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Background: Premenopausal patients with breast cancer and more than 10 positive axillary nodes (BC>10) have a poor prognosis: In these patients the best adjuvant therapy (CT) has not yet been established., Patients and Methods: Forty-two BC>10 received, in sequence, the following adjuvant treatments: luteinizing hormone releasing hormone (LH-RH) analog for 5 years; anthracycline-based induction chemotherapy; radiation therapy; platinum-based high-dose CT, with autologous bone marrow transplantation; immunotherapy with interleukin 2 (IL2) and 13-cis retinoic acid (RA); anastrazole given 5 years to estrogen receptor-positive patients. Primary endpoints of the study were disease-free survival (DFS) and overall (OS) survival. A secondary endpoint was toxicity., Results: The median age of patients was 41 years, and the mean number of positive axillary nodes was 14. Estrogen and progesterone receptors were positive in 57% and 29% of patients respectively, while 14% of patients had triple-negative disease. With a median follow-up of 120 months for patients remaining alive at the end of study, median DFS and OS, had not yet been reached. The 20-year DFS and OS rates were 63.8%, and 81.6%, respectively. One to two years after the end of the therapy, three patients had had four full-term pregnancies., Conclusion: Treatment with LH-RH analog, high-dose CT, peripheral blood progenitor cells and IL2 with RA for patients with BC>10 is feasible, has moderate toxicity, while preserving ovarian function, seems to improve the expected DFS and OS for these high-risk patients., (Copyright© 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

Background: Poor prognosis is associated with estrogen- and/or progesterone receptor-positive (ER(+), PGR(+)) premenopausal breast cancer (PM-BC) with high Ki-67 labeling index and extensive axillary lymph node involvement. The role of adjuvant chemotherapy (CT) and hormonal therapy have not yet been established in these patients., Patients and Methods: Twenty-five PM-BC patients received, in sequence, leuprorelin, taxane-anthracycline induction chemotherapy, radiation therapy, a platinum-based intensification high-dose CT, followed by leuprorelin and anastrazole for five years. Vascular endothelial growth factor (VEGF) levels were measured as the primary end-point; secondary end-points were 10-year relapse-free survival (RFS) and overall survival (OS) rates., Results: The median patient age was 44 years, and the mean number of positive axillary nodes was 14. All patients were ER(+) and/or PGR(+), with a median Ki-67 index of 33%. Five patients were Cerb-B2 positive. Grade 4 hematologic toxicity was observed in all patients, no patient showed a decrease of cardiac ejection fraction and hot flashes and arthralgias were of moderate intensity. After a median follow-up of 70 months, VEGF levels significantly decreased (p<0.001); 10-year RFS and OS were 76% and 78%, respectively., Conclusion: Total estrogen blockade and high-dose CT in PM-BC patients is feasible, has moderate toxicity, significantly reduces VEGF levels, and seems to improve the expected RFS and OS.

Background: Failure to eradicate all cancer stem cells, lymphocytopenia, and high levels of vascular endothelial growth factor (VEGF) may explain the limited efficacy of high dose-chemotherapy (HDCT) with peripheral progenitor cell transplantation (PBPCT) in high-risk early breast cancer with more than 10 axillary nodes (HRBC)., Patients and Methods: With the aim of increasing patient's lymphocyte count and reducing VEGF, wich could translate into an improved immune function and a better clinical outcome, patients with HRBC, received HDCT, PBPCT and immunotherapy with interleukin-2 (IL-2) and 13-cis retinoic acid (RA)., Results: A total of 30 HRBC patients were entered into the study. Grade 4 hematological toxicity was universal, while major adverse effects of IL-2 were fever, rash and autoimmune reactions. After a median follow-up of 61 months, immune function improved with a statistically significant increase of lymphocyte count and a decrease in VEGF levels. This translated into an unexpected 5-year relapse-free and overall survival rates of 76% and 85%, respectively., Conclusion: These data show that IL-2 and RA administration after HDCT and PBPCT is feasible and, as well as giving a statistically significant improvement in lymphocyte count and a decrease of VEGF, also seems to improve the expected clinical outcome.

Background: Patients with metastatic solid tumors (MST) with less than a complete response to chemotherapy (L-CR), a depressed immune system and elevated serum vascular endothelial growth factor (VEGF) lack defined treatment options. The primary endpoint evaluated in this study was whether interleukin-2 (IL-2) and 13-cisretinoic acid (RA) treatment reduced VEGF and improved immune function in such patients. Secondary endpoints were objective response, relapse-free survival (RFS), and overall survival (OS)., Patients and Methods: One hundred consecutive MST patients with L-CR and a mean serum VEGF of 421.0 pg/mm3 were enrolled. Patients self-administered subcutaneous IL-2 1.8 x 10(6) IU/day, and oral RA 0.5 mg/kg/day x 5 days/week for 2 cycles of 3 weeks/month for 1 year and continued until progression., Results: After a median follow-up of 78 months, a statistically significant VEGF decrease and improvements in lymphocyte, NK, and CD4+/CD8+ ratio were observed. Twenty-four patients were converted to a CR; their 5-year RFS and OS rates were each 96%. No WHO grade 3 or 4 toxicities were observed., Conclusion: Administration of IL-2/RA to this patient population produced a significant decrease in VEGF, improvement of prognostically relevant immunological parameters, and durable response in 25% of patients.

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.

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.

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.

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.

Purpose: Peripheral blood progenitor cell (PBPC) transplantation, introduced into clinical practice to decrease the hematological toxicity of high-dose chemotherapy (HDCT), is both a costly procedure and a potential source of tumor cell reinfusion. The maximum tolerated dose of carboplatin (CB), cyclophosphamide (CT) and etoposide (VP) administered with growth factors without PBPC was determined in a previous phase I study. The aim of this phase II study was to evaluate the activity and toxicity of HDCT with CB, CT and VP administered with growth factors, without PBPC in a group of patients with advanced solid tumors., Patients and Methods: Forty patients with a median age of 52 years received two consecutive courses of chemotherapy every four weeks, consisting of CT 1500 mg/m2, VP 400 mg/m2 and CB AUC of 7-8. Following chemotherapy, hematological growth factors were administered for 14 days., Results: Grade 4 leukopenia and thrombocytemia occurred in 40 and 21 patients, respectively. An overall response rate of 72.5% was achieved. After a median 81 months follow-up, median time to progression and overall survival were 29 and 38 months, respectively., Conclusion: These data indicate that HDCT chemotherapy may be delivered safely without PBPC support. Prolonged responses were observed in patients that had few therapeutic options.

Purpose: This multicenter phase II study evaluated the activity and toxicity of the combination of fractionated camptothecin (CPT-11) and 5-fluorouracil/leucovorin (5-FU/LV) (de Gramont regimen) for the treatment of metastatic colorectal cancer (MCC) patients who had received no prior chemotherapy for metastatic disease., Patients and Methods: Fifty-four patients with a median age of 63.5 years (range: 43-75), received, every two weeks, a regimen consisting of 2 daily doses of CPT-11, 90 mg/m2 administered over a period of 90 minutes, followed by LV, 200 mg/m2 administered over 2 hours and 5-FU 400 mg/m2 as a bolus and 600 mg/m2 as a 22-hour continuous infusion. Sixty-five percent of patients had synchronous metastatic disease at diagnosis, while 35% of the patients had received adjuvant chemotherapy after radical surgery., Results: All 54 patients, receiving a total of 561 cycles of chemotherapy (median 12 per patient, range 1-26), were assessable for toxicity and response to treatment. The most common toxicities (grade 3-4) among treated patients were as follows: diarrhea in 3 patients, (6%), neutropenia in 9 patients (17%) and asthenia in 3 patients (6%), with no treatment-related death. We observed 4 complete (7.4%) and 18 partial responses (33.3%), giving an overall response rate of 40.7% (95% CI: 28% to 55%); 22 patients had stable disease (40.7%) and 10 patients progressed (18.5%). After a median follow-up of 22 months, the median time to progression was 8.7 months (range 2.3-43.9+), while overall median survival was 18.8 months (range 0.7-43.9+)., Conclusion: The fractionated bimonthly schedule of CPT-11 plus 5-FU/LV showed a lower gastrointestinal toxicity profile than expected, with substantial activity in patients with MCC.

Background: The objective of this phase II study was to determine the activity and toxicity of gemcitabine, ifosfamide and vinorelbine, in the treatment of patients with advanced non-small cell lung cancer (NSCLC)., Patients and Methods: Chemotherapy-naïve patients with unresectable, stage IIIB and stage IV NSCLC, measurable lesions and an Eastern Cooperative Oncology Group (ECOG) performance status < or = 3, were entered into the trial. The treatment consisted of ifosfamide 1500 mg/m2 on days 1 to 3 with vinorelbine 25 mg/m2 and gemcitabine 1000 mg/m2 on days 3 and 8, every 3 weeks., Results: Fifty-four patients with stage IIIB (24%) and stage IV (76%) were enrolled into the trial. The median age of the patients was 65 years. The performance status was 0-1, 2 and 3 in 48%, 43% and 9% of patients, respectively. The histology was mainly squamous cell carcinoma (52%), which was poorly-differentiated in 30% of patients. All patients, receiving a total of 249 chemotherapy courses, were assessable for response and toxicity on an intent-to-treat basis. Objective responses included complete response in 3 (5.6%) patients (95% CI: 1.1% to 15.3%), partial response in 26 (48.1%) patients (95% CI: 34.3% to 62.2%), giving an overall response rate of 53.7% (95% CI: 39.6% to 674%). Stable disease was observed in 20 (37%) patients (95% CI: 24.3% to 51.2%) and progressive disease in 5 (9.3%) patients (95% CI: 3% to 20.3%). The median time to progression was 8.8 months (range: 2-55+ months). The median overall survival was 13.2 months (range: 2-55+). The 1-year survival rate was 56% for all patients, comprising 78% and 47% for stage IIIB and stage IV patients, respectively (p=0.088). Myelosuppression was the main side-effect with (WHO) grade 3/4 neutropenia and thrombocytopenia in 56% and 13% of the patients, respectively., Conclusion: Our results showed that even patients with a poor performance status may benefit from gemcitabine, ifosfamide and vinorelbine treatment, with acceptable toxicity.

Background: Colorectal cancer (CRC) incidence increases sharply with age. In this study we assessed activity, toxicity and both the activity of daily living (ADL) and instrumental activity of daily living (IADL) of the De Gramont schedule in a series of advanced CRC patients aged > or = 70 years., Patients and Methods: Sixty-two previously untreated advanced CRC patients entered the study. Median age was 75 (range 70-88)., Results: 447 courses were delivered. All of the 62 patients were evaluable for toxicity, 55 for response and ADL-IADL indexes. We recorded 2 complete and 9 partial responses, for an overall response rate of 20%. ADL and IADL indexes improved in 33%, remained stable in 49% and worsened in 18% of evaluable patients. Treatment was very well-tolerated with no serious hematological or non-hematological toxicities., Conclusions: The De Gramont schedule was very well tolerated in advanced CRC elderly patients, although our work could not confirm the original reported activity. ADL and IADL indexes improved or remained stable in 82% of evaluable patients.

Background: Thirteen-cis retinoic acid (RA) has been shown to have growth-inhibitory and differentiative activity on non-small cell lung cancer (NSCLC) cells in vitro. This promoted the rationale for combining RA with three active drugs, cisplatin (CDDP) vindesine (VDS) and mitomycin-c (MMC) in the treatment of advanced NSCLC., Patients and Methods: Patients with a histologically confirmed non-resectable NSCLC, measurable lesion, performance status < or = 3, and informed consent were enrolled. The chemotherapy schedule included cisplatin 60 mg/m2 and mitomycin-c 10 mg/m2 day 1 and vindesine 3 mg/m2 on days 1 and 5, every 4 weeks. RA was administered orally, at a dose of 0.5 mg/kg, 5 days per week, during chemotherapeutic intervals and to responding patients until disease progression was observed., Results: Thirty patients, receiving a total of 163 chemotherapy courses, were evaluated for response and toxicity. Objective responses included complete response in 2 patients (7%), partial response in 10 patients (33%), stable disease in 9 patients (30%) and progressive disease in 9 patients (30%), (response rate 40%: Confidence interval 95% 22.7% to 59.4%). Median time to progression was 8.6 months (range 3.9-45+). Median overall survival was 11.3 months (range 1-45+). The 1-year survival rate was 47%. Toxicity (WHO) included nausea and vomiting grade 2 in 6 patients, transient ileus in 3 patients and grade 3-4 leukopenia in 5 patients. Two patients underwent surgical resection of residual disease and remain in CR., Conclusions: The addition of RA to cisplatin, vindesine and mitomycin-c is feasible and shows some activity in the treatment of NSCLC, with manageable toxicity.

Background: Patients with advanced squamous cell carcinoma of the head and neck (SCC) have a depressed immune system whose function is worsened by chemotherapy. In a pilot phase II study, in order to improve the immune function during chemotherapy, we combined to cisplatin (CDDP) and 5-fluorouracil (5-FU) two biological response modifiers, retinyl palmitate (R) and Thymopentin (TP-5) for the treatment of SCC., Patients and Methods: Fifty patients with recurrent or metastatic SCC of the head and neck were treated with Cisplatin 24 mg/m2 from day 1 to 5 and 5-FU 1,000 mg/m2 by a 120 hour continuous infusion. Retinyl palmitate was administered orally 50,000 i.u. b.i.d and Thymopentin 50 mg subcutaneously 3 times a week., Results: Chemotherapy treatment was well tolerated with G3 hematological toxicity in 30% of patients and G2 gastrointestinal toxicity in 20% of patients. 16 patients (32%) had a complete response (CR), 13 patients had partial response (PR) (26%), (response rate 58%, 95% c.i. 43%-72%); stable disease (SD) was observed in 7 patients (14%), while 14 patients progressed (PD) (28%). Median time to progression was 12 months (range 2.8-94.5). Median overall survival was 13.5 months (range 2-104)., Conclusions: The association of CDDP and 5-FU with Retinyl Palmitate and TP5 has a major activity in the treatment of advanced head and neck cancer and a relatively well tolerated toxicity.

Background: In this phase-II pilot study a cisplatin-based treatment was combined with biological agents capable of inducing differentiation in non-small-cell lung cancer (NSCLC) cells with the aim of ameliorating response to chemotherapy., Patients and Methods: Forty patients (PTS) with inoperable stage III-B or IV NSCLC were treated with cisplatin (CDDP) 24 mg/m2 on days 1 to 5, 5-fluorouracil (5-FU) 500 mg/m2, by continuous infusion on days 1 to 5 and vindesine (VDS) 3 mg/m2 on days 1 and 5. Beta-interferon (beta-IFN) 1 x 10(6) IU/m2 subcutaneously 3 times a week and retinyl palmitate (R) 50,000 IU orally BID were administered between chemotherapy cycles. Responders were maintained with the same dose of beta-IFN plus R 15,000 IU BID. Half of the PTS had an ECOG performance status of 0-1, 62% of tumours were of squamous histology and 77.5% of PTS had stage IV disease. A median of four courses of chemotherapy per PT was delivered., Results: Forty PTS were evaluable. Seventeen PTS responded, (RR 42%, 95% C.I. 27%-57%). Of the 17 responders 13 had squamous histology. The median response duration was 5.1 months. The median overall survival was 9.1 months. Gastrointestinal toxicity occurred in 58% of PTS, anaemia in 20%, leukopenia in 30%., Conclusions: The association of CDDP, VDS, 5-FU, beta-IFN and R shows activity in NSCLC, particularly in tumours with squamous histology, with a substantial toxicity.