Improved survival in stage III non-small-cell lung cancer: seven-year follow-up of cancer and leukemia group B (CALGB) 8433 trial.

BACKGROUND: For many years, high dose radiation therapy was the standard treatment for patients with locally or regionally advanced non-small-cell lung cancer (NSCLC), despite a 5-year survival rate of only 3%-10% following such therapy. From May 1984 through May 1987, the Cancer and Leukemia Group B (CALGB) conducted a randomized trial that showed that induction chemotherapy before radiation therapy improved survival during the first 3 years of follow-up. PURPOSE: This report provides data for 7 years of follow-up of patients enrolled in the CALGB trial. METHODS: The patient population consisted of individuals who had clinical or surgical stage III, histologically documented NSCLC; a CALGB performance status of 0-1; less than 5% loss of body weight in the 3 months preceding diagnosis; and radiographically visible disease. Patients were randomly assigned to receive either 1) cisplatin (100 mg/m2 body surface area intravenously on days 1 and 29) and vinblastine (5 mg/m2 body surface area intravenously weekly on days 1, 8, 15, 22, and 29) followed by radiation therapy with 6000 cGy given in 30 fractions beginning on day 50 (CT-RT group) or 2) radiation therapy with 6000 cGy alone beginning on day 1 (RT group) for a maximum duration of 6-7 weeks. Patients were evaluated for tumor regression if they had measurable or evaluable disease and were monitored for toxic effects, disease progression, and date of death. RESULTS: There were 78 eligible patients randomly assigned to the CT-RT group and 77 randomly assigned to the RT group. Both groups were similar in terms of sex, age, histologic cell type, performance status, substage of disease, and whether staging had been clinical or surgical. All patients had measurable or evaluable disease at the time of random assignment to treatment groups. Both groups received a similar quantity and quality of radiation therapy. As previously reported, the rate of tumor response, as determined radiographically, was 56% for the CT-RT group and 43% for the RT group (P = .092). After more than 7 years of follow-up, the median survival remains greater for the CT-RT group (13.7 months) than for the RT group (9.6 months) (P = .012) as ascertained by the logrank test (two-sided). The percentages of patients surviving after years 1 through 7 were 54, 26, 24, 19, 17, 13, and 13 for the CT-RT group and 40, 13, 10, 7, 6, 6, and 6 for the RT group. CONCLUSIONS: Long-term follow-up confirms that patients with stage III NSCLC who receive 5 weeks of chemotherapy with cisplatin and vinblastine before radiation therapy have a 4.1-month increase in median survival. The use of sequential chemotherapy-radiotherapy increases the projected proportion of 5-year survivors by a factor of 2.8 compared with that of radiotherapy alone. However, inasmuch as 80%-85% of such patients still die within 5 years and because treatment failure occurs both in the irradiated field and at distant sites in patients receiving either sequential chemotherapy-radiotherapy or radiotherapy alone, the need for further improvements in both the local and systemic treatment of this disease persists.

Failure of low-dose, total-body irradiation to augment combination chemotherapy in extensive-stage small cell carcinoma of the lung.

In a pilot study, 21 consecutive eligible patients with extensive-stage small cell carcinoma of the lung were scheduled for treatment with combination chemotherapy followed by total-body irradiation (TBI), prophylactic cranial irradiation, and consolidative chemotherapy. Induction chemotherapy consisted of VP16-213, vincristine, cyclophosphamide, and doxorubicin (VOCA). TBI was given as 100 rads in 10 fractions over 2 wk. Consolidation chemotherapy consisted of cyclophosphamide, methotrexate, and hexamethylmelamine (CMH). VOCA chemotherapy was well tolerated, with a 79% response rate in 19 evaluable patients. TBI was successfully given after four cycles of VOCA without excessive morbidity in 11 patients, although subsequent CMH chemotherapy in 8 patients has required dose reductions and some delays in therapy. Unfortunately, TBI did not increase the degree of response, and 2 patients relapsed during this therapy. Median survival in this study was 40-44 wk. One patient has survived 78 wk and remains in remission. TBI can be safely given following induction chemotherapy in extensive-stage small cell carcinoma of the lung, but it does not appear to add to the therapeutic benefit of combination chemotherapy alone.

Alternating irradiation and chemotherapy in stage III A and B nonsmall cell lung cancer: report of a cancer and Leukemia Group B phase II study 8636.

PURPOSE: A pilot trial testing the feasibility of chemotherapy and radiotherapy was done in Stage III A and B nonsmall cell lung cancer. The schedule was designed to be consistent with the laboratory model of Looney and Hopkins. METHODS AND MATERIALS: Treatment began with thrice-per-day radiotherapy for 3 days (16.2 Gy/nine fractions), followed by chemotherapy (cis-platinum 100 mg/m2 day 10, and vinblastine 4 mg/m2 days 10 and 12). A second cycle started on day 22, a third on day 43, and a fourth on day 64. We treated three cohorts. The first cohort received three cycles of radiotherapy alone, (48.6 Gy). The second cohort received three completed cycles, and the third received three completed cycles and a fourth radiotherapy course (64.8 Gy). Patients were evaluated for toxicity, protocol compliance, response, and survival. RESULTS: The patients in the first cohort experienced no toxicity. Fifty-six percent (56%) of the patients treated in cohort 2 experienced severe or life-threatening myelosuppression as did 82% of those in cohort 3. Nonhematologic toxicity was not severe; one case of Grade 3 esophagitis, one of reversible adult respiratory distress syndrome, and one radiation pneumonitis. We closed the trial after accrual to the third cohort because of significant myelosuppression. CONCLUSION: This schedule is too myelosuppressive to be used without modification.

Bleomycin, cyclophosphamide and radiotherapy in regionally advanced epidermoid carcinoma of the head and neck.

We have treated 24 patients with squamous carcinoma of the head and neck and advanced regional (N2-3) disease. The regimen consisted of 3 cycles, each of 28 days. Cyclophosphamide (1 gm/m2 I.V.) was given on day 1, bleomycin (15 u I.M.) on days 2, 4, 9 and 11, and ionizing radiation (60Co, 180 rad/fraction) days 1-5, and 8-12. No therapy was given on days 13-28. After three cycles of therapy, 13 patients had a complete response; following further therapy (surgery, interstitial or external beam radiation), 16 patients were free of disease. However, remissions were not durable and 11/16 patients recurred loco-regionally with a median time to recurrence of 5 months; most (7/11 also developed distant metastases. These patients have biologically aggressive disease and may have a worse prognosis than patients who are Stage IV based on a T4 primary lesion only.

High dose rate intraluminal irradiation in recurrent endobronchial carcinoma.

Palliative therapy for previously irradiated patients with symptomatic recurrent endobronchial malignancy is a difficult problem. We have had the opportunity to treat 20 such patients with high dose rate (50-100 rad/min) endobronchial brachytherapy. Eligible patients had received previous high dose thoracic irradiation (TDF greater than or equal to 90), a performance status of greater than or equal to 50, and symptoms caused by a bronchoscopically defined and implantable lesion. The radiation is produced by a small cobalt-60 source (0.7 Ci) remotely afterloaded by cable control. The source is fed into a 4 mm diameter catheter which is placed with bronchoscopic guidance; it may oscillate if necessary to cover the lesion. A dose of 1,000 rad at 1 cm from the source is delivered. We have performed 22 procedures in 20 patients, four following YAG laser debulking. Most had cough, some with hemoptysis. Eight had dyspnea secondary to obstruction and three had obstructive pneumonitis. In 12, symptoms recurred with a mean time to recurrence of 4.3 months (range 1-9 months). Eighteen patients were followed-up and reexamined via bronchoscope 1-2.5 months following the procedure; two were lost to follow-up. All had at least 50 percent clearance of tumor, and six had complete clearance; most regressions were documented on film or videotape. In six, the palliation was durable. The procedure has been well tolerated with no toxicity. We conclude that palliative endobronchial high dose rate brachytherapy is a useful palliative modality in patients with recurrent endobronchial symptomatic carcinoma.

Radical radiation therapy for lung cancer.

Radical radiotherapy of lung cancer has been studied for over 30 years. Results of early trials are often cited to justify a wait-and-see approach for all nonresectable patients. Because of more accurate staging, better radiotherapy treatment planning and delivery, and recognition of nonanatomic prognostic factors, a 2-year survival rate of 20 to 30% is being credibly reported by national cooperative groups. Radical radiotherapy for lung cancer is a sophisticated process. Treatment planning to maximize the therapeutic ratio, adequate hardware, and an understanding and minimization of radiation complications are all necessary to optimize treatment.

Recent advances in radiation therapy of head and neck cancer.

The major advances in radiation oncology in this century was the development of megavoltage radiation in the 1950s, which greatly expanded the clinical utility of ionizing radiation in the treatment of many forms of cancer, including cancers of the head and neck. The combination of radiation and surgery for improved control of local and regional cancers followed. The use of interstitial implant therapy is growing rapidly because of new materials and techniques, thus expanding the radiotherapeutic options available to the oncologist. Investigations into several other therapeutic modalities currently are being carried out. These modalities include the use of particle radiation, oxygen-mimicking drugs, and hyperthermia, primarily in efforts to overcome the need for the oxygen effect in tumors. New uses of chemotherapy in combination with radiation also are being explored. Details of these activities within the field of radiation oncology are discussed.

Interstitial-implant radiotherapy in upper-aerodigestive-tract malignancy.

In the treatment of upper-aerodigestive-tract malignancy, interstitial-implant radiotherapy differs in several physical and biologic respects from conventional external-beam therapy: unlike external-beam therapy, it can deliver a high central dose with a rapid fall-off, which overcomes the central hypoxic resistance effect and yet greatly improves normal tissue tolerance. External-beam and interstitial-implant therapy can also be combined to the patient's benefit; in many cases, this combination offers advantages over external-beam therapy alone, preoperative external-beam therapy, or aggressive surgery. The recent upsurge of interest in this modality has come about because of three developments: more suitable radioactive sources, after-loading, and computerized dosimetry. The early results in upper-aerodigestive-tract malignancy, both as primary and as salvage therapy, are promising; but the precise role of this treatment in our therapeutic armamentarium remains to be established.

Bleomycin: its utilization in the treatment of head and neck cancer.

Originally isolated as an antibiotic, bleomycin is a complex mixture of glycopeptides currently utilized against a variety of malignancies, among them epidermoid, cancer of the head and neck. Because of unique independent pharmacological properties, bleomycin may be effectively used at several points in the natural history of tumors. Use of bleomycin as a single agent, as an adjunct to surgery and irradiation and as a palliative drug in head and neck cancer, is now advocated in scattered reports. The rationale for the utilization of bleomycin at the University of California, San Diego and San Diego Veterans Administration Hospitals is discussed. In addition, examples from the authors' personal series of both response and adverse effects, suggestions for appropriate clinical monitoring to detect early toxicity, and tennets for management of side effects are included in the presentation.

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.

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.

Prognostic factors in the management of metastatic epidural spinal cord compression.

The results of 51 patients with metastatic spinal cord compression were analyzed. There were seven paralyzed patients, three received radiotherapy (RT) alone and four received laminectomy (L) + RT. No patient regained any motor function. Of six ambulatory patients, half received RT and half L + RT. All remained ambulatory after the treatment. Of 38 paraparetic patients, 20 underwent L + RT. Their complete, partial and nonresponse (CR, PR, NR respectively) rates were 25%, 60% and 15%, respectively. This result was clearly better than 18 other patients treated by RT alone of which only 22% regained ambulation (CR = 22%) while 67% were NR and 11% had a PR. In this series combined modality therapy appears better in paraparetic patients. Five patients with radiosensitive tumors all had CR/PR whether treated by RT or L + RT. Patients with epithelial tumors treated by L + RT had a PR (CR + PR) of 71% while RT alone gave only 25%. On the basis of this analysis we conclude: (1) ambulatory patients respond satisfactorily to RT alone; (2) paraparetic patients with radiosensitive tumors do well with RT alone while such patients with epithelial tumors merit L + RT; but (3) paraplegic patients rarely benefit from either modality; (4) pain control appears a useful measure of minimally adequate radiation dose in individual patients.

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. METHODS: Review of pretreatment chest radiographs and CT scans with determination of TNM status and stage was done by the consensus of three readers, who were unaware of which treatment each patient had received (radiation therapy alone [RT] or chemo-RT). RESULTS: Patient characteristics in the two treatment arms were similar. Fifty-five percent of patients receiving RT had Stage IIIa and 33% Stage IIIb disease; in the chemo-RT treatment arm, 73% had Stage IIIa and 25% Stage IIIb disease (P = 0.11). Seven patients (12%) who received RT and one in the chemo-RT treatment arm (2%) had Stage I-II disease on CT scan. Patients with Stage IIIa disease had superior survival to those with Stage IIIb disease (median, 16.5 versus 10.5 months, respectively; P = 0.0045). Within each substage, survival was superior in the chemo-RT (versus RT) treatment arm (Stage IIIa, 17.2 versus 10.7 months, respectively; P = 0.16; Stage IIIb, 12.0 versus 6.9 months, respectively; P = 0.089). CONCLUSIONS: The survival advantage for selected patients with Stage III NSCLC treated with chemo-RT in this study did not result from a more favorable pretreatment radiologic Stage III substage. An advantage for induction chemotherapy was seen in patients with Stage IIIa and IIIb disease. Future studies in this population should prospectively assess and consider stratification for Stage III substage.

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.

Patterns of disease failure after trimodality therapy of nonsmall cell lung carcinoma pathologic stage IIIA (N2). Analysis of Cancer and Leukemia Group B Protocol 8935.

BACKGROUND: The impact of sequential trimodality therapy on the pattern of first site disease failure in pathologic Stage IIIA (N2) nonsmall cell lung carcinoma (NSCLC) was analyzed. METHODS: Seventy-four eligible patients with histologically documented Stage IIIA (N2) NSCLC underwent sequential trimodality therapy on Cancer and Leukemia Group B (CALGB) Protocol 8935. Treatment consisted of 2 cycles of induction cisplatin at 100 mg/m2 intravenously (i.v.) (Days 1 and 29) and vinblastine at 5 mg/m2 i.v. weekly for 5 weeks followed by surgery. Surgery included a thoracotomy with resection of the primary tumor and hilar lymph nodes and a mediastinal lymph node dissection. Patients with resected disease then received an additional a cycles of cisplatin at 100 mg/m2 i.v. and vinblastine at 5 mg/m2 i.v. biweekly for 2 total of 4 doses followed by consolidative thoracic irradiation. Patients with completely resected disease received 54 Gray (Gy) whereas those with incompletely resected disease received 59.4 Gy at 1.8 Gy/fraction (fx) once a day. Patients with unresectable disease underwent thoracic radiation therapy (TRT) treatments only to 59.4 Gy at 1.8 Gy/fx without any additional chemotherapy. Disease recurrence was determined by clinical, radiographic, or histologic criteria. Pattern of disease failure was identified by site of involvement at first recurrence as indicated by the CALGB Respiratory Follow-Up Form. RESULTS: Sixty-three of the 74 patients completed the induction chemotherapy as planned. Forty-six of the 63 patients underwent resection of disease whereas the remaining 17 were unresectable. Thirty-three of the 46 resected patients completed the entire adjuvant postoperative chemoradiation treatment as planned. Ten of 17 patients with unresectable disease completed postsurgical TRT. At a median follow-up interval of 27 months (range, 4-43), the 3-year overall survival and failure-free survival were 23% and 18%, respectively, for all 74 eligible patients. Overall, disease failure has occurred in 52 (70%) of the 74 eligible patients: local only: 13 (25%); distant only: 16 (31%); and both local and distant: 23 (44%), (P = not significant [NS]). Ten patients progressed during induction chemotherapy: local only: six patients; and both local and distant failure: four patients. Twenty-eight of 46 resected patients recurred: local only: 1 (4%); both local and distant failure: 11 (39%); and distant only: 16 (57%); (P < 0.001). Disease progression occurred in 14 of 17 patients with unresectable disease: local only: 6; both local and distant sites: 8. Among the 52 total patients experiencing disease relapse, isolated or combined local failure occurred commonly among patients during induction chemotherapy (n = 10, [28%]), in those with unresectable disease (n = 14, [39%]), or in those with resected disease (n = 12, [33%]), (P = NS). However, isolated or combined distant failure was more likely to occur among patients with resected disease (n = 27, [69%]) than either during induction chemotherapy (n = 4, [10%]) or in those with unresected disease (n = 8, [21%]), (P < 0.05). Among patients who relapsed, brain metastases occurred in 13 of 52 (25%) patients overall and in 12 of 28 (43%) patients with resected disease. CONCLUSIONS: Overall, disease failure was just as likely to occur in local, distant, or combined sites on CALGB Protocol 8935 using sequential trimodality therapy in the treatment of pathologic Stage IIIA (N2) NSCLC: Isolated or combined local failure occurred commonly during sequential tri-modality therapy whereas isolated or combined distant relapse was prevalent among patients with resected disease. In addition, isolated local failure was rare among patients with resected disease. The pattern of disease failure on CALGB Protocol 8935 reflects the biology of locoregional NSCLC as much as the therapeutic impact of trimodality therapy.

Combined modality trials of the Cancer and Leukemia Group B in stage III non-small-cell lung cancer: analysis of factors influencing survival and toxicity.

BACKGROUND: Combined modality therapy (CMT) is the standard of care for patients with unresectable stage III non-small-cell lung cancer (NSCLC); however, insufficient data are available regarding prognostic factors in this disease setting. PATIENTS AND METHODS: Six hundred and ninety-four patients included in five trials conducted by the Cancer and Leukemia Group B evaluating CMT in stage III NSCLC were included in this analysis. The primary objective was to identify factors that were predictors of survival and selected radiation-related toxicities using Cox regression models and logistic regression analysis. RESULTS: The Cox model shows that performance status (PS) 1 [hazard ratio (HR) 1.24; 95% confidence interval (CI) 1.06-1.45; P=0.009] and thoracic radiation therapy (TRT) only (HR 1.58; 95% CI 1.22-2.05; P=0.001) predicted for poorer survival, while baseline hemoglobin >/=12 g/dl predicted for improved survival (HR 0.67; 95% CI 0.55-0.81; P 5% weight loss (OR 2.9; 95% CI 1.3-6.6; P=0.008) and patients receiving concurrent chemoradiation (OR 7.3; 95% CI 3.4-15.6; P=0.0001). CONCLUSIONS: Baseline hemoglobin and PS, as well as the use of CMT, have the greatest effect on survival in unresectable stage III NSCLC. The use of concurrent chemoradiation increases the risk of esophagitis, which remains the primary radiation-related toxicity.

Non-cross-resistant chemotherapy and consolidation radiotherapy for small cell carcinoma of the lung.

Fifty-six patients with small cell carcinoma of the lung were treated with a two-cyclic induction course of hexamethylmelamine, vincristine, doxorubicin, and cyclophosphamide. Patients with limited disease (LD) who responded and patients with extensive disease (ED) who had a complete response received prophylactic whole-brain radiotherapy, as well as radiotherapy to thoracic and abdominal sites of disease. Concurrently with radiotherapy, consolidation chemotherapy was given with doxorubicin, cyclophosphamide, methotrexate, and etoposide. The complete response rate was 35% for ED patients and 68% for LD patients. The median survival time for complete responders was 54 weeks for ED patients and 65 weeks for LD patients. The toxicity of the program was moderate, and the effectiveness was comparable to that of other reported combined-modality treatment programs.