Five-year survival after hyperfractionated radiation therapy for non-small-cell carcinoma of the lung (NSCCL): results of RTOG protocol 81-08.

RTOG Protocol 81-08, a feasibility study of hyperfractionated radiation therapy (HFX) with 1.2 Gy twice daily separated by 4-6 hours for non-small-cell cancer of the lung (NSCCL), was completed in 1983. Encouraging short-term results in a recently closed trial of HFX for NSCCL (RTOG 83-11) led to assessment of long-term outcome in the earlier trial. Of 120 evaluable patients who were assigned to total doses from 50.4 Gy to 74.4 Gy, all 5 of the 5-year survivors came from the 79 patients assigned to receive 69.6 Gy. The 5-year survival rates for the 79 patients were 14.3 +/- 9.4% for clinical RTOG Stage II, 5.9 +/- 4.0% for Stage III, and 3.2 +/- 3.2% for Stage IV. Combined Stage II and III 5-year survival rates were 8.3 +/- 4.0% for HFX 69.6 Gy compared to 5.6 +/- 1.5% for standard once-a-day irradiation in concurrent RTOG trials.

Hyperfractionated radiation and chemotherapy for unresectable localized adenocarcinoma of the pancreas. The Gastrointestinal Tumor Study Group experience.

Eighteen patients with unresectable localized adenocarcinoma of the pancreas were treated by a combination of chemotherapy plus hyperfractionated radiation therapy to the pancreas for 4080 cGy with an additional 960 cGy to the pancreatic tumor and a surrounding margin. One hundred and twenty cGy were given twice daily 4 to 6 hours apart. High-energy photon or electron beams were used with treatment planning based on computed tomographic (CT) scans. Patients were given chemotherapy in the form of 5-fluorouracil (5-FU) at 350 mg/m2 on the first 3 and last 3 days of radiation therapy. On day 53, chemotherapy was given that included 600 mg/m2 IV of 5-FU, 1 gm/m2 of streptozotocin, and 10 mg/m2 IV of mitomycin C. The 5-FU and streptozotocin were repeated on days 60, 81, and 88, and the stretozotocin and mitomycin (SMF) cycles were repeated every 8 weeks until progression. Radiation toxicity was generally tolerable with one of 18 evaluable patients having severe nausea and vomiting and two of 18 patients having severe diarrhea. One patient had total liver failure and died 3 months after initiation of therapy. Six patients had severe hematopoietic toxicity during chemotherapy. Overall, the severe toxicity rate was higher (67%) than in previous studies. Median survival was 35 weeks, the 1-year survival rate was 39%, and the patient who survived the longest died at 68 months. Although this schedule of hyperfractionated radiation and chemotherapy was disappointing, combined experimental radiation approaches plus chemotherapy for localized unresectable adenocarcinoma of the pancreas deserve additional research.

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.

Definitive irradiation and chemotherapy for radiosensitization in management of anal carcinoma: interim report on Radiation Therapy Oncology Group study no. 8314.

Following documented evidence of the synergism of 5-fluorouracil (5-FU) and radiation therapy and an additive effect with mitomycin and irradiation, pilot studies have demonstrated the potential for definitive radiation therapy in the management of squamous cell and basaloid carcinomas of the anal canal, allowing sphincter preservation. Our study explored the long-term effectiveness of combined therapy at this disease site and examined the feasibility of a Radiation Therapy Oncology Group study involving concomitant radiation therapy and chemotherapy. Between 1983 and 1987, 79 assessable patients with any primary tumor stage of anal canal carcinoma were treated by external-beam irradiation combined with mitomycin given by bolus iv injection and 5-FU given by continuous infusion. Radiation was delivered to the perineum and pelvis to a total dose of 4,080 cGy in 4.5-5 weeks. The inguinal nodal areas received 4,080 cGy, calculated at a 3-cm depth in the center of the nodal area. A 96-hour infusion of 5-FU was started on days 2 and 28 of the irradiation at a dose of 1,000 mg/m2 over 24 hours, and a bolus injection of mitomycin was administered on day 2 at a dose of 10 mg/m2. The overall survival rates are 97% at 1 year and 73% at 3 years. Patients with lesions less than 3 cm in diameter and those treated strictly according to the protocol did significantly better than those with larger lesions and those whose treatment did not comply with the protocol. The interim outcome of the study demonstrates that this combined therapy is effective for patients with anal cancer and allows preservation of the sphincter and of sexual function.

Local superficial hyperthermia in combination with low-dose radiation therapy for palliation of locally recurrent breast carcinoma.

From September 1984 through March 1987, 30 patients with locally recurrent breast carcinoma who had been heavily pretreated with conventional modes of therapy (radiation, chemotherapy, and hormonal therapy) were entered into a phase II study of hyperthermia and low-dose irradiation. The purpose of the study was to determine the feasibility, effectiveness, and morbidity of this treatment combination. Radiation therapy was administered twice weekly, 4 Gy per fraction, to a total dose of 32 Gy, with 6 or 9 MeV electrons depending on the thickness of the lesions. Hyperthermia generated by microwave frequencies of 200 to 700 MHz was administered immediately after radiation therapy, with a time and temperature aim of 60 minutes at 43 degrees C. Complete response (CR) was achieved in 17 patients (57%), and partial response (PR) in 11 patients (36%). Response was positively correlated with tumor size; lesions less than 5 cm in diameter achieved CR significantly more frequently than lesions greater than or equal to 5 cm (P less than .001). Eighty percent of the complete responders continued to experience sustained control of the treated site from 6 to 32 months but showed evidence of progressive systemic disease or locoregional progression to the adjacent untreated sites, reflecting the natural history of this disease and extensive dermal lymphatic permeation. True recurrence within the treated volume occurred in three patients. Nonhealing ulceration developed in nine patients and seven of those were associated with persistent tumor. This study confirms the palliative value of hyperthermia in combination with radiotherapy for previously irradiated recurrent chest wall tumors and sets the scene for its comparative clinical evaluation against radiation therapy alone as first line therapy for locally recurrent breast carcinoma.

Preoperative radiation and chemotherapy for localized squamous cell carcinoma of the esophagus: a RTOG Study.

Forty-one evaluable patients with localized squamous cell carcinoma of the thoracic esophagus were treated by a course of radiation therapy (3000 cGy in 3 weeks), 5-Fluorouracil (5-FU) and Cis-platinum (Pt). This was followed by an esophagectomy in medically eligible patients who agreed to the procedure and who had no evidence of extrathoracic tumor. If tumor was found in the specimen, an added 2000 cGy of radiation therapy and additional 5-FU and Pt were given. One-year survival was 44%, 2-year survival 15%, and 3-year survival 8%. All 3-year survivors had tumor-free specimens, but one patient with tumor in the thorax and subdiaphragmatic metastasis survived 2 years.

Post-operative thoracic irradiation with or without levamisole in non-small cell lung cancer: results of a Radiation Therapy Oncology Group Study.

The Radiation Therapy Oncology Group conducted a Phase III single blind trial to evaluate the addition of Levamisole to post-operative thoracic irradiation (200 cGy five times weekly to a total of 5000 cGy plus 1000 cGy boost) in patients with resected RTOG Stage II-III non-small cell lung cancer with positive nodes. Between February 1980 and February 1983, 74 patients from 18 RTOG institutions were randomized; accrual to this study was prematurely terminated due to poor accrual and the inferior survival observed in the levamisole-treated patients on another RTOG trial. Sixty-four patients were evaluable; 32 assigned to levamisole and 32 were assigned to placebo. Over 95% of the patients have been followed for a minimum of 4 years or to death. Two patients on placebo and 5 on levamisole experienced Grade 3 pneumonitis or esophagitis; 1 patient on placebo and 2 on levamisole experienced Grade 3 pulmonary fibrosis. Three patients on levamisole experienced other Grade 3 or 4 toxicity: 1 case of intractable nausea and vomiting and 2 with Grade 4 neutropenia (less than 500 per mm3). There were no fatal complications. Median disease-free survival was 13 months in the placebo group and 9 months for the levamisole group. Median time to distant metastases was 18 and 12 months, and median survival was 20 and 13 months, respectively. We concluded that this study failed to demonstrate an advantage for levamisole.

Comparison of three treatment strategies for esophageal cancer within a single institution.

Fifty-seven patients with esophageal cancer were treated with curative intent between January 1979 and June 1985. Seventeen were treated with radical radiation therapy alone (TD 4000-6500 cGy in 200-250 cGy fractions). Twenty-five were treated using radiation therapy (3000 cGy in 200 cGy fractions, day 1-19, and 2600-3000 cGy in 200 cGy fractions, day 50-68) and concomitant chemotherapy (5-FU and Cis-platinum). Fifteen were treated preoperatively by radiation therapy (3000 cGy at 200 cGy fractions) and concomitant chemotherapy (5-FU and Cis-platinum) followed by esophagectomy in 2-3 weeks. Chi square tests showed no significant baseline differences between the patients in the three different treatment groups with respect to A.J.C. stage, T status, location of tumor or histology. Median survival and 2-year survival for the three treatment groups were RT alone: 5 months and 0%, RT and chemotherapy: 12 months and 37%, RT, chemotherapy and surgery 13 months and 38%. A Cox multivariate analysis revealed significant predictor variables for increased survival were treatment strategy, RT dose delivered and T status. Increased local control was seen with either multimodality approach compared to radiation therapy alone. Our data suggests that a multimodality approach is superior as a curative treatment strategy, compared to RT alone, in esophageal cancer. In our series no significant differences were seen with respect to treatment outcome between the two multimodality approaches used.

Combined therapies for squamous-cell carcinoma of the esophagus, a Southwest Oncology Group Study (SWOG-8037).

Conservative treatment of esophageal cancer with radiation therapy has afforded few long-term survivors. In order to improve outcome, patients with locoregional disease were treated using a combined modality approach. Patients were treated with chemotherapy consisting of a 96-hour continuous infusion of 5-fluorouracil (5-FU), 1,000 mg/m2/d, days 1 to 4 and days 29 to 32; cisplatin 75 mg/m2, day 1 and 29; and radiation 3,000 rad, days 1 to 19. In the absence of progressive disease, patients underwent esophagectomy. One hundred twenty-eight patients were registered of whom 113 were eligible and 106 were evaluable. Toxicity included gastrointestinal (GI) symptoms, mucositis, and myelosuppression. One hundred two patients completed chemoradiotherapy. Following its completion, 11 patients refused surgery, six were considered poor surgical risks, and 14 had progressive disease. Of the remaining 71 patients, 16 had unresectable disease, 13 had residual disease which was incompletely resected, 24 had disease which could be completely resected, and 18 were without disease on pathologic examination. The overall operability rate was 63% and the overall resectability rate, 49%. Surgical mortality was 11%. Eighty-nine of 113 eligible patients have died, with a median survival of 12 months and a 2-year survival of 28%. The median postsurgical survival for all 71 patients was 14 months and was 32 months for those patients attaining complete remission (CR). Combined modality therapy remains an investigational approach. Attempts should be directed at increasing response rate to initial therapy. A randomized comparison between combined modality treatment and radiation therapy is necessary to definitively determine the usefulness of this more aggressive approach.

Initial combination therapy with YAG laser photoresection and irradiation for inoperable non-small cell carcinoma of the lung. A preliminary report.

Patients presenting with inoperable non-small cell carcinoma of the lung and major symptomatic bronchial obstruction were treated initially with debulking of the airways by YAG laser, followed by conventional external-beam radiotherapy. The former method was used to minimize postobstructive pneumonitis or respiratory failure (or both) that often complicates major brochial obstruction and also to lessen the burden of tumor to be treated by radiotherapy. The preliminary results of 19 patients treated in this manner are reported, emphasizing the impact of this combined method on morbidity and mortality.

The response of atelectasis from lung cancer to radiation therapy.

Between January 1981 and June 1983, 33 newly diagnosed patients with lung cancer presented with radiological findings of atelectasis. These patients were treated by primary radiation therapy, with doses ranging from 1200 to 6000 cGy. The response of atelectasis to radiation therapy was established on the basis of follow-up chest roentgenograms. Of the 28 patients with non-small cell carcinoma of lung, there were 17 (61%) who had improvement of the atelectasis. Among these, 13 patients were treated with doses ranging from 5000 to 6000 cGy in 5 to 8 weeks; 9 of these (70%) responded. By histological subtype, the numbers, though small, show that three of eight patients with adenocarcinoma responded, as compared to 2 out of 4 with large cell undifferentiated carcinoma and 12 of 16 patients with squamous cell carcinoma. In patients treated by more than 5000 cGy, four of eight (50%) patients with squamous cell carcinoma had a complete response and three (37.5%) had a partial relief of atelectasis, for a total response of 87.5%. The study indicates the importance of radiation therapy in the management of atelectasis caused by primary lung cancer.

Hyperfractionation in the radiation therapy of unresectable non-oat cell carcinoma of the lung: preliminary report of a RTOG Pilot Study.

Patients with localized unresectable non-oat cell carcinoma of the lung were treated by supervoltage radiation therapy to the primary tumor, mediastinum and supraclavicular lymph nodes with 50.4 Gy, 42 fractions of 1.2 Gy, twice daily, 4 to 6 hours apart, 5 times a week. Small field treatment to the known involved areas of primary and lymph nodes was given from 9.6 to 24 Gy, also with 1.2 Gy, twice daily. One hundred twenty-five patients were entered, three of whom were cancelled and two were ineligible. Of the remaining 120 eligible patients, 10 patients received a dose of 50.4 Gy, 20 received 60.0 Gy, 79 received 69.6 Gy and 11 patients received 74.4 Gy. Of these, nine patients were unable to complete hyperfractionated radiation therapy for various reasons. Treatment was discontinued or stopped in 14 patients because of early death or deterioration of the patient's condition. Four additional patients were found to have unacceptable doses to tumor or normal tissues, for a total of 27 patients with protocol violations. Complete regression occurred in 19% of T1-T3, N0-N2 patients with 9% among T3.3b, T4 or N3 patients. Partial regression was 29 and 41%, respectively. There were six cases of severe and two of life-threatening toxicity, but there were no fatalities attributable to the treatment. Toxicity consisted mainly of pneumonitis and pulmonary fibrosis as well as esophagitis. Median survival of the entire group was 7.2 months, which is consistent with previous experience with the treatment of localized inoperable non-oat cell carcinoma of the lung by radiation therapy. Further study of this method of treatment is warranted.

Prophylactic versus no brain irradiation in regional small cell lung carcinoma.

Among 104 complete responders entered in a randomized prospective trial of treatments for regional small cell undifferentiated carcinoma of the lung, 52 received prophylactic irradiation of the brain, 3,000 rad in 10 fractions, and 52 did not. The median survivals were 53 and 52 weeks respectively, and the incidences of brain metastases were 5% and 20%. Prophylactic brain irradiation was not associated with significant long-term toxicity.

Cancer of the anal canal. Model for preoperative adjuvant combined modality therapy.

An analysis of preoperative multimodality adjuvant therapy with 5-fluorouracil, mitomycin-C, and radiation therapy revealed that 38 of 45 patients (84 percent) treated were rendered free of cancer after chemotherapy/radiation therapy. No recurrence of tumor has been noted in those patients rendered free of disease by the preoperative treatment. Seven patients (15 percent) with residual macroscopic or microscopic cancer after preoperative therapy have had recurrence, all in distant sites. These seven patients have died from the disease. The prognosis for patients in this series depended on the success of the preoperative therapy in eradicating all tumor prior to surgery. Mitomycin-C and 5-fluorouracil are cytotoxic for local disease and for microscopic distant disease as well. Abdomino-perineal resection is unnecessary for patients whose primary tumor is eradicated by the preoperative therapy. The role of the relatively low dose of radiation therapy needs to be further defined.

Preoperative chemotherapy and radiation therapy for patients with cancer of the esophagus: a potentially curative approach.

Twenty-one patients with squamous cell cancer of the esophagus were entered into a pilot clinical trial using preoperative chemotherapy (5-fluorouracil and cis-platinum) and radiation with the intent of improving cure rate and survival. After the preoperative treatment was complete, 15 patients (71%) were resected for cure. Seven (47%) of 15 had no histologic evidence of cancer in the resected esophagus, but two of these had microscopic cancer in resected lymph nodes. The median survival for all patients entered in the trial was 18 months, whereas for those with no cancer in the resected esophagus the median survival was 24 months. The six patients who either refused surgery (two patients) or were unresectable at surgery (four patients) died within nine months. Our conclusion in this trial is that survival and potential cure are clearly linked to successfully clearing the esophagus and nodes of histologic evidence of tumor through preoperative treatment.