Carboplatin/etoposide/radiation plus escalating doses of paclitaxel in stage III non-small cell lung cancer: a preliminary report.

Large randomized studies have shown superior survival results for sequential chemoradiotherapy compared with radiation alone in stage III non-small cell lung cancer. Similarly, chemotherapy followed by surgery was associated with longer survival than surgery alone in small randomized trials. Despite these results, disease recurs in most stage III patients. To improve these results, we are studying escalating doses of paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) combined with platinum/etoposide and simultaneous thoracic irradiation as preoperative and curative therapy. Initially, paclitaxel was given at a starting dose of 35 mg/m2 intravenously (i.v.) over 24 hours on days 1 and 8; carboplatin (area under the concentration time curve) 4 mg/mL.min) i.v. was given on day 2 and etoposide 5 mg/d orally on days 1 to 5 and 8 to 12; cisplatin 50 mg/m2 i.v. was given on day 23, and radiation 2 Gy was given on days 1 to 5 and 8 to 12. Courses were repeated every 28 days. Four of five patients treated at the second paclitaxel dose level (90 mg/m2) experienced grade 4 toxicity. The treatment regimen was changed to paclitaxel given at a starting dose of 80 mg/m2 i.v. over 3 hours on day 1, carboplatin (area under the concentration time curve 4 mg/mL.min) i.v. given immediately after paclitaxel, etoposide 40 mg/m2 i.v. given over 1 hour on days 2 to 5, and radiation 2 Gy given on days 1 to 5 and 8 to 12. No grade 4 toxicity was observed in five patients treated at the first paclitaxel dose level (80 mg/m2). After two courses, pulmonary resection (lobectomy and pneumonectomy) was performed without fatalities in five patients. Although more data are needed, pulmonary resection appears feasible following treatment with this paclitaxel-containing regimen. Patient accrual is continuing to determine the maximum tolerated dose of paclitaxel.

Escalating paclitaxel doses combined with carboplatin/etoposide and thoracic radiotherapy as preoperative or definitive treatment for stage III non-small cell lung cancer.

We have evaluated escalating doses of paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) in combination with carboplatin, cisplatin, etoposide, and concurrent thoracic radiotherapy in patients with stage III non-small cell lung cancer. Dose-limiting toxicity was observed at paclitaxel 90 mg/m2. Subsequent modifications resulted in a new regimen, which consists of a 3-hour paclitaxel infusion on day 1 (three dose levels: 80, 100, and 120 mg/m2), etoposide 40 mg/m2 intravenously over 1 hour daily on days 2 to 5, and carboplatin given at an area under the concentration-time curve of 4 mg/mL x min on day 1 after paclitaxel. Treatment courses were repeated every 28 days. Eleven patients considered eligible for surgery received two courses. Nonsurgical patients (five) received three courses. No episodes of grade > or = 3 nausea and vomiting, dermatitis, anorexia, esophagitis, or thrombocytopenia were observed. The dose-limiting toxicity (grade 4 granulocytopenia) occurred in three of five patients at 120 mg/m2 paclitaxel (level 3). Grade 3 radiation pneumonitis was observed in three patients. Nine patients have undergone pulmonary resection: four pneumonectomies, four lobectomies, and one segmental resection. No operative deaths, respiratory insufficiency, or cardiovascular complications were observed. Clinical partial remissions have been observed in 11 of 16 patients overall, and two histologic complete remissions were achieved in nine surgical patients. Our preliminary results show that pulmonary resection is feasible following treatment with radiation and concurrent paclitaxel-containing chemotherapy. Although the maximum tolerated paclitaxel dose in the present study was relatively low, favorable initial responses warrant further study of paclitaxel-containing combination chemotherapy and concurrent radiation. We next plan to delete etoposide from our chemoradiotherapy regimen and escalate the paclitaxel dose.

Postoperative bronchopulmonary complications in stage III lung cancer patients treated with preoperative paclitaxel-containing chemotherapy and concurrent radiation.

We previously observed encouraging results and acceptable toxicity in phase II trials testing preoperative split-course thoracic radiation and simultaneous cisplatin, etoposide, and 5-fluorouracil in stage III non-small cell lung cancer patients. We decided to delete 5-fluorouracil and to incorporate paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) into our combined-modality treatment. The first group of patients received carboplatin dosed at an area under the concentration-time curve of 4 on day 2, etoposide 50 mg orally days 1 to 5 and 8 to 12, cisplatin 50 mg/m2 on day 21, and paclitaxel 35 mg/m2 escalated to 45 mg/m2 on days 1 and 8. Group 2 patients received carboplatin dosed at an area under the concentration-time curve of 4 on day 1, etoposide 45 mg/m2 intravenously daily on days 2 to 5, and paclitaxel 80 mg/m2 (escalating to 120 mg/m2) on day 1. Patients in group 3 received carboplatin dosed at an area under the concentration-time curve of 4 on day 1 and paclitaxel 120 mg/m2 (escalating to 140 mg/m2) on day 1. Each patient received radiation 2 Gy daily on days 1 to 5 and 8 to 12, and a total of two cycles was given at 28-day intervals. Twenty-one patients received preoperative chemoradiotherapy: group 1, five patients; group 2, 11 patients; and group 3, five patients. Thoracotomy was not done in five patients due to cerebrovascular accident in one and progressive tumor in four. The remaining 16 patients had the following procedures: pneumonectomy, eight; lobectomy, six; chest wall resection, one; and no resection, one. Postoperative complications included bronchopleural fistula in one patient each in groups 1 and 3, hypoxia in one patient in group 1, pulmonary hypertension in one patient in group 2, pneumonia in one patient in group 2, and adult respiratory distress syndrome in one patient in group 3, which proved lethal. Thus, six of 16 patients had serious postoperative complications. The relatively high incidence of postoperative bronchopulmonary complications suggests that the use of preoperative paclitaxel-containing chemotherapy and simultaneous thoracic radiation may not be feasible.

Should multicentric disease be an absolute contraindication to the use of breast-conserving therapy?

PURPOSE: Multicentric cancer is present in a large proportion of mastectomies performed as treatment of breast cancer; it has been considered a contraindication to breast conservation. METHODS AND MATERIALS: We reviewed the records of our patients with Stage I or II breast cancer treated with breast conserving surgery and radiation therapy over a 13-year period. Twenty-seven patients had two or more nodules of grossly visible cancer separated by histologically normal breast tissue. All patients had grossly negative margins of excision; however, four patients had microscopically positive margins. Nine patients had positive axillary nodes. All patients received radiation therapy to the breast postoperatively, with a median dose of 50.4 Gy in 28 fractions; 11 patients also received a boost dose of 6-20 Gy to the tumor bed. Eleven patients were given adjuvant chemotherapy and one patient was given adjuvant tamoxifen. RESULTS: With a median follow-up of 53 months, only one patient has relapsed in the breast (3.7%); that patient relapsed in multiple distant sites at the same time. Three patients have died of disseminated disease; the actuarial survival and disease-free survival rates at 4 years are 89%. CONCLUSION: Breast conservation may be considered for patients with multicentric breast cancer discovered at the time of histologic examination. For patients with multicentric disease detected prior to surgery, breast conserving therapy may be appropriate as long as: (1) all clinically and radiographically apparent abnormalities are removed, (2) clear margins of resection are achieved, and (3) there is no extensive intraductal component.

CT and PET lung image registration and fusion in radiotherapy treatment planning using the chamfer-matching method.

PURPOSE: We present a validation study of CT and PET lung image registration and fusion based on the chamfer-matching method. METHODS AND MATERIALS: The contours of the lung surfaces from CT and PET transmission images were automatically segmented by the thresholding technique. The chamfer-matching technique was then used to register the extracted lung surfaces. Arithmetic means of distance between the two data sets of the pleural surfaces were used as the cost function. Matching was then achieved by iteratively minimizing the cost function through three-dimensional (3D) translation and rotation with an optimization method. RESULTS: Both anatomic thoracic phantom images and clinical patient images were used to evaluate the performance of our registration system. Quantitative analysis from five patients indicates that the registration error in translation was 2-3 mm in the transverse plane, 3-4 mm in the longitudinal direction, and about 1.5 degree in rotation. Typical computing time for chamfer matching is about 1 min. The total time required to register a set of CT and PET lung images, including contour extraction, was generally less than 30 min. CONCLUSION: We have implemented and validated the chamfer-matching method for CT and PET lung image registration and fusion. Our preliminary results show that the chamfer-matching method for CT and PET images in the lung area is feasible. The described registration system has been used to facilitate target definition and treatment planning in radiotherapy.

Integration of surgery in multimodality therapy for esophageal cancer.

BACKGROUND: While adding chemotherapy to radiation for the treatment of esophageal cancers has been shown to be beneficial, surgery usually follows treatment or is omitted. In either case, regional control remains problematic. The purpose of this study was to test the feasibility of using chemotherapy and radiation following surgery in the treatment of of esophageal cancer and to assess the impact of this approach on regional control and survival. PATIENTS AND METHODS: Twenty-five patients with esophageal cancer were treated in a phase I pilot protocol consisting of initial esophagectomy with gastroesophagostomy and subsequent combined chemotherapy and radiation. Chemotherapy consisted of cisplatin given on day 1 and 5-fluorouracil (FU) on days 1-5 by continuous infusion. Radiation therapy was administered in varying fractionation schedules of once or twice daily concomitantly with the chemotherapy. Treatment was repeated every other week for two to four cycles. Median follow-up was 42 months. RESULTS: Acute toxicities (mucositis and cytopenias) were common but not worse than grade 3. Higher doses of 50 Gy with 2 Gy b.i.d. hyperfractionation caused late complications in four of 10 patients, (two lethal). Control of local disease for all patients was excellent with only two known and two possible local recurrences (16%) but distant metastases were common (46%). Disease-free survival was 58 and 30% at 1 and 2 years, respectively. Survival was 58 and 32% at 1 and 2 years, respectively (median survival, 19 months). CONCLUSION: The local control rate and survival were better than those in our historical experience with cisplatin and 5-FU chemotherapy and radiation given prior to surgery. A dose-fractionation schedule of < 2 Gy up to a total of 50 Gy b.i.d. is recommended to avoid late adverse effects. The role of surgery will be defined by randomized studies. Better systemic therapy is needed to impact on systemic failure.

Delaying the initiation of intact breast irradiation for patients with lymph node positive breast cancer increases the risk of local recurrence.

BACKGROUND: The impact of delaying irradiation to the intact breast for patients receiving chemotherapy for lymph node positive breast cancer is controversial. METHODS: From 1974 to 1989, 474 patients underwent lumpectomy and intact breast irradiation for early stage invasive breast cancer. Chemotherapy was administered to 84 patients (1 patient with bilateral breast cancer) because of positive axillary lymph nodes. Time from definitive breast surgery (lumpectomy or reexcision) to the initiation of breast irradiation was 21-314 days, with a median of 124 days. Forty-two patients began receiving radiation therapy before 120 days (early) and 42 more than 120 days after surgery (delayed). In the early group, cyclophosphamide/methotrexate/5-fluorouracil (CMF) was administered to 32 patients, doxorubicin, cyclophosphamide or cyclophosphamide, doxorubicin, 5-fluorouracil (AC or CAF) to 6 patients, and other regimens to 4 patients; in the delayed group, CMF was given to 29 patients, CAF to 12 patients, and L-PAM/5-fluorouracil to 1 patient. RESULTS: Median follow-up was 62 months. There was one breast recurrence in the early group, compared with six in the patients receiving delayed irradiation. The actuarial relapse rates for these groups at 5 years were 2% and 14%, respectively (P = 0.05). Survival and distant disease free survival were not significantly different between the two groups. CONCLUSIONS: Delays in the initiation of irradiation are associated with increased risk of relapse in the breast. When possible, the interval between definitive breast surgery (lumpectomy or reexcision) and the initiation of radiation therapy should be fewer than 120 days.

Combined modality therapy for locally advanced non-small cell lung carcinoma.

Multi-modality treatment consisting of cisplatin, VP-16, and 5-fluorouracil chemotherapy given concomitantly with external beam radiation was used to treat 64 patients with locally advanced Stage III non-small cell lung carcinoma. This regimen was used in a preoperative fashion for four cycles in patients considered surgically resectable and with curative intent for six cycles in the remainder of patients. The clinical response rate for the entire group was 84% and the overall local control rate was 74%. The median survival was 13 months with a median follow-up for live patients of 19 months. The actuarial 3-year survival and disease-free survival rates were 30% and 23%, respectively. Histologic complete response was 39% and appeared to predict for survival. The 3-year actuarial survival and disease-free survival rates for 23 resected patients were 69% and 45%, respectively, with the complete histologic responders having a disease-free survival of 78%. The pattern of first recurrence did not appear to differ by histology or presence of lymph nodes in this subset of patients. The actuarial 3-year survival and disease-free survival rates for inoperable patients receiving six cycles of treatment were 18% and 23%, respectively. The local control was 67% with the majority of these patients having Stage IIIB disease. The Mountain International staging system appeared to predict for operability, local recurrence, and survival. This concomitant treatment regimen is feasible, with the major toxicities being leukopenia, nausea, and vomiting.

Long-term results of curative irradiation in pathologically staged IA and IIA Hodgkin disease.

One hundred seventy-six patients with pathologically staged IA and IIA Hodgkin disease (HD) treated with irradiation alone were evaluated for long-term survival and freedom from relapse (FFR). Most of the patients received treatment to mantle and paraaortic fields; chemotherapy was not given except as salvage therapy. For pathologically staged IA disease, the 5-, 10-, and 15-year survival rates were 94%; the corresponding FFR rates were 96%, 93%, and 93%. For pathologically staged IIA disease, respective survival rates were 93%, 89%, and 80%, with FFR rates of 86%, 84%, and 84%. Twenty-one patients (12%) had relapse of HD; salvage therapy was successful in 11 of these patients. Pelvic recurrence was uncommon (three of 176 cases [2%]). No patient developed leukemia, and only two patients developed second malignancies (lung cancer in both cases). The authors conclude that radiation therapy is effective in treatment of early-stage HD.

Concomitant cisplatin/5-FU infusion and radiotherapy in advanced head and neck cancer: 8-year analysis of results.

BACKGROUND: The purpose of this study was to analyze long-term follow-up of a single institution's experience with a regimen of concomitant cisplatin/fluorouracil (5-FU) infusion and radiation given every other week. This analysis was stimulated by results of a randomized trial showing superiority for this regimen over induction cisplatin/5-FU chemotherapy followed by radiotherapy, especially in regional disease control. METHODS: All patients with stage III/IV disease who were referred by surgeons for nonoperative therapy and had a follow-up of at least 2 years were included. Concomitant chemoradiotherapy was administered days 1-5 of a 2-week treatment cycle, for a total of 7 cycles, with cisplatin 60 mg/m2 day 1, 5-FU 800 mg/m2 given over 24 hours days 1-5, and radiation 2 Gy days 1-5. RESULTS: Seventy-eight patients with stage III (n = 16) or IV (n = 62) were treated and followed for a median of 8 years. Six patients died during treatment, of aspiration pneumonia, sudden death, gastrointestinal bleeding, and stroke. When assessed 6 weeks after the end of treatment, 45 patients (63%) had no clinical evidence of disease, whereas 27 (37%) still had some persistent abnormality. However, 17 of these "partial responders" have not recurred. In all, 24 patients (31%) have recurred or progressed, 13 at the primary site, 5 after 3 years. None of 16 stage III and 24 (39%) of 62 stage IV patients ever progressed. Tongue and glottic larynx did best, with only 1 of 22 patients ever failing (none locally). Supraglottic and oral cavity cancers other than tongue had the worst failure rates. Nineteen patients (24%) died of other causes (DOC), tumor-free. Patients who DOC correlated strongly with T stage (p < .002) but not with N stage or with AJC stage. The 5-year progression-free survival was 60% (confidence interval [CI] = 49% to 72%), and overall survival was 43% (CI = 33% to 56%). CONCLUSIONS: Disease control for this advanced head and neck cancer population was excellent. This regimen was especially effective in advanced tongue and glottic cancers and all stage III disease sites. Advanced supraglottic and hypopharynx cancers are problematic. These, and especially T4 lesions, are associated with high DOC rates, possibly in part related to swallowing malfunction. Nevertheless, the long-term survival without surgical intervention was high with this regimen.