A phase I-II trial of induction chemotherapy with carboplatin and fluorouracil in locally advanced head and neck squamous cell carcinoma: a report from the UCL-Oncology Group, Belgium.

Eighty-three patients (median age, 56 years and Karnofsky performance status greater than or equal to 70) were treated with carboplatin (Carbo) and fluorouracil (5Fu) for stage III and IV head and neck squamous cell carcinoma (HNSCC). 5Fu (1 g/m2/d) was administered from day 1 to 4 by continuous infusion. Carbo was given on day 1 and, in order to evaluate its maximum-tolerated dose (MTD), the dose level was progressively increased from 250 mg/m2 to 450 mg/m2. The effectiveness of this association and its potential role in local control were also evaluated. Three patients received Carbo at a dose of 250 mg/m2, 13 received 300 mg/m2, one received 330 mg/m2, 12 received 350 mg/m2, six received 375 mg/m2, 26 received 400 mg/m2, 18 received 420 mg/m2, and four received 450 mg/m2. Two (13 of 83) or three courses (64 of 83), repeated every 4 weeks, were administered. The overall (primary tumor and node) response and complete response (CR) rates were 33% and 14%, respectively. For primary tumor, the response rate (RR) was 57% with 32% CR and 18% pathologic complete response (PCR); the RR was higher for patients with oropharyngeal tumor (76%, P = .037) and for patients treated with Carbo greater than or equal to 350 mg/m2 (65%, P = .02); the tumor size (T1 + T2 v T3 + T4) was a good prognostic factor for RR (90% v 46%, P = .001), CR (65% v 20%, P less than .001), and PCR (45% v 8%, P less than .001). For nodes, the RR was 33% with 11% CR. Grade 3-4 neutropenia and thrombocytopenia were experienced by 17% and 28% of the patients treated with 420 mg/m2 of Carbo and by 50% of the patients treated with 450 mg/m2. The MTD can be fixed at 420 mg/m2 and the proposed dose at 400 mg/m2. Thirty-eight patients were treated with surgery plus radiotherapy, 33 with radiotherapy alone, and seven with surgery alone. The median follow-up is 12 months. The 18-month disease-free survival (DFS) is 78% for overall complete responders and 39% for the others (P = .04). There is no primary tumor recurrence among the 12 patients with a primary tumor PCR treated by radiotherapy alone for tumor control (median follow-up, 17.3 months). The association of Carbo-5Fu is a safe induction chemotherapy regimen for HNSCC. The proposed dose of Carbo for future treatment is 400 mg/m2.(ABSTRACT TRUNCATED AT 400 WORDS)

Dose-dependent interleukin-3 stimulation of thrombopoiesis and neutropoiesis in patients with small-cell lung carcinoma before and following chemotherapy: a placebo-controlled randomized phase Ib study.

PURPOSE: To evaluate the safety, tolerance, and hematologic effects of recombinant human interleukin-3 (IL-3) in patients with small-cell lung cancer (SCLC) before and following multiagent antineoplastic therapy in a placebo-controlled, randomized, double-blind study. PATIENTS AND METHODS: Twenty-eight patients (22 men and six women; median age, 60 years) with previously untreated SCLC entered the study. Patients were assigned to six groups of escalating-dose IL-3 ranging from 0.25 to 10 micrograms/kg/d administered by continuous infusion for 7 days, with one patient in each group receiving placebo. After a 1-week interval, the first of three cycles of carboplatin, etoposide (VP16), and epirubicin (CVE) given every 3 weeks was administered. The second cycle of CVE was followed by 7 days of IL-3 administered at the same daily dose as administered during the first infusion. RESULTS: The maximum-tolerated dose was not encountered in this study. Fever was the most frequently observed side effect. Before any chemotherapy, World Health Organization (WHO) grade II fever only appeared at doses > or = 2.5 micrograms/kg/d. Other side effects included rash, headache, and myalgia. During the first infusion of IL-3, before administration of chemotherapy, dose-dependent increases in peripheral-platelet counts (r = .613; P < .001) and neutrophil counts (r = .505; P = .007) were observed. Following the second cycle of CVE, recovery of peripheral platelet counts was faster as compared with the first cycle of CVE for patients treated with 7.5 and 10 micrograms/kg of IL-3 (P = .021). Chemotherapy postponements due to myelotoxicity were also less frequent following the second cycle of CVE as compared with the first for patients treated with > or = 2.5 micrograms/kg of IL-3 (P = .036). Compared with an age-matched historical group receiving identical chemotherapy (n = 191), administration of IL-3 did not modify either disease-free survival or overall patient survival rates. CONCLUSION: IL-3 is well tolerated at doses up to 10 micrograms/kg/d. In the absence of chemotherapy, biologic effects on both neutrophils and platelets were seen at doses > or = 2.5 micrograms/kg/d. IL-3 infusion following the second cycle of CVE appears to reduce chemotherapy-induced myelosuppression, but does not alter tumor response or patient survival rates.

Late intensification chemotherapy with autologous bone marrow transplantation in selected small-cell carcinoma of the lung: a randomized study.

A multicentric randomized prospective trial was conducted to test whether late intensification chemotherapy would increase the remission rate, the relapse-free survival, and the survival of small-cell lung cancer patients responding to induction chemotherapy. Autologous bone marrow transplantation was used as support to reduce the duration of the aplasia induced by very high-dose chemotherapy. As induction chemotherapy, 101 patients received, during a period of 5 months, a total dosage of 120 mg/m2 methotrexate, 4.5 mg/m2 vincristine, 1,800 mg/m2 cyclophosphamide, 180 mg/m2 doxorubicin, 160 mg/m2 cisplatin, 750 mg/m2 VP-16-213, and 30 Gy prophylactic cranial irradiation. Forty-five patients, selected for their sensitivity to this induction treatment, were randomized to a last cycle of chemotherapy that combined cyclophosphamide, BCNU, and VP-16-213 either at a conventional dosage of 750 mg/m2 intravenously (IV), 60 mg/m2 IV, and 600 mg/m2 orally or alternatively at a very high dosage of 6 g/m2 IV, 300 mg/m2 IV, and 500 mg/m2 IV, respectively. In the late intensification group, the complete remission rate increased from 39% before randomization to 79% after high-dose chemotherapy. Median relapse-free survivals after randomization for intensified and control chemotherapy groups were 28 and 10 weeks, respectively (P = .002). Median overall survival after induction therapy was 68 weeks for the intensified group compared with 55 weeks for the conventional therapy group (P = .13). Four patients died during intensification. Patients in both groups relapsed at the primary site. It can thus be concluded that late intensification chemotherapy for sensitive small-cell lung cancer increases the complete remission rate and resulted in a statistically significant increase in the relapse-free survival. However, since relapse occurred at the primary site and toxicity was high, overall survival was not significantly improved.

Clearance kinetics of CD34+ cells from peripheral blood: an independent predictor of hematologic recovery after high-dose chemotherapy and hematopoietic stem cell transplantation.

We measured the concentration of CD34+ cells in peripheral blood (PB) (1/2) h prior to and (1/2), 1, 3, 6, and 12 h following hematopoietic stem cell (HSC) infusion in 34 breast cancer patients treated with high-dose chemotherapy (HDC). The decrease in these concentrations over time enabled us to determine the clearance kinetics of CD34+ cells from PB. The absolute number of CD34+ cells in PB generally peaked at (1/2) h after infusion, then rapidly declined from 1 to 3 h post infusion and continued to fall until 12 h post transplant, but more slowly. In univariate analysis, CD34+cells/kg infused, CFU-GM/kg infused, the CD34+ count at (1/2) h, and the 12-h clearance of CD34+ cells from PB were predictors of hematologic recovery, as were each of the two phases of clearance when the slope was divided into rapid and slow phases (from (1/2) to 3 and from 3 to 12 h post transplant, respectively). We then stratified our population by the number of CD34+ cells/kg infused. In group 1, patients received 7.5 x 10(6) CD34+ cells/kg. After adjusting for CD34+ cells injected, age, and purged or unpurged graft in multivariate analysis, the 12 h clearance remained a predictor of hematologic recovery in group 1. In addition, the second phase of clearance (from 3 to 12 h after infusion) was an even better predictor than the 12 h clearance. In group 2, however, no statistically significant correlation was observed, even with the number of HSC injected. Results suggest that rapidity of clearance of CD34+cells from PB is an independent indicator of hematologic recovery in patients receiving lower doses of CD34+ cells. When the cell dose injected is over a threshold, PB clearance correlations with hematologic recovery are masked.

The administration of 10 microg/kg granulocyte colony-stimulating factor (G-CSF) alone results in a successful peripheral blood stem cell collection when previous mobilization with chemotherapy and hematopoietic growth factor failed.

Some heavily pretreated cancer patients fail to mobilize enough peripheral blood stem cells (PBSC) after stimulation with chemotherapy and hematopoietic growth factors. For these patients the best way to obtain an adequate PBSC collection is unknown. Here we report 6 heavily pretreated cancer patients who failed to mobilize sufficient PBSC after stimulation with chemotherapy and G-CSF 5 microg/kg/day. In these cases, we used G-CSF 10 microg/kg/day alone for six days at least 3 weeks after the last chemotherapy. After three consecutive leukaphereses starting on day 5, five patients had adequate PBSC collections. With 6 days of G-CSF 10 microg/kg/day alone, 2.8 x 10(6) (+/- 1) CD34+ cells/kg were collected. This was significantly higher than the number of CD34+ cells/kg collected after chemotherapy and G-CSF 5 microg/kg 0.3 x 10(6) (+/- 0.1) [P = 0.05]. Four patients received high-dose chemotherapy with PBSC support. Hematologic recovery observed in these patients was as expected. In conclusion, G-CSF 10 microg/kg alone can mobilize progenitor cells into peripheral blood when previous mobilization with chemotherapy and G-CSF 5 microg/kg fails.

Oral versus intramuscular high-dose medroxyprogesterone acetate (HD-MPA) in advanced breast cancer. A randomized study of the Belgian Society of Medical Oncology.

Ninety postmenopausal women with advanced breast cancer were randomly assigned to be treated with HD-MPA administered either by oral route (daily dose 900 mg) or by intramuscular injections (1 g IM daily X 5 q w during 4 consecutive weeks followed by maintenance with 1 g twice weekly). Among 78 evaluable cases, most heavily pretreated, remissions, lasting for a median duration of 11 months, were more frequent on oral (8/37 = 22%) than on IM therapy (5/41 = 12%). In both arms, high estrogen receptor levels and various clinical factors were associated with higher response rates i.e., age greater than 60, Karnofsky greater than 70, light prior systemic treatment. Side-effects, consisting mainly of weight gain, hypertension and tremor occurred with equal frequency on oral or IM treatment. Five patients complained of pain at the sites of IM injections. Thus, we recommended that, whenever possible, the oral route should be preferred. During the same study, in 20 patients (11 on oral and 9 on IM therapy), blood was drawn at 0, 30, and 60 days of treatment for the assessment of MPA and hormone levels. In both arms, at 60 days, comparable levels of circulating MPA were obtained, with a very significant drop of cortisol, androstenedione, and estrone. These endocrine results, together with our clinical data, indicate that HD-MPA therapy is active on estrogen-dependent tumors with the same specificity as that of other modalities aiming to suppress the adrenal function. Its antineoplastic action in humans could be ascribed at least in part to its suppressive action on the adrenals, resulting in a severe estrogenic deprivation in postmenopausal women.

Longitudinal follow-up of breast cancer patients with the tumor markers CA 549 and CA 15.3.

In order to verify the efficiency of the tumor markers CA 15.3 and CA 549 in the follow-up of breast cancer patients, it was necessary first to check the cutoff levels of each tumor marker in women with an increased age-related risk, but with no evidence of disease. From 132 serum samples in this age group, we confirmed the CA 549 cutoff level of 12.1 U/ml. However, the cutoff of CA 15.3 was 34 U/ml, which is higher than previously reported in the literature. Fifty-two breast cancer patients with or without metastases at the time of entry into the study were followed for 2 to 3 years with both tumor markers. The sensitivity, specificity and the test efficiency for the presence of metastases were analyzed with each tumor marker. Taking into account the different cutoff levels, we concluded that both tumor markers can be used independently to follow the clinical situation of patients. In several cases an increase in both tumor markers was observed before a clinical diagnosis of metastases could be made. Combination of these two tumor markers gave no more significant information about the patient's clinical situation than each tumor marker alone.

[Efficiency of high-dose FEC chemotherapy for the mobilization of hematopoietic stem cells into peripheral blood]. / Efficacité d'une chimiothérapie FEC à forte dose pour la mobilisation des cellules souches hématopoïétiques dans le sang périphérique.

The best regimen for mobilizing hematopoietic stem cells (HSC) into peripheral blood is not yet defined. The efficiency of FEC chemotherapy in the treatment of breast cancer is well established and the effects of FEC on HSC mobilization have been characterized. We tested the feasibility and the toxicity of a high-dose FEC regimen which may improve the mobilizing capacity of conventional FEC. Twenty patients with poor prognosis breast cancer received high-dose FEC and filgrastim 5 micrograms/kg. Three leukaphereses were performed on each patient for 3 consecutive days. Total numbers of CFU-GM and CD34+ cells were assessed, and a retrospective analysis was made. The numbers of CFU-GM/kg and CD34+ cells/kg collected (mean +/- standard error) were respectively 12.2 x 10(5) (+/- 2.4) and 14.6 x 10(6) (+/- 2.5). Extra-hematologic toxicity was negligible. Hematologic recovery after CTCb high-dose chemotherapy and HSC infusion was rapid. High-dose FEC is efficient for collecting HSC in peripheral blood. Extra-hematologic toxicity is weak and hematologic recovery after autograft is normal. Increased dosage of epirubicin and cyclophosphamide could allow a single leukapheresis collection of sufficient HSC from peripheral blood.

Adjuvant chemotherapy of rectal cancer.

The basic principles as well as the possible indications for adjuvant chemotherapy are discussed. An overview of the studies testing chemotherapy alone or combined with radiation or immunotherapy is presented.

Severe anal condylomata acuminata following high-dose chemotherapy and autologous hematopoietic stem cell transplantation: a case report.

We report the case of a 37 years old male patient who developed severe anal condylomata acuminata after high-dose chemotherapy and autologous hematopoietic stem cell transplantation for follicular non-Hodgkin's lymphoma. Anal warts were particularly disabling, refractory to the treatment and finally imposed diversion colostomy. The role of cellular immunodeficiency observed after high-dose chemotherapy and autologous hematopoietic stem cell transplantation as etiology of anal condylomata is discussed.

Meropenem versus ceftazidime as empirical monotherapy for febrile neutropenic cancer patients.

A total of 101 cancer patients with 121 febrile neutropenia episodes were randomised to receive empirical treatment with i.v. meropenem (1g/8 h) or ceftazidime (2 g/8 h). After 3 days, 89% of patients were on unmodified therapy in the meropenem group, compared with 83% in the ceftazidime group. Of the evaluable episodes (n = 106), the success rate with unmodified empirical therapy until the end of the treatment course was slightly higher with meropenem than with ceftazidime (48% vs 38%, P=0.39). Furthermore, initial success with further infections was observed in 22% of episodes treated with meropenem and in 13% of episodes treated with ceftazidime. Glycopeptides were used as first modification in 28% and 39% of meropenem and ceftazidime recipients, respectively. Both treatments were well tolerated and there were no reports of drug-related nausea/vomiting or seizures. No significant differences in response rate or in tolerability were observed when analysing only the first febrile episodes. In conclusion, meropenem seems to be as efficacious and well tolerated as ceftazidime and may be associated with a lesser requirement for the addition of glycopeptides.

Domperidone (R 33812) in the prophylactic treatment of chemotherapy-induced emesis. A multicentre evaluation.

Domperidone (R 33812) was injected i.v. for the prevention of nausea and vomiting in a total of 395 cytostatic treatment courses in 172 patients. The total dose ranged from 1 to 40 mg and was given in one or several doses. Even after the administration of severely emetic substances, vomiting and nausea were largely prevented in hospitalized patients, but the results were rather poor in ambulatory patients. In all of the cytostatic treatment schedules very favourable results were obtained.

Thrombopoietic effects and toxicity of interleukin-6 in patients with ovarian cancer before and after chemotherapy: a multicentric placebo-controlled, randomized phase Ib study.

Recombinant human interleukin-6 (IL-6) has previously been shown to increase platelet counts in normal and sublethally irradiated mice, dogs, and primates. To assess its tolerance and efficacy in clinical use, we performed a randomized phase Ib study in patients with ovarian carcinoma. IL-6 was administered during an initial 7-day cycle before any chemotherapy. Beginning 7 days later, six cycles of chemotherapy containing carboplatin were administered every 3 weeks. During chemotherapy cycles 2 to 6, IL-6 was administered from day 4 through day 17 at escalating dose levels from 0.5 to 10 micrograms/kg/d. At each level, three patients received IL-6 and one patient received a placebo. During the prechemotherapy cycle of IL-6, a dose-dependent increase in platelet count was observed from day 12 to 15 and was maximal on day 15 (r = .77; P < .01). The median ploidy of bone marrow megakaryocytes shifted from 16 N to 32 N after 7 days of the initial prechemotherapy IL-6 administration. Dose-dependent increases in C-reactive protein (CRP) and fibrinogen levels were observed on day 8 (P < .0001 for both). A significant decrease in hemoglobin level occured rapidly after initiation of IL-6 therapy and was maximal on day 8 (P < .001). When given after chemotherapy, IL-6 accelerated platelet recovery after chemotherapy cycles 2 to 6. Postponements of scheduled chemotherapy due to thrombocytopenia were less frequent in patients treated with IL-6. No difference in either neutrophils or peripheral blood progenitor assays was observed during or after IL-6 treatment. Toxicity of IL-6 appeared mild and was not dose-limiting up to 10 micrograms/kg/d. Systemic symptoms such as fever, headache, and myalgia were the main side effects and were easily relieved by acetaminophen administration. No biologic toxicity was observed. The data indicate that IL-6 is a well-tolerated cytokine and capable of accelerating platelet recovery in patients receiving chemotherapy.

Skeletonizing en bloc esophagectomy for cancer.

OBJECTIVE: To evaluate the long-term outcome of patients with esophageal cancer after resection of the extraesophageal component of the neoplastic process en bloc with the esophageal tube. SUMMARY BACKGROUND DATA: Opinions are conflicting about the addition of extended resection of locoregional lymph nodes and soft tissue to removal of the esophageal tube. METHODS: Esophagectomy performed en bloc with locoregional lymph nodes and resulting in a real skeletonization of the nonresectable anatomical structures adjacent to the esophagus was attempted in 324 patients. The esophagus was removed using a right thoracic (n = 208), transdiaphragmatic (n = 39), or left thoracic (n = 77) approach. Lymphadenectomy was performed in the upper abdomen and lower mediastinum in all patients. It was extended over the upper mediastinum when a right thoracic approach was used and up to the neck in 17 patients. Esophagectomy was carried out flush with the esophageal wall as soon as it became obvious that a macroscopically complete resection was not feasible. Neoplastic processes were classified according to completeness of the resection, depth of wall penetration, and lymph node involvement. RESULTS: Skeletonizing en bloc esophagectomy was feasible in 235 of the 324 patients (73%). The 5-year survival rate, including in-hospital deaths (5%), was 35% (324 patients); it was 64% in the 117 patients with an intramural neoplastic process versus 19% in the 207 patients having neoplastic tissue outside the esophageal wall or surgical margins (P <.0001). The latter 19% represented 12% of the whole series. The 5-year survival rate after skeletonizing en bloc esophagectomy was 49% (235 patients), 49% for squamous cell versus 47% for glandular carcinomas (P =.4599), 64% for patients with an intramural tumor versus 34% for those with extraesophageal neoplastic tissue (P <.0001), and 43% for patients with fewer than five metastatic nodes versus 11% for those with involvement of five or more lymph nodes (P =.0001). CONCLUSIONS: The strategy of attempting skeletonizing en bloc esophagectomy in all patients offers long-term survival to one third of the patients with resectable extraesophageal neoplastic tissues. These patients represent 12% of the patients with esophageal cancer suitable for esophagectomy and 19% of those having neoplastic tissue outside the esophageal wall or surgical margins.