Adjuvant chemotherapy for completely resected stage III non-small-cell lung cancer. Results of a randomized prospective study. The Japan Clinical Oncology Group. A randomised controlled trial of pre-operative chemotherapy followed, if feasible, by resection versus radiotherapy in patients with inoperable stage T3, N1, M0 or T1-3, N2, M0 non-small cell lung cancer. Effect of ABVD chemotherapy with and without mantle or mediastinal irradiation on pulmonary function and symptoms in early-stage Hodgkin's disease. A randomized trial of postoperative adjuvant chemotherapy in non-small cell lung cancer (the second cooperative study). The Study Group of Adjuvant Chemotherapy for Lung Cancer (Chubu, Japan). Randomized trial addressing risk features and time factors of surgery plus radiotherapy in advanced head-and-neck cancer. Early compared with late radiotherapy in combined modality treatment for limited disease small-cell lung cancer: a London Lung Cancer Group multicenter randomized clinical trial and meta-analysis. Phase III study comparing chemotherapy and radiotherapy with preoperative chemotherapy and surgical resection in patients with non-small-cell lung cancer with spread to mediastinal lymph nodes (N2); final report of RTOG 89-01. Radiation Therapy Oncology Group. Adjuvant radiotherapy in non-small cell lung cancer with pathological stage I: definitive results of a phase III randomized trial. Medically Inoperable Lung Carcinoma: The Role of Radiation Therapy.
Two hundred nine patients with completely resected stage III non-small-cell lung cancer were randomized to receive postoperative cisplatin and vindesine chemotherapy or no further treatment. Before randomization, patients were stratified by the histologic characteristics of their tumors (squamous versus nonsquamous cell carcinoma). Prognostic variables such as histology, performance status, extent of operation, and tumor and nodal status of the eligible patients in chemotherapy (n = 90) and control groups (n = 91) were equally distributed. There was no statistically significant difference in disease-free and overall survival between the two groups. The 3-year disease-free survivals of the chemotherapy and control groups were 37% and 42%, respectively. The median survival times (5-year survival) were 31 months (35%) in the chemotherapy group and 37 months (41%) in the control group. These was no different pattern in the first site of recurrence (local versus systemic) between the two groups. This study failed to demonstrate the therapeutic benefits of postoperative cisplatin and vindesine chemotherapy. The majority of patients with stage T3, N1, M0 or T1-3, N2, M0 non-small cell lung cancer are considered inoperable, and receive radical radiotherapy. This randomised trial aimed to assess whether, in this group of inoperable patients, a policy of neo-adjuvant chemotherapy (with mitomycin, ifosfamide and cisplatin (MIC) or mitomycin, vinblastine and cisplatin (MVP)) followed, if feasible, by surgery (CT-S), would result in better outcomes than radical radiotherapy (RT). The trial closed due to poor accrual, with only 48 patients randomised in 3 years. Only 4 of the 24 patients in the CT-S group had a complete resection, and of these, the 2 patients who had a pneumonectomy both died 12 days after surgery. There was no evidence of an improved survival in the CT-S group (median survival 13.8 months, compared with 11.3 months for the RT group), but because the trial failed to recruit we were unable to reach any reliable conclusions about these two treatment options. To evaluate the effect of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) chemotherapy alone and of ABVD with mantle or mediastinal irradiation (RT) on the pulmonary function of patients with early-stage Hodgkin's disease.
                Between 1989 and 1993, 60 patients with clinical stage I to IIIA HD enrolled onto randomized trials at Memorial Sloan-Kettering Cancer Center (MSKCC) underwent prospective evaluation of pulmonary function. All patients received six cycles of ABVD, and 30 patients received mantle or mediastinal RT. Pulmonary function tests (PFTs) and symptom evaluation were conducted before, during, and after completion of chemotherapy and RT, and at various intervals thereafter. The median follow-up time was 30 months.
                During chemotherapy, symptoms of cough and dyspnea on exertion developed in 32 of 60 patients (53%) and declines in pulmonary function occurred in 22 of 60 patients (37%). Discontinuation of bleomycin was necessary in 14 of 60 patients (23%). Following chemotherapy, there was a significant decline in median forced vital capacity (FVC) and diffusing capacity of carbon monoxide (DLCO). In patients who received mantle or mediastinal RT, there was a further decline in FVC following radiation therapy. At the most recent follow-up evaluation, five of 29 patients (18%) who received ABVD alone and nine of 30 (30%) who received ABVD and RT reported persistent mild pulmonary symptoms (P = .36), which did not significantly affect normal daily activity.
                ABVD chemotherapy induced acute pulmonary toxicity that required bleomycin dose modification in a substantial number of patients. The addition of RT resulted in a further decrease in FVC; however, this did not significantly affect the functional status of patients. A prospective randomized trial (the second cooperative study) was conducted from July 1985 to December 1987 to investigate the benefits of postoperative adjuvant chemotherapy in patients for whom non-small cell lung cancer had been resected completely. Patients were randomly assigned either to a chemotherapy group (group A) treated postoperatively with CDDP (66 mg/m2 x 1), ADM (26 mg/m2 x 1) and UFT (8 mg/kg/day) during 6 months, or to a control group (group B) which had undergone surgery only. Three hundred and thirty-three resected cases were registered. Among them, 24 cases (7.2%) were excluded, because of incomplete resection (15), pathologically benign tumour (3), small cell lung cancer (2) and other factors (4). Three hundred and nine cases were eligible: 155 cases in group A (p-Stage I 93, II 19, III 43) and 154 in group B (I 109, II 10, III 35). The 5-year survival rate in group A was 61.8%, and that in group B 58.1%. The 5-year disease-free survival rate for each group was 61.8% and 57.4%, respectively. There were no significant differences in the 5-year survival between the two groups. However, since a significant difference was observed between the two groups regarding pathological lymph node metastasis (pN), the prognostic factors were adjusted using Cox's proportional hazard model. Thereafter the adjusted survival rate and disease-free survival rate for group A became significantly higher than for group B (P = 0.044 and P = 0.036, respectively). Thus, from these results, it is concluded that the role of surgery for non-small cell lung cancer still remains of primary importance, and postoperative adjuvant chemotherapy is effective to improve the results of surgery and prolong life of patients with non-small cell lung cancer. A multi-institutional, prospective, randomized trial was undertaken in patients with advanced head-and-neck squamous cell carcinoma to address (1) the validity of using pathologic risk features, established from a previous study, to determine the need for, and dose of, postoperative radiotherapy (PORT); (2) the impact of accelerating PORT using a concomitant boost schedule; and (3) the importance of the overall combined treatment duration on the treatment outcome.
                Of 288 consecutive patients with advanced disease registered preoperatively, 213 fulfilled the trial criteria and went on to receive therapy predicated on a set of pathologic risk features: no PORT for the low-risk group (n = 31); 57.6 Gy during 6.5 weeks for the intermediate-risk group (n = 31); and, by random assignment, 63 Gy during 5 weeks (n = 76) or 7 weeks (n = 75) for the high-risk group. Patients were irradiated with standard techniques appropriate to the site of disease and likely areas of spread. The study end points were locoregional control (LRC), survival, and morbidity.
                Patients with low or intermediate risks had significantly higher LRC and survival rates than those with high-risk features (p = 0.003 and p = 0.0001, respectively), despite receiving no PORT or lower dose PORT, respectively. For high-risk patients, a trend toward higher LRC and survival rates was noted when PORT was delivered in 5 rather than 7 weeks. A prolonged interval between surgery and PORT in the 7-week schedule was associated with significantly lower LRC (p = 0.03) and survival (p = 0.01) rates. Consequently, the cumulative duration of combined therapy had a significant impact on the LRC (p = 0.005) and survival (p = 0.03) rates. A 2-week reduction in the PORT duration by using the concomitant boost technique did not increase the late treatment toxicity.
                This Phase III trial established the power of risk assessment using pathologic features in determining the need for, and dose of, PORT in patients with advanced head-and-neck squamous cell cancer in a prospective, multi-institutional setting. It also revealed the impact of the overall treatment time in the combination of surgery and PORT on the outcome in high-risk patients and showed that PORT acceleration without a reduction in dose by a concomitant boost regimen did not increase the late complication rate. These findings emphasize the importance of coordinated interdisciplinary care in the delivery of combined surgery and RT. To replicate an earlier National Cancer Institute of Canada (NCIC) trial that examined the effect on survival of the timing of thoracic radiotherapy (TRT) in patients with limited disease small-cell lung cancer (SCLC).
                Patients received three cycles of cyclophosphamide, doxorubicin, and vincristine alternating with three cycles of etoposide and cisplatin. Three hundred twenty five chemotherapy- and radiotherapy-naïve patients were randomly assigned to either early TRT administered concurrently in the second cycle or late TRT administered concurrently with the sixth cycle; the dose was 40 Gy in 15 fractions over 3 weeks.
                TRT was received by 92% and 82% of patients in the early and late arms, respectively (P = .01). Sixty-nine percent of patients in the early arm received all six courses of chemotherapy compared with 80% in the late arm (P = .003). There was no evidence of a survival difference; median overall survival time was 13.7 and 15.1 months in the early and late arms, respectively (P = .23). In a meta-analysis of all eight trials that compared early and late TRT, there were three in which the proportion of patients who completed their planned chemotherapy was similar between the TRT arms (hazard ratio [HR] = 0.73; 95% CI, 0.62 to 0.86) and five in which proportionally fewer patients in the early TRT arm completed their chemotherapy (HR = 1.06; 95% CI, 0.97 to 1.17).
                This study failed to show a survival advantage for early TRT with chemotherapy in limited-stage SCLC, unlike the NCIC trial. However, the results of a meta-analysis suggest that it is essential to ensure that the delivery of chemotherapy is optimal when administered with early TRT. To compare the outcome of treatment of mediastinoscopy-verified N2 non-small-cell lung cancer treated with induction chemotherapy followed by either surgery or radiotherapy (RT), with both options followed by consolidation chemotherapy.
                A randomized Phase III trial for Stage IIIA (T1-T3N2M0) non-small cell lung cancer was conducted by the Radiation Therapy Oncology Group (RTOG) and Eastern Cooperative Oncology Group between April 1990 and April 1994. After documentation of N2 disease by mediastinoscopy or anterior mediastinotomy, patients received induction chemotherapy with cisplatin, vinblastine, and mitomycin-C. Mitomycin-C was later dropped from the induction regimen. Patients were then randomized to surgery or RT (64 Gy in 7 weeks) followed by cisplatin and vinblastine.
                RTOG 89-01 accrued 75 patients, of whom 73 were eligible and analyzable. Twelve patients received induction chemotherapy but were not randomized to RT or surgery thereafter. Forty-five patients were randomized to postinduction RT or surgery. Of the analyzable patients, 90% had a Karnofsky performance score of 90-100, 18% had weight loss >5%, 37% had squamous cell histologic features, and 54% had bulky N2 disease. The distribution of bulky N2 disease was uniform among the treatment arms. The incidence of Grade 4 toxicity was 56% in patients receiving mitomycin-C and 29% in those who did not. Only 1 patient in each group had acute nonhematologic toxicity greater than Grade 3 (nausea and vomiting). No acute Grade 4 radiation toxicity developed. The incidences of long-term toxicity were equivalent across the arms. Three treatment-related deaths occurred: 2 patients in the surgical arms (one late pulmonary toxicity and one pulmonary embolus), and 1 patient in the radiation arm (radiation pneumonitis). Induction chemotherapy was completed in 78% of the patients. Complete resection was performed in 73% of 26 patients undergoing thoracotomy. Consolidation chemotherapy was completed in 75% of the patients. No statistically significant difference was found among the treatment arms. The overall progression-free survival rate was 53% at 1 year and 17% at 3 years. The median progression-free survival was 14 months. No difference in the 1-year survival rate (70% vs. 66%) or median survival time (19.4 vs. 17.4 months) between the surgery and RT arms. The median survival in the patients receiving induction chemotherapy only was 8.9 months. Mitomycin-C had no impact on survival (p = 0.75). No statistically significant difference was noted in the time to local failure between the surgical and RT arms.
                The patient accrual to this trial made its results inconclusive, but several observations are notable. In this trial, histologic confirmation of N2 disease in the surgical and nonsurgical arms eliminated the usual biases from clinical staging. In this setting, local control and survival were essentially equal between the surgical and RT arms. The 3- and 5-year survival rates of nonsurgical therapy were comparable to published surgical trials of N2 disease. To evaluate the benefits and the drawbacks of post-operative radiotherapy in completely resected Stage I (a and b) non-small cell lung cancer (NSCLC).
                Patients with pathological Stages Ia and Ib NSCLC have been randomized into two groups: Group 1 (G1) received adjuvant radiotherapy, Group 0 (G0) the control group did not receive any adjuvant therapy. Local control, toxicity and survival have been evaluated.
                Between July 1989 and June 1997, 104 patients with pathological stage I NSCLC have been enrolled in this study. Fifty-one patients were randomized to G1 and 53 to G0. Six patients have been excluded from the study due to incomplete follow-up data. Regarding local control, one patient in the G1 group had a local recurrence (2.2%) while in the G0 12 local recurrences have been observed (23%). Seventy-one percent of patients are disease-free at 5 years in G1 and 60% in G0 (P=0.039). Overall 5-year survival (Kaplan-Meier) showed a positive trend in the treated group: 67 versus 58% (P=0.048). Regarding toxicity in G1, six patients experienced a grade 1 acute toxicity. Radiological evidence of long-term lung toxicity, with no significant impairment of the respiratory function, has been detected in 18 of the 19 patients who have been diagnosed as having a post-radiation lung fibrosis.
                Adjuvant radiotherapy gave good results in terms of local control in patients with completely resected NSCLC with pathological Stage I. Overall 5-year survival and disease-free survival showed a promising trend. Treatment-related toxicity is acceptable. Although surgery has traditionally been the treatment of choice for patients with resectable non-small cell lung cancer, for those with significant medical problems where surgery is contraindicated, radiation therapy (RT) is a reasonable treatment modality. In contrast to the widely held belief that RT confers little benefit to these patients, a review of the literature and our own series of 245 patients shows that RT can provide significant tumor shrinkage, improved symptoms, and in a small but not negligible number of patients, cure. Several prognostic factors have emerged, including patient performance status, prior weight loss, tumor size, and radiation dose. Patients with a good performance status and a small tumor treated to a dose of 65 Gy or more have a real possibility of long-term survival and cure. Larger tumors demand strategies to improve the therapeutic ratio, such as hyperfractionation, conformal RT, brachytherapy boosts, or chemotherapy. Patients with medically inoperable lung cancer should be offered RT with curative intent, rather than the option of no treatment.
PORT is detrimental to patients with early stage completely resected non-small cell lung cancer and should not be used in the routine treatment of such patients. The role of PORT in the treatment of N2 tumours is not clear and may justify further research.