Esophageal carcinoma advances in treatment results for locally advanced disease: review.

The treatment results of patients with locally advanced esophageal carcinomas have evolved since the publication of the first trial of concurrent mitomycin C and 5-fluorouracil with radiotherapy (RT) in 1983. Subsequent studies refined and improved on the concurrent chemotherapy (chemo) with administration of cisplatin and 5-fluorouracil infusion (PF). Chemo (PF) before surgery improved overall survival (OS) in those patients in most of the randomized trials and in meta-analyses. Two courses of PF concurrent with irradiation followed by additional two courses of PF were superior to RT alone without surgery for both groups. Concurrent chemoradiotherapy followed by surgery was found to have statistically improved OS as compared with surgery only in randomized trials and meta-analyses. In most of these studies, it was found that those patients with pathologic complete response to the initial treatment(s) did better than those who had no improvement at all. Current treatment outcome for these diseases is disappointing; newer strategies including induction chemo with the optimal combination, proper dosage of each drug, and proper number of courses before concurrent chemoradiotherapy; improvement in RT; and immunotherapy with or without subsequent surgery are exciting and definitely need to be investigated in prospective randomized trial(s).

Sparing of the hippocampus and limbic circuit during whole brain radiation therapy: A dosimetric study using helical tomotherapy.

INTRODUCTION: The study aims to assess the feasibility of dosimetrically sparing the limbic circuit during whole brain radiation therapy (WBRT) and prophylactic cranial irradiation (PCI). METHODS AND MATERIALS: We contoured the brain/brainstem on fused MRI and CT as the target volume (PTV) in 11 patients, excluding the hippocampus and the rest of the limbic circuit, which were considered organs at risk (OARs). PCI and WBRT helical tomotherapy plans were prepared for each patient with a 1.0-cm field width, pitch = 0.285, initial modulation factor = 2.5. We attempted to spare the hippocampus and the rest of the limbic circuit while treating the rest of the brain to 30 Gy in 15 fractions (PCI) or 35 Gy in 14 fractions (WBRT) with V(100) >or= 95%. The quality of the plans was assessed by calculating mean dose and equivalent uniform dose (EUD) for OARs and the % volume of the PTV receiving the prescribed dose, V(100). RESULTS: In the PCI plans, mean doses/EUD were: hippocampus 12.5 Gy/14.23 Gy, rest of limbic circuit 17.0 Gy/19.02 Gy. In the WBRT plans, mean doses/EUD were: hippocampus 14.3 Gy/16.07 Gy, rest of limbic circuit 17.9 Gy/20.74 Gy. The mean V(100) for the rest of the brain (PTV) were 94.7% (PCI) and 95.1% (WBRT). Mean PCI and WBRT treatment times were essentially identical (mean 15.23 min, range 14.27-17.5). CONCLUSIONS: It is dosimetrically feasible to spare the hippocampus and the rest of the limbic circuit using helical tomotherapy while treating the rest of the brain to full dose.

The influence of gender on survival and tumor recurrence following adjuvant therapy of completely resected stages II and IIIa non-small cell lung cancer.

This study evaluates the influence of gender on survival and tumor recurrence following adjuvant therapy of completely resected stages II and IIIa non-small cell lung cancer (NSCLC). The Eastern Cooperative Oncology Group conducted a randomized prospective trial of adjuvant therapy in patients with completely resected stages II and IIIa NSCLC. A laboratory correlative study assessed the prevalence and prognostic significance of p53 and K-ras mutations. Patients were randomized to receive either radiotherapy (RT) alone or four cycles of cisplatin and VP-16 administered concurrently with radiotherapy (CRT). Median survival was 35 months for the 285 men and 41 months for the 203 women enrolled in the study (P = 0.12). The relative risk (RR) of death for men vs women was 1.19 (95% confidence interval [CI], 0.95-1.49). Median survival of the 147 men and 95 women randomized to the RT arm was 39 months each (P = 0.35). Median survival of the 138 men and 108 women randomized to the CRT arm was 30 and 42 months, respectively (P = 0.18). Disease recurrence patterns were similar between the genders. Univariate and multivariate analyses demonstrated improved survival for women with tumors of non-squamous histology (P < 0.01). The distribution of p53 and K-ras mutations was similar between the genders and had no influence on survival. Gender does not influence survival following adjuvant RT or CRT administered to patients with completely resected stages II and IIIa NSCLC. However, women with non-squamous histology have increased survival when compared to men.

A randomized trial of postoperative adjuvant therapy in patients with completely resected stage II or IIIA non-small-cell lung cancer. Eastern Cooperative Oncology Group.

BACKGROUND: We conducted a randomized trial to determine whether combination chemotherapy plus thoracic radiotherapy is superior to thoracic radiotherapy alone in prolonging survival and preventing local recurrence in patients with completely resected stage II or IIIa non-small-cell lung cancer. METHODS: After surgical staging and resection of the tumor (usually by lobectomy or pneumonectomy), the patients were randomly assigned to receive either four 28-day cycles of cisplatin (60 mg per square meter of body-surface area intravenously on day 1) and etoposide (120 mg per square meter intravenously on days 1, 2, and 3) administered concurrently with radiotherapy (a total of 50.4 Gy, given in 28 daily fractions) or radiotherapy alone (a total of 50.4 Gy, given in 28 daily fractions). RESULTS: Of the 488 patients who were enrolled in the study, 242 were assigned to receive radiotherapy alone and 246 were assigned to receive chemotherapy and radiotherapy. The median duration of follow-up was 44 months. Treatment-associated mortality was 1.2 percent in the group given radiotherapy alone and 1.6 percent in the group given chemotherapy and radiotherapy. The median survival was 39 months in the group given radiotherapy and 38 months in the group given chemotherapy and radiotherapy (P= 0.56 by the log-rank test). The relative likelihood of survival among patients assigned to receive chemotherapy and radiotherapy, as compared with those assigned to receive radiotherapy alone, was 0.93 (95 percent confidence interval, 0.74 to 1.18). Intrathoracic disease recurred within the radiation field in 30 of 234 patients (13 percent) in the group given radiotherapy and in 28 of 236 patients (12 percent) in the group given chemotherapy and radiotherapy (P=0.84); data on recurrence were not available for 18 patients. CONCLUSIONS: As compared with radiotherapy alone, adjuvant radiotherapy and chemotherapy with cisplatin and etoposide does not decrease the risk of intrathoracic recurrence or prolong survival in patients with completely resected stage II or IIIa non-small-cell lung cancer.

Accelerated hyperfractionation in patients with non-small cell bronchogenic cancers as a cost-effective and user- and patient-friendly schedule.

We developed an accelerated hyperfractionation schedule with acceptable effect and toxicity in non-small cell bronchogenic carcinomas. An evolutionary institutional pilot was initiated in March 1995 as a modification of Radiation Therapy Oncology Group (RTOG) 9205, thrice-daily fractionation schedule. Twenty-nine patients with bronchogenic and 7 with head and neck cancers had treatment initiated and completed. A dose of 1.2 Gy was delivered to a mediastinal plus tumor field concomitantly with synchronous boost of 0.6 Gy to a limited volume of gross tumor (twice daily for 21 treatments days in 4 weeks) with a total dose being 75.60 Gy to the primary gross tumor and 50.4 Gy to the elective volume. The bronchogenic cancers were stages IB (medically unresectable, n = 3), IIB (n = 4), IIIA (n = 4), or IIIB (n = 18). Eleven patients had squamous cell cancers, 13 adenocarcinomas, 1 large cell, and 2 carcinomas not specified. With 12 months median follow-up, tolerance has been excellent without any patient complaining of at least Oncology Nursing Society (ONS) grade 3 esophagitis; treatment interruptions occurred in only one patient after 8 days. Weight loss occurred in 12 patients, averaging 4.8% for these patients and 2% overall. Seven patients had a complete response and 20 a partial response. Median survival was 12 months, 1-year survival 58%, 2-year 21%, and 3-year 18%. Seven patients with bronchogenic cancer are still alive. Seven head and neck cancer patients were treated, in which five had base of tongue tumors stage T2 to 4, N0 to N1. Pharyngitis and mucositis were problematic in at least four patients. The outcomes are comparable with other RTOG experience. Hyperfractionated synchronous concomitant boost of total tumor dose to 75.6 Gy in 4 weeks for bronchogenic patients was well tolerated and acceptable to physicians and patients.

Accelerated hyperfractionation for bronchogenic cancer: Radiation Therapy Oncology Group 9205.

RTOG 92-05 was a phase II trial developed to evaluate the feasibility, toxicity, and acceptance of a three times daily accelerated hyperfractionation radiation therapy schedule delivering 110 cGy, three times daily, to 79.2 Gy uncorrected tumor dose in 72 fractions, in 24 treatment days, in patients with bronchogenic cancer. The radiographically visible tumor received accelerated hyperfractionation and the other radiation volume received standard hyperfractionation. Three times a day, a dose of 110 cGy was delivered, with an interfractional interval of 4 hours; the middle fraction was a gross tumor boost. This schedule allowed treatment to be completed in approximately 4 1/2 weeks in an effort to minimize repopulation, to have a better biologically modeled therapeutic ratio than other schedules that have been completed in cooperative groups, and to use doses within cooperative group experience. In 33 months 35 patients were entered into the study; 15 of the patients had squamous cell carcinomas, 10 had adenocarcinomas, 8 had large-cell undifferentiated carcinomas, and 2 had unspecified non-small-cell cancers. Nineteen patients had AJCC stage IIIB; 13, IIIA; 14, T4; 10, T3; 13, N2; and 7, N3. Twenty-one patients (60%) had greater than 5% weight loss. The Karnofsky performance status was 90 to 100 in 12 patients and 70 to 80 in 23 patients. Treatment was completed in 91% of patients. Acute toxicity >RTOG grade II occurred in three patients: one skin, one lung, and two esophagus (one each III and IV, the only grade IV in the study). Overall late toxicity > or = grade III occurred in six patients: three lung, one thyroid, one esophagus, and one subcutaneous tissue (all grade III). The median survival was 10.5 months, 1-year survival was 42%, and 3-year survival was 18%. The outcome in this group of patients with many adverse prognostic variables compared favorably to prior RTOG radiation-alone studies.

A phase I/II study of external beam radiation, brachytherapy, and concurrent chemotherapy for patients with localized carcinoma of the esophagus (Radiation Therapy Oncology Group Study 9207): final report.

BACKGROUND: A multiinstitutional, prospective study of the Radiation Therapy Oncology Group (RTOG) was designed to determine the feasibility and toxicity of chemotherapy, external beam radiation, and esophageal brachytherapy (EB) in a potentially curable group of patients with adenocarcinoma or squamous cell carcinoma of the esophagus. A preliminary analysis indicated a 17% 1-year actuarial risk of treatment-related fistulas. A final analysis of this study was considered important to determine the median survival time, local control, and late toxicity associated with this treatment regimen. METHODS: Planned treatment was 50 grays (Gy) of external beam radiation (25 fractions given over 5 weeks) followed 2 weeks later by EB (either high-dose-rate 5 Gy during Weeks 8, 9, and 10, for a total of 15 Gy, or low-dose-rate 20 Gy during Week 8). Chemotherapy was given during Weeks 1, 5, 8, and 11, with cisplatin 75 mg/m(2) and 5-fluorouracil 1000 mg/m(2)/24 hours in a 96-hour infusion. RESULTS: Of the 49 eligible patients, 45 (92%) had squamous histology and 4 (6%) had adenocarcinoma. Forty-seven patients (96%) completed external beam radiation plus at least 2 courses of chemotherapy, whereas 34 patients (69%) were able to complete external beam radiation, EB, and at least 2 courses of chemotherapy. The estimated survival rate at 12 months was 49%, with an estimated median survival of 11 months. Life-threatening toxicity or treatment-related death occurred in 12 (24%) and 5 (10%) cases, respectively. Treatment-related esophageal fistulas occurred in 6 cases (12% overall, 14% of patients starting EB) at 0.5-6.2 months from the first day of brachytherapy, leading to death in 3 cases. CONCLUSIONS: In this study, severe toxicity, including treatment-related fistulas, occurred within 7 months of brachytherapy. Based on the 12% incidence of fistulas, the authors continue to urge caution in employing EB, particularly when used in conjunction with chemotherapy.

Chemoradiotherapy of locally advanced esophageal cancer: long-term follow-up of a prospective randomized trial (RTOG 85-01). Radiation Therapy Oncology Group.

CONTEXT: Carcinoma of the esophagus traditionally has been treated by surgery or radiation therapy (RT), but 5-year overall survival rates have been only 5% to 10%. We previously reported results of a study conducted from January 1986 to April 1990 of combined chemotherapy and RT vs RT alone when an interim analysis revealed significant benefit for combined therapy. OBJECTIVE: To report the long-term outcomes of a previously reported trial designed to determine if adding chemotherapy during RT improves the survival rate of patients with esophageal carcinoma. DESIGN: Randomized controlled trial conducted 1985 to 1990 with follow-up of at least 5 years, followed by a prospective cohort study conducted between May 1990 and April 1991. SETTING: Multi-institution participation, ranging from tertiary academic referral centers to general community practices. PATIENTS: Patients had squamous cell or adenocarcinoma of the esophagus, T1-3 N0-1 M0, adequate renal and bone marrow reserve, and a Karnofsky score of at least 50. Interventions Combined modality therapy (n = 134): 50 Gy in 25 fractions over 5 weeks, plus cisplatin intravenously on the first day of weeks 1, 5, 8, and 11, and fluorouracil, 1 g/m2 per day by continuous infusion on the first 4 days of weeks 1, 5, 8, and 11. In the randomized study, combined therapy was compared with RT only (n = 62): 64 Gy in 32 fractions over 6.4 weeks. MAIN OUTCOME MEASURES: Overall survival, patterns of failure, and toxic effects. RESULTS: Combined therapy significantly increased overall survival compared with RT alone. In the randomized part of the trial, at 5 years of follow-up the overall survival for combined therapy was 26% (95% confidence interval [CI], 15%-37%) compared with 0% following RT. In the succeeding nonrandomized part, combined therapy produced a 5-year overall survival of 14% (95% CI, 6%-23%). Persistence of disease (despite therapy) was the most common mode of treatment failure; however, it was less common in the groups receiving combined therapy (34/130 [26%]) than in the group treated with RT only (23/62 [37%]). Severe acute toxic effects also were greater in the combined therapy groups. There were no significant differences in severe late toxic effects between the groups. However, chemotherapy could be administered as planned in only 89 (68%) of 130 patients (10% had life-threatening toxic effects with combined therapy vs 2% in the RT only group). CONCLUSION: Combined therapy increases the survival of patients who have squamous cell or adenocarcinoma of the esophagus, T1-3 N0-1 M0, compared with RT alone.

Phase II study of hyperfractionated radiotherapy and concurrent weekly alternating chemotherapy in limited-stage small cell lung cancer.

Despite recent advances in combined modality therapy, long-term survival remains elusive in most patients with limited-stage small cell lung cancer (SCLC). The present study was designed to evaluate the activity and toxicity of concurrent hyperfractionated radiotherapy and weekly, alternating-regimen chemotherapy. Twelve patients with limited-stage SCLC and performance status 0-1 were treated with cyclophosphamide 250 mg/m2, etoposide 100 mg/m2, and cisplatin 50 mg/m2 on day 1 every other week, and vincristine 1 mg/m2 on day 8, and ifosfamide 1.2 mg/m2 on days 8 and 9 every other week. Hyperfractionated thoracic radiotherapy, consisting of three daily doses of 1.1 Gy for 20 days to a total dose of 66 Gy, was started on day 1 of chemotherapy. Ten patients (83%) exhibited an objective response (9 CRs and 1 PR) with a median duration of response of 8.6 months. Two complete responders died at 50 and 53 months without evidence of progression and two remain alive and free of SCLC at 73 and 87 months. Median survival was 19.8 months with 2- and 5-year survival rates of 50 and 17%, respectively. Severe toxicity, including grade 3-4 esophagitis (67%) and granulocytopenia (83%), as well as debilitating fatigue and pneumonitis, prompted early termination of the trial. Hyperfractionated radiotherapy and concurrent weekly alternating-regimen chemotherapy resulted in promising response and survival rates, but induced excessive toxicity, in patients with limited-stage SCLC.

Recursive partitioning analysis of 1592 patients on four Radiation Therapy Oncology Group studies in inoperable non-small cell lung cancer.

Survival outcome of 1592 analyzable patients on four Radiation Therapy Oncology Group (RTOG) studies in inoperable non-small cell lung cancer were studied utilizing a recursive partitioning analysis (RPA). This approach creates a regression tree according to prognostic variables which partitions into homogenous subsets according to survival. Four protocols, RTOG 83-11, 83-21, 84-03 and 84-07 were analyzed. 83-11 and 84-07 were studies utilizing irradiation with alterfractionation; 83-21 and 84-03 were studies evaluating thymocin with irradiation and prophylactic cranial irradiation with thoracic irradiation respectively. Nine pretreatment variables and one treatment variable were analyzed. Adjustment for radiotherapy effect was made in the accelerated treatment protocol (84-07). Overall, median survival for the entire group was 9.0 months with 17% alive at 2 years. Univariate analysis suggests that KPS, < or = 70 vs. 80-100, pleural effusion, weight loss, < or = 5% vs. 5%, age, 60+ vs. < 60, T stage (T1 and T2 vs. T3 and T4) and N stage (N- vs. N+) were important prognastic factors. Radiation dose, sex, race and histology were not univariate prognastic factors. RPA identified KPS as the most significant covariate (median survival 5.9 mos. < or = 70 vs. 9.9 mos. 80-100). Within KPS 80-100 other splits occurred for N stage, age, weight loss and radiation therapy dose. KPS < or = 70 split at pleural effusion only. The best overall RPA tree has four distinct classes with median survival times ranging from 3.3 to 12.6 months. The RPA classes were validated in an independent non-small cell lung cancer dataset. This analysis may allow more intelligent stratification and study-design for future RTOG trials in inoperable non-small cell lung cancer.

American Brachytherapy Society (ABS) consensus guidelines for brachytherapy of esophageal cancer. Clinical Research Committee, American Brachytherapy Society, Philadelphia, PA.

INTRODUCTION: There is wide variation in the indications, treatment regimens, and dosimetry for brachytherapy in the treatment of cancer of the esophagus. No guidelines for optimal therapy currently exist. METHODS AND MATERIALS: Utilizing published reports and clinical experience, representatives of the Clinical Research Committee of the American Brachytherapy Society (ABS) formulated guidelines for brachytherapy in esophageal cancer. RESULTS: Recommendations were made for brachytherapy in the definitive and palliative treatment of esophageal cancer. (A) Definitive treatment: Good candidates for brachytherapy include patients with unifocal thoracic adeno- or squamous cancers < or = 10 cm in length, with no evidence of intra-abdominal or metastatic disease. Contraindications include tracheal or bronchial involvement, cervical esophagus location, or stenosis that cannot be bypassed. The esophageal brachytherapy applicator should have an external diameter of 6-10 mm. If 5FU-based chemotherapy and 45-50-Gy external beam are used, recommended brachytherapy is either: (i) HDR 10 Gy in two weekly fractions of 5 Gy each; or (ii) LDR 20 Gy in a single course at 0.4-1 Gy/hr. All doses are specified 1 cm from the midsource or mid-dwell position. Brachytherapy should follow external beam radiation therapy and should not be given concurrently with chemotherapy. (B) Palliative treatment: Patients with adeno- or squamous cancers of the thoracic esophagus with distant metastases or unresectable local disease progression/recurrence after definitive radiation treatment should be considered for brachytherapy with palliative intent. After limited dose (30 Gy) EBRT, the recommended brachytherapy is either: (i) HDR 10-14 Gy in one or two fractions; or (ii) LDR 20-25 Gy in a single course at 0.4-1 Gy/hr. The need for external beam radiation in newly diagnosed patients with a life expectancy of less than 3 months is controversial. In these cases, HDR of 15-20 Gy in two to four fractions or LDR of 25-40 Gy at 0.4-1 Gy/hr may be of benefit. CONCLUSION: ABS guidelines for esophageal brachytherapy now exist and will be updated by the ABS in the future, as clinical data using more uniform treatment techniques becomes available.

A phase I/II study of external beam radiation, brachytherapy and concurrent chemotherapy in localized cancer of the esophagus (RTOG 92-07): preliminary toxicity report.

PURPOSE: A multi-institutional, prospective study was designed to determine the feasibility and tolerance of external beam irradiation plus concurrent chemotherapy and esophageal brachytherapy (EB) in a potentially curable group of patients with adenocarcinoma or squamous cell carcinoma of the esophagus. METHODS AND MATERIALS: Planned treatment was 50 Gy external beam radiation (25 fractions/5 weeks) followed 2 weeks later by EB [either high dose rate (HDR) 5 Gy, weeks 8, 9, and 10, for a total of 15 Gy, or low dose rate (LDR) 20 Gy, week 8]. The protocol was later revised to delete the LDR alternative, owing to poor accrual, and to decrease the HDR dose to 10 Gy (i.e. 5 Gy, weeks 8 and 9). Chemotherapy was given weeks 1, 5, 8, and 11 with cisplatin 75 mg/m2 and 5-fluorouracil 1000 mg2/m per 24 h, 96-h infusion. The study closed in January 1995 after 56 patients had been entered on the HDR arm. Six patients were declared ineligible owing to tumor extension to the gastroesophageal junction (three patients) or involved celiac lymph nodes (three patients). Of the 50 eligible patients, the planned EB dose was 15 and 10 Gy in 40 and 10 patients, respectively. Forty-six (92%) of the eligible patients had squamous histology, and three (6%) adenocarcinoma. RESULTS: Life-threatening toxicity or treatment-related death occurred in 13 (26%) and 4 (8%) of the 50 eligible patients, respectively. Treatment-related esophageal fistulas occurred in three patients (12% overall, 14% of patients starting EB) at 0.5-6.2 months from the first day of brachytherapy, leading to death in three. The fourth death was secondary to renal toxicity and infection attributed to chemotherapy. No correlation was found between the development of fistula and location of primary tumor, brachytherapy active length or applicator diameter. So far, 5 of the 6 treatment-related fistulas have occurred following 15 Gy EB. The other fistula occurred after only 5 Gy of a planned 15 Gy was delivered. CONCLUSION: Thirty-five patients (70%) were able to complete external beam, EB, and at least two courses of chemotherapy. Estimated survival rate at 12 months is 48%, with an estimated 11-month median survival rate. Survival following external beam radiation plus concurrent chemotherapy and EB does not appear to be significantly different from survival seen following external beam radiation and chemotherapy only. The development of six fistulas in the 35 patients completing EB is of concern. Based on the high incidence of fistulas, we urge extreme caution in employing EB as a boost following concurrent external beam radiation and chemotherapy.

Progress report of combined chemoradiotherapy versus radiotherapy alone in patients with esophageal cancer: an intergroup study.

PURPOSE: The present intergroup phase III randomized study compared combined chemotherapy (CT) plus radiotherapy (RT) treatment versus RT only in patients with locally advanced esophageal cancer. MATERIALS AND METHODS: Two courses of chemotherapy during 50 Gy RT followed by additional two courses of the same CT, versus 64 Gy RT alone were investigated. CT consisted of cisplatin 75 mg/m2 on day 1 [corrected] and fluorouracil (5FU) 1,000 mg/m2/d on days 1 to 4 every 4 weeks with RT and every 3 weeks post-RT. The main objective of the study was to compare overall survival between the two randomized treatment groups. Patients were stratified by tumor size, histology, and degree of weight loss. RESULTS: Sixty-two assessable patients were randomized to receive RT alone, and 61 to the combined arm. Patients characteristics were as follows: squamous cell cancer, 90% versus 85%; weight loss greater than 10 lb, 61% versus 69%; and tumor size, > or = 5 cm, 82% versus 80% on the RT and CT-RT arms, respectively. Systemic side effects, which consisted of nausea, vomiting, and renal and myelosuppression, occurred more frequently on the combined arm, while local side effects were similar in both groups. With a minimum follow-up time of 5 years for all patients, the median survival duration was 14.1 months and the 5-year survival rate was 27% in the combined treatment group, while the median survival duration was 9.3 months with no patients alive at 5 years in the RT-alone group (P < .0001). Additional patients (69) were treated with the same combined therapy and were analyzed. The results of the last group confirmed all of the results obtained with combined CT-RT in the randomized trial, with a median survival duration of 17.2 months and 3-year survival rate of 30%. CONCLUSION: We conclude that cisplatin and 5FU infusion given during and post-RT of 50 Gy is statistically superior to standard 64-Gy RT alone in patients with locally advanced esophageal cancer.

Combination of 5-Fluorouracil and Radiation in Esophageal Cancer.

A review of the trends in the clinical practice of esophageal cancer treatment is presented. The preponderance of evidence indicates that concomitant chemotherapy and radiation is superior to either modality above. Chemotherapy usually, but not invariably, consists of 5-fluorouracil (5-FU) and cisplatin; radiotherapy is usually 50 Gy. Attempts to escalate to higher dose by external-beam boost or brachytherapy is still experimental. Combination treatment with surgery is also successful, but the inclusion of esophagectomy in the treatment is not universally accepted and is unlikely to be tested. A suggestion to base treatment selection on response is proposed.

Evaluation of multimodality treatment of locoregional esophageal carcinoma by Southwest Oncology Group 9060.

BACKGROUND: Continuous infusion 5-fluorouracil (CI5-FU) has been utilized concurrently with radiotherapy to improve tumor control. In this pilot trial, cisplatin, CI5FU, and radiotherapy were utilized for the treatment of locoregional esophageal carcinoma. It was postulated that the combination would be well tolerated and associated with high response rate and survival duration. METHODS: Thirty-two eligible patients with locoregional squamous cell carcinoma and adenocarcinoma of the esophagus received a regimen consisting of the following: radiotherapy, 50 Gray (Gy) (30 Gy anteroposterior/posteroanterior regional with 20 Gy AP/LPO/RPO boost) over 5 weeks, with CI5-FU 250 mg/m2/d for the duration of radiotherapy and cisplatin 25 mg/m2/day on Days 1-3 during Weeks 1 and 4 of the radiotherapy cycle. Upon completion of radiotherapy, two additional course, of cisplatin 75 mg/m2 on Days 1 and 29 and CI5-FU 300 mg/m2/day on Days 1-21 and 29-50 were delivered. Following imaging and endoscopic reassessment, patients with no evidence of disease received more chemotherapy. Surgery was suggested only for patients with residual local disease. RESULTS: Complete response was demonstrated in 44% of patients, clinically in 12 patients, and during surgery in 2 others. The median survival was 20 months, and the 1-year survival rate was 59%. Toxicity was severe, comprised of esophagitis, infection, and gastrointestinal complications. Dose delays and reductions occurred in the majority of patients. Four early deaths were noted. CONCLUSIONS: The regimen that was the focus of this trial has been active in the treatment of esophageal carcinoma. However, compared with existing regimens, its complexity and toxicity preclude its future use without modifications.

Phase I/II study of treatment of locally advanced (T3/T4) non-oat cell lung cancer with concomitant boost radiotherapy by the Radiation Therapy Oncology Group (RTOG 83-12): long-term results.

PURPOSE: This pilot study was undertaken to evaluate the effect of high dose-per-fraction radiotherapy given to the tumor primary concurrently with conventional fractionated radiotherapy to the electively irradiated regional lymph nodes (concomitant boost). This article reports the late results of toxicity and survival. METHODS AND MATERIALS: Fifty-nine patients with histologically proven clinical Stage T3-T4, N1-3 nonsmall cell lung cancer were prospectively enrolled in this study. Fifty-six were evaluable for late effects. The treatment delivered 2.68 Gy daily to the primary tumor, 5 days a week, to a total dose of 75 Gy in 28 fractions in 5.5 weeks. At the same treatment sessions, the electively irradiated nodal areas received 1.8 Gy daily, 5 days per week, to a total dose of 50.4 Gy. All doses were calculated with heterogeneity corrections for lung density. RESULTS: Presently, one patient remains alive at 7.7 years. Median survival was 10.0 months with 1-, 2-, 3-, and 5-year survival rates of 41%, 25%, 18%, and 4%, respectively. Three patients developed severe late complications, including pulmonary fibrosis and osteonecrosis. The remainder of the patients, however, developed only grade 1 or 2 pulmonary fibrosis and/or pneumonitis. CONCLUSION: We conclude that concomitant boost radiotherapy in the manner reported resulted in acceptable late toxicity. The 2- and 3-year survivals compared favorably with the best-reported results in the literature with either hyperfractionated or chemoradiotherapy treatment. Studies that deliver higher radiotherapy doses to the gross tumor combined with chemotherapy are in order.

Chemoradiotherapy of esophageal carcinoma.

BACKGROUND: Chemoradiotherapy has demonstrated efficacy in esophageal cancer but rarely is curative. To improve local control and decrease metastases, a 7-month regimen was used with standard-dose radiotherapy (RT), cisplatin (DDP), and continuous infusion (CI) 5-fluorouracil (5-FU) in patients with locoregional squamous/adenocarcinoma of the esophagus. METHODS: Initial treatment consisted of RT to the esophagus (4000-5000 cGy) for 5-6 weeks, CI 5-FU (300 mg/m2/day) concurrent with RT, and DDP (25 mg/m2/day x 3) for Days 1-3 and 21-23. Two monthly cycles of DDP (75 mg/m2 Day 1) and 5-FU (300 mg/m2 x 21 days) followed. Patients were restaged with endoscopy and computed tomography scan. Patients without evidence of residual disease received three more cycles of chemotherapy (CT); those with persistent tumor underwent esophagectomy or additional CT/RT, and those with disease progression were offered alternative CT. RESULTS: From December 1987 to September 1991, 18 men and 8 women, including 2 with adenocarcinoma, were eligible for inclusion in the study. All were evaluable for toxicity and response. The median age was 61.5 years (range, 50-80 years), the median pretreatment weight loss was 9 lbs, and the median serum albumin level was 4.3 mg%. Therapy was toxic; 19 patients were hospitalized for treatment-related esophagitis, thrombosis, or infection. Grade III and IV leucopenia were seen in 12 patients and 1 patient, respectively. One patient had Grade IV thrombocytopenia. Of 26 patients, 17 (65%) had no tumor on restaging. Five patients had recurrences in the esophagus (1), liver (3), and lung (2). Three patients had second neoplasms. The median survival was 24 months. CONCLUSION: This treatment regimen provides high frequency of local tumor resolution, but with significant toxicity.

A phase I/II study to evaluate accelerated fractionation via concomitant boost for squamous, adeno, and large cell carcinoma of the lung: report of Radiation Therapy Oncology Group 84-07.

PURPOSE: A Phase I/II trial was conducted by the Radiation Therapy Oncology Group from 1984 to 1989 for 355 evaluable patients with non-small-cell lung cancer to assess tolerance to and efficacy of accelerated fractionation irradiation via concomitant boost. METHODS AND MATERIALS: "Large" fields (primary tumor and locoregional lymph nodes) received 1.8 Gy followed after 4 to 6 hr by 1.8 Gy two to three times weekly to reduced "boost" fields (primary and involved nodes only). The total doses escalated during the study and started with 63 Gy in 5 weeks (45 Gy "large" field and 18 Gy "boost") for 61 patients. After follow-up for ongoing toxicity assessment, the total dose was increased to 70.2 Gy in 5.5 weeks (50.4 Gy "large" field and 19.8 Gy "boost") for the next 180 patients. The last 114 patients received 70.2 Gy in 5 weeks (45 Gy "large" field and 25.2 Gy "boost"). RESULTS: Pretreatment patient characteristics were well balanced between the three treatment arms. Grade 3 acute toxicity was 7% for the 63 Gy arm; it was 14% and 17% for the two 70 Gy arms. Grade 4 or greater acute toxicities (esophagitis and pneumonitis) were 2 to 3% for all three arms. Late toxicities ranged between 5 and 9% (> or = Grade 3) and 0 to 2% (> or = Grade 4), not statistically different among the three arms. There was no difference between the three regimens in median survival (9 months) or 1-year survival (39 to 44%). However, the 2-year survivals ranged from 16% (63 Gy) to 21% ("shortened" 70.2 Gy). Among 176 patients who had the same criteria as Cancer and Leukemia Group B protocol 84-33 (American Joint Committee on Cancer Staging, 1984, Stage III; Karnofsky performance status 70 to 100; < 6% weight loss), the 2-year survival rates ranged from 18 to 22%. CONCLUSION: Concomitant boost accelerated fractionation irradiation regimens for non-small cell lung cancer may offer improved long-term survival without enhanced late toxicity. While acute toxicity is somewhat increased, further refinement of the relationship of "large" to "boost" field doses may improve the therapeutic ratio. Further Phase I/II testing seems justified and necessary, before concomitant boost accelerated fractionation irradiation is tested in Phase III trials for NSCLC.

Total nodal radiation in progressive sarcoidosis. Case report.

The subject of this article is a patient with sarcoidosis with neurological involvement, who failed to respond to high dose steroid therapy and cyclophosphamide. Low doses (20 Gy) of total nodal and craniospinal irradiation resulted in an excellent response, the patient being alive and in good health 3 years after irradiation without any further steroid therapy.

Combined chemotherapy and radiotherapy compared with radiotherapy alone in patients with cancer of the esophagus.

BACKGROUND: The efficacy of conventional treatment with surgery and radiation for cancer of the esophagus is limited. The median survival is less than 10 months, and less than 10 percent of patients survive for 5 years. Recent studies have suggested that combined chemotherapy and radiation therapy may result in improved survival. METHODS: This phase III prospective, randomized, and stratified trial was undertaken to evaluate the efficacy of four courses of combined fluorouracil (1000 mg per square meter of body-surface area daily for four days) and cisplatin (75 mg per square meter on the first day) plus 5000 cGy of radiation therapy, as compared with 6400 cGy of radiation therapy alone, in patients with squamous-cell carcinoma or adenocarcinoma of the thoracic esophagus. The trial was stopped after the accumulated results in 121 patients demonstrated a significant advantage for survival in the patients who received chemotherapy and radiation therapy. RESULTS: The median survival was 8.9 months in the radiation-treated patients, as compared with 12.5 months in the patients treated with chemotherapy and radiation therapy. In the former group, the survival rates at 12 and 24 months were 33 percent and 10 percent, respectively, whereas they were 50 percent and 38 percent in the patients receiving combined therapy (P less than 0.001). Seven patients in the radiotherapy group and 25 in the combined-therapy group were alive at the time of the analysis. The patients who received combined treatment had fewer local (P less than 0.02) and fewer distant (P less than 0.01) recurrences. Severe and life-threatening side effects occurred in 44 percent and 20 percent, respectively, of the patients who received combined therapy, as compared with 25 percent and 3 percent of those treated with radiation alone. CONCLUSIONS: Concurrent therapy with cisplatin and fluorouracil and radiation is superior to radiation therapy alone in patients with localized carcinoma of the esophagus, as measured by control of local tumors, distant metastases, and survival, but at the cost of increased side effects.