Phase I study of escalating doses of low-dose-rate, locoregional irradiation preceding Cytoxan-TBI for patients with chemotherapy-resistant non-Hodgkin's or Hodgkin's lymphoma.

PURPOSE: In patients in whom bone marrow transplantation (BMT) fails, recurrence often occurs at sites known to have contained disease before initiating BMT. The purpose of this study was to find the maximal tolerable dose of locoregional irradiation (LRT) between 1000 and 2000 cGy that could be integrated with our Cytoxan-total body irradiation (TBI) BMT conditioning regimen in the treatment of lymphoma. METHODS AND MATERIALS: Patients had Hodgkin's or non-Hodgkin's lymphoma in chemotherapy-refractory relapse. All patients received LRT to a maximum of three sets of fields encompassing either all current or all previously known sites of disease. Cytoxan-TBI consisted of cyclophosphamide 50 mg/kg daily for 4 days followed by TBI of 1200 cGy given in four fractions. RESULTS: Twenty-one patients were enrolled. Radiation Therapy Oncology Group Grade 3 in-field acute toxicity was observed in 1 patient at each dose level up to 1500 cGy and in 3 of 6 patients receiving 2000 cGy. Clinically evident late toxicities were limited to hypothyroidism and one second malignancy occurring outside the LRT fields. CONCLUSION: Low-dose-rate, LRT with concurrent Cytoxan-TBI before BMT has acceptable rates of in-field toxicity for doses up to 1500 cGy in five fractions. This regimen safely permits the use of a total combined radiation dose of up to 2700 cGy during 2 weeks, with encouraging in-field response rates in treatment-refractory patients.

Intensified adjuvant therapy for pancreatic and periampullary adenocarcinoma: survival results and observations regarding patterns of failure, radiotherapy dose and CA19-9 levels.

PURPOSE: Primary endpoints were 1. To determine if, in the context of postoperative adjuvant therapy of pancreatic and nonpancreatic periampullary adenocarcinoma, continuous infusion (C.I.) 5-fluorouracil (5-FU) and leucovorin (Lv), combined with continuous-course external-beam radiotherapy (EBRT) to liver (23.4-27.0 Gy), regional lymph nodes (50.4-54.0 Gy) and tumor bed (50.4-57.6 Gy), followed by 4 months of C.I. 5-FU/Lv without EBRT could be given with acceptable toxicity. 2. To determine an estimate of disease-free and overall survival (DFS, OS) with this treatment in this context. Secondary endpoints were 1. To observe the effects of therapy at two different dose levels of irradiation, and 2. To observe for correlations among DFS, OS and CA 19-9 levels during therapy. METHODS: Patients received C.I. 5-FU 200 mg/m2 and Lv 5 mg/m2 Monday through Friday during EBRT, and 4 cycles of the same chemotherapy without EBRT were planned for each 2 weeks of 4, beginning 1 month following the completion of EBRT. Therapy was to begin within 10 weeks of surgery and patients were monitored for disease recurrence, toxicity, and CA 19-9 levels before the start of EBRT/5-FU/Lv, before each cycle of C.I. 5-FU/Lv, and periodically after the completion of therapy. There were two EBRT dosage groups: Low EBRT, 23.4 Gy to the whole liver, 50.4 Gy to regional nodes and 50.4 Gy to the tumor bed; High EBRT, 27.0 Gy to the whole liver, 54.0 Gy to regional nodes, and 57.6 Gy to the tumor bed. RESULTS: 29 patients were enrolled and treated (23 with pancreatic cancer, and 6 with nonpancreatic periampullary cancer). Of these, 18 had tumor sizes > or = 3 cm and 23 had at least one histologically involved lymph node; 6 had histologically positive resection margins. Mean time to start of EBRT/5-FU/Lv was 53 +/- 2 days following surgery. The first 18 patients were in the Low EBRT Group and the last 11 in the High EBRT Group. Toxicity was moderate and manageable, including a possible case of late radiation hepatitis. Median DFS was 8.3 months (pancreatic cancer patients 8.5 months) and OS was 14.1 months (pancreatic cancer patients 15.9 months). Among patients with pancreatic cancer, results were similar for the Low and High EBRT Groups (DFS: 8.3 vs. 8.6 months; OS: 14.4 vs. 16.9 months, respectively). With a mean follow up of 2.6 +/- 0.3 years for the surviving patients and a minimal follow-up of 2.5 years, 27 of 29 pts have relapsed and 25 pts have died. A rise in CA 19-9 levels preceded clinical relapse by 9.1 +/- 1.5 months. Time to first relapse by site showed inverse correlation with dose of radiotherapy to that site: peritoneal (5 +/- 1 month), hepatic (7 +/- 0.9 months), regional nodes/tumor bed (9.6 +/- 1.8 months). Mean postresection CA 19-9 level was 63.3 +/- 16.2 U/ml. Postresection CA 19-9 values did not correlate with survival, margin status, or with the identification of metastatic carcinoma in resected lymph nodes. However, among patients with histologically involved nodes in the resected specimen, postresection CA 19-9 values did correlate with the number of positive nodes identified (p = 0.05). CONCLUSIONS: Although toxicity was acceptable, survival results were not improved over those seen with standard adjuvant treatment. Most patients relapsed before the planned chemotherapy cycles were completed, or within 100 days thereof, suggesting disease resistance to C.I. 5-FU/Lv as used in this study. Although this regimen is not recommended for further study, the doses of EBRT utilized may be suitable for evaluation with other chemotherapy combinations. Postoperative CA 19-9 levels did not correlate with survival, but did correlate with the number of histologically involved lymph nodes found in the resected specimen among node-positive patients. Moreover, rising CA 19-9 levels anticipated ultimate clinical failure by 9 months.

Metastatic nonresectable fibrolamellar hepatoma: prognostic features and natural history.

Fibrolamellar hepatoma has a clinical course distinct from that of typical histologic hepatocellular carcinoma. The clinical behavior and prognostic features of nonresectable metastatic fibrolamellar hepatoma have not previously been fully addressed and are the focus of this report. Retrospective chart review of all patients (n = 17) with nonresectable metastatic fibrolamellar hepatoma referred to the Johns Hopkins Oncology Center from 1985 through 1990 was carried out. All patients had hepatic parenchymal involvement and regional node metastases at the time of referral. Metastases were limited to regional nodes in four patients. The remaining patients had lung metastases (n = 4), peritoneal metastases (n = 5), or both (n = 4). To assess the impact of the fibrolamellar variant, characteristic-matched control patients with typical histologic hepatocellular carcinoma were obtained from the Radiation Therapy Oncology Group database. Actuarial median survival from treatment was 14 months in the patients with fibrolamellar hepatoma and 7.7 months in the patients with hepatocellular carcinoma (p < 0.001). Karnofsky performance status and hepatic tumor volume at time of referral were important prognostic features. Multimodality treatment included radiation therapy and radiolabelled antibody, cisplatin-based chemotherapy, or both; results are discussed. Thirteen patients died, nine of liver failure, three of metastatic disease, and one of sepsis. Fibrolamellar histologic type, liver function tests, tumor volume, and patient performance status were significant predictors of survival. The cause of death in fibrolamellar hepatoma differs considerably from that observed in typical histologic hepatocellular carcinoma in the United States. The techniques of treatment of this uncommon disease were modeled after advances in the multimodality treatment of hepatocellular carcinoma and are discussed. Median survival was 14 months in patients with metastatic nonresectable fibrolamellar hepatoma.

Survival results among patients with alpha-fetoprotein-positive, unresectable hepatocellular carcinoma: analysis of three sequential treatments of the RTOG and Johns Hopkins Oncology Center.

PURPOSE: To analyze the observed therapeutic impact of the post-induction components of three treatment programs utilized sequentially between 1983 and 1991 for patients with unresectable alpha-fetoprotein-positive hepatoma. METHODS: Over a 7.5-year period, three treatment regimens were sequentially utilized: (1) RTOG 83-19, (2) a Johns Hopkins Oncology Center Institutional Pilot Program, and (3) RTOG 88-23. Each treatment program began with an induction phase of external-beam hepatic irradiation (2100 cGy/7 fractions), with concurrent doses of intravenous chemotherapy intended to be radiosensitizing. After induction, patients received cycles of one of the following: (1) intravenous doxorubicin and 5-fluorouracil (5-FU) with or without 131I-polyclonal antiferritin (RTOG 83-19); (2) intrahepatic artery cisplatin (Hopkins Institutional Pilot); or (3) intrahepatic artery cisplatin with or without 131I-polyclonal antiferritin (RTOG 88-23). Analysis of survival results was performed with multivariate and Cox regression methods. RESULTS: The addition of intravenous 131I-polyclonal antiferritin to post-induction cycles of either intravenous doxorubicin and 5-FU or intrahepatic artery cisplatin did not enhance survival. Intrahepatic artery cisplatin treatment yielded median survival duration of 9.1 months and survival at 12 and 24 months of 37% and 9%, respectively. These results were significantly superior to those resulting from use of intravenous doxorubicin and 5-FU (P = 0.0001; median survival duration 3.6 months; 12- and 24-month survival results 17% and 4%, respectively). A significant survival difference for the cisplatin regimen remained even when patients were stratified by previously identified prognostic factors and the results were appropriately adjusted. CONCLUSION: Patients with unresectable alpha-fetoprotein-positive hepatocellular carcinoma experienced improved survival and decreased toxicity when managed with post-induction cycles of intra-arterial cisplatin as compared with intravenous doxorubicin and 5-FU. Intravenous 131I-polyclonal antiferritin did not improve survival when added to either post-induction regimen but dramatically increased hematologic toxicities.

Influence of prognostic groupings and treatment results in the management of unresectable hepatoma: experience with Cisplatinum-based chemoradiotherapy in 76 patients.

PURPOSE: Internationally, hepatoma is a common cause of cancer death. Although the only curative therapy is surgical, most tumors are unresectable and cause death. The value of nonsurgical, antineoplastic therapy for such tumors is controversial. This study was undertaken to extend and confirm promising, but preliminary, treatment observations in the unresectable context. METHODS AND MATERIALS: From 1988 to 1993, 76 patients with unresectable, biopsy proven, hepatoma underwent uniform pretreatment assessment followed by induction therapy with external beam radiotherapy (21 Gy/7 fractions/10 days) and intravenous Cisplatinum, 50 mg/m2. One month later patients began monthly intrahepatic artery Cisplatinum, 50 mg/m2. Clinical course and treatment outcomes were correlated with previously published prognostic factors and groupings (Nomura et al., Okuda et al., Stillwagon, et al.). RESULTS: The toxicity of this therapy was modest and nonlimiting. Twenty-four patients (32%) progressed during induction and prior to receiving two cycles of intrahepatic artery Cisplatinum without evidence of benefit. Patients showing this early progression were more likely to be Stillwagon unfavorable than favorable (p = 0.013), Okuda Stage II than Stage I (p = 0.024), and slightly but not statistically more likely to be alpha-fetoprotein positive than alpha-fetoprotein negative (p = 0.098). The overall objective response rate was 43% (38% among AFP positive and 62% among AFP negative patients) (p = 0.15). Although 21 patients had evidence of extra hepatic metastases, survival for these patients did not differ from patients without metastases (p = 0.09) and patients with extra hepatic metastases were just as likely to show intrahepatic response (p = 0.84). CONCLUSION: The chemoradiotherapy program utilized produced objective response and minimal toxicity. One-third of patients progressed rapidly in spite of treatment. Among the remaining patients, response occurred frequently. This treatment appears to represent an important therapeutic option for many, but not all, patients with unresectable hepatoma.

Hodgkin and non-Hodgkin lymphoma: local-regional radiation therapy after bone marrow transplantation.

PURPOSE: To assess the acute toxicity and therapeutic effect of local-regional radiation therapy after bone marrow transplantation performed for lymphoma in resistant relapse. MATERIALS AND METHODS: Twenty-one patients with Hodgkin (n = 12) or non-Hodgkin lymphoma (n = 9) underwent local-regional radiation therapy after bone marrow transplantation. Posttransplantation radiation was delivered to the dominant site of pretransplantation disease. Three patients with Hodgkin lymphoma and four with non-Hodgkin lymphoma underwent radiation therapy for posttransplantation recurrence. Total body irradiation was used in 10 patients. Mean radiation dose was lower in patients who underwent total body irradiation than in those who did not (P = .05). RESULTS: Nineteen of 21 patients completed local-regional therapy. Nonhematologic toxicity was mild in 20 patients. Hematologic toxicity was severe in five patients, four of whom began radiation therapy with low platelet counts. In-field disease progression occurred in six of 15 patients with relapse, including four with disease progression at the start of radiation therapy. Median progression-free survival was 12 months in patients with Hodgkin lymphoma and 1 month in patients with non-Hodgkin lymphoma. CONCLUSION: Posttransplantation local-regional radiation therapy can be safely administered in patients with lymphoma. Severe hematologic toxicity is a concern, however, in patients with low platelet counts.