Stephen L. Seagren

A Randomized Trial of Induction Chemotherapy plus High-Dose Radiation versus Radiation Alone in Stage III Non-Small-Cell Lung Cancer

BACKGROUND For patients with locally or regionally advanced non-small-cell lung cancer radiation is the standard treatment, but survival remains poor. We therefore conducted a randomized trial to determine whether induction chemotherapy before irradiation improves survival. METHODS All the patients had documented non-small-cell cancer of the lung with Stage III disease established by clinical or surgical staging. Eligibility requirements included excellent performance status, minimal weight loss, and visible disease on radiography. Patients randomly assigned to group 1 received cisplatin (100 mg per square meter of body-surface area given intravenously on days 1 and 29) and vinblastine (5 mg per square meter given intravenously on days 1, 8, 15, 22, and 29) and then began radiation therapy on day 50 (60 Gy over a 6-week period). Patients assigned to group 2 received the same radiation therapy but began it immediately and received no chemotherapy. RESULTS The eligible patients in group 1 (n = 78) and group 2 (n = 77) were comparable in terms of age (median, 60 years), sex, performance status, histologic features, stage of disease, and completeness of radiation therapy. The median survival was greater for those in group 1-13.8 versus 9.7 months (P = 0.0066 by log-rank test). Rates of survival in group 1 were 55 percent after one year, 26 percent after two years, and 23 percent after three years, as compared with 40, 13, and 11 percent, respectively, in group 2. Those in group 1 had a higher incidence of serious infections requiring hospitalization (7 percent, vs. 3 percent in group 2) and severe weight loss (14 percent vs. 6 percent), but there were no treatment-related deaths. CONCLUSIONS In patients with Stage III non-small-cell lung cancer, induction chemotherapy with cisplatin and vinblastine before radiation significantly improves median survival (by about four months) and doubles the number of long-term survivors, as compared with radiation therapy alone. Since three quarters of the patients still die within three years, however, further improvements in systemic and local therapy are needed.

A targeted supradose cisplatin chemoradiation protocol for advanced head and neck cancer

BACKGROUND Hypothesizing that cisplatin (DDP) drug resistance is dose dependent and the radiosensitizing effect of DDP is clinically beneficial, we conducted a chemoradiation protocol using extremely high doses of DDP delivered intra-arterially (IA) to locally advanced head and neck tumors. PATIENTS AND METHODS Twenty-nine patients with untreated stage IV disease received 4 weekly infusions of 150 mg/m2, simultaneous systemic DDP neutralization with intravenous (IV) bolus sodium thiosulfate, and concomitant radiotherapy (180 to 200 cGy/day x 35 fractions). RESULTS The complete response rate of the 24 evaluable patients as determined with repeat biopsies was 23/24 (96%). Of the 29 patients evaluable for toxicity, central nervous system complications related to the infusion technique occurred with 2/110 infusions, both of which were reversible. The rate of grade III to IV chemotoxicity was 13%. The median length of follow-up was 22 months. There have been 6 recurrences: 1 local; 3 regional; and 2 at distant sites. The projected overall and disease-free 3-year survival was 88% and 53%, respectively. CONCLUSION We conclude that the combination of rapid selective delivery of supradose DDP/IV thiosulfate neutralization and concomitant radiotherapy can be safely and effectively applied to patients with advanced head and neck cancer. Preliminary survival analysis indicates that this approach may improve the prognosis for patients with an otherwise devastating disease.

Infusional 5‐fluorouracil and x‐ray therapy for non‐resectable esophageal cancer

Six patients with unresectable carcinoma of the esophagus received a combined course of external radiation therapy (1000 rads in four fractions in four days commencing on day 2) combined with constant infusional 5‐fluorouracil (20 mg/kg every 24 hours for five days beginning on day 1). This program was repeated every other week to give a total x‐ray dose of 6000 rads. This regimen has been well‐tolerated by the majority of the patients and resulted in a complete response rate within the x‐ray treatment field of 83% (5/6). All patients who showed a demonstrable systemic response to 5‐fluorouracil reached complete response. The median survival has not yet been reached at six months with post‐treatment survivors alive and without disease (four patients) at one, six, nine, and 22 months. Our previous median survival by x‐ray therapy alone was 4 1/2 months. Toxicity consists primarily of hematologic suppression at a subclinical level. Although the length of therapy is substantial (11 weeks), the program appears tolerable and is capable of inducing long‐term remissions. The program is currently being studied for dose escalation because neither local nor systemic side effects of a doselimiting nature have been observed at 20 mg/kg 5‐FU. Cancer 45:703‐708, 1980.

Phase I Study of Accelerated Conformal Radiotherapy for Stage I Non–Small-Cell Lung Cancer in Patients With Pulmonary Dysfunction: CALGB 39904

PURPOSE The optimal treatment for medically inoperable stage I non-small-cell lung cancer (NSCLC) has not been defined. PATIENTS AND METHODS Cancer and Leukemia Group B trial 39904 prospectively assessed accelerated, once-daily, three-dimensional radiotherapy for early-stage NSCLC. The primary objectives were to define the maximally accelerated course of conformal radiotherapy and to describe the short-term and long-term toxicity of therapy. Entry was limited to patients with clinical stage T1N0 or T2N0 NSCLC (< 4 cm) and pulmonary dysfunction. The nominal total radiotherapy dose remained at 70 Gy, while the number of daily fractions in each successive cohort was reduced. RESULTS Thirty-nine eligible patients were accrued (eight patients each on cohorts 1 to 4 and seven patients on cohort 5) between January 2001 and July 2005. One grade 3 nonhematologic toxicity was observed in both cohort 3 (dyspnea) and cohort 4 (pain). The major response rate was 77%. After a median follow-up time of 53 months, the actuarial median survival time of all eligible patients was 38.5 months. Local relapse was observed in three patients. CONCLUSION Accelerated conformal radiotherapy was well tolerated in a high-risk population with clinical stage I NSCLC. Outcomes are comparable to prospective reports of alternative therapies, including stereotactic body radiation therapy and limited resection, with less apparent severe toxicity. Further investigation of this approach is warranted.

Observations on control of N2 and N3 neck disease in squamous cell carcinoma of the head and neck by intra-arterial chemoradiation

Patients with head and neck squamous cell cancer with N2 and N3 neck disease have a poor prognosis and are at risk to fail regionally despite combined surgery and radiation. Twenty‐two patients with N2 and N3 neck disease (and T3‐4 primaries) were treated with intra‐arterial, high‐dose cisplatin (CDDP), 150 mg/m2 per week for 4 weeks, and concurrent radiation. All patients were followed for at least 2 years or until death from any cause. Twenty patients had a complete response at the primary site. Two of the 20 with a complete response later had a neck recurrence and died. Five patients with palpable nodes after treatment underwent fine‐needle aspiration (FNA), one of which was positive and two suggestive of cancer. Six neck dissections were performed in this group, only two of which had positive nodes. This chemoradiation protocol may offer reasonable control of N2 and N3 neck disease in advanced head and neck squamous cell cancer. Neck dissection appeared to be necessary in only those patients with nodes 8 weeks after treatment in whom FNA was positive or suggestive of cancer. Because of the relatively small size of this series, additional accrual and monitoring of such patients is planned.

Mohs for head and neck mucosal cancer: Report on 111 patients

Microscopically Oriented Histologic Surgery (MOHS) has been applied to primary epidermoid cancers of the mucosal tissues of the head and neck since 1979. In that time we have treated 170 patients and maintained excellent records, losing no patients to follow‐up. One hundred three patients have been followed for 2 years. Of this group, only nine patients have developed local recurrences; three were salvaged, six were not.

Effect of radiologic stage III substage on nonsurgical therapy of non-small cell lung cancer

Background. Patients with Stage III non–small cell lung cancer (NSCLC) whose cases are staged or treated surgically have different prognoses, depending on the substage (IIIa, IIIb). It is not known whether the prognostic differences apply to clinically staged nonsurgical cases. The authors wanted to determine whether radiologic Stage III substages, determined by computerized axial tomography (CT) scans, are prognostically important in these patients with NSCLC. In addition, they wanted to determine whether the observed superior survival of selected patients with Stage III NSCLC receiving chemotherapy in addition to radiation therapy (chemo‐RT) (Cancer and Leukemia Group B protocol 8433: N Engl J Med 1990; 323:940–5) was influenced by an imbalance in the radiologic Stage III substage.

Extensive disease small cell carcinoma of the lung. Trial of non‐cross resistant chemotherapy and consolidation radiotherapy

Twenty‐nine patients with extensive disease, small‐cell carcinoma of the lung, were treated with two cycles of intensive combination chemotherapy: HexaVAC (hexamethylmelamine, vincristine, Adriamycin, cyclophosphamide). Responders received prophylactic cranial radiation (2000 rad/10 fractions) and non cross resistant chemotherapy via a schedule of alternating cycles of CMV (cyclophosphamide, methotrexate, VP‐16–213) and AMV (Adriamycin, methotrexate, VP‐16–213). Whenever a complete response was achieved, consolidation radiotherapy was given to the lung primary (4000 rad/20 fractions, split dose) and abdominal metastases (2000 rad/10 fractions) synchronous with CMV therapy. The complete response rate was 14% with HexaVAC, but increased to 38% during CMV/AMV. Total response rate (complete and partial) was 59% and median survival was 42 weeks. Prophylactic brain radiation prevented clinical relapse in the brain in all 14 patients who received it. However, consolidation radiotherapy failed to prevent clinical relapse in the lung and/or liver, and therapeutic brain radiation (3000 rad) failed to prevent relapse in that site. The simultaneous administration of radiotherapy and chemotherapy was well‐tolerated although two patients with poor performance status died of infectious complications while leukopenic. In spite of the high response rate, durable remissions with prolonged disease free survival were rare. Further evaluation of induction, consolidation, and maintenance modes of therapy are indicated.

Treatment of locally advanced squamous cell carcinoma of the head and neck with concurrent bleomycin and external beam radiation therapy

Abstract Nineteen patients with advanced head and neck cancer were treated with bleomycin (15u BM and irradiation (180 rad, 5d/week, 5040 rad) and have analyzed the effects. Most patients went on to further radical treatment. Both epithelial toxicity and tumor regression seemed enhanced. Approaching 1 year minimum follow-up (2 years maximum) crude survival is 68% and disease-free survival is 57%. Late complications do not seem to be enhanced. Regression in advanced nodal disease was less impressive.

Recent Outcomes for Patients with Carcinoma of the Lung

We undertook a retrospective study of all lung cancer patients diagnosed between 1978 to 1982 and seen at the University of California San Diego affiliated hospitals. There were 390 evaluable patients; the vast majority were men. Overall median survival was 8 months and was similar for all histologic types. Completely asymptomatic patients had a median survival of 20.1 months while symptomatic patients had a median survival of 5-8 months. Retrospective application of the new clinical staging system for lung cancer increased the survival distinction between clinical Stage I and Stage II disease. Median survival for small cell carcinoma of the lung was 10 months: 16.6 months for disease limited to the chest, and 5.8 months for metastatic disease. Median survival for Stage III nonsmall cell lung cancer patients was only 5 months. Only those asymptomatic patients with small lesions which were detected incidentally or by screening chest x-ray had any likelihood of long-term, disease-free survival with more than 60% alive two years after diagnosis. This study suggests that screening and early detection programs in existence during the period of observation were not effective in detecting early disease, and that no therapy of advanced diseases [Stages II through IV] was sufficiently efficacious to be considered standard.