based upon its findings, the treatment sequence, surgery-chemotherapy-radiotherapy, was chosen as the experimental arm for a new phase III study. This study was subsequently adopted by the head and neck intergroup mechanism as its study (INT 0034/RTOG 8503). RTOG has investigated the optimal timing of radiotherapy with surgery. The 7303 study established that postoperative radiotherapy achieved significantly better locoregional control but not improved absolute survival. Approximately 30% of the patients on each arm failed to complete both modalities. Even when comparison is restricted to patients who completed both modalities, postoperative radiotherapy still produced the better locoregional control. Efforts to overcome the limitations imposed by tumor hypoxia through use of carbogen (95% O2 and 5% CO2) breathing or the radiosensitizer misonidazole during radiotherapy have been unsuccessful. In a phase I study, RTOG showed that 15 to 18 sessions of sensitized radiation can be safely delivered with the new radiosensitizer SR 2508 in contrast to only six such sessions with misonidazole. This promising radiosensitizer is now being tested in a phase III trial. RTOG has also investigated variations in fraction size, fraction number, and total radiation dose. In the 7102 study, split-course irradiation achieved equivalent antitumor results as compared to continuous daily irradiation but with less social alteration and cost to the patient. In the hyperfraction pilot study 7703, twice a day irradiation with 120 cGys up to 6,000 cGys proved to be tolerable.(ABSTRACT TRUNCATED AT 400 WORDS)

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.

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.

Protocol variations and their influence on the final outcome: critical review of the split-course base of tongue study of the RTOG.

A critical review of the protocol variations in an RTOG prospective randomized multi-institutional clinical trial has been conducted. The objective of the review was to identify variables that might have affected the results of the study. Compliance with general guidelines and specific technical treatment parameters of the Split-Course Radiation Therapy Protocol for Carcinoma of the Base of the Tongue (RTOG #71-02) was analyzed. A +/- 5% variation of the time-dose-fractionation factors, using the NSD and TDF formulae and their respective protocol ratios (ratio between actual case NSD and TDF level and what the protocol recommended), has been defined as fully acceptable. Seventy-two percent of the 141 study cases were within this category. Minor variation has been defined as one resulting in a +/- 6% to +/- 15% deviation from the study values (15.3% of cases). Major and unacceptable variation was a deviation of +/- 16% or more from the research plan (12.7% of cases). After identifying the different variations and correlating them with the clinical results, we conclude that these deviations did not affect the final results to a significant or identifiable degree.

Hyperfractionated photon radiation therapy in the treatment of advanced squamous cell carcinoma of the oral cavity, pharynx, larynx, and sinuses, using radiation therapy as the only planned modality: (preliminary report) by the Radiation Therapy Oncology Group (RTOG).

From August 1979 to June 1983, the RTOG conducted a prospective Phase III study that compared a standard schedule with five fractions per week of 180 to 200 cGy per day to a total dose of 6600-7380 cGy, with a hyperfractionation regimen consisting of two fractions of 120 cGy per day, separated by a rest period of 3 to 6 hours for a total of 6000 cGy. A total of 210 patients were entered, of which 187 are analyzed. Complete initial tumor clearance in the head and neck was achieved by radiotherapy in 61% of the patients assigned to the standard schedules and in 59% of those assigned to the continuous hyperfractionation schedule; surgical salvage contributed towards achieving complete response in 5% and 7% of patients, respectively. The Kaplan-Meier estimates for loco-regional control of tumor at 1 and 2 years was 39% and 29% for the standard schedules, and 43% and 30% for the hyperfractionation schedule. The endpoints examined to evaluate therapeutic effects do not indicate that the stated hyperfractionation schedule is different than the standard RTOG treatment schedule for head and neck cancer. Acute normal tissue reactions appear to be more severe with the hyperfractionation schedule but the incidence of late reactions is similar in both groups. There is a tendency toward more severe acute reactions when the interval between the two fractions per day is 4.5 hrs or less in comparison to intervals longer than 4.5 hrs.

Prognostic factors for loco/regional control and metastasis and the impact on survival.

For the identification of predictive factors for local (head and neck) control and metastases and impact on survival in squamous cell cancer of the head and neck, we have used data from over 2000 patients from the Patterns of Care Study (PCS) and the Radiation Therapy Oncology Group (RTOG) studies. Complete local response (C.R.) is significantly related to T stage, N stage, general performance status (Karnofsky), and site of primary tumor. There is a strong association between T and N stage. T1N0 tumors showed a C.R. of 99%, whereas, T1N3 had a C.R. of 57%. T4N0 showed a C.R. of 75%, but this went down to 31% in the T4N3 lesions. Glottic tumors showed a C.R. of 96% versus the other sites, which ranged from 81% for the nasopharynx to 59% for the hypopharynx. Patients with a performance status (KPS) of less than 90% showed a C.R. of 60% versus 88% for AKPS 90% or higher. Absence of local recurrence after C.R. is significantly related to T stage, N stage, and the site of primary tumor (glottis versus the rest). The appearance of distant metastases is significantly related only to N stage and primary site. This relationship persists in control of loco/regional tumors. In Stages III & IV in non-glottic head and neck cancer, metastases as the cause of death play an increasingly important role. This can be as high as 30%. The appearance of new malignant tumors and death unrelated to cancer, that is, death related to lifestyle, assumes an important role in patients with advanced head and neck cancer. The number of advanced glottic larynx was too small to examine this question. The use of a surgical procedure in carcinomas of the anterior tongue and floor of the mouth was associated with a smaller percentage of infield recurrences at 2 years, than when radiation therapy alone was used (27% versus 88% p less than .01). The same observation was noted at 3 years in the glottic and supraglottic Stage III & IV tumors (p less than .01).

Misonidazole and unconventional radiation in advanced squamous cell carcinoma of the esophagus: a phase II study of the Radiation Therapy Oncology Group.

This is a report on Radiation Therapy Oncology Group (RTOG) Protocol No. 78-32, a Phase I/II prospective study aimed at determining tolerance, tumor response, and survival of squamous cell carcinoma of the esophagus treated with unorthodox fractionation radiotherapy combined with misonidazole. Misonidazole was administered by mouth 4 to 6 hr prior to radiation, at a dose of 1.0 to 1.25 Gm/.m2; blood levels were measured at about 4 hr after intake of the drug and reported in micrograms/ml. Radiotherapy was administered at 4 to 6 hr post-misonidazole dose and given with 400 rad fractions, alternating 2 or 3 times/week, up to 4,800 rad. A total of 43 patients were entered; 26 are evaluable for survival at 1 year post accession. Thirty patients (88%) received the planned radiation course. Twenty-eight patients (78%) received the planned misonidazole dosage. Tumor response, evaluable in 18 patients, showed a complete regression (C.R.) in only 2 patients (11%); and partial response (P.R.) in 6 patients (33%). Eight patients (44%) showed no tumor response to planned therapy. Toxicity was acceptable and in 38 evaluable patients only 4 reported (11%) nausea and vomiting, 7 reported mild paresthesias (18%). The median survival was only five months. In 26 patients evaluable for 1 year survival determination, only 1 survived (3.8%) this period. In view of the poor tumor response and low survival observed, we do not recommend that this particular fractionation regimen with misonidazole be used in a Phase III randomized trial in squamous cell carcinoma of the esophagus.

Dose-response for local control with hyperfractionated radiation therapy in advanced carcinomas of the upper aerodigestive tracts: preliminary report of radiation therapy oncology group protocol 83-13.

A prospective, randomized Phase Ilate/II trial of hyperfractionated radiation therapy was conducted: 1.2 Gy minimum tumor dose was administered twice daily with a minimum interval of 4 hr, 5 days per week. Patients with Stage III and IV carcinomas of the oral cavity, oropharynx, nasopharynx, hypopharynx, and supraglottic larynx were stratified by site, presence or absence of nodal metastases, and performance status. They were assigned to four total doses between 67.2 Gy and 81.6 Gy to all known tumors. The highest dose arm was opened after preliminary assessment indicated acceptable late morbidity rates with the three lower doses. Of 479 patients entered, 260 patients were randomized to the three lower total doses and 237 were analyzed for this preliminary report: 63 were assigned to receive 67.2 Gy, 58 to 72.0 Gy, and 116 to 76.8 Gy. Estimates of grade 4 necrosis at 2 years were 10.0%, 5.1%, and 13.9%, respectively, for patients who received total doses of 67.2 Gy, 72.0 Gy, and 76.8 Gy. There was a suggestion of a trend toward increased local control at 24 months (Kaplan-Meier estimates of 25% for 67.2 Gy, 37% for 72.0 Gy, and 42% for 76.8 Gy) (p = .08). No difference was observed in survival. Assessment of the results using Cox regression models to correct for slight inequalities of pretreatment prognostic variables supported a total dose-tumor control relationship (p = .054). Results for the lowest dose arm were comparable to previous RTOG studies of common fractionation with similar total doses. The higher local control rates with 72.0 and 76.8 Gy using hyperfractionated radiation therapy suggest an improvement in outcome with radiation therapy for advanced carcinomas of the upper aerodigestive tracts. These preliminary findings have led to a Phase III comparison of hyperfractionated radiation therapy with 1.2 Gy b.i.d. with standard fractionation.

Logistics in designing clinical trials for etanidazole (SR 2508): an RTOG experience.

In a Phase II study of etanidazole (SR 2508), the dose of 17 x 2 g/m2 (total drug dose: 34 g/m2) was tested in 33 patients and the toxicity was deemed acceptable. A Phase III trial is now in progress comparing conventional radiotherapy with conventional radiotherapy plus etandizole (2 g/m2 i.v. 30 to 60 min before radiotherapy each Monday, Wednesday, and Friday to 34 g/m2 in 17 doses) in patients with unresectable head and neck carcinomas. A recent analysis showed only 14.7% grade 1 and 3.9% Grade 2 peripheral neuropathy. In the initial study design, 133 evaluable patients per treatment arm could achieve an 80% level of power of detecting a 15% difference in local-regional control rates between the radiotherapy arm (25% local-regional control at 2 years) and the radiotherapy plus etanidazole arm (assuming a 40% rate). Allowing for 20 ineligible cases in each arm, a total number of 306 was required. An interim analysis showed that 27% of the patients assigned to radiotherapy plus etanidazole are receiving less than 14 doses of the drug. It is assumed that less than 14 drug doses will not produce any therapeutic gain, therefore, a true 40% local-regional control rate in the radiotherapy plus etanidazole arm will be observed as a 36% rate when analyzed by assigned treatment. Using this information, the study was modified to have an 80% level of power in detecting a difference between a 25% local-regional control rate in the radiotherapy group and a 36% rate in the radiotherapy plus etanidazole group. Allowing for a 10% patient ineligibility rate, 518 patients are required. With 12 patients entered per month, it is estimated that patient accrual to this study will continue through October 1991.

Hormonal cytoreduction in locally advanced carcinoma of the prostate treated with definitive radiotherapy: preliminary results of RTOG 83-07.

RTOG 83-07 is a Phase II randomized protocol designed to compare the efficacy and toxicity of Megestrol vs Diethylstilbestrol (DES) used as cytoreductive agents prior to and during radiotherapy. The end-points of this study include tumor clearance rate, effect on serum testosterone, local-regional control, disease-free interval, and survival. Eligible patients were those with histologically confirmed locally advanced adenocarcinoma, clinical Stage B2 and C without regional lymph node involvement, or with lymph node involvement limited to the pelvis. Patients with medical conditions potentially predisposing to cardiovascular (thromboembolic) sequelae of endocrine therapy were not eligible. Patients were stratified by clinical stage, histological grade, and nodal status and were randomized to receive either Megestrol 40 mg PO tid or Diethylstilbestrol 1 mg PO tid. The drugs were started 2 months prior to initiation of radiotherapy and were continued throughout the radiotherapy course. Radiotherapy consisted of 44 to 46 Gy, 1.8 to 2 Gy per day to the regional lymphatics followed by a boost to the prostate consisting of 20 to 25 Gy, 1.8 to 2 Gy per day to a total of 65 to 70 Gy. Serum testosterone levels were recorded throughout the treatment course. Tumor response was assessed clinically and radiographically (CT scan). From March 1983 through June 1986 a total of 203 patients were accessioned to the study; 197 were analyzable. Correlation of the incidence of drug related toxicity and treatment arm assignment revealed a significantly higher incidence of complications in the Diethylstilbestrol (DES) arm. The most prominent were the differences in the incidence of gynecomastia (55% vs 7%) and fluid retention (21% vs 6%). The incidence of thromboembolic phenomena was comparable (8% vs 5% in the Megestrol arm). Although patients on the DES arm demonstrated a significantly greater median decrease in testosterone level, correlation of the treatment assigned to the rate of tumor regression and the incidence of complete response revealed no significant difference between the arms. At 3 years only 6.5% of the evaluable patients manifested evidence of local failure. The results of the study indicate comparable efficacy (using tumor clearance as an end-point) of DES and Megestrol. While DES appears more effective in suppressing testosterone it is also associated with a higher incidence of toxicity. The cytoreduction (using either DES, Megestrol, or an alternative regimen) concept remains to be tested in a Phase III study comparing it to radiotherapy alone.

The effect of local-regional control on distant metastatic dissemination in carcinoma of the head and neck: results of an analysis from the RTOG head and neck database.

A retrospective analysis of the effect of local control on the development of distant metastases was performed in 2648 patients with carcinoma of the head and neck selected from the RTOG database. The 5-year time-adjusted incidence of distant metastases was 21% for patients who were in local-regional control at 6 months after the start of treatment, compared to 38% for local-regional failure patients (p less than 0.001). The incidence of distant metastases detected between the interval of 6 months to 2.5 years after treatment was significantly increased in patients with tumors of the oral cavity, oropharynx, supraglottic larynx, and glottis who developed local-regional failure within this time period, compared to those who remained locally controlled (19% distant metastases for local-regional failure vs 7% for local-regional control (p less than 0.001)). In contrast, there as no difference in the incidence of distant metastases in patients with carcinoma of the nasopharynx or hypopharynx regardless of the local-regional disease status. A Cox proportional hazards regression analysis demonstrated that local-regional control was the most significant variable affecting the development of distant metastases, followed by tumor site, N-stage, and T-stage. For all tumor sites, except for the hypopharynx and nasopharynx, improvements in local-regional control are likely to improve survival. Tumors of the hypopharynx and nasopharynx have a higher probability of micro-metastatic dissemination at the time of initial diagnosis, and until effective methods to treat disseminated disease are developed, the effect of local control on survival will not be readily discerned.

Comparison of 1 vs 2 or more intracavitary brachytherapy applications in the management of carcinoma of the cervix, with irradiation alone.

Four hundred ninety-eight patients treated in the USA in 1978 for cancer of the cervix by external beam and intracavitary irradiation have been studied to determine the effect of using a single intracavitary (IC) application versus more than one. Most of the patients (46%) underwent intracavitary (IC) treatment after external radiation therapy (RT), 40% during external RT, and 14% prior to external RT. Five-year actuarial survival for all stages was 66% for greater than or equal to 2 applications versus 59% for 1 application, p less than .01. When survival was analyzed by stage, there was a trend toward improved survival with greater than or equal to 2 applications in Stage II (p .10). The rate of infield recurrence for all stages was higher in the 1 IC group (30% vs 17%, p less than .01). These were more frequent in the 1 IC group (53% vs 34%, p less than .05), in Stage III patients, but no significant difference was noted in the other stages. Distant metastases were more frequent in the 1 IC group (19% vs 11%, p .01). The incidence of major complications was the same in both groups. An analysis of patient characteristics and other variables that would explain the difference in results revealed that older patients (p .03), worse Karnofsky (p .056), and more parametrial involvement (p less than .01) accrued more in the 1 IC group. Higher paracentral point doses were administered when greater than or equal to 2 IC applications were used (p less than 0.01); this group also received higher bladder and rectal doses and lower whole pelvic doses. The use of two or more intracavitary insertions affords an opportunity to administer higher paracentral point doses, which appear to be related to higher pelvic tumor control, lower rate of distant metastasis, and better survival.

Elapsed treatment days--a critical item for radiotherapy quality control review in head and neck trials: RTOG report.

For all randomized trials since 1978, the Radiation Therapy Oncology Group has required the study chairman for radiation therapy to review the treatment given to each patient. The chairman scores the compliance of the treatment borders, total dose, fraction, and total elapsed time relative to the protocol prescription at the primary site, regional nodes, and any critical structure. The individual parameters are then considered together to derive an "overall" treatment score. For two RTOG head and neck studies in patients with moderately and very advanced carcinomas, the "overall" treatment was classified as unacceptable if the treatment at primary was scored unacceptable with respect to dose, fractionation, and field borders. However, prolonged elapsed treatment was not included. Analysis of these studies with 426 evaluable patients was performed to assess the relationship of unacceptable "overall" treatment compliance with outcome. Patients with prolonged treatment elapsed days (14 days beyond the protocol prescription) exhibited significantly poorer loco-regional control (13% vs. 27% at 3 years with p = .007) and absolute survival (13% vs. 26% at 3 years with p = .01). As a result, the criteria for unacceptable "overall" treatment were revised to include prolonged elapsed treatment days. Further multivariate analyses showed the revised criteria identified patients with significantly poorer loco-regional control and absolute survival even after adjusting for other prognostic factors.

ASTRO plenary: interfraction interval is a major determinant of late effects, with hyperfractionated radiation therapy of carcinomas of upper respiratory and digestive tracts: results from Radiation Therapy Oncology Group protocol 8313.

A prospective, randomized, multi-institutional, Phase I(LE)/II trial of HFX was conducted by the RTOG between 1983 and 1987. Patients with histologically proven, inoperable squamous cell carcinoma of the upper respiratory and digestive tracts stratified by site, nodal status, and performance status, were assigned to one of three arms, were assigned to one of three arms, 67.2 Gy, 72.0 Gy, or 76.8 Gy. Fractions of 1.2 Gy were given twice daily, 5 days per week: intervals of 4 to 8 hours were permitted between fractions. After acceptable rates of acute normal tissue effects were found, the randomization was changed to evaluate a new higher total dose, 81.6 Gy. Of 479 patients entered, 447 were analyzed, 63 on 67.2 Gy, 129 on 72.0 Gy, 117 on 76.8 Gy, and 138 on 81.6 Gy. The treatment arms were well balanced with respect to pretreatment characteristics. Acute reactions consisted almost entirely of pseudomembranous inflammation. "Severe" (Grade 3) acute reactions were reported in 33% to 41% and grade 4 reactions were found in 0 to 3% of patients, with no differences in frequencies among the four arms. Toxicities that developed or persisted beyond 90 days after the first treatment (408 patients evaluable greater than 90 days) did not differ among arms: grade 3+ reactions occurred in 10% to 14%, and grade 4+ effects (necroses) were reported in 5% at 67.2 Gy, 3% at 72.0 Gy, 7% at 76.8 Gy, and 2% at 81.6 Gy. Grade 3+ acute reactions occurred in 40% of patients when the interfraction interval was less than or equal to 4.5 hours versus 31% with greater than 4.5 hours (p = .03). Interfraction intervals less than or equal to 4.5 hours were associated with higher frequencies of grade 4+ late effects in all four arms, 8% of 197 patients with less than or equal to 4.5 hours versus 1% of 211 patients with greater than 4.5 hours. Estimates of late toxicity at 1, 2, and 3 years were 5.5%, 9.8%, and 15.4% with intervals less than or equal to 4.5 hours, versus 1.7% at all three periods for greater than 4.5 hours (p = .006). Local-regional control at 2 years was 25% for the assigned dose of 67.2 Gy compared to 43% to 45% for the three higher doses (p = .01), but a similar comparison for survival showed no significant difference (p = .35). There was no evidence for an effect of interfraction interval on either local-regional control (p = .38) or survival (p = .28).(ABSTRACT TRUNCATED AT 400 WORDS)

Results of a phase II trial of external beam radiation with etanidazole (SR 2508) for the treatment of locally advanced prostate cancer (RTOG Protocol 90-20).

PURPOSE: RTOG Protocol 90-20 was designed to evaluate the effect of the hypoxic cell sensitizer Etanidazole (SR-2508) on locally advanced adenocarcinoma of the prostate treated with concurrent external beam irradiation. METHODS AND MATERIALS: Patients with biopsy-proven adenocarcinoma of the prostate with locally advanced T2b, T3, and T4 tumors were eligible for this study. No patients with disease beyond the pelvis were eligible. Serum prostate specific antigen (PSA) was mandatory. All patients received definitive external beam irradiation using standard four-field whole pelvis treatment to 45-50 Gy, followed by a cone down with a minimum total dose to the prostate of 66 Gy at 1.8-2.0 Gy/fraction over 6.5-7.5 weeks. Etanidazole was delivered 1.8 g/m2 given 3 times a week to a total of 34.2 g/m2 or 19 doses. RESULTS: Thirty-nine patients were entered onto the study. Three patients refused treatment; therefore, 36 patients were eligible for further evaluation. Median follow-up was 36.9 months from treatment end. All patients had elevated initial PSA levels, and 18 patients had PSAs of > 20 ng/ml. Tumor classification was T2, 12 patients (33.3%); T3, 22 patients (61.1%); and T4, 2 patients (5.6%). Complete clinical response, defined as PSA < 4 ng/ml and complete clinical disappearance, was attained in 17.9% of (5/28 pts) with information at 90 days and 56% of patients by 12 months following treatment. Relapse-free survival was 13% at 3 years with PSA < 4 ng/ml. There were no Grade 4 or 5 toxicities, either acute (during treatment) or in follow-up. CONCLUSIONS: Results of this trial regarding PSA response and clinical disappearance of disease are similar to historical controls and do not warrant further investigation of etanidazole as was done in this trial. Drug toxicity that, in the past, has been unacceptably high with other hypoxic cell sensitizers does not appear to be a significant problem with this drug.

Phase II trial of hormonal cytoreduction with megestrol and diethylstilbestrol in conjunction with radiotherapy for carcinoma of the prostate: outcome results of RTOG 83-07.

PURPOSE: RTOG 83-07 is a Phase II randomized protocol designed to compare the efficacy and toxicity of Megestrol vs. Diethylstilbestrol (DES) used as cytoreductive agents prior to and during radiotherapy. The end points of this study include tumor clearance rate, effect on serum testosterone, loco-regional control, disease-free interval, and survival. METHODS AND MATERIALS: Eligible patients were those with histologically confirmed locally advanced adenocarcinoma, clinical Stage B2 (T2B) and C (T3) without regional lymph node involvement, or with lymph node involvement limited to the pelvis. Patients were stratified by clinical stage, histological grade, and nodal status, and were randomized to receive either Megestrol 40 mg three times per day by mouth, or Diethylstilbestrol 1 mg three times per day by mouth. The drugs were started 2 months prior to initiation of radiotherapy and were continued throughout the radiotherapy course. Radiotherapy consisted of 44-46 Gy, 1.8-2 Gy per day to the regional lymphatics, followed by a boost to the prostate consisting of 20-25 Gy, 1.8-2 Gy per day, to a total of 65-70 Gy. Serum testosterone levels were recorded throughout the treatment course. Tumor response was assessed clinically and radiographically (CT scan). From March 1983 through June 1986 a total of 203 patients were accessioned to the study; 198 were analyzable. RESULTS: Correlation of the incidence of drug-related toxicity and treatment arm assignment revealed a significantly higher incidence of complications in the Diethylstilbestrol (DES) arm. The most prominent were the differences in the incidence of gynecomastia (55% vs. 7%) and fluid retention (21% vs. 6%). The incidence of thromboembolic phenomena was comparable (8% vs. 5% in the Megestrol arm). Patients on the DES arm demonstrated a significantly greater median decrease in testosterone level. Correlation of the treatment arm assignment and the rate of tumor regression and the incidence of complete response revealed no significant difference between the arms. At 7 years, 16% of patients on the Megace arm and 21% of patients on the DES arm manifested evidence of local failure. CONCLUSIONS: The results of the study indicate comparable efficacy (using tumor clearance as an end point) of DES and Megestrol. Although DES appears more effective in suppressing testosterone, it is also associated with a higher incidence of drug-related toxicity.

Split-course versus continuous pelvis irradiation in carcinoma of the uterine cervix: a prospective randomized clinical trial of the Radiation Therapy Oncology Group.

In August 1980, the Radiation Therapy Oncology Group (RTOG) completed a prospective randomized clinical trial for the comparison of a split-course versus a standard continuous course of pelvic irradiation for carcinoma of the uterine cervix Stages II-B, III-A, III-B, and IV-A. The split-course consisted of 10 fractions of 250 rad each, 5 times a week, up to 2500 rad followed by a rest period of approximately 2 weeks and then another 2500 rad was given (250 X 10). The continuous course consisted of 30 fractions of 170 rad each, 5 times per week, for a total of 5100 rad. In both groups the external pelvis irradiation was followed by intracavitary brachytherapy in the uterus and vagina, with tandem-colpostat or tandem only, for a dose of 3000 rad at point A for the former, or at 2 cm from the center of the linear source for the latter. In cases where brachytherapy was not possible, a boost of external irradiation with reduced field, with a dose of 1600 rad (200 X 8) was advised. Three hundred and one patients were registered, of which 287 are currently evaluable. No differences between the treatments were detected for the following study end-points: treatment tolerance in terms of acute normal tissue reactions and completion of therapy, tumor control in the pelvis, severe late normal tissue reactions, and survival. In the entire study population the estimated tumor control in the pelvis at two years after initiation of therapy was: 81% for Stage II-B, 67% for III-A, 53% for Stage III-B, and 32% for Stage IV-A. The estimated two-year survival was: 70% for Stage II-B, 58% for III-A, 46% for III-B, and 23% for IV-A.

Predicting the response of head and neck cancers to radiation therapy with a multivariate modelling system: an analysis of the RTOG head and neck registry.

Two thousand and sixty-six patients with primary head and neck cancers were entered in the RTOG Head and Neck Cancer Registry between 1977 and 1980. Nine hundred and ninety-seven (997) evaluable patients were treated initially with radiation therapy alone. Tumor site, T-stage, N-stage, histology, degree of infiltration, degree of differentiation, patient age, sex and Karnofsky performance score were all prospectively recorded. T-stage (p less than .001), N-stage (p = .007), primary site (p less than .001), and initial Karnofsky performance score (p less than .001) proved to be significant factors independently predictive of primary tumor clearance. Using these factors, a multivariate response model was constructed to predict primary tumor response. The predictive accuracy of the model proved to be highly reliable, and was tested by comparing the predicted vs. observed complete tumor clearance rates for each independent variable. For primary sites, the predicted number of complete responses vs. observed were: oral cavity, 139.8 predicted vs. 139 observed; nasopharynx, 51.8 predicted vs. 51 observed; oropharynx, 174.8 predicted vs. 176 observed, supraglottic larynx, 314.4 predicted vs. 318 observed; glottic larynx, 314.4 predicted vs. 318 observed; and hypopharynx, 49.4 predicted vs. 46 observed. For the entire group of patients predicted to have a 90% or better complete primary tumor response (including T3 and T4 tumors), 94% remained in initial complete remission at the primary site at one year, and 87% at two years. An accurate multivariate response model, such as the one presented in this paper, should prove to be a useful tool in selecting patients with head and neck cancers suitable for treatment with radiation therapy alone.

Second malignancies in patients who have head and neck cancer: incidence, effect on survival and implications based on the RTOG experience.

The development of second malignant tumors (SMTs), in patients who have had their first tumor treated successfully, represents a serious limitation of current therapeutic strategies for head and neck cancers. To improve our understanding of the current magnitude of the problem and the various factors that might influence its importance, we reviewed the Radiation Therapy Oncology Group's (RTOG) prospectively collected registry of all head and neck patients seen in participating member institutions between February 1977 and April 1980. A total of 928 patients were identified who had squamous cell carcinomas of the head and neck region, no prior or coincident history of another malignant tumor, and whose planned treatment consisted of radiation therapy only. A total of 110 second, independent, malignant tumors occurred in these patients. Overall, the estimated risk of developing a second tumor within 3 years of radiotherapy was 10%, within 5 years 15%, and within 8 years 23%. Minor differences in frequency were observed for different primary sites. These SMTs unquestionably influenced subsequent survival adversely. Analysis of the database also revealed that the extent of the primary tumor influenced the risk of a second; most occurred in patients who presented with the smallest primary tumors because of their better survival. Our data indicate that preventive medicine should have its greatest impact in those patients who are treated for an early stage primary tumor.

Impact of initial quality control review on study outcome in lung and head/neck cancer studies--review of the Radiation Therapy Oncology Group experience.

The Radiation Therapy Oncology Group (RTOG) initiated cooperative clinical trials in 1971. In 1978, RTOG developed a formalized program of Quality Control (QC) divided into initial and final phases. The initial review process consisted of two steps. The first phase of review is an evaluation performed by a radiation oncologist to verify treatment plan and field borders. The second portion of the initial review process originally consisted of dosimetry calculation verification based on machine data provided by the regional Radiological Physics Center and treatment planning data provided by the accessioning institution. Between 1978 and December 31, 1987, a total of 11,343 cases in 96 RTOG protocols, excluding particle studies, underwent initial review. Of this number, 2227 patients were entered in lung cancer studies and 1341 patients were entered in head/neck cancer studies. Initial review was carried out in 2089 (93.8%) of the lung cancer cases. Missing or delayed data accounted for 138 (6.2%) cases not reviewed initially. In head/neck cancer trials, 1251 (93.2%) received initial review and 90 (6.8%) did not. Our findings suggest that there are sharply defined but long lasting learning experiences involved in clinical trial participation. Consideration may be given to modifying the initial review process to use random sampling of cases accessioned by experienced investigators in ongoing clinical trials and to continuing the total case evaluation on all new studies and cases entered by inexperienced investigators or investigators/institutions with unsatisfactory performance. Recommendations regarding initial review of other sites will await evaluation of the impact of initial review on those sites.

Randomized study of preoperative versus postoperative radiation therapy in advanced head and neck carcinoma: long-term follow-up of RTOG study 73-03.

This is a report of a 10-year median follow-up of a randomized, prospective study investigating the optimal sequencing of radiation therapy (RT) in relation to surgery for operable advanced head and neck cancer. In May 1973, the Radiation Therapy Oncology Group (RTOG) began a Phase III study of preoperative radiation therapy (50.0 Gy) versus postoperative radiation therapy (60.0 Gy) for supraglottic larynx and hypopharynx primaries. Of 277 evaluable patients, duration of follow-up is 9-15 years, with 7.6% patients lost to follow-up before 7 years. Loco-regional control was significantly better for 141 postoperative radiation therapy patients than for 136 preoperative radiation therapy patients (p = 0.04), but absolute survival was not affected (p = 0.15). When the analysis was restricted to supraglottic larynx primaries (60 postoperative radiation therapy patients versus 58 preoperative radiation therapy patients), the difference for loco-regional control was highly significant (p = .007), but not for survival (p = 0.18). In considering only supraglottic larynx, 78% of loco-regional failures occurred in the first 2 years. Thirty-one percent (18/58) of preoperative patients failed locally within 2 years versus 18% (11/60) of postoperative patients. After 2 years, distant metastases and second primaries became the predominant failure pattern, especially in postoperative radiation therapy patients. This shift in the late failure pattern along with the increased number of unrelated deaths negated any advantage in absolute survival for postoperative radiation therapy patients. The rates of severe surgical and radiation therapy complications were similar between the two arms. Because of an increased incidence of late distant metastases and secondary primaries, additional therapeutic intervention is required beyond surgery and postoperative irradiation to impact significantly upon survival.