Dose-finding study of docetaxel added to ifosfamide and cisplatin followed by concomitant capecitabine and radiotherapy in the treatment of locally advanced squamous cell carcinoma of the head and neck.

BACKGROUND: Docetaxel (DOC) is a promising new drug in the management of squamous cell carcinoma of the head and neck. The aim of this phase I study was to determine the toxicity and maximum tolerated dose (MTD) as well as to obtain preliminary data on the activity of DOC combined with fixed doses of ifosfamide (IFO) and cisplatin (CDDP), followed by concomitant capecitabine (C) and radiation therapy in the organ-sparing treatment of patients with locally advanced, inoperable squamous cell carcinoma of the head and neck (A-SCCHN). PATIENTS AND METHODS: Chemotherapy and radiotherapy-naive patients with A-SCCHN were treated in cohorts of three with escalating doses of DOC administered on day 1. The doses of DOC ranged from 40 mg/m2 up to the dose-limiting toxicity (DTL). Fixed doses of IFO (1200 mg/m2) with mesna and CDDP (20 mg/m2) were administered on days 1 to 4, every 4 weeks. Patients who had achieved a response received definitive radiation therapy (6000 cGy) concomitantly with C (1000 mg/m2/day). RESULTS: Twenty-four patients were entered into the study. The MTD of DOC was 70 mg/m2. A total of 99 courses of chemotherapy were given. Grade 3 and 4 hematological toxicities were observed in twelve and nine patients, respectively, while grade 3 gastrointestinal toxicity occurred in four patients. Concomitant C and radiation therapy demonstrated a tolerable toxicity profile. An overall response rate of 83.3% (95% CI: 65.6% to 95.2%) was obtained, with a median time to progression and overall survival of 15.6 and 22.3 months, respectively. CONCLUSION: Out-patient administration of DOC, IFO and CDDP for A-SCCHN was safe and did not affect the ability to administer chemoradiotherapy on schedule. Myelosuppression was the DLT.

Cardiac metastases in malignant fibrous histiocytoma. A case report.

Malignant fibrous histiocytoma metastasizing to the left ventricle is an uncommon form of cardiac malignancy. This report describes a rare case of left ventricular metastases from a malignant fibrous histiocytoma of the posterior compartment of the right thigh, recurring five years after treatment with surgery, hyperthermic perfusion of the limb and radiotherapy. As the patient presented symptoms of cardiac tamponade, open heart surgery was performed through a median sternotomy; however, the tumor was not resectable and only a biopsy was performed. A partial response was obtained with standard and high-dose chemotherapy with peripheral blood progenitor cell transplantation. The response continued to improve with immunotherapy. The patient returned to normal physical activity. He died four years later due to a ventricular arrhythmia.

Interleukin-2 and 13-cis retinoic acid as maintenance therapy in advanced ovarian cancer.

The primary objective was to assess whether low-dose Interleukin-2 (IL-2) and 13-cis-retinoic acid (RA) could decrease serum vascular endothelial growth factor (VEGF) and improve the immune function of patients with advanced ovarian cancer (AOC) responsive to chemotherapy. The secondary end-point was to compare the response of these patients with that of a group of control patients, treated with standard care. Forty-four patients with AOC, responding to chemotherapy and with elevated serum levels of VEGF, were entered into the study from 04/98 to 12/02. After chemotherapy, patients received self-administered subcutaneous IL-2, 1.8x10(6) IU and oral RA, 0.5 mg/kg for 5 days/week for 2 consecutive cycles of 3 weeks, with a 1-week rest, for 1 year and with intermittent schedules for up to 5 years. Eighty-two well-matched controls were selected from a large cohort of patients of similar disease status, treated with standard therapies. A statistically significant decrease of VEGF was observed amongst the 44 evaluable patients. Lymphocyte NK counts and CD4+/CD8+ ratio improved with respect to both baseline values and controls. The progression-free survival (PFS) and overall survival (OS) curves showed a statistically significant improvement in IL-2/RA-treated patients. These preliminary data show that, after chemotherapy for AOC, the administration of low-dose subcutaneous IL-2 and oral RA is feasible, has low toxicity, is cost-effective and improves both PFS and OS.

Paclitaxel plus gemcitabine in advanced non-small cell lung cancer patients with low performance status.

BACKGROUND: The aim was to determine the efficacy and safety of a platinum-free regimen combining gemcitabine and paclitaxel for the treatment of patients with advanced non-small cell lung cancer (NSCLC) and a low performance status (PS). PATIENTS AND METHODS: Patients with histologically confirmed unresectable NSCLC, no previous chemotherapy, measurable lesion and a PS of 2 or 3 according to the Eastern Cooperative Oncology Group (ECOG) scale were elegible. Chemotherapy consisted of paclitaxel 200 mg/m2 on day 1 plus gemcitabine 1000 mg/m2 on days 1 and 8, every 3 weeks, for a maximum of 8 cycles. RESULTS: Twenty-nine consecutive patients were enrolled. PS was 2 and 3 in 93% and 7% of patients, respectively. A total of 149 courses of chemotherapy were delivered (median 4.6). Responses: complete response 1 (3.4%), partial response 11 (37.9%), stable disease 12 (41.3%), progressive disease 5 (17.2%) (response rate 41.3%, 95% CI. 23.5% to 61.6%). Median time to progression was 8.3 months (range 2.9-31.7); median overall survival was 13.6 months (range 3.2-31.7). Grade 3 leukopenia occurred in 3% of patients, while grade 3 thrombocytopenia was observed in 25% of patients. CONCLUSION: Reasonable response rates and a satisfactory clinical benefit can be obtained with a platinum-free regimen in NSCLC patients with a low PS.

Phase II randomized study of interleukin-2 with or without 13-cis retinoic acid as maintenance therapy in patients with advanced cancer responsive to chemotherapy.

AIM: In a previous phase 1B study, we determined the optimal biological dose of interleukin-2 (IL-2) and 13-cis retinoic acid (RA), given as maintenance therapy to patients with a variety of solid tumors, responding to chemotherapy, with a high risk of relapse. This therapy produced a statistically significant increase of the CD4+/CD8+ ratio, natural killer (NK) and lymphocyte cell counts and a decrease of vascular endothelial growth factor (VEGF). The aim of this phase II randomized study was to verify the role of RA in this drug combination. PATIENTS AND METHODS: One hundred and twelve patients, with locally advanced or metastatic tumors responding to chemotherapy, were randomized to receive IL-2, 1.8 x 10(6) I.U. for 5 days/week for 2 consecutive cycles of 3 weeks, with a 1-week interval (arm A), or the same regimen plus oral RA, 0.5 mg/Kg (arm B). VEGF, the CD4+/CD8+ ratio, NK and tumor markers were assessed every 2 months and response every 4 months. RESULTS: The baseline characteristics were well balanced between the two treatment arms for age, performance status, type of disease, amount of previous chemotherapy and baseline values of NK, CD4+/CD8+ and VEGF. Toxicity was minor in both arms. After a median follow-up of 42 months, all immunological parameters improved in both arms with respect to the baseline values; this improvement was statistically more significant in arm B. There was no statistically significant difference in progression-free and in overall survival between the two arms. CONCLUSION: These data show that low-dose IL-2 and oral RA is more effective than IL-2 alone in improving all known prognostically significant parameters in a variety of solid tumors, including an increase of lymphocytes and a decrease of VEGF.

Interleukin-2 and 13-cis retinoic acid in the treatment of minimal residual disease: a phase II study.

Interleukin-2 (IL-2) which has no cross-resistance with chemotherapy, has given responses in tumors resistant to chemotherapy, and shown to be more effective when tumor burden is low. 13-cis retinoic acid (RA) has immunomodulatory properties, potentially synergistic with IL-2. The objective of this pilot phase II study was to verify the immunomodulatory properties, activity and toxicity of outpatient immunotherapy with subcutaneous low dose IL-2 and oral RA, identified in a previous phase-I study, in patients with advanced solid cancer in whom a response or stable disease as a result of standard chemotherapy had been achieved. Eighty patients with advanced solid tumors after standard chemotherapy, were treated with IL-2: 1.8 x 106 IU and RA: 0.5 mg/kg for 5 days/week for 2 consecutive cycles of 3 weeks, with a 1-week rest, for up to 1 year. A total of 511 courses of IL-2/RA therapy were administered (median 6.4 per patient). Tumor markers, T4/T8 ratio and NK were monitored every 2 months. Response evaluation was carried out every 4 months. After a median follow-up time of 31 months there was a statistically significant improvement in the number of total lymphocytes, T4/T8 ratio and NK after IL-2 and RA therapy. Responses and disease stabilization were maintained for a median time of 19.3 months. Six patients were converted from partial to complete response, while 5 patients progressed. Median survival time was not reached yet. Grade 2 cutaneous toxicity and fever were observed in 29 and 13% of patients, respectively. These preliminary data show that after chemotherapy the administration of low-dose subcutaneous IL-2 and oral RA is feasible and has low toxicity. A sustained increase in the immunological parameters known to be prognostically relevant was observed and a clear benefit on tumor response from immunotherapy was obtained in 7.5% of patients.

Oxaliplatin fractionated over two days with bimonthly leucovorin and 5-fluorouracil in metastatic colorectal cancer.

PURPOSE: To evaluate the efficacy and safety of oxaliplatin (L-OHP) fractionated over two days with bimonthly 5-fluorouracil (5-FU) and leucovorin (LV), as first-line treatment of metastatic colorectal cancer (MCC) patients. PATIENTS AND METHODS: Fifty-four patients with inoperable MCC (median age, 60 years) were entered into the study. Outpatient treatment consisted of L-OHP 50 mg/m2 and LV 200 mg/m2 administered in a 2-hour i.v. infusion, followed by 5-FU 400 mg/m2 bolus and 5-FU 600 mg/m2 in a 22-hour continuous infusion, on days 1 and 2 every 2 weeks. RESULTS: A total of 488 courses of chemotherapy were administered. Responses were as follows: 3 complete responses (5.6%) and 24 partial responses (44.4%) giving an overall response rate of 50% (95% CI: 36% to 64%). Median time to progression and overall survival were 10.3 and 19.2 months, respectively. Grade 3-4 neutropoenia, leucopoenia, thrombocythopoenia and anaemia occurred in 33%, 9%, 2% and 2% of patients, respectively, while peripheral neuropathy occurred in 10% of patients. CONCLUSION: The fractionated bimonthly schedule of L-OHP plus de Gramont gave a less than anticipated neurological toxicity profile, while maintaining expected efficacy.

Chemoimmunotherapy in the treatment of metastatic gastric cancer.

Docetaxel, capecitabine and 5-fluorouracil have been shown to be active in the treatment of metastatic gastric adenocarcinoma. Consistent with this finding, the aim of this study was to test this combination in a clinical trial. Forty-one patients with metastatic gastric adenocarcinoma and a median age of 64 years were recruited for the study. The treatment was based on the administration of docetaxel 60 mg/m2 every 4 weeks, leucovorin 200 mg/m2, 5-fluorouracil 400 mg/m2 bolus, and capecitabine 1000 mg/m2 twice daily on days 1 and 2 every 2 weeks. Patients achieving a clinical benefit were treated, as maintenance immunotherapy, with low-dose interleukin-2 and 13-cis-retinoic acid. The primary end point of this phase II study was the response rate. The secondary end points relied on the evaluation of the immunological parameters, toxicity, and progression-free survival and overall survival. The overall response rate in the 41 evaluable patients was estimated to be 49%. Median progression-free and overall survival was 9.5 and 21.1 months, respectively. Grade 3 and 4 hematological toxicities were neutropenia and thrombocytopenia in 44 and 5% of patients, respectively. A sustained improvement of evaluated immunological parameters with a negligible toxicity profile was observed in the 27 patients treated with interleukin 1-2/13-cis-retinoic acid. Docetaxel in combination with leucovorin, 5-fluorouracil and capecitabine followed by low-dose interleukin 1-2 and 13-cis-retinoic acid is well tolerated, and shows a significant activity in patients with metastatic gastric adenocarcinoma.

Multicenter phase II study of chemo-immunotherapy in the treatment of metastatic renal cell carcinoma.

The purpose of this study was to evaluate the potential efficacy of a chemo-immunotherapy regimen for the treatment of metastatic renal cell carcinoma (MRCC). Forty-one patients with progressing MRCC and with a median age of 63 years were recruited. Planned treatment consisted of 6 courses of capecitabine 1000 mg/m twice daily on days 1 to 14 every 4 weeks, pegylated alpha-interferon 2b 50 microg every week, interleukin-2 1.8 M IU subcutaneously, and oral 13-cis-retinoic acid 0.5 mg/kg, all given 5 days/wk, 3 weeks of each month. After 6 courses of concomitant biochemotherapy, biotherapy was continued in patients who had a clinical benefit. The primary end point was response; secondary end points were the evaluation of the immunologic parameters, toxicity, progression-free, and overall survival. The treatment was well-tolerated. Grade 3 and 4 neutropenia and thrombocytopenia occurred in 5% and 7% of patients, respectively. The overall response rate in the 41 evaluable patients was 53.6% (95% confidence interval 37%-69%). Median progression-free and overall survivals were 14.7 and 27.8 months, respectively. A sustained improvement in all evaluated immunologic parameters was observed in the 36 patients treated with maintenance biotherapy. Six cycles of biochemotherapy, being followed by maintenance immunotherapy is well-tolerated and shows significant activity in patients with MRCC.

A multicenter phase II study of pegylated liposomal doxorubicin and oxaliplatin in recurrent ovarian cancer.

OBJECTIVE: Pegylated liposomal doxorubicin (PLD) and oxaliplatin (LOHP) are active as single agents in the treatment of recurrent ovarian cancer (ROC). This phase II study investigated the safety and activity of PLD and LOHP used in combination to treat ROC. METHODS: Eligibility criteria included disease recurrence after one (45%) or more lines (55%) of chemotherapy, performance status 3 months. Treatment was 40 mg/m(2) PLD and 120 mg/m(2) LOHP, administered over 2 days, every 3 weeks. Response to therapy was assessed using the RECIST criteria. RESULTS: Forty patients with ROC enrolled in the study from 10/2001 to 10/2005; 27 patients were platinum-sensitive and 13 were platinum-resistant. Major toxicities included grade 3-4 neutropenia (37%) and grade 2 palmar-plantar erythrodysesthesia (10%). The overall response rate was 67.5%, with 30% stable disease rate and 2.5% progressive disease rate. The median progression-free survival (PFS) was 9.6 months, while median overall survival was 18.3 months, with no statistically significant difference in PFS between platinum-resistant and platinum-sensitive patients. CONCLUSION: We conclude that the combination of PLD and LOHP shows activity in ROC with a manageable toxicity profile and can be safely administered in heavily pre-treated patients.

Phase II study of interleukin-2 and 13-cis-retinoic acid as maintenance therapy in metastatic colorectal cancer.

PURPOSE: We have previously shown that low-dose interleukin-2 (IL-2) and 13-cis-retinoic acid (13-cis-RA) improved lymphocyte and natural killer (NK) cell count of patients with advanced tumors showing a clinical benefit from chemotherapy. The primary endpoint of this study was to ask whether IL-2 and 13-cis-RA improved (> or =30%) lymphocyte and NK cell count in patients with metastatic colorectal cancer (MCRC) that had a clinical benefit from induction chemotherapy. Secondary endpoint was the evaluation of toxicity, progression-free survival (PFS), and overall survival (OS). PATIENTS AND METHODS: Forty patients with MCRC, showing a clinical benefit from chemotherapy, were treated with subcutaneous low-dose IL-2 (1.8 x 10(6) IU) and oral 13-cis-RA (0.5 mg/kg) in order to maintain responses and improve survival through the increase of lymphocyte and NK cells. The biological parameters and the clinical outcome of these patients were compared with those of a control group of patients (80) with a similar disease status, including clinical benefit from chemotherapy. RESULTS: The most common adverse events were mild cutaneous skin rash and fever. After 4 months and 2 years of biotherapy, a statistically significant improvement was observed in lymphocyte and number of NK cells with respect to baseline values and to controls. After a median follow-up of 36 months, median PFS was 27.8 months, while median OS was 52.9 months. CONCLUSION: These data show that maintenance immunotherapy with low-dose IL-2 and oral 13-cis-RA in patients with MCRC showing a clinical benefit from chemotherapy is feasible, has a low toxicity profile, improves lymphocyte and NK cell count. An improvement in the expected PFS and OS was also observed. A randomized trial is warranted.

Gonadotropin-releasing hormone analogues added to adjuvant chemotherapy protect ovarian function and improve clinical outcomes in young women with early breast carcinoma.

BACKGROUND: The objective of the current study was a retrospective evaluation of 100 consecutive premenopausal women with high-risk, early breast carcinoma who received a gonadotropin-releasing hormone (Gn-RH) analogue as ovarian protection during adjuvant chemotherapy. METHODS: After surgery, patients received a Gn-RH analogue and adjuvant chemotherapy, which was tailored to their peculiar biologic features. The median patient age was 43 years (range, 27-50 yrs). Fifty-two women had positive estrogen receptor (ER) status, and 48 women had negative ER status. There were 64 women with Stage II breast carcinoma and 36 women with UICC Stage III breast carcinoma. All patients had their serum estradiol suppressed to values<40 pg/mL. The chemotherapy regimens administered included cyclophosphamide, methotrexate, and 5-fluorouracil (n=26 patients) and anthracycline-based regimens (n=74 patients, including 9 patients who had >10 positive axillary lymph nodes, who also received high-dose chemotherapy with autologous peripheral blood progenitor cell transplantation). Patients with positive c-erb-2 status also received a taxane. Eighty patients received radiation therapy. During therapy with the Gn-RH analogue, patients who had a positive ER status after chemotherapy received an aromatase inhibitor. RESULTS: After a median follow-up of 75 months, normal menses were resumed by all patients younger than age 40 years and by 56% of patients older than age 40 years. Three pregnancies were observed that resulted in two normal deliveries and one voluntary abortion. The projected recurrence-free survival rates at 5 years and 10 years were 84% and 76%, respectively; and the projected overall survival rates at 5 years and 10 years were 96% and 91%, respectively. CONCLUSIONS: The current data showed that, in premenopausal women with early breast carcinoma, the addition of a Gn-RH analogue to adjuvant therapy and temporary total estrogen suppression in patients with ER-positive disease was tolerated well, protected long-term ovarian function, and appeared to improve the expected clinical outcome.

Multicenter phase 2 study of interleukin-2 and 13-cis retinoic acid as maintenance therapy in advanced non-small-cell lung cancer.

High serum levels of vascular endothelial growth factor (VEGF) are a poor prognostic factor for patients with advanced non-small-cell lung cancer (NSCLC). We have previously shown that low-dose interleukin (IL)-2 and 13-cis retinoic acid (RA) decreased VEGF and improved the immune function of patients with advanced tumors treated with chemotherapy. The primary end point of this study was to verify whether IL-2 and RA decreased serum VEGF in NSCLC patients showing a clinical benefit from chemotherapy. The secondary end point was the evaluation of clinical outcome. We treated 38 patients with advanced NSCLC who had a complete or partial response or disease stability to chemotherapy and had a median serum VEGF level of 508 ng/mL; as maintenance therapy, they received subcutaneous IL-2 (1.8 x 10(6) IU) and oral RA. Matched controls (n = 87) were selected from a large cohort of patients with a similar disease status, including clinical benefit from chemotherapy. The most common adverse events were mild cutaneous skin rash and fever. Serum VEGF decreased to a mean level of 152 ng/mL (P = 0.0002). A statistically significant improvement in immune function was observed (lymphocyte and natural killer cell numbers and CD4+/CD8+ ratio) with respect to baseline values and controls. An improvement in the clinical outcome was also observed compared with controls. These data show that the administration of low-dose subcutaneous IL-2 and oral RA to patients with advanced NSCLC showing a clinical benefit from chemotherapy is feasible with a low-toxicity profile, decreases VEGF, and seems to improve progression-free and overall survival.

Goserelin as ovarian protection in the adjuvant treatment of premenopausal breast cancer: a phase II pilot study.

The aim of the present trial was to investigate the protective effects on ovarian function, and the efficacy and tolerability of goserelin added to adjuvant chemotherapy for early breast cancer. Following surgical treatment, 64 premenopausal patients with early breast cancer received goserelin 3.6 mg (every 28 days for 1 year) and an adjuvant treatment which was chosen according to the patient's prognosis. Median age was 42 years (range 27-50). ECOG performance status was 0-1 in all patients. Twenty-eight patients (44%) had estrogen receptor (ER)+ tumors and 36 (56%) patients had ER- tumors. Fifty-two (81%) patients had stage II disease and 12 (19%) had stage III disease. Eighteen patients received cyclophosphamide, methotrexate and 5-fluorouracil chemotherapy, 46 patients received an anthracycline-based regimen, and nine of them received high-dose chemotherapy and autologous peripheral blood progenitor cell transplantation. Fifty-one patients (80%) were irradiated. ER+ patients also received tamoxifen for 5 years. Serum estradiol was suppressed to values below 40 pg/ml in all patients. After a median follow-up of 55 months, 86% of patients had resumed normal menses, 84% of patients were disease-free and 94% were alive. The 1-, 3- and 5-year projected recurrence-free survival rates were 100, 81 and 75%, respectively. Five years after treatment one patient had a pregnancy that ended with a normal childbirth. No unexpected adverse events were reported. These data show that the addition of goserelin to adjuvant therapy of premenopausal patients with early breast cancer is well tolerated and protects long-term ovarian function.

Phase I study of liposomal doxorubicin and oxaliplatin as salvage chemotherapy in advanced ovarian cancer.

Oxaliplatin (L-OHP) and stealth pegylated liposomal doxorubicin (PLD) have been shown to be active in pre-treated advanced ovarian cancer (PAOC). The aim of this phase I study was to determine the maximum tolerated dose (MTD) of L-OHP, combined with fixed doses of PLD as salvage treatment of PAOC. Twenty patients with recurrent ovarian cancer previously treated with two (30%) or three lines (70%) of chemotherapy were entered into the trial. Patients had a median age of 64 years (52-77) and a median platinum-free interval of 13 months (range 6-35). Patients received a fixed dose of PLD 40 mg/m2, combined with escalating doses of L-OHP from 80 to 130 mg/m2 administered in 1 day, every 3 weeks. Dose escalation was interrupted if 30% or more patients of a given cohort (three patients) exhibited dose-limiting toxicity in the first treatment cycle. The MTD of L-OHP was 130 mg/m2 as two out of three patients of this cohort showed dose-limiting thrombocytopenia and/or neutropenia during the first cycle of treatment. Amongst 20 evaluable patients, we observed an overall response rate of 55% (95% confidence interval 31.5-76.9%). With a median follow-up of 12 months (3.4+/-19.2), median time to progression was 9.7 months, while median survival was not reached yet. We conclude that a combination of PLD and L-OHP has a manageable toxicity profile, and can be safely administered as outpatient chemotherapy for heavily pre-treated patients with relapsed ovarian cancer. Promising anti-tumor activity was observed.