Beta-interferon, retinoids and tamoxifen as maintenance therapy in metastatic breast cancer. A pilot study

BACKGROUND: Chemotherapy (CT), fundamental for the treatment of metastatic breast cancer (MBC), rarely cures, due to the presence of minimal residual disease (MRD). Based on the synergistic antiproliferative effect of interferon, retinoids and tamoxifen on breast cancer cell lines, we designed a pilot study to test if a combination of beta-interferon (beta-IFN), retinoids and tamoxifen could improve the progression free survival and overall survival in patients (PTS) treated with CT for MBC. METHODS: Thirty-six patients, with stage IV carcinoma of the breast, were treated with a combination of Cyclophosfamide, 5-fluorouracil, 4-epidoxorubicin, vincristine and prednisone every 3 weeks for six courses (FECPV), followed by two courses of methotrexate, mitomycin-c and mitoxantrone (MMM). Treatment was continued, in response, with low dose beta-interferon, retynil palmitate and tamoxifen until disease relapse. RESULTS: Among 36 evaluable PTS, 23 achieved a clinical response (64%) (95% c. i. 48 x 80%), 7 had disease stability (19%), and 6 (17%) progressed. Leukopenia occurred in 15 patients, thrombocytopenia in six, and anemia in 11. 16 patients had nausea/vomiting; stomatitis was observed in nine patients and diarrhea in three. Toxicity of maintenance therapy was mild and mainly hepatic. Median response duration was 31 months (range 5-75+). Median overall survival was 32 months (9-83+). CONCLUSIONS: Our study shows that this regimen is feasible and shows activity in MBC with an acceptable toxicity.     

Paclitaxel, carboplatin, and extended-schedule etoposide in the treatment of small-cell lung cancer: comparison of sequential phase II trials using different dose-intensities

PURPOSE: In two sequential phase II studies, we evaluate the feasibility and efficacy of adding paclitaxel to a standard platinum/etoposide regimen in the first-line treatment of small-cell lung cancer. PATIENTS AND METHODS: One hundred seventeen patients with small-cell lung cancer were treated between June 1993 and July 1996. The first 38 patients received a lower-dose regimen: paclitaxel 135 mg/m2 by 1-hour infusion, carboplatin at an area under the concentration-time curve (AUC) of 5.0, and etoposide 50 mg alternating with 100 mg orally on days 1 to 10. When only mild myelosuppression was observed, doses of paclitaxel and carboplatin were increased in the subsequent 79 patients (paclitaxel 200 mg/m2 by 1-hour infusion and carboplatin at an AUC of 6.0). All patients received four courses of treatment, administered at 21-day intervals. Patients with limited-stage small-cell lung cancer also received thoracic radiation therapy (1.8 Gy/d; total dose, 45 Gy) administered concurrently with courses 3 and 4 of chemotherapy. RESULTS: Seventy-two of 79 patients (91%) who receive the higher-dose regimen had major responses. Thirty-two of 38 (84%) with extensive-stage disease responded (21% complete response rate); median survival was 10 months for this group. With limited-stage disease, the overall response rate was 98%, with 71% complete responses; the median survival time has not been reached at 16 months. Median survival in extensive-stage patients was longer in patients who received the higher-dose regimen (10 months) than in the previous group treated with lower doses (7 months; P = .008). The higher-dose regimen was well tolerated, with myelosuppression being the major toxicity. Compared with the lower-dose regimen, grade 3/4 neutropenia increased from 8% to 38% of courses, but the incidence of hospitalization for neutropenia and fever did not increase. Other nonhematologic toxicities were uncommon, and did not increase substantially with the higher-dose regimen. CONCLUSION: Paclitaxel can be added at full dose (200 mg/m2) to a carboplatin/etoposide combination while maintaining a tolerable toxicity profile. Median survival times in both extensive- and limited-stage patients compare favorably with other reported regimens. This regimen merits further investigation, and a randomized trial to compare this regimen with a standard carboplatin/etoposide combination is underway.     

Phase I and pharmacologic study of weekly doxorubicin and 1 h infusional paclitaxel in patients with advanced breast cancer

Doxorubicin and paclitaxel both display strong antitumor activity in the treatment of breast cancer. The optimal schedule of this combination, however, remains undefined. In this phase I and pharmacologic study, we administered weekly 12 mg/m2 doxorubicin as a bolus infusion immediately followed by a 1 h 80 mg/m2 paclitaxel infusion to patients with metastatic breast cancer. A total of 119 weekly courses were delivered to seven patients. Grade IV neutropenia was observed in two patients at the first dose level, thus already defining the maximum tolerated dose. Pronounced non-hematologic toxicities were mild neuropathy (grade I: 39%) and stomatitis (grade I: 19%, grade II: 8%). No signs of cardiac toxicity were observed with this dose schedule. Three partial responses were achieved in this group of heavily pretreated patients. The pharmacokinetics of paclitaxel, doxorubicin and Cremophor EL with this schedule were analyzed. Overall, the schedule was well tolerated and combined with its preliminary response rate justifies further evaluation in phase II studies.     

Phase I/II trial of dexverapamil, epirubicin, and granulocyte-macrophage-colony stimulating factor in patients with advanced pancreatic adenocarcinoma

BACKGROUND: The purpose of this study was to determine the maximum tolerated dose (MTD) of a cytotoxic regimen consisting of the second-generation chemosensitizer dexverapamil (DVPM), high dose epirubicin, and recombinant human granulocyte-macrophage-colony stimulating factor (GM-CSF) in pancreatic carcinoma. PATIENTS AND METHODS: Twenty-eight previously untreated patients with locally advanced or metastatic adenocarcinoma of the pancreas were studied. Treatment consisted of oral DVPM at a dose of 1000-1200 mg/day for 3 days, epirubicin administered as an intravenous bolus injection on Day 2 with an initial dose of 90 mg/m2, and a dose of GM-CSF of 400 micrograms administered subcutaneously from Day 5s through 14. Epirubicin dose escalation levels were 90, 105, 120 and 135 mg/m2. Consecutive cohorts of four to eight patients were planned at each dose level. Treatment cycles were repeated every 3 weeks. RESULTS: Hematologic toxicity, specifically granulocytopenia, constituted the dose-limiting toxicity with an MTD of 120 mg/m2 for epirubicin. Despite routine supportive therapy with GM-CSF, four, two, and five patients experienced Grade 4 granulocytopenia during their first two treatment courses at levels 105, 120, and 135 mg/m2, respectively. Grade 4 granulocytopenia was observed in two, three, and one additional patients during subsequent courses with these levels. Nonhematologic toxicity was uncommon, generally modest, and did not correlate clearly with the anthracycline dose. Dexverapamil-related cardiovascular symptoms occurred frequently, but they never resulted in serious toxicity requiring active medical intervention or permanent discontinuation of therapy. Nine of 28 patients achieved partial responses to this therapy. Stable disease was observed in nine patients, and tumor progress occurred in 10. CONCLUSION: The MTD of epirubicin for this regimen with DVPM and GM-CSF was 120 mg/m2 every 3 weeks. Though it remains uncertain whether the encouraging response activity observed in this disease-oriented Phase I study was, in fact, due to successful modulation of multidrug resistance, these results suggest that this regimen is likely to be an effective and tolerable treatment strategy for patients with pancreatic cancer, which should be evaluated further.     

Confocal microscopic localization of anti-myelin-associated glycoprotein autoantibodies in a patient with peripheral neuropathy initially lacking a detectable IgM gammopathy

AIMS AND BACKGROUND: The neutropenia induced by six courses of an intensified FEC regimen is expected to be checked by early primary administration of G-CSF which is stopped eight days before the next chemotherapy course. Less information is available about megakaryocytic and erythroid toxicity over six courses. METHODS AND STUDY DESIGN: Sixty-six consecutive patients with metastatic breast cancer completed six courses of a randomized treatment with two FEC regimens administered every 21 days, in which 600 mg/m2 of cyclophosphamide and 5-FUwas associated with 60 or 120 mg/m2 of epirubicin (60FEC, 35 patients, vs 120FEC, 31 patients). 120FEC was supported by early primary G-CSF (days 4 to 13). Blood counts were obtained seven times during each course. RESULTS: The non-hematologic toxicity over 364 courses was similar in 60FEC and 120FEC. No cumulative hematologic toxicity was observed for white blood cells (WBC) and platelets (PLT), while for hemoglobin (Hb) a somewhat higher cumulative toxicity was observed with 120FEC than with 60FEC. WBC, PLT and Hb grade III-IV toxicity occurred in 40.1% and 45.6% (P=ns), in 23.1% and 0.8% (P <.0001) and in 15.6% and 3.0% (P <.005) of the two regimens, respectively. There were no febrile or hemorrhagic episodes. The epirubicin relative dose intensity delivered was 1.95 in 120FEC with respect to 60FEC. CONCLUSIONS: Our G-CSF schedule permitted to deliver six courses of 120FEC without any clinically relevant side effects. Grade III-IV leukopenia was similar with 120FEC and 60FEC, while grade III-IV thrombocytopenia and anemia occurred more often with 120FEC than with 60FEC.     

Graves'' ophthalmopathy and tobacco smoking

BACKGROUND: Despite standard treatment, surgery and/or radiotherapy, most patients with muscle invasive bladder carcinoma die early of distant metastasis. CMV chemotherapy has demonstrated a high response rate with moderate toxicity in advanced bladder carcinoma. In an attempt to eradicate undetectable metastatic disease and to avoid cystectomies, 36 patients were given up-front CMV. MATERIALS AND METHODS: The patients were 34 males and 2 females with a median age of 62 years (45-75); performance status 0-1 (WHO) in 34 patients; histology: 34 transitional carcinomas and 2 anaplastic carcinomas (grade II: 8, grade III: 28). Clinical staging was T2-3a: 19 patients, T3b: 14 patients and T4: 3 patients. Nineteen patients had complete trans-urethral resections (TUR) at diagnosis. The multimodal protocol started with 3 CMV courses (cisplatin 100 mg/m2 i.v. d 1, methotrexate 30 mg/m2 i.v. d 1, 8 and vinblastine 4 mg/m2 i.v. d 1, 8 every 3 weeks). Patients who yielded clinical complete responses (cCR) by cystoscopy, TUR biopsies and imaging techniques were given 3 additional courses. Cystectomy was performed in non-cCR patients and as salvage treatment. RESULTS: Following 3 CMV cycles, 29 patients (81%) responded (20 cCR and 9 cPR) and 7 (19%) did not (NR). Currently, with a median follow-up of 23.5 months (13-59), 13 have died and 23 are alive, 12 of whom retain their bladders. The projected overall survival is 51% at 4.5 years. Grade 3-4 hematological toxicity was presented in 8% of the cycles. No toxic deaths were observed. CONCLUSION: The CMV regimen, after TUR, produces a high response rate with tolerable toxicity. Bladders could be preserved in half of the CR patients.     

Randomized trial of dose-intensity with single-agent carboplatin in patients with epithelial ovarian cancer. London Gynaecological Oncology Group

PURPOSE: We have examined the role of an increase in cisplatin dose-intensity in patients with advanced epithelial ovarian cancer by means of single-agent carboplatin therapy. PATIENTS AND METHODS: Two hundred twenty-seven patients were randomized to treatment and eligible for analysis. The dose of carboplatin was calculated according to the Calvert formula. One hundred seventeen patients received carboplatin at an area under the concentration time curve (AUC) of 6 for six courses, administered every 28 days, and 110 patients received carboplatin at an AUC of 12 for four courses, administered every 28 days. Patients were eligible provided they had not received prior chemotherapy or radiotherapy and had International Federation of Gynecology and Obstetrics stages II to IV or relapsed stage I epithelial ovarian cancer. RESULTS: The planned total-dose increase was 33% for the patients treated with carboplatin AUC 12, but the received percentage total-dose increase was 20%. There were no differences in progression-free or overall survival between the two treatment arms; the overall survival rate at 5 years was 31% and 34% of patients treated at AUCs 6 and 12, respectively. There was significantly more toxicity associated with carboplatin AUC 12, which resulted in more treatment delays and/or dose reductions (52% v 18%; P < .001). CONCLUSION: We have shown that carboplatin can be delivered at an AUC of 12 for four courses without granulocyte colony-stimulating factor support, although significant hematologic toxicity occurs. Nonhematologic toxicities were not clinically significant. Carboplatin offers an opportunity to intensify cisplatin therapy, but a greater than two-fold increase in dose-intensity probably needs to be achieved before significant effects on survival will be produced and hematologic support will be required.     

Clerodane diterpenoids, long chain esters of coumaric acid and other compounds from Baccharis myrsinites

PURPOSE: To compare 1-year survival and acute toxicity rates between an accelerated hyperfractionated (AH) radiotherapy (1.6 Gy b.i.d.) to a total dose of 54.4 Gy vs. an accelerated fractionation (AF) of 30 Gy in 10 daily fractions in patients with unresected brain metastasis. METHODS AND MATERIALS: The Radiation Therapy Oncology Group (RTOG) accrued 445 patients to a Phase III comparison of accelerated hyperfractionation vs. standard fractionation from 1991 through 1995. All patients had histologic proof of malignancy at the primary site. Brain metastasis were measurable by CT or MRI scan and all patients had a Karnofsky performance score (KPS) of at least 70 and a neurologic function classification of 1 or 2. For AH, 32 Gy in 20 fractions over 10 treatment days (1.6 Gy twice daily) was delivered to the whole brain. A boost of 22.4 Gy in 14 fractions was delivered to each lesion with a 2-cm margin. RESULTS: The average age in both groups was 60 years; nearly two-thirds of all patients had lung primaries. Of the 429 eligible and analyzable patients, the median survival time was 4.5 months in both arms. The 1-year survival rate was 19% in the AF arm vs. 16% in the AH arm. No difference in median or 1-year survival was observed among patients with solitary metastasis between treatment arms. Recursive partitioning analysis (RPA) classes have previously been identified and patients with a KPS of 70 or more, a controlled primary tumor, less than 65 years of age, and brain metastases only (RPA class I), had a 1-year survival of 35% in the AF arm vs. 25% in the AH arm (p = 0.95). In a multivariate model, only age, KPS, extent of metastatic disease (intracranial metastases only vs. intra- and extracranial metastases), and status of primary (controlled vs. uncontrolled) were statistically significant (at p < 0.05). Treatment assignment was not statistically significant. Overall Grade III or IV toxicity was equivalent in both arms, and one fatal toxicity at 44 days secondary to cerebral edema was seen in the AH arm. CONCLUSION: Although a previous RTOG Phase I/II report had suggested a potential benefit in patients with limited metastatic disease, a good Karnofsky performance status, or neurologic function when treated with an AH regimen, this randomized comparison could not demonstrate any improvement in survival when compared to a conventional regimen of 30 Gy in 10 fractions. Therefore, this accelerated hyperfractionated regimen to 54.4 Gy cannot be recommended for patients with intracranial metastatic disease.     

Weekly paclitaxel and cisplatin with concurrent radiotherapy in locally advanced non-small-cell lung cancer: a phase I study

PURPOSE: Both cisplatin (CDDP) and paclitaxel have shown good antitumor activity in non-small-cell lung cancer (NSCLC) patients and are able to potentiate the antitumor effects of radiation therapy (RT). This study aimed to determine the maximum-tolerated doses (MTDs) of CDDP and paclitaxel (escalated alternately) when given concurrently with RT and to define the nature of the dose-limiting toxicity (DLT). PATIENTS AND METHODS: Chemotherapy-naive patients with locally advanced NSCLC received six weekly administrations of a CDDP-paclitaxel combination with concurrent local RT. The starting doses of CDDP and paclitaxel were 30 mg/m2/wk and 35 mg/m2/wk, respectively. RT was initially given at the dose of 1.2 Gy twice daily for 5 days per week for 5 weeks (total dose, 60 Gy) and at a single daily dose of 2 Gy for 5 days per week for 6 weeks in the last two cohorts of patients. The drug doses were escalated alternately until DLT occurred in more than one third of the patients in a given cohort. RESULTS: Overall, 25 patients were recruited through five different cohorts. All were assessable for toxicity. Esophagitis was the main toxicity and occurred in 16 of 25 patients (64%) and was grade 3 or 4 in five of them. At step 3 (CDDP 35 mg/m2/wk and paclitaxel 45 mg/m2/wk), two of five patients had to discontinue treatment because of severe esophagitis and one of these died of complications related to grade 4 esophagitis. However, keeping the same doses of chemotherapy and replacing hyperfractionation with a standard single-day fraction, weekly doses of CDDP and paclitaxel of 35 mg/m2 and 45 mg/m2 could be safely administered. Neutropenia was by far the most relevant hematologic toxicity and occurred in 33 of 141 weekly delivered courses, but it was of grade 4 in only four courses. Substantial pulmonary or neurologic toxicity was not observed in this study. Two complete responses (CRs) and 13 partial responses (PRs) were observed, for a 60% overall response rate (95% confidence interval [CI], 39% to 79%). The median survival time was 16 months, with a 66% 1-year survival probability. CONCLUSION: CDDP 35 mg/m2/wk and paclitaxel 45 mg/m2/wk can be safely administered with concurrent standard RT. The use of hyperfractionation is associated with a more frequent occurrence of severe esophagitis and requires a reduction of the CDDP dose to 30 mg/m2/ wk. Only future randomized trials will elucidate which of these two approaches (standard or hyperfractionated RT) is the better option to improve the outcome of patients with locally advanced NSCLC.     

Thought control strategies in acute stress disorder

Relapse after transplant for malignant lymphomas remains the main cause of treatment failure. Most conditioning regimens contain total body irradiation (TBI). We investigated the toxicity and efficacy of an intensified chemotherapy conditioning regimen without TBI in patients with relapsed or high-risk malignant lymphoma who had received prior radiation therapy and were therefore not eligible for TBI. Twenty patients with a median age of 38 (18-56) and relapsed or high-risk malignant non-Hodgkin's lymphoma (NHL, n = 16) or Hodgkin's disease (HD, n = 4) underwent high-dose chemotherapy consisting of busulfan (16 mg/kg), cyclophosphamide (120 mg/kg) and etoposide 30 mg/kg (n = 8) or 45 mg/kg (n = 12) followed by peripheral stem cell support (n = 14), autologous bone marrow (n = 3), allogeneic (n = 2) or syngeneic (n = 1) transplantation. All but two had chemosensitive disease before high-dose chemotherapy. The main toxicity -- according to the Bearman score -- was mucositis II in 18 (90%) patients; five patients (25%) suffered a grade I hepatic toxicity. GI toxicity I occurred in three (15%) and renal toxicity I in two patients (10%). Sixty percent of the patients developed transient dermatitis with erythema and three of them (15%) had skin desquamation; one patient experienced asymptomatic pancreatitis. Toxicity was slightly higher in patients treated with 45 mg/kg etoposide. One patient (5%) died of treatment-related venoocclusive disease. After a median follow-up of 50 months (24-84) the disease-free and overall survival were 50% and 55%. One of the nine relapsing patients developed secondary AML 18 months after transplant. High-dose busulfan, cyclophosphamide and etoposide is an effective regimen resulting in long-term disease-free survival in 50% of patients with relapsed malignant lymphoma and prior radiation therapy. The toxicity is moderate with a low treatment-related mortality (5%).     

Scaling of movement velocity: a measure of neuromotor retardation in individuals with psychopathology

The combination of ifosfamide, carboplatin and etoposide (modified ICE), was evaluated for its toxicity and activity in relapsed or refractory aggressive non-Hodgkin's lymphoma. Twenty patients, 14-69 years of age, with relapsed (19 cases) or refractory (one case) aggressive non-Hodgkin's lymphoma were treated with modified ICE therapy, consisting of ifosfamide 6 g/m2 (1.2 g/m2 day 1-5), carboplatin 400 mg/m2 (day 1) and etoposide 500 mg/m2 (100 mg/m2 day 1-5). The regimen was repeated at approximately 28-day intervals. All patients had undergone a doxorubicin-containing regimen before modified ICE therapy. Median total dose of previously received doxorubicin was 406 mg/m2 (range: 200-825 mg/m2). The median interval from diagnosis to modified ICE therapy was 9.4 months (range: 3.6-121 months). Two patients achieved CR and five achieved PR out of 16 patients with measurable lesions (response rate 43.8%; 95% confidence interval 19.0-68.6%). Median overall survival was 227 days (range: 41-552 days) from the start of modified ICE therapy. Myelosuppression was the most serious toxicity, namely 16 patients (80%) and 11 patients (55%) showed grade 4 neutropenia and grade 4 thrombocytopenia after the first course, respectively. Modified ICE therapy might be an active regimen with acceptable toxicity as a salvage chemotherapy in aggressive non-Hodgkin's lymphoma.     

Specificity of the BAX polymerase chain reaction system for detection of the foodborne pathogen Listeria monocytogenes

PURPOSE: The purpose of this study was to evaluate the toxicity and efficacy of twice-daily external irradiation to the pelvis and para-aortics with brachytherapy and concurrent chemotherapy for carcinoma of the cervix with positive para-aortic lymph nodes. METHODS AND MATERIALS: This study was designed to administer twice-daily radiation doses of 1.2 Gy to the pelvis and para-aortics at 4- to 6-h intervals, 5 days per week. The total external radiation doses were 24 to 48 Gy to the whole pelvis, 12 to 36 Gy parametrial boost, and 48 Gy to the para-aortics with an additional boost to a total dose of 54 to 58 Gy to the known metastatic para-aortic site. One or two intracavitary applications were performed to deliver a total minimum dose of 85 Gy to point A. Cisplatin (75 mg/m2, days 1 and 22) and 5-FU (1000 mg/m2/24 h x 4 days; days 1 and 22) were given for two or three cycles. RESULTS: Twenty-nine patients with clinical Stages I to IV carcinoma of the cervix with biopsy-proven para-aortic lymph nodes were enrolled in this study. Hyperfractionated external radiotherapy was completed in 86% (25 of 29). Brachytherapy was given in two applications to 48% (14 of 29), 31% (9 of 29) had one intracavitary application, 14% (4 of 29) had no brachytherapy, one had three applications, and one had five HDR applications. Radiotherapy was completed per protocol in 69%. Three courses of chemotherapy were given to 24% (7 of 29), 72% (21 of 29) received two courses, and one patient did not receive chemotherapy. The acute toxicity from chemotherapy was Grade 1 in 3%, Grade 2 in 17%, Grade 3 in 48%, and Grade 4 in 28%. Radiotherapy toxicity was Grade 1 in 7%, Grade 2 in 34%, Grade 3 in 21%, and Grade 4 in 28%. One Grade 5 toxicity occurred and the patient died from a myocardial infarction from chemotherapy and radiotherapy colitis during her course of therapy. The median follow-up time was 18.9 months. The overall survival estimates were 59% at 1 year and 47% at 2 years. The probability of local-regional failure was 38% at 1 year and 49% at 2 years. The probability of disease failure at any site was 45% at 1 year and 59% at 2 years. CONCLUSION: The results suggest that twice-daily external irradiation to the pelvis and para-aortics with brachytherapy and concurrent chemotherapy resulted in an unacceptably high rate (31%, 9 of 29) of Grade 4 nonhematologic toxicity. One patient died from complications of therapy. Radiotherapy was completed per protocol in 69%. The survival estimates appear no better than standard fractionation radiotherapy without chemotherapy. Additional follow-up is necessary for long-term survival estimates.     

Randomized trial of alternating versus sequential radiotherapy/chemotherapy in limited-disease patients with small-cell lung cancer: a European Organization for Research and Treatment of Cancer Lung Cancer Cooperative Group Study

PURPOSE: To evaluate the effectiveness of alternating or sequential schedules of cyclophosphamide, doxorubicin, and etoposide (CDE) chemotherapy and irradiation in patients with previously untreated small-cell lung cancer (SCLC). MATERIALS AND METHODS: A total of 335 eligible patients were randomized between five courses of CDE chemotherapy followed by thoracic irradiation 50 Gy in 20 daily fractions (S) and the same total dose of chemotherapy and irradiation split into four courses of five daily fractions delivered on days 14 to 21 of the second and subsequent chemotherapy courses (A). Patients had a median age of 61 years (range, 33 to 75); 224 (66%) were male; the Eastern Cooperative Oncology Group (ECOG) performance status (PS) was 0 or 1 in 311; and 254 had weight loss less than 10%. RESULTS: The overall median survival duration was 15 months, with 62% (95% confidence interval [CI], 57% to 67%) 1-year, 25% (95% CI, 20% to 30%) 2-year, and 14% (95% CI, 10% to 18%) 3-year survival rates. There was no significant difference between the arms. The median survival time was 14 months in A and 15 months in S. One-year survival was 60% in A (95% CI, 53% to 67%) and 64% in S (95% CI, 57% to 71%); 2-year survival was 26% in A (95% CI, 19% to 33%) and 23% in S (95% CI, 16% to 30%); and 3-year survival was 12% in A (95% CI, 6% to 18%) and 15% in S (95% CI, 9% to 21%). World Health Organization (WHO) grade 3 and 4 neutropenia occurred in 90% of A and 77% of S patients (P < .001) and WHO grade 3 and 4 thrombocytopenia in 33% of A and 20% of S patients (P < .001). Rates of other acute and late toxicities were similar in both arms. Hematologic toxicity compromised treatment dose delivery; less than 50% of A patients received greater than 95% of prescribed chemotherapy and 77% their full radiation course, compared with 60% and 93% for arm S (P < .009). Local relapse was the site of first failure in 60% of all patients and 75% of these suffered an in-field relapse; no difference could be seen between the two arms. CONCLUSION: This trial failed to confirm the superiority of an alternating schedule of delivery. For this combination of chemotherapy and irradiation, hematologic toxicity compromised treatment delivery and could have contributed to the overall result. The poor rates of local control are disappointing and require intensification of the radiation therapy strategy.     

Biologic and clinical effects of continuous infusion interleukin-2 in patients with non-small cell lung cancer

BACKGROUND: Interleukin-2 (IL-2) has shown antitumor activity in some neoplasms, such as melanoma and renal carcinoma, but toxicity derived from bolus administration is significant, particularly at the cardiorespiratory level. METHODS: To test feasibility, antitumor activity, pulmonary and systemic immunologic effects, and pulmonary function changes of continuous-infusion recombinant IL-2 given to patients with non-small cell lung cancer, eleven subjects with Stage III-IV disease were treated in a standard pulmonary medicine unit with a dose of 18 million IU/m2/day from day 1 to day 13 with 1-day rest on day 7. A second induction course was given after a 3-week rest. In patients with nonprogressive disease, four maintenance courses of 6 days' duration at the same dose were planned. Immunologic tests, including lymphocyte phenotype analysis and assays for the detection of tumor necrosis factor (TNF) and of anti-IL-2 antibodies, were performed before and after treatment in serum and bronchoalveolar lavage fluid (BAL). Cardiopulmonary function tests, including spirometry, arterial blood gas analysis, diffusion capacity, and echocardiography, were obtained before, during, and after treatment. RESULTS: Twenty-one cycles (15 induction courses plus 6 maintenance courses) were administered. No patient was able to complete the six planned courses, and only 3 patients entered the maintenance phase. Reasons for discontinuation included progressive disease in five cases, toxicity in three cases, and patient request in three cases. The most common side effects were fever, hypotension, oliguria, and elevated serum creatinine and liver enzyme levels. No patient required intubation or intensive care. No objective response was seen, and the median survival time was 10 months. Lymphocytosis and eosinophilia were observed in all patients. Surface marker analysis revealed a statistically significant increase in the percentage of CD3+, CD4+, CD25+ and DR+ cells in peripheral blood. Lymphoid cells derived from BAL disclosed an increased natural killer activity after IL-2 treatment, and TNF was increased in BAL fluid. Pulmonary function tests evidenced an increased alveolar-arterial difference for oxygen allied with a decrease of forced expiratory volume in 1 second, forced vital capacity, and carbon monoxide transfer coefficient consistent with a significant, albeit not clinically relevant, interstitial lung defect. CONCLUSION: Continuous-infusion IL-2 is feasible in patients with advanced lung cancer even outside an intensive care unit, but overall compliance is poor. Although clinical pulmonary toxicity is negligible, small but statistically significant alterations of the pulmonary function are evident. In addition, this regimen produces a significant activation of the immune system at the pulmonary level.     

Trends in surgical management of astrocytomas and other brain gliomas

PURPOSE: Retrospective analysis of the influence of clinical and technical factors on local control and survival after radiosurgery for brain metastasis. PATIENTS AND METHODS: From January 1994 to December 1996, 42 patients presenting with 71 metastases underwent radiosurgery for brain metastasis. The median age was 56 years and the median Karnofsky index 80. Primary sites included: lung (20 patients), kidney (seven), breast (five), colon (two), melanoma (three), osteosarcoma (one) and it was unknown for three patients. Seventeen patients had extracranial metastasis. Twenty-four patients were treated at recurrence which occurred after whole brain irradiation (12 patients), surgical excision (four) or after both treatments (eight). Thirty-six sessions of radiosurgery have been realized for one metastasis and 13 for two, three or four lesions. The median metastasis diameter was 21 mm and the median volume 1.7 cm3. The median peripheral dose to the lesion was 14 Gy, and the median dose at the isocenter 20 Gy. RESULTS: Sixty-five metastases were evaluable for response analysis. The overall local control rate was 82% and the 1-year actuarial rate was 72%. In univariate analysis, theoretical radioresistance (P = 0.001), diameter less than 3 cm (P = 0.039) and initial treatment with radiosurgery (P = 0.041) were significantly associated with increased local control. Only the first two factors remained significant in multivariate analysis. No prognostic factor of overall survival was identified. The median survival was 12 months. Six patients had a symptomatic oedema (RTOG grade 2), only one of which requiring a surgical excision. CONCLUSION: In conclusion, 14 Gy delivered at the periphery of metastasis seems to be a sufficient dose to control most brain metastases, with a minimal toxicity. Better results were obtained for lesions initially treated with radiosurgery, theoretically radioresistant and with a diameter less than 3 cm.     

Randomized comparison of cisplatin and etoposide and either bleomycin or ifosfamide in treatment of advanced disseminated germ cell tumors: an Eastern Cooperative Oncology Group, Southwest Oncology Group, and Cancer and Leukemia Group B Study

PURPOSE: To compare standard therapy with bleomycin, etoposide, and cisplatin (BEP) to experimental therapy with etoposide, ifosfamide, and cisplatin (VIP) as primary treatment of men with advanced, disseminated germ cell tumors. PATIENTS AND METHODS: A total of 304 men with advanced disseminated germ cell tumors were randomly allocated to receive four courses of BEP or VIP. Two hundred ninety-nine patients were assessable for toxicity and 286 were assessable for response. Complete response rates, favorable response (complete remission, surgical free of disease, continuous partial remission for 2+ years), time to treatment failure, and overall survival were assessed. RESULTS: Overall complete remission rate (VIP, 37%; BEP, 31%), favorable response rate (VIP, 63%; BEP, 60%), failure-free at 2 years (VIP, 64%; BEP, 60%), and 2-year overall survival (VIP, 74%; BEP, 71%) were not significantly different between the two treatments. Grade 3 or worse toxicity, particularly hematologic and genitourinary toxicity, was significantly more common in patients who received VIP. CONCLUSION: BEP and VIP produce comparable favorable response rate and survival in patients with poor-risk germ cell tumors. The substitution of ifosfamide for bleomycin, however, was associated with significantly greater toxicity. Four courses of BEP remain the standard treatment for advanced disseminated germ cell tumors.     

Corticosteroids significantly delay the onset of docetaxel-induced fluid retention: final results of a randomized study of the European Organization for Research and Treatment of Cancer Investigational Drug Branch for Breast Cancer

PURPOSE: To confirm the efficacy of docetaxel in patients with breast cancer previously treated with one chemotherapy regimen for advanced or metastatic disease and to compare the incidence of fluid retention (FR) and skin toxicity when docetaxel is administered with and without prophylactic corticosteroids. PATIENTS AND METHODS: Eighty-three patients, pretreated with one chemotherapy regimen for metastatic breast cancer (MBC) with bidimensionally measurable and progressive disease, were eligible for this randomized trial. Docetaxel with prophylactic oral antihistamine was administered at a dose of 50 mg/m2 as a 1-hour infusion on days 1 and 8 every 21 days and patients were randomized to receive methylprednisolone (40 mg days -1, 0, 1, 7, 8, and 9 of each cycle) (arm A) or no methylprednisolone (arm B). RESULTS: Twenty-eight patients (34%, 95% confidence interval [CI], 23% to 45%) achieved on objective response. The median time to disease progression and median overall survival time were 5 and 13.5 months, respectively. In total, 415 cycles of docetaxel were administered (arm A: N = 219, median = six; arm B: N = 196, median = five). The most common toxicity observed was grade 3 or 4 neutropenia, which occurred in 79% of patients. Clinically significant nonhematologic side effects included skin reactions and asthenia. In an intent-to-treat analysis, patients who received methylprednisolone premedication had a delayed onset of FR (median time to onset of FR: arm A, 84 days; arm B, 62 days; P = .01) and received a higher median cumulative dose of docetaxel before the onset of FR (arm A, 333 mg/m2; arm B, 215 mg/m2; P = .001). There was no statistically significant difference in the incidence of skin toxicity between the two arms. CONCLUSION: Docetaxel, at this dose and schedule, has definite antitumor activity in pretreated MBC patients. Moreover, this is the first randomized trial to show that corticosteroids have a favorable impact on docetaxel-induced FR.     

Doxorubicin-containing regimen with or without interferon alfa-2b for advanced follicular lymphomas: final analysis of survival and toxicity in the Groupe d'Etude des Lymphomes Folliculaires 86 Trial

PURPOSE: To compare progression-free survival (PFS), overall survival (OS), and toxicity of a doxorubicin-containing regimen administered alone or in combination with interferon alfa-2b (IFNalpha) in patients with low-grade follicular lymphoma (FL) and poor prognostic factors. PATIENTS AND METHODS: Two hundred sixty-eight patients with advanced-stage FL received cyclophosphamide, doxorubicin, teniposide, and prednisone (CHVP) monthly for 6 months, then every 2 months for 12 months. After randomization, 242 patients were evaluated for efficacy: 119 received CHVP alone, and 123 also received IFNalpha at a dose of 5 million units three times weekly for 18 months. RESULTS: After a 6-year median follow-up, the patients treated with CHVP + IFNalpha showed significantly longer median PFS than those who received CHVP alone (2.9 years v 1.5 years, respectively; P = .0002) and significantly longer median OS (not reached v 5.6 years, respectively; P = .008). Although some side effects, which included neutropenia, asthenia, fever, elevated serum transaminase levels, flu-like symptoms, and thrombocytopenia, were more frequently observed in patients who received the combination regimen, these reactions were moderate. IFNalpha was withdrawn because of toxicity in 10% of the patients, and a dosage reduction or temporary suspension was required in 28%. CONCLUSION: With long-term follow-up of 6 years, these results confirm that the addition of IFNalpha to a doxorubicin-containing regimen for patients with advanced-stage and clinically aggressive FL not only increased PFS, as in most other similar trials, but also prolonged OS. Toxicity was moderate. The beneficial effects of this combined chemotherapy and IFNalpha regimen on OS probably reflect the selection of FL patients with poor prognostic factors.     

Cycles of dose-intensive chemotherapy with peripheral stem cell support in persistent or recurrent platinum-sensitive ovarian cancer

OBJECTIVE: The objective was to determine the toxicity and surgically documented response rate of sequential high-dose chemotherapy with peripheral stem cell support in patients with persistent or recurrent cisplatin-sensitive ovarian cancer. METHODS: Fourteen patients (average age, 45 years) were treated with cyclophosphamide (4.5 g/m2), followed by granulocyte colony-stimulating factor (G-CSF)-stimulated peripheral stem cell harvests. The subsequent regimen prescribed three courses of carboplatin (1 g/m2) and cyclophosphamide (1.5 g/m2 with 2-mercaptoethanesulfonate) every 2 weeks with stem cell support. This was followed by three courses of paclitaxel at 250 mg/m2 every 2 weeks with G-CSF support only. Six patients were entered on the basis of a positive second-look laparotomy and 8 patients had a first recurrence after at least a 6-month disease-free interval. RESULTS: Fourteen patients were entered and 12 patients completed all planned courses of therapy (mean time, 13 weeks). Normal hematopoiesis was reestablished after each cycle. Hospitalization for neutropenic fever occurred in 11/93 cycles (11.8%). Thirteen patients required blood transfusions and in 12 patients platelet transfusions were given. One patient had grade 3 neurotoxicity. An initial elevated CA 125 returned to normal in 7/8 patients (88%) and 71% of patients with measurable disease responded to therapy. There were 2 pathologic complete responders (PCR), making the PCR rate 2/14 or 14% (0-35%). CONCLUSION: Although this regimen was well tolerated and clinical response rates were high, the surgically documented response rate was not clearly superior to conventional salvage regimens in platinum-sensitive patients.     

Remission induction therapy of untreated acute myeloid leukemia using a non-cytarabine-containing regimen of idarubicin, etoposide, and carboplatin

BACKGROUND: The safety and efficacy of idarubicin, etoposide, and carboplatin as remission induction therapy for patients younger than 60 years with untreated acute myeloid leukemia was studied as an alternative to standard regimens based on cytarabine plus anthracycline. METHODS: Eligible patients received idarubicin (36-40 mg/m2), etoposide (500 mg/m2), and carboplatin (1000-1500 mg/m2) over 5 days. Those who achieved complete remission received a single course of cytarabine 1.5 gm/m2 every 12 hours for a total of 12 doses. D-xylose absorption was studied as a marker for cytotoxic therapy-induced gut mucosal damage. Cytogenetic and immunophenotyping studies were performed at the time of diagnosis and examined for prognostic importance. RESULTS: Remission was achieved in 29 (67%) of 43 patients with a single induction course. The median leukemia free and overall survival times were 15.4 months (95% CI 6.5-24.2) and 12.5 months (95% CI 5.9-19.1), respectively. Induction mortality was 14%. Karyotype (normal, simple, or complex vs. very complex) was the strongest predictor of remission (79% vs. 25%, P=0.01), leukemia free survival (odds ratio [OR] 19.3, 95% CI 2.7-138.9), and overall survival (OR 5.4, 95% CI 2.1-13.9). Dose-limiting gut mucosal toxicity was greatest during Weeks 2 and 3. Bloodstream infections occurred in 49% of patients at a median of 12 days. Grade 3-4 diarrhea, nausea, stomatitis, esophagitis/dysphagia, and vomiting developed in 33%, 26%, 23%, 9%, and 2% of cases, respectively, at a median of 17, 16, 11, 15.5, and 21 days, respectively. CONCLUSIONS: This regimen was active in adults younger than 60 years with untreated acute myeloid leukemia and normal, simple, or complex karyotypes. Remission duration was confounded by karyotype. Mucosal toxicity limited the tolerability of this regimen. These adverse effects might be overcome by increasing the intensity of postremission therapy and modifying the dosing schedule.