Michele Basso

Final analysis of colorectal cancer patients treated with irinotecan and 5-fluorouracil plus folinic acid neoadjuvant chemotherapy for unresectable liver metastases

We have previously reported that neoadjuvant therapy with modified FOLFIRI enabled nearly a third of patients with metastatic colorectal cancer (mCRC) to undergo surgical resection of liver metastases. Here, we present data from the long-term follow-up of these patients. Forty patients received modified FOLFIRI: irinotecan 180 mg m−2, day 1; folinic acid, 200 mg m−2; and 5-fluorouracil: as a 400 mg m−2 bolus, days 1 and 2, and a 48-h continuous infusion 1200 mg m−2, from day 1. Treatment was repeated every 2 weeks, with response assessed every six cycles. Resected patients received six further cycles of chemotherapy postoperatively. Nineteen (47.5%) of 40 patients achieved an objective response; 13 (33%) underwent resection. After a median follow-up of 56 months, median survival for all patients was 31.5 months: for non-resected patients, median survival was 24 months and was not reached for resected patients. Median time to progression was 14.3 and 5.2 months for all and non-resected patients, respectively. Median disease-free (DF) survival in resected patients was 52.5 months. At 2 years, all patients were alive (8 DF), and at last follow-up, eight were alive (6 DF). Surgical resection of liver metastases after neoadjuvant treatment with modified FOLFIRI in CRC patients achieved favourable survival times.

Predictors of survival in patients with advanced hepatocellular carcinoma who permanently discontinued sorafenib

Treatment with sorafenib of patients with advanced hepatocellular carcinoma is challenged by anticipated discontinuation due to tumor progression, liver decompensation, or adverse effects. While postprogression survival is clearly determined by the pattern of tumor progression, understanding the factors that drive prognosis in patients who discontinued sorafenib for any reason may help to improve patient management and second‐line trial design. Patients consecutively admitted to three referral centers who were receiving best supportive care following permanent discontinuation of sorafenib for any reason were included. Postsorafenib survival (PSS) was calculated from the last day of treatment to death or last visit available. Two hundred and sixty patients were included in this prospective study, aged 67 years, 60% with hepatitis C, 51% Child‐Pugh A, 83% performance status (PS) ≥1, 41% with macroscopic vascular invasion, and 38% with extrahepatic tumor spread. Overall, median PSS was 4.1 (3.3‐4.9) months, resulting from 4.6 (3.3‐5.7) months for 123 progressors, 7.3 (6.0‐10.0) months in 77 with adverse effects, and 1.8 (1.6‐2.4) months in 60 decompensated patients (P < 0.001). Postsorafenib survival was independently predicted by PS, prothrombin time, extrahepatic tumor spread, macrovascular invasion, and reason for discontinuation. Two hundred patients potentially eligible for second‐line therapy had a PSS of 5.3 (4.6‐7.1) months, which was dependent on reasons of discontinuation (P = 0.004), PS (P < 0.001), macrovascular invasion (P < 0.001), and extrahepatic metastases (P < 0.002). Conclusion: Discontinuation due to adverse effects in the absence of macrovascular invasion, extrahepatic metastases, and deteriorated PS predicts the best PSS in compensated patients, thereby setting the stage for both improved patient counseling and selection for second‐line therapy. (Hepatology 2015;62:784–791)

Docetaxel and oxaliplatin combination in second-line treatment of patients with advanced gastric cancer

BackgroundIn advanced gastric cancer few data are available on the efficacy or safety of new drug combination regimens after progression following first-line chemotherapy.MethodsPatients with histologically confirmed advanced gastric cancer and Eastern Cooperative Oncology Group (ECOG) performance status (PS) less than 2, progressing after first-line chemotherapy, were eligible. Patients were treated with docetaxel 75 mg/m2 on day 1 and oxaliplatin 80 mg/m2 on day 2, every 3 weeks, until progression or unacceptable toxicity.ResultsBetween May 2002 and April 2005, 38 patients were enrolled. Men accounted for 73.7% of the patients and the median age was 59 years. The primary tumor was not resected in 47.4% of the patients; the peritoneum was the most frequent metastatic site (60.5%). The first-line treatment was cisplatin, epirubicin, and infusional 5-fluorouracil (ECF) in 81.5% of the patients and cisplatin and infusional 5-fluorouracil (CF) in 15.7%. The median number of cycles was 4.3. The treatment was well tolerated, with no toxic deaths. National Cancer Institute (NCI) grade III-IV neutropenia was frequent (26.3%), but no febrile neutropenia was reported. Severe asthenia (15.7%) and severe nausea (15.7%) required dose reductions in 2 patients and treatment discontinuation in another. The overall response rate was 10.5%, and 18 patients (47.3%) experienced disease stabilization (7 of them with significant clinical benefit). Median time to progression was 4.0 months (range, 2–8 months) and median overall survival was 8.1 months (range, 3–26 months). Thirteen patients (34.2%) also received third-line chemotherapy, with an irinotecan-containing regimen, and their median overall survival was higher than that of the other patients (16.3 vs 6.0 months)ConclusionThe combination of oxaliplatin and docetaxel shows only marginal activity as second-line treatment, but it has a good tolerability profile. This suggests that there is room for optimizing the schedule as well as for planning sequential treatments in gastric cancer.

Long-Term Follow-Up of a Pilot Phase II Study with Neoadjuvant Epidoxorubicin, Etoposide and Cisplatin in Gastric Cancer

Objective: The prognosis in T3–T4 or N+ gastric cancer is dismal, and the role of adjuvant therapy remains uncertain. Neoadjuvant chemotherapy could improve both resectability and survival. Here, we report the results of the long-term follow-up of a pilot study aimed at evaluating a neoadjuvant treatment in a group of patients carefully staged by computed tomography (CT), endoscopic ultrasound and laparoscopy. Methods: Twenty-five stage II–III patients with histologically proven gastric adenocarcinoma were enrolled in the study. All patients gave informed consent and were thoroughly staged. Patients were treated with epidoxorubicin (40 mg/m2 i.v.) on days 1 and 4, etoposide (VP-16; 100 mg/m2) on days 1, 3 and 4 and cisplatinum (80 mg/m2) on day 2, every 21–28 days for 3 pre-operative cycles before CT clinical restaging followed by laparotomy and D2 gastrectomy. Three further cycles of chemotherapy were planned after radical surgery. Results: Twenty-four patients received the planned pre-operative chemotherapy and underwent surgical resection; total (13 patients) or subtotal (7 patients) R0 D2 gastrectomy was possible in 20 patients. One patient died as a result of gastric bleeding. Perioperative complications occurred in 5 patients (failure of anastomosis in 1 patient and wound infection in the other 4). The pathologic response rate included 7 partial responses (29.1%) and 10 patients with stable disease (41.7%). The main toxicity was grade 3/4 neutropenia (68%), which occurred more frequently during the postoperative chemotherapy, and fatigue (68%). Fever or infection, however, were never observed. The median disease-free survival was 37 months, and median survival has not been reached after 40 months of median follow-up. One-, 2- and 3-year survival rates were 80, 64 and 60%, respectively. Conclusion: The notable long-term survival in the present study suggests a comparison between the neoadjuvant approach, including new drug combinations, and adjuvant chemo- or chemoradio-therapy in locally advanced gastric cancer.

Hormone Receptor Status and HER2 Expression in Primary Breast Cancer Compared With Synchronous Axillary Metastases or Recurrent Metastatic Disease.

Estrogen receptor (ER), progesterone receptor (PR), and HER2/neu are the most important tissue markers in the management of breast cancer, in the adjuvant setting and in the setting of metastatic disease. Many studies have demonstrated a discordance of expression between primary breast cancer, synchronous axillary metastases, and metastatic sites. The aim of this article is to review studies on discordance of expression of these predictive parameters to better understand the importance of a reassessment of biomolecular status to modify treatment strategies. We performed a literature review to identify studies that assessed ER, PR, and HER2 discordance between primary breast cancer, synchronous axillary lymph node metastasis, and other metastatic sites. We reviewed these data related to (1) relevance of discordance rates in clinical practice and (2) therapeutic consequences of discordance rate. Results were analyzed qualitatively. Changes in ER and particularly in PR are observed in locoregional and in distant metastases reaching a rate of 10% to 30% for ER and 20% to 50% for PR. The loss of PR is more frequent than ER loss. High HER2 concordance between primary tumors and axillary lymph node or distant metastases has been demonstrated in many studies; in the discordant cases, it is more frequent to have HER2-positive metastases with negative primary tumors than the opposite. A reassessment of biomolecular status in residual tumors after neoadjuvant treatment or in metastatic sites is advisable, whenever it is possible, to correct/modify the treatment schedule and to estimate the actual prognosis.

KRAS mutational status affects oxaliplatin-based chemotherapy independently from basal mRNA ERCC-1 expression in metastatic colorectal cancer patients

Background:In this study, we evaluated the possibility that KRAS mutational status might be predictive of oxaliplatin (OXA) efficacy. We also explored the role of excision repair cross complementing group-1 (ERCC-1).Methods:Ninety anti-epidermal growth factor receptor-naive advanced colorectal cancer patients were retrospectively analysed. In all patients KRAS mutational status was assessed. In 60 patients mRNA ERCC-1 expression was also investigated. Response rate (RR) and progression-free survival (PFS) after FOLFOX-6±bevacizumab were evaluated according to KRAS status and mRNA ERCC-1 expression.Results:Among 90 patients 47% wild-type (wt) and 53% mutated (mt) KRAS tumours were found. Response rate was 26% in the wt KRAS group, whereas it was 56% in the mt KRAS group; the difference is statistically significant in the total sample (P=0.008) and when only patients receiving FOLFOX-6±bevacizumab as first-line are considered (P=0.01). Progression-free survival was longer in mt than in wt KRAS patients over all patients (10 vs 8 months, respectively, P=0.001) and in those treated as first-line (10 vs 8 months, respectively, P=0.0069). Mt KRAS patients experienced a longer survival (24 vs 18 months; P=0.01). ERCC-1 mRNA expression was not found to correlate with FOLFOX activity in our analysis.Conclusion:Our results suggest that activating mutation of KRAS oncogene may predict response to OXA. Basal expression of ERCC-1 mRNA does not explain the high efficacy of FOLFOX-6 in mt KRAS patients.

A survey of therapy for advanced renal cell carcinoma

Renal cell carcinoma (RCC) is very resistant to both chemotherapy and radiotherapy. Localized disease can be cured by surgery but most patients are diagnosed when distant metastases are already present and about 30% of patients relapse after nephrectomy. Until 2 years ago, cytokine-based immunotherapy (interleukin-2 and interferon-alpha) was the only therapeutic option for advanced RCC patients. Fewer than 20% of patients benefit from this treatment, but some of these may experience very prolonged complete responses and progression-free intervals, suggesting a possibility of cure in a very few cases. Thanks to our expanding knowledge of the biology and pathogenesis of RCC, the treatment of this disease has recently undergone a major advance, through the development of potent angiogenesis inhibitors and targeted agents. Bevacizumab, an antibody directed against vascular endothelial growth factor (VEGF), has shown significant activity in combination with interferon-alpha (IFN-alpha). Sunitinib and sorafenib, multikinase inhibitors with proven antiangiogenic activity, have also been approved for the treatment of this tumor. Finally, temsirolimus and everolimus, which belong to the family of mammalian target of rapamycin (mTOR), have shown some activity in selected patients. The aim of this paper is to review clinical trials with these new agents, describing their activity and profiles of toxicity, and to evaluate potential future developmental strategies.

A phase II study of sunitinib in advanced hepatocellular carcinoma

BACKGROUND In 2007, sorafenib was the first drug able to improve overall survival in patients with advanced hepatocellular carcinoma. AIM In 2005 we designed a phase II study to assess safety and efficacy of sunitinib. METHODS This is a single arm, open-label, single-centre phase II trial. Eligibility criteria were advanced hepatocellular carcinoma; no prior chemotherapy, performance status 0-1; and Child≤B8. The treatment schedule was 50mg each day orally, 4 weeks on, 2 weeks off. RESULTS Between 10/2007 and 10/2010, 34 patients were enrolled. A significant worsening of liver functional reserve after sunitinib was observed. Grade 3/4 adverse effects occurred in 80% of patients and included fatigue (47%), nausea (15%), liver failure (15%), encephalopathy (12%) and upper gastrointestinal bleeding (12%). Six patients (18%) died within 60 days of enrolment. A partial response was observed in 4 patients (12%). Median time to tumour progression was 2.8 months and median overall survival was 5.8 months. CONCLUSION A dose of 50mg/d induces a high rate of severe adverse events. Toxicity remains a key concern also at the dose of 37.5mg/d. However, sunitinib is able to induce a prolonged response in some patients. Positron Emission Tomography/Computed Tomography scans may select good responders.

Anastrozole-related acute hepatitis with autoimmune features: a case report.

BackgroundTwo cases of acute hepatitis occurring during treatment with anastrozole have previously been reported, but the underlying mechanisms of liver injury are still uncertain. We report the case of anastrozole-related acute hepatitis with some autoimmune features.Case presentationA 70-year-old woman developed acute hepatitis associated with serum antinuclear antibodies during anastrozole treatment; after drug withdrawal, liver function parameters rapidly improved and serum auto-antibodies were no longer detectable.ConclusionsAnastrozole-induced hepatotoxicity is a very rare event. Drug-drug interactions or metabolically-mediated damage might be involved, with a possible role of individual susceptibility. Our report suggests that an immune-mediated mechanism may also be considered in anastrozole-related liver injury.

A reversible coma after oxaliplatin administration suggests a pathogenetic role of electrolyte imbalance.

Sir, Oxaliplatin (OXA) is a third generation derivative of platinum compounds [1]. Unlike cisplatin and carboplatin, it is very effective in the treatment of colorectal cancer [2, 3]. Unfortunately, about 15% of patients treated with OXA gradually develop a dose-limiting severe chronic peripheral sensory neuropathy. Another less frequent neurotoxic manifestation is an acute type of peripheral neurotoxicity. Together, these side effects affect the overall efficacy of the treatment because they necessitate the interruption of OXA administration even in responding or potentially responding patients. The mechanism involved in OXA-linked neurotoxicity is still not well known, although the hypothesis that a product of OXA metabolic cleavage could interfere with the function of a peripheral nerve channel is generally accepted. Most authors agree that the voltage-gated sodium channels are involved [4, 5]. Case report