Giovanni Pietro Ianniello

Gemcitabine Plus Vinorelbine Compared With Cisplatin Plus Vinorelbine or Cisplatin Plus Gemcitabine for Advanced Non–Small-Cell Lung Cancer: A Phase III Trial of the Italian GEMVIN Investigators and the National Cancer Institute of Canada Clinical Trials Group

PURPOSE Platinum-containing chemotherapy regimens are the standard treatment for patients with advanced non-small-cell lung cancer (NSCLC), although toxicity is common and may significantly affect the patients quality of life (QoL). This trial aimed to assess whether a combination of gemcitabine and vinorelbine had benefits in terms of QoL, without influencing negatively on survival, compared with cisplatin-containing regimens. PATIENTS AND METHODS Patients with stage IIIB (effusion and supraclavicular nodes) or IV documented NSCLC who were younger than 70 years of age were randomly assigned gemcitabine plus vinorelbine (GemVin) or either gemcitabine plus cisplatin or vinorelbine plus cisplatin (cisplatin-based). European Organization for Research and Treatment of Cancer scales were used for QoL analysis. RESULTS Five hundred one patients were randomly assigned to treatment. The median age was 62 years. There were no significant differences in global QoL scores between the two arms after 2 months of treatment. However, worsening scores for appetite, vomiting, and alopecia were significantly more common in the cisplatin-based arm. Median survival was 38 v 32 weeks and median progression-free survival was 23 v 17 weeks in the cisplatin-based versus GemVin arms, respectively. For the GemVin arm the hazard ratio for death was 1.15 (90% confidence interval [CI], 0.96 to 1.37) and the hazard ratio for progression was 1.29 (90% CI, 1.10 to 1.52). Grade 3 or 4 myelosuppression, vomiting, alopecia, and ototoxicity were significantly more frequent with cisplatin-based treatment. CONCLUSION Global QoL is not improved with GemVin, although advantages in some components of QoL were apparent. GemVin is less toxic than standard cisplatin-based chemotherapy. There is a nonsignificant slight survival advantage with cisplatin-based chemotherapy. GemVin could be offered to advanced NSCLC patients who express concern about toxicity.

Chemotherapy-induced neutropenia and treatment efficacy in advanced non-small-cell lung cancer: a pooled analysis of three randomised trials

BACKGROUND Chemotherapy is the standard treatment for advanced non-small-cell lung cancer, and myelosuppression is a common side-effect. We aimed to assess whether haematological toxic effects could be a biological measure of drug activity and a marker of efficacy. METHODS We analysed data for 1265 patients who received chemotherapy (vinorelbine, gemcitabine, gemcitabine and vinorelbine, cisplatin and vinorelbine, or cisplatin and gemcitabine) within three randomised trials. Primary landmark analyses were restricted to 436 patients who received all six planned chemotherapy cycles and who were alive 180 days after randomisation. Neutropenia was categorised on the basis of worst WHO grade during chemotherapy: absent (grade 0), mild (grade 1-2), or severe (grade 3-4). All statistical analyses were stratified by treatment allocation. Analyses were repeated in the out-of-landmark group (829 patients), stratifying by treatment allocation and number of chemotherapy cycles. The primary endpoint was overall survival. FINDINGS In the landmark group, hazard ratios of death were 0.65 (0.46-0.93) for patients with severe neutropenia and 0.74 (0.56-0.98) for those with mild neutropenia. Median survival after the landmark time of 180 days was 31.4 weeks (95% CI 25.7-39.6) for patients without neutropenia compared with 42.0 weeks (32.7-59.7) for patients with severe neutropenia, and with 43.7 weeks (36.6-66.0) for those with mild neutropenia (severe vs mild vs no neutropenia p=0.0118). Findings were much the same for the out-of-landmark group. INTERPRETATION Neutropenia during chemotherapy is associated with increased survival of patients with advanced non-small-cell lung cancer, and its absence might be a result of underdosing. Prospective trials are needed to assess whether drug dosing guided by the occurrence of toxic effects could improve efficacy of standard regimens.

Activity and toxicity of gemcitabine and gemcitabine+vinorelbine in advanced non-small-cell lung cancer elderly patients: Phase II data from the Multicenter Italian Lung Cancer in the Elderly Study (MILES) randomized trial

BACKGROUND Following the demonstration that vinorelbine improves survival and quality of life compared with best supportive care in elderly patients with advanced non-small-cell lung cancer (NSCLC), we started the three-arm prospective Multicenter Italian Lung Cancer in the Elderly Study (MILES) trial of vinorelbine, gemcitabine and gemcitabine + vinorelbine. DESIGN Within the randomized phase 3 trial, pilot single-stage phase 2 studies were planned for gemcitabine and for gemcitabine + vinorelbine. Eligible patients are aged 70 or more, with stage IV or IIIb (with metastatic supraclavear nodes or malignant pleural effusion) NSCLC. Single-agent gemcitabine is given at 1200 mg/m(2) on days 1 and 8; in the combination, gemcitabine is given at 1000 mg/m(2) and vinorelbine at 25 mg/m(2), both on days 1 and 8, every 3 weeks. RESULTS As planned 49 patients were enrolled in each group. Median age was 74 in both groups. Two-thirds of patients had stage IV disease. The response rate was 18.4% (95% exact CI 8.8-32.0) with both treatments. With single-agent gemcitabine main toxicities were grade 4 thrombocytopenia and grade 2 hepatic toxicity, in one patient each, and grade 2 pulmonary toxicity in two patients. With gemcitabine + vinorelbine combination there were grade 4 neutropenia and thrombocytopenia (one patient each), grade 3 anemia requiring red blood cell transfusion (two patients), and grade 4 fever in two patients. Four patients, with severe cardiac comorbidities, suffered grade 3 heart toxicity with atrial flutter or fibrillation, followed by congestive heart failure responsive to treatment. CONCLUSION Both single-agent gemcitabine and the gemcitabine + vinorelbine combination are sufficiently active and tolerable to allow continuation of the MILES study.

Prevalence and management of pain in Italian patients with advanced non-small-cell lung cancer

Pain is a highly distressing symptom for patients with advanced cancer. WHO analgesic ladder is widely accepted as a guideline for its treatment. Our aim was to describe pain prevalence among patients diagnosed with advanced non-small-cell lung cancer (NSCLC), impact of pain on quality of life (QoL) and adequacy of pain management. Data of 1021 Italian patients enrolled in three randomised trials of chemotherapy for NSCLC were pooled. QoL was assessed by EORTC QLQ-C30 and LC-13. Analgesic consumption during the 3 weeks following QoL assessment was recorded. Adequacy of pain management was evaluated by the Pain Management Index (PMI). Some pain was reported by 74% of patients (42% mild, 24% moderate and 7% severe); 50% stated pain was affecting daily activities (30% a little, 16% quite a bit, 3% very much). Bone metastases strongly affected presence of pain. Mean global QoL linearly decreased from 64.9 to 36.4 from patients without pain to those with severe pain (P<0.001). According to PMI, 616 out of 752 patients reporting pain (82%) received inadequate analgesic treatment. Bone metastases were associated with improved adequacy and worst pain with reduced adequacy at multivariate analysis. In conclusion, pain is common in patients with advanced NSCLC, significantly affects QoL, and is frequently undertreated. We recommend that: (i) pain self-assessment should be part of oncological clinical practice; (ii) pain control should be a primary goal in clinical practice and in clinical trials; (iii) physicians should receive more training in pain management; (iv) analgesic treatment deserves greater attention in protocols of anticancer treatment.

Gemcitabine plus vinorelbine in advanced non-small cell lung cancer: a phase II study of three different doses

Our aim was to study the activity and toxicity of the gemcitabine plus vinorelbine (Gem Vin) combination and to identify the optimal dose. Previously untreated patients aged < 70 years, with stage IV or IIIb (not candidates for radiotherapy) non-small cell lung cancer were eligible. Studied dose-levels of Gem Vin, administered on days 1 and 8 every 3 weeks, were (mg m–2): level I = 1000/25; level II = 1200/25; level III = 1000/30; level IV = 1200/30. A feasibility study was performed at each dose-level, followed by a single-stage phase II study. Dose-level IV was unfeasible because of grade 4 neutropenia. Overall, out of 126 patients enrolled in phase II studies, there were one complete and 32 partial responses (response rate 26%: 95% CI 18–34%). Response rates were 27.9%, 21.4% and 29.3% at levels I, II and III, respectively. The treatment was well tolerated. Toxicity was less frequent and severe at level I. Overall median survival was 33 weeks (95% CI 28–40). Descriptive quality of life analysis showed that patients with a worse baseline global health status score tended to drop out of the study earlier than those with a better score. Gem Vin is feasible at different doses. It is sufficiently active and well tolerated. A phase III study to compare the effect on quality of life of Gem Vin (level I) vs cisplatin-based chemotherapy is ongoing.

Carboplatin plus vinorelbine, a new well-tolerated and active regimen for the treatment of extensive-stage small-cell lung cancer: a phase II study. Gruppo Oncologico Centro-Sud-Isole.

PURPOSE To evaluate the activity and toxicity of the combination carboplatin plus vinorelbine in extensive small-cell lung cancer (SCLC). PATIENTS AND METHODS A two-stage optimal Simon design was applied. To proceed after the first stage, responses from 8 of 11 treated patients were needed. Overall, 31 responses of 43 treated patients were required to comply with the design parameters. Inclusion criteria were cytohistologically proven SCLC; extensive disease; age of 70 years or less; Eastern Cooperative Oncology group performance status (ps ECOG) of 2 or less; normal cardiac, hepatic, renal, and bone marrow functions; and no previous chemotherapy. Patients were staged by physical examination; biochemistry; chest radiograph; brain, thoracic; and abdominal computed tomographic (CT) scans, and bone scan. All patients received carboplatin 300 mg/m2 intravenously (i.v.) day 1 and vinorelbine 25 mg/m2 i.v. on days 1 and 8 every 4 weeks up to six cycles. Of 43 enrolled patients, 36 were men and 7 women, with a median age of 63 years (range, 46 to 70 years). RESULTS All patients were assessable for response and toxicity. We observed 32 (74%) objective responses, with 23% complete responses. Median time to progression was 25 weeks, and median survival was 37 weeks. The treatment was well tolerated. The reported main toxicities were leukopenia grade 3 in 21% of patients and grade 4 in 5% of patients, anemia grade 2 in 11% of patients and grade 3 in 2% of patients, and thrombocytopenia grade 3 in 7% of patients. CONCLUSION These data show that carboplatin plus vinorelbine is an active and well-tolerated regimen in extensive SCLC. In view of the activity, low toxicity, and ease of administration, it may be a reasonable alternative to more toxic cisplatin-containing regimens.

Supportive care in patients with advanced non-small-cell lung cancer.

The present study describes supportive care (SC) in patients with advanced non-small-cell lung cancer (NSCLC), evaluating whether it is affected by concomitant chemotherapy, patients performance status (PS) and age. Data of patients enrolled in three randomised trials of first-line chemotherapy, conducted between 1996 and 2001, were pooled. The analysis was limited to the first three cycles of treatment. Supportive care data were available for 1185 out of 1312 (90%) enrolled patients. Gastrointestinal drugs (45.7%), corticosteroids (33.4%) and analgesics (23.8%) were the most frequently observed categories. The mean number of drugs per patient was 2.43; 538 patients (45.4%) assumed three or more supportive drugs. Vinorelbine does not produce substantial variations in the SC pattern, while cisplatin-based treatment requires an overall higher number of supportive drugs, with higher use of antiemetics (41 vs 27%) and antianaemics (10 vs 4%). Patients with worse PS are more exposed to corticosteroids (42 vs 30%). Elderly patients require drugs against concomitant diseases significantly more than adults (20 vs 7%) and are less frequently exposed to antiemetics (12 vs 27%). In conclusion, polypharmacotherapy is a relevant issue in patients with advanced NSCLC. Chemotherapy does not remarkably affect the pattern of SC, except for some drugs against side effects. Elderly patients assume more drugs for concomitant diseases and receive less antiemetics than adults.

The role of immunotherapy in solid tumors: report from the Campania Society of Oncology Immunotherapy (SCITO) meeting, Naples 2014

The therapeutic approach to advanced or metastatic solid tumors, either with chemotherapy or targeted therapies, is mainly palliative. Resistance to chemotherapy occurs very frequently and is one of the most important reasons for disease progression. Immunotherapy has the potential to mount an ongoing, dynamic immune response that can kill tumor cells for an extended time after the conventional therapy has been administered. Such a long-lasting response is potentially able to completely eradicate tumor cells, rather than producing only a temporary killing of cells. The most promising immune-based treatments are monoclonal antibodies that act as checkpoint inhibitors (e.g. ipilimumab and nivolumab), adoptive cell therapy (e.g. T-cells expressing chimeric antigen receptors) and vaccines (e.g. sipuleucel-T). Ipilimumab is currently approved for the treatment of metastatic melanoma and sipuleucel-T is approved for advanced prostate cancer. There is great interest in immunotherapy in other solid tumors, potentially used alone or in a multimodal fashion with chemotherapy and/or biological drugs. In this paper, we review recent advances in immuno-oncology in solid malignancies (except melanoma) as were discussed at the inaugural meeting of the Campania Society of Oncology Immunotherapy (SCITO).

Oxycodone controlled-release as first-choice therapy for moderate-to-severe cancer pain in Italian patients: Results of an open-label, multicentre, observational study

Background and objectives:Cancer pain affects patients at all stages of the disease and there are clear guidelines for its management. Morphine is considered the first-choice strong opioid in the treatment of moderate-to-severe pain; however, numerous studies have shown that oxycodone controlled-release (CR) has a similar efficacy and safety profile. The purpose of this study was to evaluate the efficacy and tolerability of oxycodone CR as a first-line strong opioid for the treatment of moderate-to-severe pain in Italian cancer patients.Methods:This was a prospective, open-label, multicentre, observational trial carried out at 15 locations across Italy. Patients with a referral for cancer-related pain of ≥5 on a 10-point numerical rating scale were enrolled. Patients were treated with oral oxycodone CR and monitored for 21 days. Dosage was individualized for each patient and up-titrated until effective pain control was achieved. Pain, adverse events and quality-of-life scores were assessed throughout the study.Results:390 patients (174 females and 216 males) with a mean age of 66 ± 11 years were evaluated. The average daily dose ranged from 22.84 on day 1 to 40 mg/day on day 21. Pain intensity (assessed on a 10-point numerical rating scale) decreased significantly within 1 day of treatment commencement (p = 0.00001) and continued to decrease throughout the study period (from a mean 7.22 at baseline to a mean 2.11 points on day 21). Adverse events were mild to moderate in intensity and consisted of common opioid-related events. Ten patients (2.6%) discontinued the study because of adverse events and four (1 %) because of uncontrolled pain. All aspects of activities of daily life assessed were improved by study end.Conclusions:Oxycodone CR is efficacious and well tolerated as a first-line strong opioid for the treatment of moderate-to-severe cancer-related pain in Italian patients.

Carboplatin plus vinorelbine plus G-CSF in elderly patients with extensive-stage small-cell lung cancer: a poorly tolerated regimen. Results of a multicentre phase II study

PURPOSE AND METHODS A multicentre phase II trial (single-stage design) was undertaken to test the activity and toxicity of carboplatin (AUC 5 according to Calvert, day 1) plus vinorelbine (25 mg/m(2) days 1 and 8) with lenograstim support, every 3 weeks in the first line treatment of elderly patients, aged 65 or more, affected by extensive small-cell lung cancer (SCLC). The primary end-point of the trial was the objective response rate. Twenty-three responses among 37 patients were considered necessary to proceed to a phase III trial. RESULTS Twenty-eight patients were enrolled (median age 70 years). Treatment was remarkably toxic. Three patients died while on treatment. Eleven patients (39.3%, 95% exact confidence interval (CI): 21.5-59.4) had an objective response, that was complete in 2 cases. Median time to progression was 5.1 months (95% CI: 3.3-6.7). Median survival was 7.9 months (95% CI: 4.8-14.4). CONCLUSION Carboplatin plus vinorelbine is poorly tolerated and not sufficiently active to warrant phase III comparison with standard chemotherapy regimens in elderly patients with extensive SCLC.