Radiation Therapy Oncology Group (RTOG) 88-08 and Eastern Cooperative Oncology Group (ECOG) 4588: preliminary results of a phase III trial in regionally advanced, unresectable non-small-cell lung cancer.

BACKGROUND: Regionally advanced, surgically unresectable non-small-cell lung cancer represents a disease with an extremely poor prognosis. External-beam irradiation to the primary tumor and regional lymphatics is generally accepted as standard therapy. The use of more aggressive radiation regimens and the addition of cytotoxic chemotherapy to radiotherapy have yielded conflicting results. Recently, however, results from clinical trials using innovative irradiation delivery techniques or chemotherapy before irradiation have indicated that patients treated with protocols that incorporate these modifications may have higher survival rates than patients receiving standard radiation therapy. PURPOSE: On the basis of these results, the Radiation Therapy Oncology Group (RTOG)-Eastern Cooperative Oncology Group (ECOG) elected to conduct a phase III trial comparing the following regimens: 1) standard radiation therapy, 2) induction chemotherapy followed by standard radiation therapy, and 3) twice-daily radiation therapy. METHODS: Patients with surgically unresectable stage II, IIIA, or IIIB non-small-cell lung cancer were potential candidates. Staging was nonsurgical. Patients were required to have a Karnofsky performance status of 70 or more and weight loss less than 5% for 3 months prior to entry into the trial, to be older than 18 years of age, and to have no metastatic disease. Of the 490 patients registered in the trial, 452 were eligible. The disease in 95% of the patients was stage IIIA or IIIB. More than two thirds of the patients had a Karnofsky performance status of more than 80. Patients were randomly assigned to receive either 60 Gy of radiation therapy delivered at 2 Gy per fraction, 5 days a week, over a 6-week period (standard radiation therapy); induction chemotherapy consisting of cisplatin (100 mg/m2) on days 1 and 29 and 5 mg/m2 vinblastine per week for 5 consecutive weeks beginning on day 1 with cisplatin, followed by standard radiation therapy starting on day 50; or 69.6 Gy delivered at 1.2 Gy per fraction twice daily (hyperfractionated radiation therapy). RESULTS: Toxicity was acceptable, with four treatment-related deaths. Three patients subsequently died of chronic pulmonary complications. Compliance with protocol treatment was acceptable. One-year survival (%) and median survival (months) were as follows: standard radiation therapy--46%, 11.4 months; chemotherapy plus radiotherapy--60%, 13.8 months; and hyperfractionated radiation therapy--51%, 12.3 months. The chemotherapy plus radiotherapy arm was statistically superior to the other two treatment arms (logrank P = .03). CONCLUSIONS: In "good-risk" patients with surgically unresectable non-small-cell lung cancer, induction chemotherapy followed by irradiation was superior to hyperfractionated radiation therapy or standard radiation therapy alone, yielding a statistically significant short-term survival advantage.

A randomized phase I/II trial of hyperfractionated radiation therapy with total doses of 60.0 Gy to 79.2 Gy: possible survival benefit with greater than or equal to 69.6 Gy in favorable patients with Radiation Therapy Oncology Group stage III non-small-cell lung carcinoma: report of Radiation Therapy Oncology Group 83-11.

A phase Ilate/II trial of hyperfractionated (HFX) radiation therapy for non-small-cell carcinoma of the lung (NSCCL) was conducted by the Radiation Therapy Oncology Group (RTOG) between 1983 and 1987. Fractions of 1.2 Gy were administered twice daily with greater than or equal to 4 hours between fractions. Patients were randomized to receive minimum total doses of 60.0, 64.8, and 69.6 Gy. After acceptable risks of acute and late effects were found, 74.4 Gy and 79.2 Gy arms were added, and the lowest total dose arms were closed. No significant differences in the risks of acute or late effects in normal tissues were found among the 848 patients analyzed in the five arms; risks of severe or life-threatening pneumonitis were 2.6% for 60.0 to 64.8 Gy, 5.7% for 69.6 to 74.4 Gy, and 8.1% for 79.2 Gy. Among 350 patients who had the same criteria as Cancer and Leukemia Group B (CALGB) protocol 84-33 (American Joint Committee on Cancer Staging [AJCCS], 1984, stage III; Karnofsky performance status [KPS] 70 to 100; less than 6% weight loss), there was a dose response for survival: survival with 69.6 Gy (median, 13.0 months; 2 years, 29%) was significantly (P = .02) better than the lower total doses. There were no differences in survival among the three highest total-dose arms. Comparisons with results in similar patients treated with 60 Gy in 30 fractions of 2.0 Gy 5 days per week for 6 weeks suggest benefit from HFX radiation therapy with 69.6 Gy. Improvement in survival with HFX radiation therapy at 69.6 Gy total dose without increase in normal tissue effects, justifies phase III comparison with standard fractionation alone and combined with systemic chemotherapy in this common presentation of NSCCL.

Concurrent chemoradiation therapy with oral etoposide and cisplatin for locally advanced inoperable non-small-cell lung cancer: radiation therapy oncology group protocol 91-06.

PURPOSE: Patients with locally advanced inoperable non-small-cell lung cancer (NSCLC) have a poor clinical outcome. We conducted a prospective study to evaluate the merit of chemotherapy administered concurrently with hyperfractionated thoracic radiation therapy. PATIENTS AND METHODS: Seventy-nine patients with inoperable NSCLC were enrolled onto a multicenter phase II trial of concurrent chemoradiation therapy. Treatment consisted of two cycles of oral etoposide 100 mg/d (50 mg/d if body-surface area [BSA] < 1.70 m2), intravenous cisplatin 50 mg/m2 on days 1 and 8, and hyperfractionated radiation therapy 5 days per week (1.2 Gy twice daily > 6 hours apart; total 69.6 Gy). RESULTS: Seventy-six assessable patients with a Karnofsky performance status > or = 60 and adequate organ function who had received no prior therapy were evaluated for clinical outcome and toxic effects. After a minimum follow-up duration of 21 months, the 1- and 2-year survival rates and the median survival duration were 67%, 35%, and 18.9 months overall; they were 70%, 42%, and 21.1 months for patients with weight loss of < or = 5%. Toxicity was significant; 57% developed grade 4 hematologic toxicity, 53% grade 3 or 4 esophagitis, and 25% grade 3 or 4 lung toxicity. However, only 6.6% of patients had grade 4 or lethal nonhematologic toxicity, which included three treatment-related deaths (two of pneumonitis and one of renal failure). CONCLUSION: Concurrent chemoradiation therapy with oral etoposide and cisplatin plus hyperfractionated radiation therapy is feasible. The survival outcome from this regimen compares favorably with that of other chemoradiation trials and even of multimodality trials that have included surgery.

Phase III trial of androgen suppression using goserelin in unfavorable-prognosis carcinoma of the prostate treated with definitive radiotherapy: report of Radiation Therapy Oncology Group Protocol 85-31.

PURPOSE: Although androgen suppression results in a tumor response/remission in the majority of patients with carcinoma of the prostate, its potential value as an adjuvant has not been substantiated. MATERIALS AND METHODS: In 1987, the Radiation Therapy Oncology Group (RTOG) initiated a randomized phase III trial of adjuvant goserelin in definitively irradiated patients with carcinoma of the prostate. A total of 977 patients had been accessioned to the study. Of these, 945 remained analyzable: 477 on the adjuvant arm and 468 on the observation arm. RESULTS: Actuarial projections show that at 5 years, 84% of patients on the adjuvant goserelin arm and 71% on the observation arm remain without evidence of local recurrence (P < .0001). The corresponding figures for freedom from distant metastases and disease-free survival are 83% versus 70% (P < .001) and 60% and 44% (P < .0001). If prostate-specific antigen (PSA) level greater than 1.5 ng is included as a failure (after > or = 1 year), the 5-year disease-free survival rate on the adjuvant goserelin arm is 53% versus 20% on the observation arm (P < .0001). The 5-year survival rate (for the entire population) is 75% on the adjuvant arm versus 71% on the observation arm (P = .52). However, in patients with centrally reviewed tumors with a Gleason score of 8 to 10, the difference in actuarial 5-year survival (66% on the adjuvant goserelin arm v 55% on the observation arm) reaches statistical significance (P = .03). CONCLUSION: Application of androgen suppression as an adjuvant to definitive radiotherapy has been associated with a highly significant improvement in local control and freedom from disease progression. At this point, with a median follow-up time of 4.5 years, a significant improvement in survival has been observed only in patients with centrally reviewed tumors with a Gleason score of 8 to 10.

Radiation-related pericardial effusions in patients with Hodgkin's disease.

Pericardial effusions following radiotherapy for Hodgkins Disease have previously been described as infrequent and related to the total dose of radiation received. Analysis of all chest x-rays on 81 patients who received upper-mantle radiotherapy for Hodgkins Disease at the Baltimore Cancer Research Center between 1968 and 1972 disclosed an incidence of pericardial effusions of 30.9% (25 of 81), with 13.6% (11 of 81) requiring limitation of activity (5) or pericardiectomy (6). Clinical presentation of radiation-related percardial effusions was subtle, with signs and symptoms a late finding if they occurred. Radiotherapy data was reviewed and no difference in total dose (rads) or time-dose relationships (rets) was found between the groups who did or did not develop effusions. Analysis of multiple pre-treatment clinical and pathological characteristics disclosed four parameters that were felt to be related to the development of pericardial effusions; elevated ESR, normal absolute lymphocyte count, initial presence of extensive mediastinal adenopathy and the addition of adjuvant chemotherapy. The presence of increasing combinations of these pretreatment 'risk factors' led to an increasing likelihood of developing a radiation-related pericardial effusion such that six of seven patients with all four 'risk factors' developed a pericardial effusion. Nine of 13 clinically significant effusions were associated with the addition of adjuvant chemotherapy. Possible pathogenetic mechanisms that include factors other than radiation dosage and the clinical management of radiation-related pericardial effusions are discussed.

Recombinant human interferon-beta (rHuIFN-beta) and radiation therapy for inoperable non-small cell lung cancer.

Fifteen patients with stage II, IIIA, and IIIB non-small cell lung cancer (NSCLC) received subcutaneous (s.c.) recombinant, glycosylated, human interferon-beta 1a (Rebif; rHuIFN-beta 1a) on each day of conventionally fractionated radiation therapy (RT) given in 2.0 Gy fractions to 60 Gy in 6 weeks. The rHuIFN-beta 1a was generated in CHO cells by recombinant DNA technology and is identical to natural IFN-beta produced by fibroblasts in primary sequence and glycosylation. Cohorts of three patients each were treated with escalating doses of rHuIFN-beta 1a: 1.5, 3, 6, 12, and 24 MIU/m2 per treatment day. Acute toxicity was assessed according to modified WHO criteria; late toxicity was graded using RTOG late toxicity criteria. The maximum tolerated dose (MTD) of rHuIFN-beta 1a was defined as the dose level immediately below that in which dose-limiting toxicity occurred in > or = two of six patients. Immunomodulatory effects and antigenicity of rHuIFN-beta 1a were assessed by 2-5A synthetase, beta 2-microglobulin, and neopterin levels and by measurement of anti-rHuIFN-beta antibodies, respectively. Fourteen of fifteen patients experienced grades 1-3 acute (early) toxicity (< or = 90 days), which was primarily gastrointestinal: dysphagia/esophagitis (14/15), nausea/vomiting (12/15), anorexia (7/15), and liver transaminasemia (6/15). One of three patients treated with 24 MIU/m2 per treatment day (total rHuIFN-beta 1a dose 672 MIU) died of complications secondary to pneumonia, sepsis, adult respiratory distress syndrome (ARDS), and radiation pneumonitis. Twelve patients were evaluable for late toxicity (> 90 days). Maximum toxicity was grade 0 in five patients, grade 1 in four patients, and grade 5 in one patient (radiation pneumonitis). Clinical responses from the combination were 1/15 CR, 6/15 PR, 6/15 stable disease, and 1/15 progressive disease. The MTD of rHuIFN-beta 1a has been estimated at 12 MIU/m2 per treatment day when given daily during conventional RT to 60 Gy in 6 weeks. Biologic response by rHuIFN-beta 1a alone was reflected by significant and dose-related increases in 2-5A synthetase, beta 2-microglobulin, and neopterin. Radiation therapy alone had no effect on these immune response parameters and did not diminish their augmentation by rHuIFN-beta 1a. There was no association of biologic modulation with clinical response or survival.

The evolution of Radiation Therapy Oncology Group (RTOG) protocols for nonsmall cell lung cancer.

Over the past 2 decades, the Radiation Therapy Oncology Group (RTOG) has played a significant role in clarifying the role of radiation therapy (RT) in the treatment of nonsmall cell lung cancer (NSCLC). RTOG lung cancer research has evolved over this time period through a systematic succession of investigations. For unresectable NSCLC, the dependence of local tumor control and survival on total dose of standard fractionation RT, as well as pretreatment performance characteristics, was demonstrated in initial RTOG trials. Subsequently, further radiation dose intensification was tested using altered fractionation RT to total doses up to 32% higher than standard RT to 60 Gy, given as either hyperfractionation or accelerated fractionation, while attempting to retain acceptable normal tissue toxicity. These higher doses required rethinking of established RT techniques and limitations, as well as careful surveillance of acute and late toxicity. A survival advantage was shown for hyperfractionation to 69.6 Gy, in favorable performance patients, compared to 60 Gy. Further testing of high dose standard RT will use three-dimensional, conformal techniques to minimize toxicity. RTOG further extended the theme of treatment intensification for unresectable NSCLC by evaluating combined chemotherapy (CT) and RT. Improved local control and survival was shown for induction CT followed by standard RT to 60 Gy, compared to standard RT (60 Gy) and altered fractionation RT (69.6 Gy). The intent of current studies is to optimize dose and scheduling of combined CT and standard RT, as well as combined CT and altered fractionation RT. Noncytotoxic RT adjuvants, such as hypoxic cell sensitizers, nonspecific immune stimulants, and biologic response modifiers have also been studied. Resectable NSCLC has also been an RTOG focus, with studies of preoperative and postoperative RT, CT, and CT/RT, including the prognostic value of serum and tissue factors. RTOG studies have yielded incremental improvements in treatment outcome for NSCLC, better understanding of the disease dynamics, and a strong foundation for future investigations.

The association of adult respiratory distress syndrome (ARDS) with thoracic irradiation (RT).

The authors report two cases of apparent adult respiratory distress syndrome (ARDS) following limited thoracic irradiation for lung cancer. Respiratory failure followed rapidly after irradiation with diffuse bilateral infiltrates, both in and out of the irradiated volume along with progressive hypoxemia unresponsive to oxygen management. Other potential causes of lung injury such as lymphangitic tumor, cardiac failure, and infections were excluded by both premortem and postmortem examination. Autopsy findings in both irradiated and unirradiated volumes of lung were consistent with hyaline membrane changes. The possible relationship between radiation therapy to limited lung volumes and the development of adult respiratory distress syndrome is discussed.

Prognostic influence of TNM staging and LDH levels in small cell carcinoma of the lung (SCCL).

To better define the prognostic factors influencing the response to therapy and survival in small cell carcinoma of the lung (SCCL), an expanded "TNM" type staging system was developed and investigated in a series of 73 protocol treated patients. Because serum LDH levels at disease presentation have been correlated to disease extent, response to therapy, and treatment outcome in a number of malignancies, including SCCL, these interrelationships were also analyzed in the protocol patients. The TNM system was found to be a more descriptive and specific "shorthand" for denoting sites of involvement and for indicating the body burden of tumor than the traditional limited-extensive disease (LD-ED) system. A clear statistical advantage could not be shown over the LD-ED system for predicting chemotherapy response or survival, although there were trends suggesting the TNM system could divide patients into three prognostic subgroups. Serum LDH proved to be a useful index of disease extent and therapy outcome. LDH levels at presentation were proportionately higher with more extensive tumor, measured by either the LD-ED or TNM staging. High LDH predicted poorer responses to chemotherapy and lower survival within similar stage subgroups compared to patients with normal LDH levels. The negative effect of elevated LDH was independent of hepatic involvement and did not predict subsequent hepatic failure in any consistent way. The SCCL TNM staging system proposed needs further refinement and should be tested with larger patient numbers. LDH, along with other tumor markers recently identified, need to be integrated into the staging system to form an overall prognostic index.

A phase I/II study to evaluate accelerated fractionation via concomitant boost for squamous, adeno, and large cell carcinoma of the lung: report of Radiation Therapy Oncology Group 84-07.

PURPOSE: A Phase I/II trial was conducted by the Radiation Therapy Oncology Group from 1984 to 1989 for 355 evaluable patients with non-small-cell lung cancer to assess tolerance to and efficacy of accelerated fractionation irradiation via concomitant boost. METHODS AND MATERIALS: "Large" fields (primary tumor and locoregional lymph nodes) received 1.8 Gy followed after 4 to 6 hr by 1.8 Gy two to three times weekly to reduced "boost" fields (primary and involved nodes only). The total doses escalated during the study and started with 63 Gy in 5 weeks (45 Gy "large" field and 18 Gy "boost") for 61 patients. After follow-up for ongoing toxicity assessment, the total dose was increased to 70.2 Gy in 5.5 weeks (50.4 Gy "large" field and 19.8 Gy "boost") for the next 180 patients. The last 114 patients received 70.2 Gy in 5 weeks (45 Gy "large" field and 25.2 Gy "boost"). RESULTS: Pretreatment patient characteristics were well balanced between the three treatment arms. Grade 3 acute toxicity was 7% for the 63 Gy arm; it was 14% and 17% for the two 70 Gy arms. Grade 4 or greater acute toxicities (esophagitis and pneumonitis) were 2 to 3% for all three arms. Late toxicities ranged between 5 and 9% (> or = Grade 3) and 0 to 2% (> or = Grade 4), not statistically different among the three arms. There was no difference between the three regimens in median survival (9 months) or 1-year survival (39 to 44%). However, the 2-year survivals ranged from 16% (63 Gy) to 21% ("shortened" 70.2 Gy). Among 176 patients who had the same criteria as Cancer and Leukemia Group B protocol 84-33 (American Joint Committee on Cancer Staging, 1984, Stage III; Karnofsky performance status 70 to 100; < 6% weight loss), the 2-year survival rates ranged from 18 to 22%. CONCLUSION: Concomitant boost accelerated fractionation irradiation regimens for non-small cell lung cancer may offer improved long-term survival without enhanced late toxicity. While acute toxicity is somewhat increased, further refinement of the relationship of "large" to "boost" field doses may improve the therapeutic ratio. Further Phase I/II testing seems justified and necessary, before concomitant boost accelerated fractionation irradiation is tested in Phase III trials for NSCLC.

The influence of field size and other treatment factors on pulmonary toxicity following hyperfractionated irradiation for inoperable non-small cell lung cancer (NSCLC)--analysis of a Radiation Therapy Oncology Group (RTOG) protocol.

PURPOSE: The risk of pulmonary toxicity, observed in an Radiation Therapy Oncology Group Phase I/II randomized dose escalation trial of hyperfractionated irradiation for nonsmall cell lung cancer, was analyzed with regard to custom vs. hand blocking and compliance to protocol specified treatment field parameters. MATERIALS AND METHODS: There were 832 evaluable cases analyzed. The protocol required field margins 2 cm beyond primary tumor and involved nodes. In 674, the field margins were considered "per protocol" or as having minor protocol variations. In 94, margins exceeded protocol specification ("excessive margin" group). In this group, the area (cm2) of the effective (blocked) field and the portion including lung was measured from simulator films with a computer scanning device. Based on size and location of the primary and nodal disease, "per protocol" fields were constructed and the area (cm2) of lung included beyond these margins was estimated. Patients from both groups who received less than 30 Gy to normal lung were excluded from analysis of pulmonary toxicity. RESULTS: Grade 1 acute lung toxicity was higher (p = .009) in the "excessive margin" group compared to the "per protocol" group, whereas late lung toxicity was not significantly different (p = .94). The risk of Grade 2 or greater acute toxicity increased as area of excess irradiated lung increased. Overall lung toxicity, defined as the greater of either acute or late toxicity, was evaluated by multivariate analysis, in relation to assigned dose, effective treated field area, and type of shielding. Overall maximum lung toxicity (> or = Grade 2) was significantly greater in the "excessive margin" group, when lung treated beyond protocol margins exceeded an area of 35 cm2, than in the "per protocol" group, but only when the effective treated field size was > or = 180 cm2 (68% vs. 37%; p = .02). This effect was independent of assigned total dose or type of shielding. CONCLUSION: For nonsmall cell lung cancer treated with hyperfractionated irradiation, the risk of overall pulmonary toxicity was increased for patients treated with field sizes in excess of protocol specified margins of tumor coverage in comparison to patients treated with protocol specified margins. This effect was seen only when the area of lung treated beyond protocol margins exceeded 35 cm2 and when the overall field size was below 180 cm2.

N2 (clinical) non-small cell carcinoma of the lung: prospective trials of radiation therapy with total doses 60 Gy by the Radiation Therapy Oncology Group.

Clinical Stage III (N2) non-small cell carcinoma of the lung encompasses a large group of patients, frequently treated with radiation therapy alone, who are now considered to have borderline-resectable tumors. Pilot studies are proceeding which use combinations of resection, radiation therapy, and chemotherapy. To place trials of combination therapy in perspective with contemporary results of radiation therapy alone, recently completed trials of the RTOG were analyzed specifically for clinical Stages T1-3N2. A prospective randomized trial of hyperfractionated radiation therapy (HFX), conducted from 1983 through 1987, compared total doses of 60.0, 64.8, and 69.6 Gy using 1.2 Gy bid with greater than or equal to 4 hr interval. After acute and late effects were considered tolerable, 74.4 Gy and 79.2 Gy arms supplanted the two lowest dose arms. Survival was compared among the five total dose arms, and with 60 Gy in 30 fractions in 6 weeks (standard fractionation-STD) from earlier RTOG studies. Of 516 HFX patients analyzed, 296 (57.3%) with Performance Status (PS) 70-100 and less than 5% weight loss (favorable) had a significantly (p = .001) better survival than those with PS 50-69 or weight loss greater than 5%. Patients with RTOG Stage III (361, 70.0%) experienced better survival (p = .027) than RTOG Stage IV M0. The 69.6 Gy total dose arm was significantly (p = .031) better in favorable RTOG Stage III patients than all other total dose arms: the 1-year survival rate was 58% and the 3-year rate was 20%. The 69.6 Gy HFX results were significantly (p = .002) better than results with STD fractionation in comparable patients from earlier RTOG trials (1-year survival = 30%, 3-year survival = 7%). A prospective, randomized Phase III comparison of STD with 60 Gy versus HFX with 69.6 Gy is underway. These results provide benchmarks for studies of surgical resection combined with chemotherapy and/or radiation therapy until results of prospective comparisons with concurrent controls are available.

Computed tomography in the staging of small cell lung cancer: implications for combined modality therapy.

Computed tomography of the thorax and abdomen, from the thoracic inlet to the renal hila, was performed as part of initial staging in 51 patients with small cell carcinoma of the lung (SCCL). The computed tomographic (CT) scans were repeated after completion of chemotherapy, as part of routine restaging and assessment of response to therapy. To identify the ways in which CT scanning uniquely benefited evaluation of initial disease extent in comparison to other diagnostic studies exclusive of CT scan, all diagnostic and clinical data were reviewed. CT scan identified more advanced intrathoracic disease than chest radiography in 82% of patients. Mediastinal node involvement not appreciated by chest radiography was seen in 61% of patients. Adrenal and retroperitoneal node involvement, not suspected by other studies, was identified by CT scan in 31% and 12% of patients, respectively. Thirty percent of the patients staged as limited disease (LD) were advanced to extensive disease (ED) by CT scan findings. While confirmation, by biopsy, of positive CT findings was not consistently accomplished, restaging CT scans provided indirect confirmation by displaying improvement or worsening that correlated with disease regression or progression. Thoraco-abdominal CT scanning more accurately identifies the extent of small cell carcinoma than other imaging procedures. This has important implications for reporting results by extent of disease. In addition, CT more accurately identifies the magnitude of intrathoracic primary and nodal tumors, which may influence the choice and conduct of local treatment--surgery and/or radiation therapy--in combination with systemic chemotherapy.

The role of consolidation irradiation in combined modality therapy of small cell carcinoma of the lung.

Forty-four patients with small cell carcinoma of the lung (SCCL) were treated with a program of combined chemotherapy and radiation therapy. Prophylactic cranial irradiation was given concurrent with the first of six planned cycles of chemotherapy consisting of Cyclophosphamide, Adriamycin, Vincristine and high dose Methotrexate (CAV-M). All patients judged as complete responders (CR) received consolidative thoracic irradiation (CTI) to the locoregional primary lung involvement. The CR rate to chemotherapy alone was 84% for patients with limited disease (LD) and 44% for extensive disease. In comparison to a prior trial, which used similar chemotherapy, but with irradiation withheld until primary site relapse, the actuarial primary site relapse rate at 2 years was reduced by CTI from 92% to 18% (P less than .01). The median primary site remission duration has not yet been reached in the CTI group and was 34 weeks without CTI (P less than .01). CTI increased the 2 year actuarial survival from 6% to 66% (P less than .01) in the chemotherapy CR patients. Median survival has not yet been reached in the CTI group, but was 48 weeks without CTI (P less than .01). Leptomeningeal spinal cord relapse in patients with no prior central nervous system (CNS) involvement occurred in 16% of patients relapsing.

Integration of chemotherapy and radiation therapy for small cell carcinoma of the lung.

Two chemotherapy trials using cyclophosphamide, doxorubicin hydrochloride and high-dose vincristine sulfate with or without methotrexate have induced a 93% incidence of complete remission in limited disease presentation of small cell bronchogenic carcinoma of the lung and 39% incidence in extensive disease. The first trial without consolidation radiotherapy had a local failure rate of 65%, which dropped to 17% with consolidation radiotherapy to the primary and mediastinum. Prophylactic whole brain radiotherapy prevented local recurrence in 98% of evaluable patients. One carcinomatous meningitis and 5 intraspinal recurrences were noted among the 38 patients in the CAV-M trial. We conclude that high-dose vincristine sulfate is associated with an improved incidence of complete remission; that prophylactic whole brain radiotherapy has been highly successful; that prevention of intraspinal recurrence will necessitate the use of craniospinal axis radiation therapy and consolidation radiation therapy improves local control of primary and mediastinum.

Development of a rat lung cancer model.

A rat lung cancer model based on intrabronchial instillation of a tumor cell suspension has been developed for use in therapy and toxicity testing. Two tumors were used in this study, a sarcoma and an adenocarcinoma, both of which were of spontaneous origin in the strain of rats used. The inoculated tumor cells implant on the bronchiolar mucosa, forming a detectable single "primary" tumor resembling the spontaneous lung cancers arising in humans. The tumor growth is detectable by use of diagnostic radiographs, weight loss and other "clinical" signs. The tumors appear on chest radiographs 3 to 5 weeks after inoculation, and the implant rate is proportional to the number of tumor cells inoculated. Untreated animals have a median survival (after radiographic detection of the tumor) of 8 days, and die of local complications of tumor growth. When a slow growing transplantable tumor line of lung origin is developed, this model will be used to evaluate radiotherapy and chemotherapy schedules.

Is prolonged survival possible for patients with supraclavicular node metastases in non-small cell lung cancer treated with chemoradiotherapy?: Analysis of the Radiation Therapy Oncology Group experience.

PURPOSE: To determine if patients with non-small cell lung carcinoma (NSCLC) and positive supraclavicular nodes (SN+) have a similar outcome to other patients with Stage IIIB NSCLC (SN-) when treated with modern chemoradiotherapy. METHODS AND MATERIALS: Using the Radiation Therapy Oncology Group (RTOG) database, data were retrospectively analyzed from five RTOG trials studying chemoradiotherapy for NSCLC: 88-04, 88-08 (chemo-RT arm), 90-15, 91-06, 92-04. Comparisons were made between the SN+ and SN- subgroups with respect to overall survival, progression-free survival (PFS), and metastases-free survival (MFS) using the log rank test. Cox multivariate proportional hazards regression analysis was used to determine the effect of several potential confounding variables, including histology (squamous vs. nonsquamous), age (>60 vs. < or = 60), Karnofsky Performance Status (KPS) (<90 vs. > or = 90), weight loss (> or = 5% vs. <5%), and gender. RESULTS: A total of 256 Stage IIIB patients were identified, of whom 47 had supraclavicular nodes (SN+) and 209 did not (SN-). Statistically significantly more SN+ patients had nonsquamous histology (p = 0.05); otherwise, known prognostic factors were well balanced. The median survival for SN+ patients was 16.2 months, vs. 15.6 months for SN- patients. The 4-year actuarial survival rates were 21% and 16% for SN+ and SN- patients respectively (p = 0.44). There was no statistically significant difference in the 4-year PFS rates (19% vs. 14%, p = 0.48). The Cox analysis did not show the presence or absence of supraclavicular nodal disease to be a prognostic factor for survival, MFS, or PFS. The only statistically significant factor on multivariate analysis was gender, with males having a 40% greater risk of mortality than females (p = 0.03). There were no clinically significant differences in toxicity when comparing SN+ vs. SN- patients. Among the 47 SN+ patients, there were no reported cases of brachial plexopathy or other > or = Grade 2 late neurologic toxicity. CONCLUSIONS: When treated with modern chemoradiotherapy, the outcome for patients with supraclavicular metastases appears to be similar to that of other Stage IIIB patients. SN+ patients should continue to be enrolled in trials studying aggressive chemoradiotherapy regimens for locally advanced NSCLC.

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.

Is adenocarcinoma/large cell carcinoma the most radiocurable type of cancer of the lung?

Radiation therapy is widely considered the primary treatment for inoperable "non-small" cell carcinoma of the lung. In clinical investigations, distinction has been infrequent among the histopathologic subtypes of non-small cell carcinoma. Studies have shown significant differences between squamous cell carcinoma and adenocarcinoma/large cell carcinoma; adenocarcinoma/large cell carcinoma has a greater propensity for extrathoracic dissemination, especially to the brain, and it is less curable by resection when regional lymph node metastases are present. No differences have been documented between adenocarcinoma and large cell carcinoma. A retrospective study was undertaken to determine the results of definitive radiation therapy by histopathologic subtype of non-small cell carcinoma of the lung. Between July 1977 and April 1983, 134 patients with non-small cell carcinoma of the lung underwent definitive radiation therapy with curative intent. All patients had performance status scores of 80 to 100 (Karnofsky), and received minimum total doses within the tumor of 60 Gy in 6 to 7 weeks, five fractions per week. The median period of observation was 63 months. Ninety patients had squamous cell carcinoma; 44 had adenocarcinoma/large cell carcinoma. The two groups of patients were comparable in respect to age and Stage; there were significantly more women with adenocarcinoma/large cell carcinoma (27%) than with squamous cell carcinoma (13%). The median survival for patients with squamous cell carcinoma was 11.5 months; the 2 and 4 year survival rates were 21 and 7%, respectively. The median survival for patients with adenocarcinoma/large cell carcinoma was 18 months; 2 and 4 year survival rates were 38 and 23%, respectively. Comparison of the overall survival experience did not show a significant difference between the two cell types (p = .12 using Gehan's generalized Wilcoxon test). However, comparison of the proportion of patients with adenocarcinoma/large cell carcinoma surviving 18 months (50%) was significantly higher (p = .02) than that with squamous cell carcinoma (30%). A small body of data from the literature also suggests a better long-term prognosis for adenocarcinoma/large cell carcinoma. This observation requires confirmation from large trials with histopathologic review. If it is confirmed, there are important implications for therapeutic strategies in future clinical investigations of inoperable carcinoma of the lung.

Interruptions of high-dose radiation therapy decrease long-term survival of favorable patients with unresectable non-small cell carcinoma of the lung: analysis of 1244 cases from 3 Radiation Therapy Oncology Group (RTOG) trials.

PURPOSE: To determine if prolonged treatment time adversely affects survival for patients with inoperable non-small cell carcinoma of the lung. METHODS AND MATERIALS: Patients enrolled on three randomized studies (RTOG 8311, 8321, 8403) between 1983-1989 formed the database. Previous analyses found that the addition of thymosin (8321) or prophylactic cranial irradiation (8403) failed to prolong survival: both studies used thoracic irradiation with standard fractionation to 55-60 Gy in 30 fractions. In 8311, patients were treated by hyperfractionated radiation therapy to randomly assigned total doses of 60.0 Gy, 64.8 Gy, 69.6 Gy, 74.4 Gy or 79.2 Gy, 1.2 Gy twice daily, 5 days per week. Patients analyzed received +/- 4% of the assigned total dose and lived > 90 days (to ensure that all patients would have completed treatment). Completion < 5 days beyond protocol specifications was classified as "per protocol." Elapsed treatment time exceeding specifications by 5-9 days was a minor deviation, 10-13 days was a major deviation-acceptable, and > or = 14 days was a major deviation-unacceptable. Absolute survival was the endpoint to evaluate the effect of delays. The log rank statistic was used to test for survival differences in the univariate setting, the Cox regression model was used in the multivariate setting. RESULTS: Of 293 patients treated with standard fractionation, eight (2.7%) had deviations from the specified treatment time (six minor, two major-acceptable). With hyperfractionation, 90 (15%) patients had deviations (40 minor, 21 major-acceptable, 29 major-unacceptable). As the assigned dose increased, the deviation rate increased (9.7% for 60.0 Gy vs. 20.8% for 79.2 Gy). Survivals for hyperfractionation patients with any deviations in treatment time were significantly shorter than those treated "per protocol" (p = 0.16): estimated 2- and 5-years rates were 24% and 10% versus 13% and 3%, respectively. Multivariate analyses showed the delay effect to be entirely in patients treated with 69.6 Gy or higher; there was also dependence upon the patients' prognosis. In patients with favorable prognosis (KPS 90-100, weight loss < or = 5%, no N3), the difference in survival was pronounced (33% and 15% vs. 14% and 0% at 2- and 5-years, respectively). Such differences were not found in patients with unfavorable prognostic factors. CONCLUSIONS: Interruptions delaying completion of planned radiation therapy were more frequent with higher total doses (> or = 69.6 Gy). Favorable patients (high KPS, little weight loss, < N3 nodal metastasis) had markedly adverse effects on long-term survival associated with delays to completion of the planned total dose.