B. Massidda

Residual neurotoxicity in ovarian cancer patients in clinical remission after first-line chemotherapy with carboplatin and paclitaxel: The Multicenter Italian Trial in Ovarian cancer (MITO-4) retrospective study

BackgroundCarboplatin/paclitaxel is the chemotherapy of choice for advanced ovarian cancer, both in first line and in platinum-sensitive recurrence. Although a significant proportion of patients have some neurotoxicity during treatment, the long-term outcome of chemotherapy-induced neuropathy has been scantly studied. We retrospectively assessed the prevalence of residual neuropathy in a cohort of patients in clinical remission after first-line carboplatin/paclitaxel for advanced ovarian cancer.Methods120 patients have been included in this study (101 participating in a multicentre phase III trial evaluating the efficacy of consolidation treatment with topotecan, and 19 treated at the National Cancer Institute of Naples after the end of the trial). All patients received carboplatin (AUC 5) plus paclitaxel (175 mg/m2) every 3 weeks for 6 cycles, completing treatment between 1998 and 2003. Data were collected between May and September 2004. Residual sensory and motor neurotoxicity were coded according to the National Cancer Institute – Common Toxicity Criteria.Results55 patients (46%) did not experience any grade of neurological toxicity during chemotherapy and of these none had signs of neuropathy during follow-up. The other 65 patients (54%) had chemotherapy-induced neurotoxicity during treatment and follow-up data are available for 60 of them. Fourteen out of 60 patients (23%) referred residual neuropathy at the most recent follow-up visit, after a median follow up of 18 months (range, 7–58 months): 12 patients had grade 1 and 2 patients grade 2 peripheral sensory neuropathy; 3 patients also had grade 1 motor neuropathy. The remaining 46/60 patients (77%) had no residual neuropathy at the moment of interview: recovery from neurotoxicity had occurred in the first 2 months after the end of chemotherapy in 22 (37%), between 2 and 6 months in 15 (25%), or after more than 6 months in 9 patients (15%). Considering all 120 treated patients, there was a 15% probability of persistent neurological toxicity 6 months after the end of chemotherapy.ConclusionA significant proportion of patients with advanced ovarian cancer treated with first-line carboplatin/paclitaxel suffer long-term residual neuropathy. This issue should be carefully taken into account before considering re-treatment with the same agents in sensitive recurrent disease.Carboplatin/paclitaxel is the chemotherapy of choice for advanced ovarian cancer, both in first line and in platinum-sensitive recurrence. Although a significant proportion of patients have some neurotoxicity during treatment, the long-term outcome of chemotherapy-induced neuropathy has been scantly studied. We retrospectively assessed the prevalence of residual neuropathy in a cohort of patients in clinical remission after first-line carboplatin/paclitaxel for advanced ovarian cancer. 120 patients have been included in this study (101 participating in a multicentre phase III trial evaluating the efficacy of consolidation treatment with topotecan, and 19 treated at the National Cancer Institute of Naples after the end of the trial). All patients received carboplatin (AUC 5) plus paclitaxel (175 mg/m2) every 3 weeks for 6 cycles, completing treatment between 1998 and 2003. Data were collected between May and September 2004. Residual sensory and motor neurotoxicity were coded according to the National Cancer Institute – Common Toxicity Criteria. 55 patients (46%) did not experience any grade of neurological toxicity during chemotherapy and of these none had signs of neuropathy during follow-up. The other 65 patients (54%) had chemotherapy-induced neurotoxicity during treatment and follow-up data are available for 60 of them. Fourteen out of 60 patients (23%) referred residual neuropathy at the most recent follow-up visit, after a median follow up of 18 months (range, 7–58 months): 12 patients had grade 1 and 2 patients grade 2 peripheral sensory neuropathy; 3 patients also had grade 1 motor neuropathy. The remaining 46/60 patients (77%) had no residual neuropathy at the moment of interview: recovery from neurotoxicity had occurred in the first 2 months after the end of chemotherapy in 22 (37%), between 2 and 6 months in 15 (25%), or after more than 6 months in 9 patients (15%). Considering all 120 treated patients, there was a 15% probability of persistent neurological toxicity 6 months after the end of chemotherapy. A significant proportion of patients with advanced ovarian cancer treated with first-line carboplatin/paclitaxel suffer long-term residual neuropathy. This issue should be carefully taken into account before considering re-treatment with the same agents in sensitive recurrent disease.

Cisplatin and gemcitabine with either vinorelbine or paclitaxel in the treatment of carcinomas of unknown primary site : Results of an Italian multicenter, randomized, phase II study

To date, the standard treatment for patients who have carcinoma of unknown primary site has not been established.

Targeting insulin-like growth factor type 1 receptor in cancer therapy

It is believed that the insulin-like growth factor receptor type 1 (IGF-1R) signaling pathway plays a pivotal role in cancer growth, progression, and resistance to anticancer therapies. Strategies are being developed to block IGF-1R as an anticancer treatment. We reviewed several potential strategies for disrupting the IGF axis. We also reviewed the effects of two drugs that target the IGF-1R: monoclonal antibodies and tyrosine kinase inhibitors. Preliminary results of studies involving these agents provided a foundation for ongoing clinical trials, whose results in the near future will help us understand how to incorporate anti IGF-1R strategies into the current anticancer armamentarium.

Prevalence of KRAS, BRAF, and PIK3CA somatic mutations in patients with colorectal carcinoma may vary in the same population: clues from Sardinia

BackgroundRole of KRAS, BRAF and PIK3CA mutations in pathogenesis of colorectal cancer (CRC) has been recently investigated worldwide. In this population-based study, we evaluated the incidence rates and distribution of such somatic mutations in genetically isolated population from Sardinia.MethodsFrom April 2009 to July 2011, formalin-fixed paraffin-embedded tissues (N = 478) were prospectively collected from Sardinian CRC patients at clinics across the entire island. Genomic DNA was isolated from tissue sections and screened for mutations in KRAS, BRAF, and PIK3CA genes by automated DNA sequencing.ResultsOverall, KRAS tumour mutation rate was 30% (145/478 positive cases). Distribution of mutation carriers was surprisingly different within the island: 87/204 (43%) in North Sardinia vs. 58/274 (21%) in Middle-South Sardinia (p<0.001). Among 384 CRC cases whose DNA was available, only one (0.3%) patient carried a mutation in BRAF gene; PIK3CA was found mutated in 67 (17%) patients. A significant inverse distribution of PIK3CA mutation rates was observed within Sardinian population: 19/183 (10%) cases from northern vs. 48/201 (24%) cases from central-southern island (p<0.001). This heterogeneity in frequencies of KRAS/PIK3CA somatic mutations is consistent with already-reported discrepancies in distribution of germline mutations for other malignancies within Sardinian population. Preliminary clinical evaluation of 118 KRAS wild-type patients undergoing anti-EGFR-based treatment indicated lack of role for PIK3CA in predicting response to therapy.ConclusionsOur findings support the hypothesis that differences in patients’ origins and related genetic backgrounds may contribute to even determine the incidence rate of somatic mutations in candidate cancer genes.

Phase III randomized study of fotemustine and dacarbazine versus dacarbazine with or without interferon-α in advanced malignant melanoma

BackgroundThe effect of the addition of fotemustine and/or interferon (IFN) to standard therapy with dacarbazine alone in patients with advanced malignant melanoma was investigated in a multicenter, randomized 2x2 factorial design trial.MethodsA total of 260 patients were randomly assigned to one of four treatment groups: (A) fotemustine and dacarbazine repeated on 3-week cycle; (B) same treatment as (A) plus IFN-α2b three times per week; (C) dacarbazine alone repeated on 3-week cycle; (D) same treatment as (C) plus IFN-α2b three times per week. Two comparisons were planned to assess the efficacy of fotemustine (groups A+B vs. C+D) and IFN-α2b (groups A+C vs. B+D).ResultsAddition of fotemustine did not significantly improve overall survival (OS) (p=0.28) or progression-free survival (PFS) (p=0.55); Hazard ratio (HR) for OS was 0.93 (95% CI 0.71-1.21). Similarly, addition of IFN-α2b did not improve OS (p=0.68) or PFS (p=0.65); HR for OS was 0.92 (95% CI 0.70-1.20). Overall response rate was not improved by the addition of either fotemustine (p=0.87) or IFN-α2b (p=0.57). The combination of all three drugs resulted in the highest occurrence of adverse events.ConclusionsNo significant improvement in outcomes were observed with the addition of either fotemustine or IFN-α2b to dacarbazine.Trial registrationClinicalTrials.gov: NCT01359956

Weekly Docetaxel and Gemcitabine as First-Line Treatment for Metastatic Breast Cancer: Results of a Multicenter Phase II Study

Objectives: We conducted a multicenter phase II study to evaluate the clinical efficacy, toxicity, and dose intensity of a new weekly schedule of docetaxel and gemcitabine as first-line treatment of metastatic breast cancer patients. Methods: We enrolled 58 patients, 52% of whom had received a previous anthracycline-containing chemotherapy. The treatment schedule was: docetaxel 35 mg/m2 and gemcitabine 800 mg/m2 i.v. on days 1, 8, 15 every 28 days. Results: All patients were assessable for toxicity and 56 for efficacy. Overall response rate was 64.3% with 16.1% of complete responses and 48.2% of partial responses. Median survival was 22.10 months (95% CI: 15.53–28.67) and median time to tumor progression was 13.6 months (95% CI: 10.71–16.49). The most common hematological toxicity was neutropenia (no febrile neutropenia), which occurred in 28 patients (48.3%) but grade 3–4 in only 8 patients (14%). Alopecia, the most common nonhematological toxicity, occurred in 20 (34.5%) patients, but only 5 patients (8.6%) experienced grade 3 alopecia. Conclusion: The activity of docetaxel and gemcitabine in metastatic breast cancer is confirmed. The promising results of the employed schedule, in agreement with other published studies, need to be further confirmed within a phase III study.

Gastrointestinal stromal tumors: should they be treated with the same systemic chemotherapy as other soft tissue sarcomas?

aDepartment of Medical Oncology, Istituto Europeo di Oncologia, Milano, bMedical Oncology Unit, Istituto Nazionale Tumori, Milano, cDepartment of Clinical Oncology, Istituto Nazionale Ricerca sul Cancro, Genova, dDepartment of Medical Oncology, Ospedale S. Chiara, Pisa, eDivision of Medical Oncology, Università di Cagliari, Cagliari, fDepartment of Medical Oncology, H. Gradenigo, Torino, gMedical Oncology Unit, Ospedali Riuniti, Bergamo, hDivision of Medical Oncology, H. Torrette, Università di Ancona, Ancona, iDivision of Medical Oncology, H. Cardarelli, Napoli, jDivision of Medical Oncology, H.S. Eugenio, Roma, kDepartment of Medical Oncology, Università degli Studi, Bologna, lDepartment of Medical Oncology/Hematology, Ordine Mauriziano-IRCC, Candiolo, mDivision of Medical Oncology, Istituto Nazionale die Tumori, Napoli, Italy

Effects of antiestrogen and progestin on immune functions in breast cancer patients

Several immunologic variables were evaluated in 14 patients with untreated primary breast cancer and 20 postmastectomized patients undergoing tamoxifen (TAM) or high‐dose medroxyprogesterone acetate (MPA) treatment. Immunologic evaluation in the peripheral blood included lymphocyte count, definition of T‐lymphocyte subsets by monoclonal antibodies (OKT3, OKT11, OKT4, and OKT8), and lymphocyte blastogenic response to phytohemagglutinin (PHA) and Concanavallin A (Con A). Moreover, the in vitro effect of TAM and MPA on the blastogenic response of peripheral lymphocytes from normal female subjects was tested. Primary breast cancer patients did not differ from controls in any of the variables tested. Similarly, the immunologic variables of the group treated with TAM were normal, with the exception of a slight reduction of the OKT4+/OKT8+ ratio. In MPA‐treated patients, a reduction of the percentage of OKT4+ cells and a decrease of the OKT4+/0KT8+ ratio were observed. Moreover, response to PHA was reduced sharply. However, the addition of interleukin‐2 (IL‐2) to the culture medium restored PHA response. Likewise, the in vitro addition of MPA to peripheral blood lymphocytes from normal female subjects resulted in a sharp dose‐dependent depression of PHA response while TAM was ineffective completely. The inhibitory effect of MPA was not evident when IL‐2 was added simultaneously to the culture medium. These results show that the administration of high‐dose MPA may alter immunocompetence as defined by T‐lymphocyte subsets and response to mitogens. The latter effect may be related to a diminished production of IL‐2. In contrast, TAM does not appear to have a significant immunodepressant action either in vitro or in vivo.

Genetic markers for toxicity of adjuvant oxaliplatin and fluoropyrimidines in the phase III TOSCA trial in high-risk colon cancer patients

We investigated 17 polymorphisms in 11 genes (TS, MTHFR, ERCC1, XRCC1, XRCC3, XPD, GSTT1, GSTP1, GSTM1, ABCC1, ABCC2) for their association with the toxicity of fluoropyrimidines and oxaliplatin in colorectal cancer patients enrolled in a prospective randomized trial of adjuvant chemotherapy. The TOSCA Italian adjuvant trial was conducted in high-risk stage II–III colorectal cancer patients treated with 6 or 3 months of either FOLFOX-4 or XELOX adjuvant chemotherapy. In the concomitant ancillary pharmacogenetic study, the primary endpoint was the association of polymorphisms with grade 3–4 CTCAE toxicity events (grade 2–4 for neurotoxicity). In 517 analyzed patients, grade ≥ 3 neutropenia and grade ≥ 2 neurotoxicity events occurred in 150 (29%) and in 132 patients (24.8%), respectively. Diarrhea grade ≥ 3 events occurred in 34 (6.5%) patients. None of the studied polymorphisms showed clinically relevant association with toxicity. Hopefully, genome-wide association studies will identify new and more promising genetic variants to be tested in future studies.

Allergy and Tumour Outcome after Primary Cancer Therapy

Background: Over the last decade several papers have dealt with the possible interference of allergies in both the infectious disease incidence and tumour development. In the light of all these observations we analysed several tumour patients for a possible interaction between a state of allergy and tumour development and progression after primary cancer therapy. Methods: This study included 1,055 patients with different types of solid tumours admitted consecutively between 1994 and 2002 to the Cagliari University Polyclinic. After primary surgery or medical therapy (or both), 92 allergic subjects and 182 non-allergic patients were studied over a follow-up period of 6–96 months (median 23). Results: Among 1,055 tumour-bearing patients, the prevalence of allergy was found to be about 8% versus 16–37% in a population of non-tumour-bearing subjects. After primary cancer therapy, allergic patients turned out to have a 20% higher probability of being cured and about a 50% lower risk of tumour progression as compared to non-allergic ones. The observed differences were statistically significant (p = 0.013). Conclusions: On the basis of our findings, we suggest that allergic subjects seem to have a better prognosis than non-allergic ones for disease outcome after cancer therapy.