Infradiaphragmatic versus supradiaphragmatic Hodgkin lymphoma: a retrospective review of 1,114 patients.

Infradiaphragmatic Hodgkin lymphoma (IDH) accounts for 4-13% of cases of stage I-II Hodgkin lymphoma (HD). It has been associated with distinct pre-treatment characteristics and outcomes when compared with supradiaphragmatic HD (SDH). The comparison of IDH vs SDH can only be made in early and intermediate stages (I-II), such a comparison is not possible for advanced stages (III-IV). This study retrospectively compared two groups of 1013 patients with stage I-II SDH and 101 patients with IDH (10%). These two sub-groups of patients were treated in 1988-1993 in 2 prospective randomized clinical trials in Germany for early and intermediate stages of Hodgkin lymphoma. IDH-patients were older (median 39 vs 31 years; p < 0.001), predominantly male (73% vs 52%; p < 0.001) and more often had involvement of 3 lymph node areas (LNA) (80% vs 55%; p < 0.001). Histology in IDH was more likely to be mixed cellularity (46.5% vs 23.6%, p < 0.001) or lymphocyte predominant (20 vs 10%, p = 0.003) and less likely nodular sclerosis (25% vs 63%, p < 0.001). In early-stage unfavorable disease, IDH was associated with a higher treatment failure rate (unadjusted hazard ratio 2, 95% CI, 1.3-3.4; p = 0.003). After controlling for age, sex, stage, histology, B-symptoms and involvement of 3 LNA, the adjusted hazard ratio was 1.25 (95% CI, 0.65-2.4; p = 0.51) so that IDH was no longer associated with a statistically significant treatment failure rate. Poorer outcomes with IDH as compared to SDH are attributable to its association with known adverse prognostic risk factors, but IDH, in itself, is not an independent adverse prognostic factor for treatment failure or survival.

Innovative treatments for non-small cell lung cancer.

Lung cancer remains the most frequent and most lethal cancer worldwide. Non-small cell lung cancer (NSCLC) comprises the vast majority of the histological types. Surgery remains the standard therapy for early stage disease but for advanced stage disease, modern treatment is unsatisfactory. However, during the past ten years, improvements in response and survival have been seen with the use of newer chemotherapy regimens. Early studies of neo-adjuvant (pre-operative) chemotherapy for resectable stage III patients have shown promising results. For patients with non-resectable NSCLC platinum-based doublets are now established as first-line treatment, either alone or in combination with radiotherapy. Innovative non-platinum based combinations are actively being evaluated. The most promising non-platinum agents at this time include gemcitabine, paclitaxel, docetaxel, irinotecan and vinorelbine. These agents appear to be effective as single agents and in combinations and also have improved toxicity profiles. Several other systemic approaches are under active evaluation; the most promising areas include anti-angiogenesis agents, immunotoxins, interleukins, vaccines and molecular therapy.

A randomized Phase II study of interleukin-2 with and without beta-interferon for patients with advanced non-small cell lung cancer: an Eastern Cooperative Oncology Group study (PZ586).

Interleukin-2 (IL-2) and beta-interferon (beta-IFN) are biologic agents with antitumor activity observed in preclinical models. Some studies of patients with advanced non-small cell lung cancer treated with IL-2 report relatively long survival, despite low response rates. Seventy-six evaluable patients with stage IV non-small cell lung cancer were treated in a randomized Phase II study with either IL-2 alone or IL-2 plus beta-IFN. Patients received either IL-2 at 6 x 10(6) Cetus units/m2 3 days weekly or the combination of IL-2 at 5 x 10(6) Cetus units/m2 plus beta-IFN at 6 x 10(6) units/m2, both given 3 days weekly. Both biologic agents were administered by intravenous bolus injection on an outpatient basis. Objective responses were observed in 3/76 (4%)) patients. Grade 4 toxicity occurred in 3/39 patients treated with IL-2 alone, and in 4/37 patients treated with IL-2 plus beta-IFN. An additional lethal respiratory toxicity occurred in a patient who received IL-2 plus beta-IFN. The median survival of all patients treated on this study was 33 weeks. Despite producing only a 4% objective response rate. IL-2 appears to have a favorable impact on survival comparable to chemotherapy. The role for this immune therapy in the management of non-small cell lung cancer requires further study.

Phase III trial of neoadjuvant chemotherapy in patients with invasive bladder cancer treated with selective bladder preservation by combined radiation therapy and chemotherapy: initial results of Radiation Therapy Oncology Group 89-03.

PURPOSE: To assess the efficacy of neoadjuvant methotrexate, cisplatin, and vinblastine (MCV) chemotherapy in patients with muscle-invading bladder cancer treated with selective bladder preservation. PATIENTS AND METHODS: One hundred twenty-three eligible patients with tumor, node, metastasis system clinical stage T2 to T4aNXMO bladder cancer were randomized to receive (arm 1, n=61 ) two cycles of MCV before 39.6-Gy pelvic irradiation with concurrent cisplatin 100 mg/m2 for two courses 3 weeks apart. Patients assigned to arm 2 (n=62) did not receive MCV before concurrent cisplatin and radiation therapy. Tumor response was scored as a clinical complete response (CR) when the cystoscopic tumor-site biopsy and urine cytology results were negative. The CR patients were treated with an additional 25.2 Gy to a total of 64.8 Gy and one additional dose of cisplatin. Those with less than a CR underwent cystectomy. The median follow-up of all patients who survived is 60 months. RESULTS: Seventy-four percent of the patients completed the protocol with, at most, minor deviations; 67% on arm 1 and 81% on arm 2. The actuarial 5-year overall survival rate was 49%; 48% in arm 1 and 49% in arm 2. Thirty-five percent of the patients had evidence of distant metastases at 5 years; 33% in arm 1 and 39% in arm 2. The 5-year survival rate with a functioning bladder was 38%, 36% in arm 1 and 40% in arm 2. None of these differences are statistically significant. CONCLUSION: Two cycles of MCV neoadjuvant chemotherapy were not shown to increase the rate of CR over that achieved with our standard induction therapy or to increase freedom from metastatic disease. There was no impact on 5-year overall survival.

Comparison of a once-a-day sustained-release morphine formulation with standard oral morphine treatment for cancer pain.

Kadian/Kapanol (K) is a capsule formulation of morphine designed for 12- or 24-hourly dosing. This double-blind study compared the efficacy and safety of K every 24 hr to K every 12 hr and MS Contin tablets (MSC) every 12 hr. One hundred fifty-two patients with cancer pain were titrated to adequate analgesia with immediate-release morphine (IRM) solution. Stabilized patients were randonized to one of the three treatments for 7 +/- 1 days. Rescue medication was IRM tablets. Efficacy and safety were assessed by time to first remedication and total dose of rescue medication, pain scores, global assessments, and incidence of morphine-related side effects. Fifty-four patients were treated with K every 24 hr. 45 with K every 12 hr. and 53 with MSC every 12 hr. Mean age was 61 years and mean total daily dose of morphine was 138 mg. Forty-six percent of the K every 24 hr patients, 51% of the K every 12 hr patients, and 55% of the MSC every 12 hr patients required rescue medication on the final day. Time to remedication was 16.0 hr for K every 24 hr, 9.1 hr for K every 12 hr and 8.7 hr for MSC every 12 hr (P = 0.0010). Patient global assessment significantly favored K every 24 hr over MSC every 12 hr (P = 0.018). There were no statistically significant differences among the treatments for any morphine-related side effects when adjusted for baseline. K had efficacy and safety profiles similar to MSC every 12 hr but had the advantage of 12- or 24-hourly administration.

Phase II study of patients with metastatic nonsmall cell carcinoma of the lung treated with paclitaxel by 3-hour infusion.

BACKGROUND: Single-agent chemotherapy produces partial responses in the range of 7-27% in patients with Stage IV nonsmall cell lung carcinoma (NSCLC). Cisplatin-based combination regimens have achieved higher response rates but with significant toxicity. Two prior studies employing 24-hour infusions of paclitaxel showed responses of 21% and 24%. The purpose of this Phase II study was to determine the effects of paclitaxel administered by short duration infusions on response rate, toxicity, and quality of life (QOL) in patients with NSCLC. METHODS: Twenty patients with histologically proven Stage IV NSCLC were enrolled in this study. All were treated on an outpatient basis with standard premedication followed by paclitaxel 200 mg/m2 infused intravenously over 3 hours. Treatments were repeated every 21 days for a maximum of 6 cycles. RESULTS: The objective response rate was 6/19 (32%; 95% confidence interval, 13-57%). The median duration of response was 6.0 months (range, 2-13 months). The median survival of the entire group was 6.0 months (range, 2-24+ months), and the 1-year survival rate was 22%. Toxicity was mild, with only one hospitalization required for treatment of catheter-related thrombosis. Nonresponding patients were found to have worsening Functional Assessment of Cancer Therapy (FACT)-G and FACT-L scores. Because this was a small clinical study, it did not demonstrate consistent improvement in FACT-G or FACT-L in responding patients. CONCLUSIONS: Paclitaxel given as a 3-hour infusion is a well-tolerated, active single agent in the treatment of Stage IV NSCLC, worthy of further study. Baseline QOL scores predicted those more likely to respond to treatment, but changes in QOL status did not correlate well with objective response status.

Development of anemia and recovery in prostate cancer patients treated with combined androgen blockade and radiotherapy.

BACKGROUND: The objective of this study was to document previously unreported anemia in prostate cancer patients treated with neoadjuvant combined androgen blockade (CAB) and pelvic radiotherapy (XRT). METHODS: Four institutions treated 141 patients (mean age +/- SD, 70.9 +/- 6.5 years) with zoladex 3.6 mg injection subcutaneous depot monthly and flutamide 250 mg orally three times per day for 2 months (CAB), followed by zoladex and flutamide with concurrent XRT (65-70 Gy) for 7-8 weeks. RESULTS: After the XRT, the patients were randomized to receive no further treatment (Z- group, 71 patients) or zoladex alone (Z+ group, 70 patients) for 2 years. Hemoglobin (Hb) levels decreased > or = 1 g/dl (mean +/- SE, 2.1 +/- 0.1 g/dl) in 98/131 patients (75%) after 2 months of CAB, and > or = 2 g/dl (3.1 +/- 0.1 g/dl; range, 0.1-6.8 g/dl) in 106/131 patients (81%) after an additional 2 months of CAB with concurrent XRT. The decrease in Hb levels paralleled the decreased in testosterone levels. No evidence of blood loss or hemolysis was found. CONCLUSIONS: There was no association between incidence or rate of Hb decrease and race, age, or pretreatment prostate-specific antigen (PSA) levels. However, the recovery from anemia after completion of CAB in African-Americans was slower than in Whites in the Z+ group (P < 0.04). Whereas grade 1 hematologic toxicity may occur in < 5% of the patients with zoladex alone, and approximately 6% with flutamide alone, in our study 81% showed mild to pronounced anemia. Since anemia has not been observed after treatment with XRT alone or XRT followed by zoladex, we conclude that the anemia was due to CAB. Recognition of this side effect should avoid unnecessary diagnostic evaluations.

Efficacy and tolerability of oral ondansetron versus prochlorperazine in the prevention of emesis associated with cyclophosphamide-based chemotherapy and maintenance of health-related quality of life.

This study compared the efficacy and tolerability of oral ondansetron (8 mg twice daily [BID] for up to 3 days) with those of phenothiazine prochlorperazine (10 mg BID for up to 3 days) in 133 cancer patients receiving cyclophosphamide-based chemotherapy. In addition, the study evaluated the impact of these treatments on patients' health-related quality of life, measured with both the Functional Living Index-Cancer and the Functional Living Index-Emesis questionnaires. The first dose of study drug was administered 30 minutes before initiation of chemotherapy. Patients received a rescue antiemetic at their request or if the investigator deemed it necessary. There was a statistically significant difference in the number of patients with no emetic episodes over the 3-day study period: 60% in the ondansetron group compared with 21% in the prochlorperazine group. Twenty-five percent of ondansetron-treated patients compared with 68% of prochlorperazine-treated patients experienced three or more emetic episodes, rescue medication use, or withdrawal from the study due to emesis or adverse events. Among patients with at least one emetic episode, the mean time to emesis was significantly longer (13 hours and 37 minutes) in the ondansetron group compared with the prochlorperazine group (9 hours and 30 minutes). Nausea and appetite scores did not differ significantly between groups. The score on the vomiting subscale of the Functional Living Index-Emesis was significantly more favorable in the ondansetron group compared with the prochlorperazine group, indicating better maintenance of health-related quality of life in ondansetron-treated patients. Both treatments were well tolerated. The most common potentially drug-related adverse event was headache, which occurred in significantly more (16%) ondansetron-treated patients compared with prochlorperazine-treated patients (3%). The results of this study demonstrate that oral ondansetron 8 mg BID for up to 3 days is more effective than prochlorperazine 10 mg BID for up to 3 days in the prevention of emesis associated with moderately emetogenic chemotherapy.

Efficacy and tolerability of oral ondansetron versus prochlorperazine in the prevention of emesis associated with cyclophosphamide-based chemotherapy and maintenance of health-related quality of life.

This study compared the efficacy and tolerability of oral ondansetron (8 mg twice daily [BID] for up to 3 days) with those of phenothiazine prochlorperazine (10 mg BID for up to 3 days) in 133 cancer patients receiving cyclophosphamide-based chemotherapy. In addition, the study evaluated the impact of these treatments on patients' health-related quality of life, measured with both the Functional Living Index--Cancer and the Functional Living Index--Emesis questionnaires. The first dose of study drug was administered 30 minutes before initiation of chemotherapy. Patients received a rescue antiemetic at their request or if the investigator deemed it necessary. There was a statistically significant difference in the number of patients with no emetic episodes over the 3-day study period: 60% in the ondansetron group compared with 21% in the prochlorperazine group. Twenty-five percent of ondansetron-treated patients compared with 68% of prochlorperazine-treated patients experienced three or more emetic episodes, rescue medication use, or withdrawal from the study due to adverse events or lack of efficacy of the study drug. Among patients with at least one emetic episode, the mean time to emesis was significantly longer (13 hours and 37 minutes) in the ondansetron group compared with the prochlorperazine group (9 hours and 30 minutes). Nausea and appetite scores did not differ significantly between groups. The score on the vomiting subscale of the Functional Living Index--Emesis was significantly more favorable in the ondansetron group compared with the prochlorperazine group, indicating better maintenance of health-related quality of life in ondansetron-treated patients. Both treatments were well tolerated. The most common potentially drug-related adverse event was headache, which occurred in significantly more (16%) ondansetron-treated patients compared with prochlorperazine-treated patients (3%). The results of this study demonstrate that oral ondansetron 8 mg BID for up to 3 days is more effective than prochlorperazine 10 mg BID for up to 3 days in the prevention of emesis associated with moderately emetogenic chemotherapy.

Cathepsins D, B, and L in malignant human lung tissue.

The levels of cathepsins in malignant and surrounding nonmalignant lung tissue were determined in 17 non-small cell lung cancer specimens. Cathepsin (Cat) D activity was assayed using hemoglobin, whereas Cat B and Cat L activities were assayed using fluorimetric substrates, benzoylcarbonyl-Ala-Arg-Arg-7-amino-4-methylcoumarine and benzoylcarbonyl-Phe-Arg-7-amino-4-methylcoumarine, respectively. Cat protein concentrations were determined using ELISAs. In malignant tissues, the activities of Cat B and Cat L were significantly higher than the activities in nonmalignant tissues (P < 0.0012 and P < 0.0003, respectively), whereas Cat D concentration was not. There was also a 5.6-fold increase in median Cat B protein (P < 0.054) and a 2.2-fold increase in Cat L protein (P < 0.069). By contrast, the aspartic proteinase, Cat D protein, was not significantly increased in tumors versus control lung tissues. Moderate but significant correlation (r = 0.5, P < 0.045) between Cat B and Cat L expression was observed, but neither correlated with Cat D. The relative increase in median Cat L activity (P < 0.037) and protein (P < 0.0005) was greater in poorly differentiated tumors than in moderate ones. Cat L activity (P < 0.003) and protein (P < 0. 005) increases were higher in adenocarcinoma than in squamous cell carcinoma. We conclude that in lung cancers the three lysosomal enzymes are regulated in a noncoordinate manner and that there is specific induction of cysteine cathepsins. Whether Cat B and/or Cat L would be of diagnostic and/or prognostic value requires further study in a larger patient population.

Neoadjuvant combined modality program with selective organ preservation for invasive bladder cancer: results of Radiation Therapy Oncology Group phase II trial 8802.

PURPOSE: This phase II study was designed to evaluate effectiveness and toxicity of a combined chemoradiotherapy program with selective bladder preservation in the management of patients with invasive bladder cancer. PATIENTS AND METHODS: Ninety-one eligible patients with invasive bladder cancer stages T2M0 to T4AM0 suitable for radical cystectomy received two courses of methotrexate, cisplatin, and vinblastine (MCV regimen) followed by radiotherapy with 39.6 Gy and concurrent cisplatin. After complete urologic evaluation, operable patients who achieved complete response were selected for bladder preservation and treated with consolidation cisplatin-radiotherapy. RESULTS: Of 91 eligible patients, 85 underwent complete urologic evaluation and 68 (75%; 95% confidence interval [CI], 59% to 84%) had documented complete responses. Fourteen operable patients with residual tumor underwent immediate cystectomy. Of 70 patients treated with consolidation cisplatin-radiotherapy, 36 subsequently developed bladder recurrences, 23 of which were invasive. Patients with invasive recurrence (n = 16), extensive noninvasive recurrence (n = 6), or severe treatment complications (n = 1) underwent salvage cystectomy. Thus, a total of 37 of 91 patients (40%) required cystectomy. The 4-year cumulative risk of invasive local failure (which includes induction failures) was 43% (95% CI, 33% to 53%). The 4-year actuarial risk of distant metastasis was 22% (95% CI, 13% to 31%). The 4-year actuarial survival rate of the entire group was 62% (95% CI, 52% to 72%). The 4-year actuarial rate of survival with bladder intact was 44% (95% CI, 34% to 54%). CONCLUSION: Initial results of this combined chemoradiotherapy program show that bladder preservation can be achieved in the majority of patients, and that overall survival is similar to that reported with aggressive surgical approaches. Long-term survival and quality-of-life assessments require longer follow-up study.

Protracted intravenous fluorouracil infusion with radiation therapy in the management of localized pancreaticobiliary carcinoma: a phase I Eastern Cooperative Oncology Group Trial.

PURPOSE: The purpose of this study was to determine the maximum-tolerated dose (MTD) of fluorouracil (5-FU) administered as a protracted intravenous (IV) infusion with concurrent radiation in patients with pancreaticobiliary carcinoma. METHODS: Twenty-five patients with recurrent, residual, or unresectable carcinoma of the pancreas or biliary tract were treated on a phase I trial of protracted IV infusions of 5-FU, beginning at 200 mg/m2/d, concurrent with radiation therapy (59.4 Gy in 33 fractions over 6 to 7 weeks). Chemotherapy began on the first day of radiation and continued through the entire course of treatment. After each cohort of five patients had been treated and observed, the daily dose was escalated in 25-mg/m2 increments until dose-limiting toxicity was encountered. An additional cohort of five patients was treated at the MTD. Clinical examination and computed tomography (CT) were used to evaluate response and patterns of progression. RESULTS: The MTD of 5-FU was 250 mg/m2/d. The dose-limiting toxicity was oral mucositis. The median survival duration of all patients treated was 11.9 months and the 2-year survival rate was 19%. Eleven of 25 patients remain free of local progression and four patients are without evidence of progression at 18+, 18+, 34+, and 44+ months following treatment. CONCLUSION: Concurrent radiation with protracted 5-FU infusion at 250 mg/m2/d is well tolerated and shows evidence of activity against tumors of the pancreas and biliary system.

Combined modality program with possible organ preservation for invasive bladder carcinoma: results of RTOG protocol 85-12.

PURPOSE: This Phase II study was designed to test the tolerance and effectiveness of concurrent cisplatin-radiotherapy in the treatment of invasive bladder cancer. Objectives were to determine toxicity, complete response rate, bladder preservation rate, and survival. METHODS AND MATERIALS: Patients with invasive bladder cancer, clinical Stages T2-4, NO-2 or NX, MO were treated with pelvic radiotherapy 40 Gy in 4 weeks and cisplatin 100 mg/m2 on days 1 and 22. Complete responders were given an additional 24 Gy bladder boost plus a third dose of cisplatin; patients with residual tumor after 40 Gy were assigned radical cystectomy. RESULTS: The complete remission rate following cisplatin and 40 Gy for evaluable cases was 31/47 (66%). Acute toxicity was acceptable with only two patients not completing induction therapy. Patients with poorly differentiated tumors were more likely to achieve complete remission. Of fully evaluable patients, 28/42 (67%) achieved complete remission with induction therapy, 11 remain continuously in remission, and eight have relapsed with bladder as the only site of failure. Five of these eight cases relapsed with noninvasive tumor. Of the 14 patients who failed to achieve complete remission, only three remain disease-free. Median survival is not reached, with 17/42 (19/48) deaths reported. Actuarial survival is 64% at 3 years. CONCLUSION: This combined cisplatin-radiotherapy regimen was moderately well-tolerated and associated with tumor clearance in 66% of patients treated. Isolated bladder recurrences with invasive carcinoma are infrequent. Better definition of pretreatment selection criteria is needed if combined modality treatment is to achieve disease control and organ preservation for patients with bladder cancer.

Second malignant neoplasms complicating Hodgkin's disease: the National Cancer Institute experience.

The medical records of all patients treated for Hodgkin's disease during the years 1964-1981 were reviewed. Four hundred seventy-three previously untreated patients were analyzed. Thirty-four subsequent second malignant neoplasms were observed in 33 patients among those treated for Hodgkin's disease. Eight cases of acute nonlymphocyctic leukemia, one case of chronic myeloid leukemia, three cases of non-Hodgkin's lymphoma, three cases of sarcoma, and 19 other tumors were identified. The ten-year estimated risk of leukemia by treatment was the following: radiotherapy only (0), chemotherapy only (0.02), initial combined radiotherapy-chemotherapy (0.06), and salvage combined radiotherapy-chemotherapy (0.09). The ten-year estimated risk of solid tumors was 0.07 overall, with all treatment groups associated with similar risks. Unlike some other reports, a greater risk of leukemia in patients who began treatment for Hodgkin's disease at age 40 or older was not found. However, a positive association was noted between increasing risk of solid tumors and increasing patient age.

"Salvage" radiation therapy for intrathoracic small cell carcinoma of the lung progressing on combination chemotherapy.

Thirty-two patients with small cell carcinoma of the lung were given chest radiotherapy to progressive intrathoracic tumor after failing chemotherapy. Two-thirds of these patients received split-course treatment at a dose of 4000 rad in 10 fractions. Sixteen of 25 evaluable patients (64%) had an objective response, but only five responders did not progress within the port during life. Median time to local progression was 16 weeks. Two patients, one of whom was given concurrent chemotherapy, survived greater than 18 months, and one is free of disease at 31+ months. Short-term palliation of chest disease and occasional long-term survival are possible with this regimen, although most patients will die with systemic disease within several months. Small cell carcinoma of the lung is less responsive to irradiation as second-line therapy than as initial therapy, but doses of greater than or equal to 4000 rad can offer symptomatic relief in many cases and, rarely, survival beyond 18 months.

Evaluation of weekly escalating doses of dichloromethotrexate in patients with hepatocellular carcinoma and other solid tumors.

Twenty-one patients with solid tumors were treated with weekly 6-h intravenous infusions of dichloromethotrexate (DCM), with escalating doses every other week. Frequently observed toxicities included leukopenia, thrombocytopenia, and mucositis. Nausea, vomiting, diarrhea, and elevation of hepatic enzymes and bilirubin occurred less often. The toxicity of DCM was dose-dependent; the maximum tolerated dosage excalation plan was 400 mg/m2 x 2 weeks, 800 mg/m2 x 2 weeks, and then 1,200 mg/m2 weekly. Plasma concentrations of DCM were measured during 61 infusions and apparent half-lives determined. The plasma elimination of DCM appears to be similar to that of methotrexate. Three objective tumor responses seen in the seven hepatocellular carcinoma patients treated warrant further investigation.