Outcomes of Platinum-Sensitive Small-Cell Lung Cancer Patients Treated With Platinum/Etoposide Rechallenge: A Multi-Institutional Retrospective Analysis.

UNLABELLED: Small-cell lung cancer has a high chemotherapeutic sensitivity but with disappointing outcome results. Patients with "sensitive disease" are those who respond to treatment with a long relapse-free interval (RFI): in these cases rechallenge with first-line chemotherapy might represent a therapeutic opportunity. Our largest retrospective experience confirmed that rechallenge is feasible with interesting outcome results; there are no statistical differences between RFI and outcome. INTRODUCTION: Patients with small-cell lung cancer (SCLC) that progresses after first-line (FL) chemotherapy have a poor prognosis and second-line (SL) chemotherapy has limited efficacy. Patients whose disease relapses/progresses > 90 days after FL platinum-based treatment are considered platinum-sensitive and could be rechallenged with a similar regimen. We conducted a multicenter retrospective analysis to evaluate outcomes of SCLC patients rechallenged with platinum/etoposide. PATIENTS AND METHODS: Records of all SCLC patients treated in 7 institutions between January 2007 and December 2011 were reviewed. The primary end point was overall survival from the time of rechallenge (OS-R); secondary end points were progression-free survival (PFS) and overall survival from the time of diagnosis (OS-D). Survival curves were calculated using the Kaplan-Meier method. RESULTS: Of the 2000 SCLC patients identified, 112 (5.6%) had sensitive disease treated with rechallenge platinum/etoposide; 65% were men with a median age of 64 years. At the time of diagnosis, 44% of patients had limited disease, 82% had an Eastern Cooperative Oncology Group performance status of 0 to 1. A median of 4 cycles of rechallenge was administered. Tumor response was 3% for complete response and 42% for partial response, 19% of patients maintained stable disease, 27% progressive disease, and 9% were not evaluable. Median PFS from the time of rechallenge was 5.5 months (95% confidence interval [CI], 4.4-6.3). Median OS-R and OS-D were 7.9 months (95% CI, 6.9-9.7) and 21.4 months (95% CI, 19.8-24.1), respectively. Subgroup analysis according to relapse-free interval (90-119 vs. 120-149 vs. > 150 days) did not show any statistically significant difference in PFS or OS-R. CONCLUSION: The outcome for SL chemotherapy for SCLC is poor. Rechallenge platinum/etoposide is a reasonable option with potentially better outcomes than standard chemotherapy.

Noninferiority trials in second-line treatments of nonsmall cell lung cancer: a systematic review of literature with meta-analysis of phase III randomized clinical trials.

BACKGROUND: To assess the role of the novel second-line treatments in nonsmall cell lung cancer (NSCLC). METHODS: A systematic review of the literature with meta-analysis of phase III randomized clinical trials (RCTs) was independently performed by 3 authors. All the trials comparing any novel treatment with every-3-weeks docetaxel (3WD) and designed as noninferiority trial were included in the analysis. One-year survival rate (SR) was the primary end point, and quality of life and safety represented the secondary end points. RESULTS: Four RCTs met the selection criteria. The outcomes of 3355 patients were analyzed in the pooled analysis. No heterogeneity was documented in the primary analysis either including all the trials or analyzing separately gefitinib and the chemotherapeutic alternatives to 3WD. The cumulative odds ratio was 0.927 (P=0.313) for 1-year SR, 0.889 (P=0.323) for the chemotherapeutic alternatives to 3WD and 0.953 (P=0.616) for gefitinib. The experimental arms showed a significant advantage in quality of life in the cumulative analysis (odds ratio=1.623, P=0.01) and in the subgroup of patients treated with gefitinib (odds ratio=1.962, P<0.001); a better safety profile for the experimental arm was observed in the cumulative analysis and in the subgroups of alternative chemotherapies or gefitinib. CONCLUSION: All the noninferiority trials demonstrated the noninferiority of pemetrexed, oral topotecan, or gefitinib in 1-year SR (primary end point), but the improvement in overall survival remains modest. The improvement in quality of life and safety (secondary end points) represents the main value of these treatments, whose aim is mainly palliative.

Bevacizumab in the treatment of advanced, non-squamous non-small cell lung cancer: an evidence-based approach.

BACKGROUND: To assess the efficacy and safety of bevacizumab-containing regimens in the treatment of advanced, chemotherapy-naive, non-squamous non-small cell lung cancer (NSCLC) on the basis of the two registrative trials [ECOG E4599 trial and BO17704 (AVAiL) trial]. METHODS: A pooled analysis of the two trials was performed using a random effect model, and the results were summarized as number-needed-to-treat (NNT) and number-needed-to-harm (NNH). A 2-step analysis was performed. The primary analysis included only the patients treated with bevacizumab 15 mg/kg in the experimental arm, whereas the secondary analysis (with descriptive aim) included the patients treated with bevacizumab 15 mg/kg or those treated with bevacizumab 7.5 mg/kg in the experimental arm. The 1-year survival and 6-month progression-free rates were assumed as indexes of efficacy, and grade III-IV side effects were assumed as index of safety in both analyses. RESULTS: 1,921 patients were potentially eligible for the pooled analysis and were included in the secondary analysis, whereas 1,576 patients were included in the primary analysis. A large heterogeneity was documented for both 6-month progression-free interval (I(2) = 88.164%, p = 0.004) and overall survival (I(2) = 73.541, p = 0.052). The absolute risk reduction of 1-year death and 6-month progression were 3.3% (95% CI = -6.5 to 13.2%, p = 0.507), with a NNT = 30; and 15.2% (95% CI = 0.07-29.6%, p = 0.04), with a NNT = 6 (both in favor of the bevacizumab-containing regimens), respectively. The absolute risk of treatment-related death was 2.4% (95% CI = 0.8-3.9%, p = 0.003), with a NNH = 41 against the bevacizumab-containing regimens; that of bleeding was 3.3% (95% CI = 1.6-4.9%, p < 0.001), with a NNH = 30; that of hypertension was 6.6% (95% CI = 4.6-8.6%, p < 0.001), with a NNH = 15; that of proteinuria was 2.1% (95% CI = 0.3-3.8%, p = 0.024), with a NNH = 47; that of neutropenia was 7.3% (95% CI = 3.2-11.4%, p < 0.001), with a NNH = 13; that of thrombocytopenia was 1.5% (95% CI = 0.2-2.7%, p = 0.021), with a NNH = 66. No significant differences were observed in the efficacy and the safety analysis when all the patients treated with bevacizumab 7.5 mg/kg and 15 mg/kg were included into the pooled analysis. CONCLUSION: Adding bevacizumab to standard chemotherapy in the treatment of advanced, chemotherapy-naive, non-squamous NSCLC seems to favor a modest improvement in the main outcomes, with a significant worsening of the safety profile. These data suggest caution in the generalized use of bevacizumab-containing regimens in the treatment of advanced, chemotherapy-naive, non-squamous NSCLC.

[Neuropathic pain in oncology. Novel evidence for clinical practice]. / Il dolore neuropatico in oncologia. Nuove evidenze per la pratica clinica.

Neuropathic pain is usually considered an "hard pain" both for the intrinsic difficulties in a correct diagnosis, and for the modest efficacy of the most part of conventional treatments. The most frequently used drugs in clinical practice are tricyclic antidepressants and anticonvulsants, while a minor role is reserved to NSAIDs or to strong opiates. Aim of our work was to systematically analyze all the evidences of literature about the treatment options against neuropathic pain in oncology, focusing our attention upon the efficacy and the safety of the different therapeutic options assessed as Number-Needed-to-Treat (NNT) and Number-Needed-to-Harm (NNH). A critical analysis of literature was finally performed using the GRADE system. On the basis of our review and the NNT and NNH ratio, gabapentin, pregabalin and strong opiates seem to be the most effective and well tolerated options against neuropathic pain in oncology, while carbamazepine, amitryptiline, tramadol and NSAIDs do not seem to be valid options in front line approach against oncologic neuropathic pain, either for a minor efficacy or for an unfavorable safety profile. Further trials comparing the different effective options are needed to better define the correct approach against neuropathic pain in oncology.

[Role of sequential chemotherapy in the treatment of metastatic colorectal cancer]. / Ruolo dei trattamenti chemioterapici sequenziali nella terapia delle neoplasie metastatiche del colon-retto.

BACKGROUND: Aim of our work was to assess the role of prognostic and predictive factors in patients to be treated with II and III line chemotherapy in metastatic colorectal cancer. METHODS: All the patients with metastatic colorectal cancer treated with at least one line of chemotherapy for metastatic disease and progressed after I line chemotherapy were considered eligible and enrolled into the trial. RESULTS: Twenty-six out of 51 consecutive, and potentially eligible patients (51%) were considered eligible and included into the analysis. The median time to progression to I line chemotherapy was 6.7 months with no significant differences between FOLFOX and FOLFIRI (respectively 10 and 6.7 months, p = 0.71). The I line response rate was 57.7% with no significant differences between FOLFOX and FOLFIRI (respectively 46.1% vs 70%, p = 0.4). A significant improve in overall survival was observed for I line responder patients (respectively, 60 and 12 months for responder and non-responder patients, p = 0.0037), with a significant correlation with the time to progression to I line chemotherapy (p = 0.041). No statistical difference was observed for the number of lines of treatment (3 vs 2, p = 0.3), the treatment sequence (FOLFOX-->FOLFIRI vs FOLFIRI-->FOLFOX, p = 0.94), patient's age (p = 0.105), patient sex (p = 0.055), II line response rate (p = 0.987) and time to progression to II line chemotherapy (p = 0.151) in multivariate analysis. CONCLUSIONS: Our data seem to suggest a prognostic significance of I line response rate and time to progression in patients with metastatic colorectal cancer.

Second line treatments in advanced platinum-resistant non small cell lung cancer. A critical review of literature.

In the last 10 years the medical approach to platinum-resistant Non Small Cell Lung Cancer (NSCLC) has radically changed, passing from a lack of evidence of any primary treatment against the tumor, to the identification of chemotherapy or EGFR inhibitors as the gold standard for clinical practice. Eight randomized clinical trials support the evidence of efficacy of second-line treatments against NSCLC, and docetaxel, pemetrexed and erlotinib are the most effective options for clinical practice. However, many aspects remain still undefined: Can a treatment with docetaxel, pemetrexed or erlotinib be considered the gold standard for all patients with platinum-resistant NSCLC, and consequently should all patients be treated with at least one of these options? Are the benefits enough to justify the side effects observed with these chemotherapeutic options? Can a schedule be preferred to the others for either efficacy or safety profile? Can the new EGFR inhibitors be considered an innovation in the treatment of platinum-resistant NSCLC, and should they be used in all patients with platinum-resistant NSCLC? A systematic review of randomized clinical trials and a critical analysis of the results were performed with the aim to clarify the real meaning of medical treatments in advanced, platinum-resistant NSCLC.

[Transdermal opiates in the treatment of moderate-severe cancer pain. Recommendations for clinical practice]. / Oppiacei transdermici nel trattamento del dolore oncologico moderato-severo. Raccomandazioni per la pratica clinica.

Although oral morphine is the gold standard in the front-line approach to moderate-severe cancer pain, transdermal opiates are largely used in clinical practice. Aims of our work were to review the evidences of literature supporting these different habits and to suggest an evidence-based criterion to guide clinical research and clinical practice. A systematic review of literature with meta-analysis of the safety data reported in randomized clinical trials comparing slow releasing oral morphine and transdermal opiates was performed using the random effect model. The quality of the evidences supporting the use of the different strategies and the strength of the recommendations was analyzed using the GRADE method. A significant advantage in favor of transdermal opiates was observed for constipation, urinary retention, need of laxative use and patient's preferences; a significant advantage in favor of slow releasing oral morphine was observed for diarrhea and sweating. The quality of the evidences supporting a front-line use of transdermal fentanyl was considered low, while those supporting the use of transdermal buprenorphine was considered very low. For the use oftransdermal fentanyl and for that oftransdermal buprenorphine a weak and a strong recommendation against their us as front-line treatment of moderate-severe cancer pain can be respectively obtained from the literature data. Transdermal opiates represent a safety and effective alternative to oral morphine against cancer pain, but they can not replace oral morphine as the gold standard first-line treatment of moderate-severe cancer pain.