International Tailored Chemotherapy Adjuvant (ITACA) trial, a phase III multicenter randomized trial comparing adjuvant pharmacogenomic-driven chemotherapy versus standard adjuvant chemotherapy in completely resected stage II-IIIA non-small-cell lung cancer.

BACKGROUND: Several strategies have been investigated to improve the 4% survival advantage of adjuvant chemotherapy in early-stage non-small-cell lung cancer (NSCLC). In this investigator-initiated study we aimed to evaluate the predictive utility of the messenger RNA (mRNA) expression levels of excision repair cross complementation group 1 (ERCC1) and thymidylate synthase (TS) as assessed in resected tumor. PATIENTS AND METHODS: Seven hundred and seventy-three completely resected stage II-III NSCLC patients were enrolled and randomly assigned in each of the four genomic subgroups to investigator's choice of platinum-based chemotherapy (C, n = 389) or tailored chemotherapy (T, n = 384). All anticancer drugs were administered according to standard doses and schedules. Stratification factors included stage and smoking status. The primary endpoint of the study was overall survival (OS). RESULTS: Six hundred and ninety patients were included in the primary analysis. At a median follow-up of 45.9 months, 85 (24.6%) and 70 (20.3%) patients died in arms C and T, respectively. Five-year survival for patients in arms C and T was of 65.4% (95% CI (confidence interval): 58.5% to 71.4%) and 72.9% (95% CI: 66.5% to 78.3%), respectively. The estimated hazard ratio (HR) was 0.77 (95% CI: 0.56-1.06, P value: 0.109) for arm T versus arm C. HR for recurrence-free survival was 0.89 (95% CI: 0.69-1.14, P value: 0.341) for arm T versus arm C. Grade 3-5 toxicities were more frequently reported in arm C than in arm T. CONCLUSION: In completely resected stage II-III NSCLC tailoring adjuvant chemotherapy conferred a non-statistically significant trend for OS favoring the T arm. In terms of safety, the T arm was associated with better efficacy/toxicity ratio related to the different therapeutic choices in the experimental arm.

Evaluation of nilotinib in advanced GIST previously treated with imatinib and sunitinib.

PURPOSE: Patients with advanced GIST following standard imatinib and sunitinib often have good performance status and need additional therapy. This study tested nilotinib, a second-generation tyrosine kinase inhibitor, in patients with advanced GIST refractory to standard therapies. METHODS: This single-center open-label phase II study has a primary objective to determine progression-free survival at 6 months. Using a novel statistical design, 17 patients were to be enrolled; if ≥ 10 were progression free (PF) at 2 months, 19 additional patients would be enrolled. The therapy was considered of benefit if ≥ 13 of 36 patients were PF at 6 months. All patients signed informed consent and entry criteria included normal cardiac function. Exploratory analyses correlating genotype with response were also performed. RESULTS: Thirteen patients were treated; 2 had received agents after imatinib and sunitinib. Treatment was well tolerated with one grade 4 anemia attributed to nilotinib. No measurable responses were observed; median time to progression was 2 months. One patient remained on study with stable disease for 12 months. Mutation testing is available from 10 primary tumors with 7 exon 11 mutations, 1 exon 9 mutation, and 2 without KIT/PDGFR mutations. Two samples from recurrent disease had 2 mutations, both primary exon 11 mutations with an additional exon 17 mutation, including the patient with prolonged stable disease. CONCLUSIONS: Nilotinib was well tolerated in these patients with advanced GIST. Accrual was halted due to insufficient clinical benefit. However, nilotinib may provide benefit to specific subsets of advanced GIST with exon 17 mutations.

[Psyche and cancer]. / Psiche e cancro.

Although the relationship between psyche and cancer dates back many centuries, and several studies were conducted on this topic during the last decades, the role of psychological factors in the development of cancer is still controversial. Although a lot of factors have been considered, attention has been focused mainly on stress, which has been evaluated also in experimental models. Generally, the results of case-control studies have been contradictory, and at times more stressfull events have been recorded in patients with benign tumors than in those with cancer. On the contrary, a higher incidence of stress-related cancers has not been documented in cohort studies. Since cancer is a genetic disease, it is difficult to hypothesize that psychological factors may permanently alter nucleotide sequence giving rise to multiple mutations needed for cancer development. At present, there is no sufficient evidence to affirm that psychological factors may contribute without doubt to cancer development.

[Skin adnexal tumors]. / Tumori degli annessi cutanei.

Adnexal skin tumors are rare neoplasms that develop from hair follicles, sebaceous glands and sweat glands. In the majority of cases these tumors are benign, although metastases have been reported in rare occasion. The diagnosis in always histologic and often it is sufficient to report the lesion simply as benign or malignant. Radical surgery is the treatment of choice. When the tumor is large, the Mohs technique can be used. Local recurrence is frequent in case of incomplete surgical removal. Etastatic disease, although rare, has a poor prognosis. Chemotherapy and radiotherapy experience is very limited. Overall, combination chemotherapy seems to be superior to single agent treatment.

First line chemotherapy in advanced or metastatic NSCLC.

The lung cancer global incidence has regularly increased during the last decades. Non Small Cell Lung Cancer (NSCLC) accounts for approximately 80% of all lung tumors. Different schedules including cisplatin plus gemcitabine or vinorelbine or paclitaxel or docetaxel or irinotecan showed advantages in terms of response rate, toxicity and quality of life, but little improvement in terms of survival. Some advantage was documented in favour of the combination including cisplatin plus a new drug versus monochemotherapy with new drugs. The large phase III studies performed with doublets containing new drugs and platinum are not free of criticism but in summary the research involving more than 3000 patients failed to indicate a standard regimen. With the aim of strengthen the phase III studies results, a meta-analysis tested the survival outcomes of published randomized trials, analysing the effects of the combination of gemcitabine and platinum compounds versus any platinum-based regimens. Gemcitabine-platinum combinations appear to offer a statistically significant superior efficacy in terms of overall survival and progression free survival as compared to other platinum-based regimens. Considering the palliative role of chemotherapy in advanced NSCLC and in order to reduce toxicity, not cisplatin-containing regimens were investigated. The results support the suggestion from the last ASCO guidelines: first-line chemotherapy of advanced NSCLC should be a two-drug combination regimen and not platin-based chemotherapy may be used as alternative to platinum-based regimens. The new frontier is represented by pharmacogenomic. The potential benefits of the pharmacogenomic approach lay in the possibility of predicting the patient chemotherapy response developing customized chemotherapeutic combinations and limiting severe side effects.

High activity of salvage treatment with biweekly paclitaxel-gemcitabine combination in heavily pretreated breast cancer patients.

The treatment of refractory metastatic breast cancer is primarily palliative, without a significant impact on overall survival. Among the innovative combinations in this unfavourable setting, paclitaxel and gemcitabine showed a possible synergistic action and an encouraging activity in some clinical trials. This phase II study was carried out to evaluate paclitaxel-gemcitabine combination in very heavily pretreated advanced breast cancer on a bi-weekly schedule.Thirty-nine women with advanced breast cancer were treated with paclitaxel 150 mg/m2 as 3 hrs infusion, and gemcitabine 1,500 mg/m2 as 30 mins infusion, both drugs administered on days 1, 15, with cycles repeated every 28 days. All but two patients received granulocyte colony stimulating factor (G-CSF) on days 7 to 9 and 20 to 22 of every cycle. More than two third (71%) of the patients had previously received two or more chemotherapy regimens for advanced disease, including almost all active agents in this disease. Objective responses were observed in 18 out of 34 evaluable patients (53%; 95% CI, 36% to 70%). Disease remained stable in 7 patients (21%). Responses by sites were 67% in soft tissue and in bone, and 48% in visceral disease. Median time to progression and overall survival were 9 and 20 months, respectively. Treatment was well tolerated, with G3-4 neutropenia in 8%, and G 1-2 thrombocytopenia in 13% of the patients; non-hematological toxicities were mild, with G3 hepatotoxicity in 5% of the patients, and G3 peripheral neurotoxicity in 10% of the patients. Biweekly paclitaxel/gemcitabine combination with G-CSF support appears to be very active as salvage therapy in heavily pretreated breast cancer patients, with a very favourable safety profile.