Ermanno Rondini

Adjuvant low-dose interleukin-2 (IL-2) plus interferon-α (IFN-α) in operable renal cell carcinoma (RCC): a phase III, randomized, multicentre trial of the Italian Oncology Group for Clinical Research (GOIRC).

There is currently no standard therapy to reduce the recurrence rate after surgery for renal cell carcinoma (RCC). The aim of this study was to assess efficacy and safety of adjuvant treatment with low doses of interleukin-2 (IL-2)+interferon-&agr; (IFN-&agr;) in operable RCC. The patients were randomized 1:1 to receive a 4-week cycle of low-dose IL-2+IFN-&agr; or observation after primary surgery for RCC. Treatment cycles were repeated every 4 months for the first 2 years and every 6 months for the subsequent 3 years. The primary endpoint was recurrence-free survival (RFS); safety; and overall survival (OS) were secondary endpoints. ClinicalTrials.gov registration number was NCT00502034. 303/310 randomized patients (156 in the immunotherapy arm and 154 in the observation group) were evaluable at the intention-to-treat analyses. The 2 arms were well balanced. At a median follow-up of 52 months (range, 12–151 mo), RFS, and OS were similar, with an estimated hazard ratio (HR) of 0.84 [95% confidence interval (CI), 0.54–1.31; P=0.44] and of 1.07 (95% CI, 0.64–1.79; P=0.79), respectively in the 2 groups. Unplanned, subgroup analysis showed a positive effect of the treatment for patients with age 60 years and younger, pN0, tumor grades 1-2, and pT3a stage. Among patients with the combined presence of ≥2 of these factors, immunotherapy had a positive effect on RFS (HR=0.44; 95% CI, 0.24–0.82; P⩽0.01), whereas patients with <2 factors in the treatment arm exhibited a significant poorer OS (HR=2.27; 95% CI, 1.03–5.03 P=0.037). Toxicity of immunotherapy was mild and limited to World Health Organization grade 1-2 in most cases. Adjuvant immunotherapy with IL-2+IFN-&agr; showed no RFS or OS improvement in RCC patients who underwent radical surgery. The results of subset analysis here presented are only hypothesis generating.

Acupuncture As an Integrative Approach for the Treatment of Hot Flashes in Women With Breast Cancer: A Prospective Multicenter Randomized Controlled Trial (AcCliMaT)

PURPOSE To determine the effectiveness of acupuncture for the management of hot flashes in women with breast cancer. PATIENTS AND METHODS We conducted a pragmatic, randomized controlled trial comparing acupuncture plus enhanced self-care versus enhanced self-care alone. A total of 190 women with breast cancer were randomly assigned. Random assignment was performed with stratification for hormonal therapy; the allocation ratio was 1:1. Both groups received a booklet with information about climacteric syndrome and its management to be followed for at least 12 weeks. In addition, the acupuncture group received 10 traditional acupuncture treatment sessions involving needling of predefined acupoints. The primary outcome was hot flash score at the end of treatment (week 12), calculated as the frequency multiplied by the average severity of hot flashes. The secondary outcomes were climacteric symptoms and quality of life, measured by the Greene Climacteric and Menopause Quality of Life scales. Health outcomes were measured for up to 6 months after treatment. Expectation and satisfaction of treatment effect and safety were also evaluated. We used intention-to-treat analyses. RESULTS Of the participants, 105 were randomly assigned to enhanced self-care and 85 to acupuncture plus enhanced self-care. Acupuncture plus enhanced self-care was associated with a significantly lower hot flash score than enhanced self-care at the end of treatment (P < .001) and at 3- and 6-month post-treatment follow-up visits (P = .0028 and .001, respectively). Acupuncture was also associated with fewer climacteric symptoms and higher quality of life in the vasomotor, physical, and psychosocial dimensions (P < .05). CONCLUSION Acupuncture in association with enhanced self-care is an effective integrative intervention for managing hot flashes and improving quality of life in women with breast cancer.

Intergroup Trial of Adjuvant Chemotherapy in Adenocarcinoma of the Stomach (ITACA-S) trial: Comparison of a sequential treatment with irinotecan (CPT-11) plus 5-fluorouracil (5-FU)/folinic acid (LV) followed by docetaxel and cisplatin versus a 5-FU/LV regimen as postoperative treatment for radically resected gastric cancer.

LBA4001 Background: Following radical resection of gastric or gastroesophageal junction (GEJ) adenocarcinoma, a meta-analysis and randomized studies demonstrated better survival in pts treated with fluoropyrimidine regimens compared to surgery alone. ITACA-S trial is a no-profit, multicenter, randomized, open-label, superiority phase III study aimed at evaluating whether a more intensive postoperative chemotherapy improves efficacy, when replace fluoropyrimidine. METHODS Pts radically resected for gastric or GEJ adenocarcinoma, with ≥D1-lymphadenectomy, node involvement (pN+) or pN0 with pT2b-3-4; within 3-8 weeks after surgery were eligible. Treatment consisted in CPT-11 180 mg/m2 on d1, LV 100 mg/m2 d1-2, 5-FU 400-600 mg/m2 d1-2, q14; for 4 cycles (FOLFIRI regimen) followed by docetaxel 75 mg/m2 d1, cisplatin 75 mg/m2 d1, q 21; for 3 cycles (arm A) vs. LV 100 mg/m2 d1-2, 5-FU 400-600 mg/m2 d1-2, q 14 for 9 cycles (arm B). The primary hypothesis on disease-free survival (DFS) requires 636 events (first recurrence or death) to detect an hazard ratio (HR) of 0.80, with 2-sided 5% significance level for the log-rank test and a power of 80%. RESULTS From February 2005 to August 2009, 1,106 pts were randomized and 1,100 were analyzed (562 arm A, 538 arm B; 6 major violations) by 123 Italian centers. By March 2012, with a median follow-up of 49 months (quartile range: 36-62) we observed 558 events for DFS (HR 0.98; 95%CI 0.83-1.16;p=0.83) accounting for 88% of the target number and 440 deaths (HR: 1.00; 95%CI 0.83-1.20;p=0.98). Toxicity was consistent with literature. Given the data observed, both under the original hypothesis and the current trend, the probability to reach a statistically significant results at the target events is <0.0001. CONCLUSIONS Adjuvant chemotherapy in gastric cancer with more intensive regimen did not result in a significant prolongation of DFS and OS when compared to bolus/infusion FU/LV regimen.

Phase II trial of non-pegylated liposomal doxorubicin and low-dose prednisone in second-line chemotherapy for hormone-refractory prostate cancer.

AIMS AND BACKGROUND Non-pegylated liposomal doxorubicin (NPLD) (Myocet) has shown marked in vitro activity in castration-resistant prostate cancer (CRPC) and also in docetaxel-resistant cells, higher than that shown by pegylated liposomal doxorubicin. Its activity would seem to be due to a high intracellular drug concentration and induction of Golgi-dependent apoptosis. On the basis of these results, a clinical study was designed to assess the activity of NPLD and low-dose prednisone in second-line therapy. METHODS Fifty-four patients were enrolled and evaluated. Eligibility criteria were histologically confirmed CRPC, PSA >20 ng/mL or measurable lesions according to the RECIST criteria, previous docetaxel-based chemotherapy, and adequate cardiac function. Patients were treated with weekly intravenous NPLD 25 mg/m2 and daily prednisone 10 mg until progression. RESULTS Median patient age was 69 years (range, 52-83) and median baseline PSA concentration was 120 ng/mL (range, 5.35-4350). Sixteen (29.6%) patients had measurable lesions. Objective or PSA responses (>50% reduction) were observed in 8 (14.8%) patients. The median time to progression was 2.8 months and the median overall survival was 11.3 months. Toxicity was generally mild (grade 1-2) and infrequent, with grade 3-4 neutropenia in 12.9% of cases. Grade 3 nonhematological toxicities included nausea in 2 patients (3.7%) and fatigue and stomatitis in 1 case (1.9%). No drug-related serious adverse events were reported. CONCLUSIONS Weekly administration of NPLD is a well tolerated treatment with proven albeit limited activity.

NEOADJUVANT CHEMOTHERAPY WITH CONTINUOUS INFUSION OF CISPLATIN AND FLUOROURACIL IN STAGE II-IV, M0 SQUAMOUS CELL CARCINOMA OF THE HEAD AND NECK

Aims and Background The aim of the study was to assess the activity and the toxicity of cisplatin (DDP) and fluorouracil (FU) administered by continuous infusion as neoadjuvant chemotherapy for patients with stage II-IV, MO squamous cell carcinoma of the head and neck. Methods Thirty previously untreated patients were submitted to chemotherapy with DDP (20 mg/m2) and FU (1000 mg/m2), both in continuous infusion for 5 days, repeated every 21 days, for a maximum of 5 cycles. Following completion of chemotherapy, the patients underwent radiotherapy; in some patients surgery was performed immediately after chemotherapy. All patients were monitored for response, time to failure, survival, treatment-related events and toxicity. Results All patients were evaluated for response; after chemotherapy the complete response rate was 27% and the partial response rate 33%. Twenty-four patients underwent radiotherapy: the overall response rate was 83% (complete response 79%). After a median follow-up of 34 months, the median survival time was 22 months with a median time to failure of 15 months. Acute vascular accidents were the main and unexpected adverse events, with 2 deaths for pulmonary embolism and 1 for stroke. The response rate to the regimen does not seem to be better than that obtained with the standard combination of cisplatin bolus and fluorouracil continuous infusion. The disadvantage of the regimen is that it causes more discomfort for the patient in that it requires hospitalization. Conclusions For this reason, we believe that there are no elements for recommending the schedule as neoadjuvant treatment of patients with squamous cell carcinoma of the head and neck or as an experimental arm in a randomized trial.

Ifosfamide bolus followed by five days continuous infusion in extensively pretreated patients with advanced breast cancer: a phase II study.

Purpose A phase II study with ifosfamide in pretreated patients with advanced breast cancer was performed to determine the objective response rate, the toxicity and the feasibility of the regimen. Methods & study design Patients enrolled had advanced breast cancer pretreated with at least one previous regimen of chemotherapy for advanced disease. Treatment consisted of ifosfamide infused at a dose of 2 g/m2 iv in 4 hrs followed by ifosfamide, 8 g/m2 iv in 120 hrs in ambulatory treatment, using a portable external pump system. The total dose of ifosfamide was 10 g/m2; mesna (4 g/m2 iv) was administered mixed with ifosfamide in 120 hrs Cycles were repeated every 3 weeks. Three patients were pretreated with neoadjuvant and 15 with adjuvant chemotherapy. All patients were treated for advanced disease (median number of regimens, 1; range, 1-3): 21 with the cyclophosphamide-containing regimen and 15 with adryamicin. Sixteen patients received one or more lines of endocrine therapy. Fifteen patients had dominant site in viscera, 6 in bone, and only one in soft tissue; 17 patients had more than one site of disease. Results Twenty-two patients were enrolled and all were assessable for response and toxicity. A partial response was reached in 5 patients (23%; 95% confidence limits 5% to 60%). Hematologic toxicity was the dose-limiting side effect; grade 4 leukopenia occurred in 10 patients (46%). Conclusions Considering the response rate obtained in our series of intensively pretreated patients, the results seem to indicate that the regimen is active and could be included among the possible options in the treatment of patients with refractory, poor-prognosis, advanced breast carcinoma.

Bolus versus 5-day continuous infusion of cisplatin with mitomycin and vindesine in the treatment of advanced non-small cell lung cancer (NSCLC): a phase III prospective randomised trial of the Italian Oncology Group for Clinical Research (GOIRC)

The aim of this randomised trial was to compare the efficacy of bolus versus continuous infusion cisplatin combined with mitomycin C and vindesine (MVP) for chemotherapy-naive patients with stage IIIB-IV non-small cell lung cancer (NSCLC). 97 patients (49 given bolus cisplatin-arm A and 48 given continuous infusion cisplatin--arm B) were evaluable for response. In arm A, 2 patients achieved a complete response (CR), 21 achieved a partial response (PR), whilst in arm B, 14 patients achieved a PR (29%) (P = 0.07). Median survival was 8 months in both arms. Myelosuppression was the most frequent and severe toxicity, with a higher incidence of grade 3-4 leucopenia in arm A when compared with arm B (44% versus 25%). In conclusion, there is no advantage for a cisplatin 5 day infusion in the MVP regimen.

Real-life clinical practice results with vinflunine in patients with relapsed platinum-treated metastatic urothelial carcinoma: an Italian multicenter study (MOVIE-GOIRC 01–2014)

BackgroundVinflunine is the only chemotherapeutic agent shown to improve survival in platinum-refractory patients with metastatic transitional cell carcinoma of the urothelium (TCCU) in a phase III clinical trial, which led to product registration for this indication in Europe. The aim of this study was to assess the efficacy of vinflunine and to evaluate the prognostic significance of risk factors in a large, unselected cohort of patients with metastatic TCCU treated according to routine clinical practice.MethodsThis was a retrospective multicenter study. Italian cancer centers were selected if, according to the Registry of the Italian Medicines Agency (AIFA), at least four patients had been treated with vinflunine between February 2011 and June 2014, after first- or second-line platinum-based chemotherapy. The primary objective was to test whether the efficacy measured by overall survival (OS) in the registration study could be confirmed in routine clinical practice. Multivariate analysis was carried out using Cox proportional hazard model.ResultsA total of 217 patients were treated in 28 Italian centers. Median age was 69 years (IQR 62–76) and 84% were male; Eastern Cooperative Oncology Group performance status (ECOG PS) was ≥ 1 in 53% of patients. The median number of cycles was 4 (IQR 2–6); 29%, 35%, and 36% received an initial dose of 320 mg/m2, 280 mg/m2 or a lower dose, respectively. Median progression-free survival (PFS) and OS for the entire population was 3.2 months (2.6–3.7) and 8.1 months (6.3–8.9). A complete response was observed in six patients, partial response in 21, stable disease in 60, progressive disease in 108, with a disease control rate of 40%. Multivariate analysis showed that ECOG PS, number of metastatic sites and liver involvement were unfavorable prognostic factors for OS. Toxicity was mild, and grade 3–4 adverse effects were mainly: neutropenia (9%), anemia (6%), asthenia/fatigue (7%) and constipation (5%).ConclusionsIn routine clinical practice the results obtained with VFL seem to be better than the results of the registration trial and reinforce evidence supporting its use after failure of a platinum-based chemotherapy.

Abstract LB-226: mTOR inhibition by Temsirolimus as second-line treatment for advanced RCC: The Medical optimization of Torisel® (MoTOR) phase II trial by the Italian Kidney Cancer Group (GIR)

Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL Background: The mammalian target of rapamycin (mTOR) kinase is an essential regulator of growth and response to hypoxic and metabolic stress and a well-established therapeutic target in renal cell carcinoma (RCC). The mTOR inhibitor Temsirolimus (CCI-779, Torisel®) is the first-line treatment of choice for RCC patients with poor-risk features. Preclinical and clinical evidence indicates that mTOR inhibitors may be effective in controlling RCC growth, even after resistance to agents targeting the VEGF/VEGFR axis ensues. Thus we designed a multicenter phase II trial to assess the activity and safety of Temsirolimus as II-line treatment for advanced RCC patients (pts). Methodology: This was an open-label, multicenter, phase II trial of Temsirolimus (25 mg/wk i.v.), administered to advanced RCC pts with documented progression after I-line treatment. Primary endpoint was PFS rate at 6 mos. Tumor response was assessed every 8 wks. Considering a 6-mo PFS rate of 20% unacceptable (p0=20%) and a 6-mo PFS rate of 40% (p1=40%) of interest, a minimum targeted accrual of 47 pts in the sunitinib-pretreated group was to be pursued in order to reach 90% power at a significance level of 5%. Pts who underwent any other I-line treatment were allowed on study until the target accrual in the sunitinib-pretreated group was met. Results: From May 2009 to January 2012, 76 pts were enrolled (median age: 67 yrs, range: 36-86; M/F: 58/18; ECOG PS 0/1/2: 51/19/6); I-line therapy included sunitinib (60 pts), bevacizumab (8), sorafenib (3), cytokines (2), or other (3). With 18/57 evaluable patients free from progression at 6 mos in the sunitinib-pretreated group the primary endpoint was met. Median PFS was 4.0 mos (95% CI: 2.7-5.3) and 4.6 mos (95% CI: 2.8-6.5) in the overall (n=71) and sunitinib-pretreated (n=57) populations, respectively; OS in the same groups was 13.7 mos (95% CI: 9.1-18.3) and 14.6 mos (95% CI: 8.9-20.3), respectively. Six out of 71 pts (8%) had PR and 33/71 (46%) had SD as their best response. Toxicity (n=68) was mild with G3 anemia, neutropenia and thrombocytopenia in 2, 1, and 1 pts, respectively; G3 hyperglycemia and G3 hypertriglyceridemia in 2 and 7 pts, respectively; G4 hypercholesterolemia in 2 pts; G3 stomatitis in 5 pts; G3 asthenia in 3 pts; G3-4 pulmonary toxicity in 2 pts; G3 diarrhea in 2 pts; G3 cutaneous rash in 1 pt. Only 1 hypersensitivity reaction occurred during Temsirolimus infusion. Treatment compliance was good, with <10% of weekly administrations omitted and 15/67 (22%) pts requiring dose reductions (to 20 mg/wk and 15 mg/wk in 11 and 4 pts, respectively). Mean number of weekly administrations received was 15. Conclusions. Temsirolimus is an active and well-tolerated II-line treatment for advanced RCC, particularly in sunitinib-pretreated pts, and may constitute a suitable therapeutic option in this setting. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-226. doi:1538-7445.AM2012-LB-226