Joseph P. Concannon

Impact of irradiation technique and tumor extent in tumor control and survival of patients with unresectable non-oat cell carcinoma of the lung. Report by the radiation therapy oncology group

An analysis of intrathoracic tumor control was carried out in 378 patients with histologically proven unresectable non‐oat cell carcinoma of the lung treated with definitive radiotherapy, randomized to one of four treatment regimens: 4000 rad split course (2000 rad in five fractions in one week, two weeks rest and additional 2000 rad in five fractions in one week) or 4000, 5000 or 6000 rad continuous courses, five fractions per week. Between 85 and 101 patients are analyzed in each treatment group. The complete plus partial response was 46–51% in the 4000 rad groups in contrast to 61–66% in the 5000 to 6000 rad groups (P = 0.008). The overall two year survival rate was 10–11% for the patients treated with 4000 rad split or continuous course, and 19% in the patients treated with 5000 to 6000 rad. The complete response in patients with tumors 3 cm or less in diameter was 16% when treated with 4000 rad in contrast to 20–31% in those treated with 5000–6000 rad. In the patients with lesions from 4 to 6 cm in diameter, complete and partial tumor regression was 48% in the 4000 rad group, 67% with 5000 rad, and 71% with 6000 rad. These differences are statistically significant (P = 0.033). Intrathoracic recurrences were correlated with the dose of irradiation given: 52% with 4000 rad, 41% with 5000 rad, and 30% with 6000 rad (P = 0.006). An analysis of protocol compliance was carried out in 301 patients with available data, irradiated at the primary site according to protocol instruction (none or minor variation). Median survival for patients treated to the ipsilateral or contralateral hilar lymph nodes according to the protocol varied from 46–50 weeks in contrast to 20–30 weeks for those with major protocol variations in nodal irradiation. Variations in ipsilateral and contralateral nodal irradiation correlated with significant reductions in tumor control (P = 0.02 and P = 0.009, respectively). In addition to patient and tumor characteristics, the technical factors of irradiation are critical parameters that affect tumor control and survival in patients with non‐oat cell bronchogenic carcinoma. Strict quality assurance criteria in radiotherapy are necessary to achieve optimal treatment results and a careful program to evaluate techniques of irradiation and protocol compliance should be maintained in cooperative group studies in order to enhance the validity of clinical trials.

A prospective randomized study of various irradiation doses and fractionation schedules in the treatment of inoperable non-oat-cell carcinoma of the lung. Preliminary report by the radiation therapy oncology group

Preliminary analysis is presented of a prospective randomized study involving 365 patients with histologically proven unresectable non‐oat‐cell carcinoma of the lung treated with definitive radiotherapy. The patients were randomized to one of four treatment regimens: 4000 rad split course (2000 rad in five fractions one week, two weeks rest, and an additional 2000 rad in five fractions in one week) or 4000, 5000, or 6000‐rad continuous courses in five fractions per week. Ninety to 100 patients were accessioned to each group. The one‐year survival rate is 50% and the two‐year survival rate, 25%. The patients treated with the split course have the lowest survival rate (10% at two years) in comparison with the other groups (range = 20–25%). The complete and partial local regression of tumor was 49% in patients treated with 4000 rad and 55% in the groups treated with 5000 and 6000 rad. For patients who achieved complete regression of the tumor following irradiation, the two‐year survival rate is 40%, in contrast to 20% for those with partial regression, and no survivors among the patients with stable or progressive disease. The incidence of intrathoracic recurrence was 33% for patients treated with 6000 rad, 39% for those receiving 5000 rad, and 44–49% for those treated with a 4000‐rad split or continuous course. At present, the data strongly suggest that patients treated with 5000 or 6000 rad have a better response, tumor control, and survival rate than those receiving lower doses. However, additional followup of patients at risk in each group will be necessary before a final conclusion is drawn. Patients with high performance status (Kornofsky index higher than 70), or with tumors in earlier stages (T1N2 or T3N0) have a two‐year survival rate of approximately 40%, in comparison with 20% for other patients. The various irradiation regimens have been well tolerated, with complications being slightly higher in the 4000‐rad split course group (10 severe and 2 life‐threatening) and in the 6000‐rad continuous course group (9 severe and 4 life‐threatening). The most frequent complications have been pneumonitis, pulmonary fibrosis, and dysphagia due to transient esophagitis. Further investigation will be necessary before the optimal management of patients with bronchogenic carcinoma by irradiation is established.

Prognostic value of preoperative carcinoembryonic antigen (CEA) plasma levels in patients with bronchogenic carcinoma

Preoperative plasma CEA levels were measured by radioimmunoassay for 149 patients with bronchogenic carcinoma. The data were used to determine the prognostic value of the CEA assay in these patients. The relationship of preoperative CEA levels with stage of disease, histology and resectability was also examined. All of the patients with CEA levels >6 ng/ml died in less than 3 years while all of the patients who survived 3 to 5 years had preoperative CEA levels ≤ 6 ng/ml. The CEA assay had no prognostic significance for patients with undifferentiated large or small cell carcinomas since all of the patients with undifferentiated large cell carcinoma had CEA levels ≤ 6.0 ng/ml and all of the patients with small cell carcinoma have died regardless of their initial preoperative plasma CEA value. The number of patients in these two histologic groups was small and perhaps the study of additional patients will show a critical CEA level for these patients as well. There was no correlation observed between CEA levels ≤ 6 ng/ml vs. >6 ng/ml and resectability of the primary tumor.

Patterns of tumor recurrence after definitive irradiation for inoperable non-oat cell carcinoma of the lung

Abstract Preliminary analysis was carried out on a prospective randomized cooperative group study involving 375 patients with histologically proven unresectable non-oat cell carcinoma of the lung who were treated with definitive radiotherapy. The patients were randomized to one of four treatment regimens: 4000 rad split course (2000 rad in five fractions one week, two weeks rest and an additional 2000 rad, five fractions in one week) or 4000, 5000 or 6000 rad continuous courses, five fractions per week. 84 to 100 patients were accessioned to each group. The one year survival rate was about 40%; the two year survival rate was 10% to 18%. The patients who were treated with the split course had the lowest survival (10% at two years) compared with the other groups (14% to 18%). Complete and partial local tumor regression was 48 % in patients who were treated with 4000 rad, 65 % in the 5000 rad and 61 % in the 6000 rad group. The rate of initial intrathoracic recurrence was 38 % in patients who were treated with 6000 rad; 45 % in those who received 5000 rad, 51 % and 64 % with 4000 rad split or continuous course, respectively. Patients who showed complete or partial regression of the tumor following irradiation exhibited an initial local recurrence rate of 42 % and 46 % respectively in contrast to 57 % for those without tumor regression. Patients with epidermoid carcinoma had an initial local failure rate of 53%, adenocarcinoma and large cell undifferentiated carcinoma 41 %. Distant metastases concurrent with or prior to intrathoracic failure were significantly higher in the patients with adenocarcinoma or large cell adenocarcinoma (63%) than in epidermoid carcinoma (33%). The present data strongly suggest that patients who were treated with 5000 or 6000 rad had a better response, tumor control and survival than those who were treated with lower doses. Additional follow-up of patients at risk in each group will be necessary before a final conclusion is drawn. Further investigations should determine the impact that a variety of prognostic factors may have in efficacy of irradiation in patients with bronchogenic carcinoma. This information will be extremely useful in the design of future therapy for these various subpopulations of patients with different manifestations of the disease.

The carcinoembryonic antigen assay in bronchogenic carcinoma

Pretreatment levels of plasma carcinoembryonic antigen (CEA) were determined for a series of patients with bronchogenic carcinoma and for a series of patients with benign pulmonary disease. These data were analyzed to determine the diagnostic and prognostic value of the CEA radioimmunoassay in bronchogenic carcinoma. CEA plasma values in patients with benign pulmonary disease indicate that the level of discrimination between positive and negative tests for bronchogenic carcinoma should be at least 5.0 ng/ml. Half the patients with bronchogenic carcinoma in this study had CEA plasma values less than 5.0 ng/ml. The data also indicate that the CEA test does not correlate well with patient survival or stage of disease at time of diagnosis, and that the CEA test frequently fails to identify patients with extensive metastatic disease. It is concluded that the pretherapy plasma CEA level will not be of value as a diagnostic or prognostic test in the management of a significant number of patients with bronchogenic carcinoma.

Combined modality treatment of regional small cell unidifferentiated carcinoma of the lung: A cooperative study of the RTOG and ECOG

Between 1975 and 1979, 271 patients with regional small cell undifferentiated (including oat cell) carcinoma of the lung were entered into a study involving treatment by radiation therapy (4500 cGy (rad) in five weeks) to the primary tumor, mediastinum and supraclavicular lymph nodes, and a randomization to receive or not receive prophylactic treatment of the brain (3000 cGy in two weeks) and a randomization to prophylactic or delayed chemotherapy (cyclophosphamide and CCNU). Analysis of the data indicates that the median survival for responders (53 weeks) was significantly longer than that of the non-responders and partial responders (37 and 34 weeks). Median survival by treatment arm was 48 weeks for thoracic irradiation (TI), brain irradiation (BI), and early chemotherapy (CT), 44 weeks for TI alone, 41 weeks for TI and CT, 38 weeks for TI and BI. Regional complete and partial tumor responses were 52 and 25% for prophylactic chemotherapy and 44 and 35% for delayed chemotherapy. The site of first failure was regional in 12%, regional and distant simultaneously in 21%, and distant only in 46%. Elective brain irradiation significantly reduced the incidence of brain metastases from 21 and 5%, but did not improve survival.

Clinical significance of the preoperative plasma carcinoembryonic antigen (CEA) level in patients with carcinoma of the large bowel

Preoperative levels of perchloric acid extractable plasma CEA were measured in 911 patients with complaints of the digestive system. A final diagnosis of benign disease was made for 579 patients; 332 patients were found to have cancer. Data for the preoperative CEA values were examined for clinical significance as an aide to diagnosis, preoperative disease staging, and prognosis.The results of our analysis support the conclusions of many investigators that the CEA assay is not a clinically useful diagnostic test, but it shows limited value in preoperative staging and a somewhat stronger correlation with prognosis.

Adjuvant specific active lung cancer immunotherapy trials. Tumor-associated antigens.

The 10‐year cumulative experiences of five year survivals of patients entered into a successful phase II specific active tumor‐associated antigen (TAA) immunotherapy trial, a successful phase III specific active immunotherapy trial A and of patients from centers with acceptable protocol violation levels of an unsuccessful specific active immunotherapy trial B are evaluated. Here the authors report the efficacy of specific active TAA immunotherapy when the protocol is adhered to strictly, where the induction of cell‐mediated immunity to TAA indicated a successful adherence to the protocol rather than the strategic result when centers from the third trial with major violations are included. The authors repeat here a summary of each of the three separate trials, each of the three trials having been reported elsewhere in their entirety, so that these total results may be compared to the present analysis. The survival experiences of a total of 234 lung cancer Stage I and Stage II patients, including all violations, from centers in northern New York, northern New Jersey, western Pennsylvania and eastern Canada show a statistically valid (P = 0.0002) 5‐year survival difference between the control groups (receiving adjuvant alone or no treatment) at 49% survival and the specific active immunotherapy groups at 69% survival. The best promise of specific active immunotherapy alone in an adjunctive treatment setting is with early stage lung cancer. In addition to tests which monitor the effect of TAA immunotherapy induction of long‐lasting cell‐mediated immunity, tests (monoclonal antibody‐derived epitope enzyme immunoassays) were developed to monitor specific, early antibody rises in the bloodstream (circulating humoral immunity).

LOCALIZED RADIATION HEPATITIS AS DEMONSTRATED BY SCINTILLATION SCANNING.

The liver has usually been considered radiation-resistant. Ingold et al. (1) recently summarized the literature on radiation effects on the liver and added some observations of their own. They noted that in 13 of 40 patients receiving radiation to the entire liver evidence of radiation “hepatitis” developed. A relationship was shown between the dose of irradiation and the incidence of radiation effect on the liver, no effect being observed with doses of less than 3,000 rads. Liver dysfunction was seen in 7 of the 17 patients who received doses in the 3,800–4,000-rad range and in 3 of the 4 patients who received doses in excess of 4,000 rads. On the other hand, they noted that “limited portions of the liver can apparently stand doses as high as 5,500 rads without detectable deleterious effects to the individual.” Ingold et al. also demonstrated alteration in some liver function tests in many of the patients in whom treatment was delivered to the entire liver. They stated that the serum alkaline phosphatase...

Carcinoembryonic Antigen (CEA) Plasma Levels in Untreated Cancer Patients and Patients with Metastatic Disease

Radioimmunoassays for determination of carcinoembryonic antigen (CEA) were performed on plasma samples from previously diagnosed but untreated cancer patients, cancer patients with metastatic disease, control groups with non-neoplastic disease, and healthy volunteers. The CEA radioirnmunoassay failed to detect 34% of those with active cancer, raising questions about the diagnostic significance and value of the CEA assay as a screening procedure for detection of cancer.