Chantal Dreyer

Changes in Tumor Density in Patients with Advanced Hepatocellular Carcinoma Treated with Sunitinib

Purpose: Response Evaluation Criteria in Solid Tumors (RECIST) may underestimate the efficacy of targeted therapies. In hepatocellular carcinoma (HCC) studies with sunitinib, RECIST-defined response rates are low, although hypodensity on computed tomography (CT) scans occurs more frequently. This exploratory analysis investigated tumor density as a surrogate endpoint of sunitinib activity in a phase II HCC study. Experimental Design: Patients received sunitinib 50 mg/d (4 weeks on/2 weeks off). Tumor size and density were assessed on CT scans by using RECIST and Choi criteria, the latter of which classify a partial response as a 15% or more reduction in tumor density or a 10% or more reduction in tumor size. The overall percentage volume of tumor necrosis was calculated with volumetric reconstruction. Tumor perfusion parameters were assessed by using perfusion CT scans with specific acquisition. Results: Among the 26 evaluable patients, 1 achieved a partial response and 22 had tumor stabilization by RECIST. In analysis of tumor density, 17 of 26 patients (65.4%) were responders by Choi criteria. Volumetric assessment showed major tumor necrosis (≥30% of tumor volume) in 10 of 21 patients (47.6%). Among four patients evaluated, tumor blood flow was reduced by 58.8% and blood volume by 68.4% after 4 weeks of treatment. The median time to progression (TTP) was 6.4 months. Patients with responses by Choi criteria had a significantly longer TTP (7.5 months) compared with nonresponders (4.8 months; HR = 0.33, two-sided P = 0.0182). Conclusions: Tumor density assessment suggested that radiologic endpoints in addition to RECIST may be considered to capture sunitinib activity in HCC. Clin Cancer Res; 17(13); 4504–12. ©2011 AACR.

New inhibitors of the mammalian target of rapamycin signaling pathway for cancer

Importance of the field: Contrasting with the broad activation of the PI3K/AKT/mammalian target of rapamycin (mTOR) survival pathway in most cancer, activity of rapalogues appears to be restricted to a few tumor types. Areas covered in this review: The analysis of molecular activity of the PI3K/AKT/mTOR pathway and resistance mechanisms of rapamycin and rapalogues led to the development of several inhibitory molecules. What the reader will gain: New anticancer agents including PI3K inhibitors, dual PI3K/mTOR inhibitors, specific mTOR inhibitors, and AKT inhibitors may have direct inhibitory effects on targets by competing with ATP or may be non-ATP-competitive allosteric modulators of protein functions. In addition, another way of blocking the abnormal activation of the PI3K/AKT/mTOR pathway may be achieved by using HSP90 inhibitors. In this paper we review novel drugs inhibiting the mTOR signaling pathway. Take home message: Several trials are ongoing with novel drugs targeting key kinases involved in the mTOR pathway. Benchmarking those agents with rapalogues in rationally designed preclinical models and conceiving clinical trials in everolimus/temsirolimus-sensitive tumor types may help to identify drugs with a real clinical potential. Understanding mechanisms associated with primary and acquired resistance to rapalogues may help to enlarge indications and provide a rationale for designing combinations that will minimize the risk of developing resistance to rapalogues.

Alternative Response Criteria (Choi, European Association for the Study of the Liver, and Modified Response Evaluation Criteria in Solid Tumors [RECIST]) Versus RECIST 1.1 in Patients With Advanced Hepatocellular Carcinoma Treated With Sorafenib

INTRODUCTION Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST 1.1), may underestimate activity and does not predict survival in patients with hepatocellular carcinoma (HCC) treated with sorafenib. This study assessed the value of alternative radiological criteria to evaluate response in HCC patients treated with sorafenib. PATIENTS AND METHODS A retrospective blinded central analysis was performed of computed tomography (CT) scans from baseline and the first tumor evaluation in consecutive patients treated with sorafenib over a 2-year period in a single institution. Four different evaluation criteria were used: Choi, European Association for the Study of the Liver (EASL), modified RECIST (mRECIST), and RECIST 1.1. RESULTS Among 82 HCC patients, 64 with Barcelona Clinic Liver Cancer stage B-C were evaluable with a median follow-up of 22 months. Median duration of sorafenib treatment was 5.7 months, and median overall survival was 12.8 months. At the time of the first CT scan, performed after a median of 2.1 months, Choi, EASL, mRECIST, and RECIST 1.1 identified 51%, 28%, 28%, and 3% objective responses, respectively. Responders by all criteria showed consistent overall survival >20 months. Among patients with stable disease according to RECIST 1.1, those identified as responders by Choi had significantly better overall survival than Choi nonresponders (22.4 vs. 10.6 months; hazard ratio: 0.43, 95% confidence interval: 0.15-0.86, p = .0097). CONCLUSION Choi, EASL, and mRECIST criteria appear more appropriate than RECIST 1.1 to identify responders with long survival among advanced HCC patients benefiting from sorafenib.

Sunitinib in Hepatocellular Carcinoma: Redefining Appropriate Dosing, Schedule, and Activity End Points

TO THE EDITOR: In a recent article, Zhu et al reported the results of a phase II study with sunitinib in patients with advanced hepatocellular carcinoma (HCC) and concluded that “sunitinib shows evidence of modest antitumor activity in advanced HCC.” Interpretation of current data from Zhu et al as well as those of other published trials with sunitinib in HCC might not be so straightforward. The dose and the schedule of sunitinib may not derive easily from previous dosefinding studies in patients with HCC who also frequently suffer from several hepatic disorders. Furthermore, although RECIST (Response Evaluation Criteria in Solid Tumors) criteria have been extensively used for evaluating efficacy of several targeted therapies, response rate evaluation in HCC on the basis of the measurement of largest diameters before and after treatment may not be the only reliable tool to detect activity in HCC using antiangiogenic agents in phase II trials. Herein we provide some clues that may help understanding why we believe current data justify additional development of sunitinib in HCC despite low response rates in most trials. In their article, Zhu et al reported the safety and activity of sunitinib administered at the dose of 37.5 mg/d for 4 weeks every 6 weeks in patients with HCC. In this article, the authors reported a 2.9% response rate, a median progression-free survival (PFS) of 3.9 months, and a median overall survival (OS) of 9.8 months. At a higher dose of 50 mg/d sunitinib administered on the same schedule, we recently reported similar results, yielding 2.7% response rate, a median PFS of 3.7 months, and a median OS of 8.0 months. The trial by Zhu et al included only Western patients, whereas our trial included both Eastern and Western populations, which may partly explain PFS and OS survival differences. When subgroup analysis was performed in our trial, we found that European and Asian populations showed median PFS and OS of 5.1 months (95% CI, 1.4 to 7.8 months) and 9.3 months (95% CI, 3.4 to 15.8 months) in Europe, as compared with 2.7 months (95% CI, 1.2 to 7.5 months) and 6.0 months (95% CI, 4.3 to 19.1 months) in Asia, respectively. Combined together, our data seem consistent with those of Zhu et al and are similar to those previously reported with sorafenib in patients with HCC in European and Asian populations. However, those data also raised two important questions: (1) on the basis of current safety data, what is the appropriate dose and schedule for sunitinib in patients with HCC? (2) Are efficacy data from reported phase II trials convincing enough to justify additional development of sunitinib in HCC? In a phase I trial, we established the dose of sunitinib at 50 mg/d for 4 consecutive weeks every 6 weeks in patients with cancer who have normal liver function. Previous studies in patients with impaired hepatic functions revealed no significant change in exposure for sunitinib and its active metabolite, suggesting that daily doses are not influenced by limited changes of routine hepatic tests. However, sticking evidence from our phase II trial demonstrated that the daily dose of 50 mg, routinely used in patients with other tumor types, was not suitable for patients with advanced HCC. Common sunitinibrelated toxicities were consistent with those reported in previous studies in other tumor types, such as renal cancer and gastrointestinal stromal tumor—that is, asthenia, hand-foot syndrome, and thrombocytopenia. Moreover, the dose of 50 mg/d sunitinib also induced a high level of complications usually observed in patients undergoing decompensated hepatic fibrosis and cirrhosis, including encephalopathy, portal hypertension with esophageal varice bleeding, ascites, and thrombocytopenia. It is likely that vascular endothelial growth factor receptor– and platelet-derived growth factor receptor–related angiogenesis, which plays an important role in the physiopathology of compensated hepatic fibrosis and cirrhosis, might be impaired during sunitinib treatment. Identifying this source of toxicity may seem of particular importance in this disease, given that appearance of signs of decompensated liver function is usually associated with sunitinib discontinuation and may jeopardize efficacy results. The dose used in our trial was also associated with more pronounced grade 3 to 4 toxicities and a higher under-therapy death rate. Overall, dose reductions were required in 43.2% of patients, strongly suggesting that the dose of 50 mg/d sunitinib was inappropriate in this patient population. Consistent with this hypothesis, Zhu et al found that sunitinib displayed a better toxicity profile when daily dose exposure was reduced by using a 37.5 mg/d schedule. However, this dose and schedule is subject to two criticisms. First, the dose used by Zhu et al accounts for a 25% dose reduction, which may have an impact in the overall efficacy of the drug. Second, the intermittent schedule, regardless of dosing, allows potential tumor angiogenesis recovery during the 2-week washout period, which may also impair efficacy of sunitinib. Recent data generated in patients with gastrointestinal stromal tumors indicated that continuous daily dose of 37.5 mg without a washout period was associated with a safe toxicity profile and did not impair the overall PFS and survival results of sunitinib. This later schedule was recently evaluated by Koeberle et al in 45 European patients with HCC, allowing achieving a median PFS of 2.8 months and an overall survival of 9.3 months. Importantly, this continuous low-dose schedule displayed a safe toxicity profile and did not alter underlying hepatic functions. Thereby, it was decided that the optimal compromise for safety and efficacy would be testing a daily dose of 37.5 mg sunitinib administered continuously without any washout period in an ongoing phase III trial comparing sunitinib with sorafenib (NTC00699374). Phase II trials are usually aimed detecting hints of antitumor activity and providing information that could be used for the setting of phase III trials. Phase II studies with sunitinib in HCC were designed using response rate according to RECIST criteria as a primary end point for efficacy. However, regardless of doses and the schedules used in the recently reported phase II trials, response rates of sunitinib in HCC barely reached the 5% level that is usually acknowledged to define a potentially active anticancer agent. This feature was also observed with sorafenib, despite additional evidence showing that this drug improved survival of patients with HCC. Despite limited JOURNAL OF CLINICAL ONCOLOGY C O R R E S P O N D E N C E VOLUME 27 NUMBER 35 DECEMBER 1

Predictive biomarkers for the activity of mammalian target of rapamycin (mTOR) inhibitors

In the quest for personalized medicine, only a few biological parameters are routinely used to select patients prior to the initiation of anticancer targeted therapies, including mTOR inhibitors. Identifying biological factors that may predict efficacy or resistance to mTOR inhibitors represents an important challenge since rapalogs may exert antitumor effects through multiple mechanisms of action. Despite the fact that no such a factor is currently available, several molecular patterns are emerging, correlating with sensitivity and/or resistance to rapalogs. While activation of the phosphatidylinositol 3 kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway, overexpression of cyclin D1, and functional apoptosis seem to sensitize tumor cells to rapalogs, Bcl2 overexpression or KRAS mutations are reported to be associated with resistance to mTOR inhibitors in several preclinical models. Translational research aimed at validating those parameters in clinical trials is ongoing.

Clinical outcome after a totally implantable venous access port-related infection in cancer patients: a prospective study and review of the literature.

AbstractMorbidity and mortality after a totally implantable venous access port (TIVAP)-related infection in oncology patients have rarely been studied. We conducted this study to assess the incidence and factors associated with the following outcome endpoints: severe sepsis or septic shock at presentation, cancellation of antineoplastic chemotherapy, and mortality at week 12. We conducted a prospective single-center observational study including all adult patients with solid cancer who experienced a TIVAP-related infection between February 1, 2009, and October 31, 2010. Patients were prospectively followed for 12 weeks. Among 1728 patients receiving antineoplastic chemotherapy during the inclusion time, 72 had an episode of TIVAP-related infection (4.2%) and were included in the study (median age, 60 yr; range, 28–85 yr). The incidence of complications was 18% for severe sepsis or septic shock (13/72 patients), 30% for definitive cancellation of antineoplastic chemotherapy (14/46 patients who still had active treatment), and 46% for death at week 12 (33/72 patients). Factors associated with severe sepsis or septic shock were an elevated C-reactive protein (CRP) level and an infection caused by Candida species; 4 of the 13 severe episodes (31%) were due to coagulase-negative staphylococci (CoNS). Factors associated with death at week 12 were a low median Karnofsky score, an elevated Charlson comorbidity index, the metastatic evolution of cancer, palliative care, and an elevated CRP level at presentation. Hematogenous complications (that is, infective endocarditis, septic thrombophlebitis, septic pulmonary emboli, spondylodiscitis, septic arthritis, or organ abscesses) were found in 8 patients (11%). In conclusion, patients’ overall condition (comorbidities and autonomy) and elevated CRP level were associated with an unfavorable clinical outcome after a TIVAP-related infection. Candida species and CoNS were responsible for severe sepsis or septic shock.

Novel anticancer agents in clinical trials for well-differentiated neuroendocrine tumors.

Neuroendocrine tumors (NETs) are rare malignancies that arise from endocrine cells located in various anatomic locations, with a dramatic increase in incidence during the last 30 years. Limited therapeutic options are currently available for patients with advanced well-differentiated NETs, including carcinoids and pancreatic NETs. Streptozotocin-based chemotherapy and somatostatin analogues are drugs that are currently used for the treatment of progressive metastatic NETs. Recently, sunitinib demonstrating efficacy in pancreatic islet cell carcinomas has opened a new avenue for the treatment of NETs, and further trials shall be considered in NET types such as carcinoids, poorly differentiated neuroendocrine carcinomas, and several other endocrine tumors that depend on vascular endothelial growth factor (VEGF)/VEGF receptor for angiogenesis. In addition, drugs with distinct mechanisms of action, such as mammalian target of rapamycin inhibitors, currently investigated in phase 3 trials, may also supply novel options to control tumor growth and metastasis. Although acknowledged as rare tumors, recent data demonstrated the feasibility of large randomized trials in this disease. Furthermore, data from large trials also showed the importance of selecting an appropriate patient population when designing randomized studies. This review focuses on novel therapeutic approaches in the treatment of well-differentiated NETs. Based on recent data, novel strategies may now be designed using those anticancer agents to optimize the current treatment of patients with NETs.

Benefit-Risk Assessment of Sunitinib in Gastrointestinal Stromal Tumours and Renal Cancer

Sunitinib is a novel, oral, multi-targeted tyrosine kinase inhibitor with antiproliferative effects against cancer cells and antiangiogenic properties. Sunitinib was recently approved for the first-line treatment of patients with advanced renal cell carcinoma (RCC) and for the treatment of patients with gastrointestinal stromal tumours (GIST) after disease progression or intolerance to imatinib therapy. The main purpose of this benefit-risk assessment is to review data on sunitinib efficacy along with its toxicity in patients with GIST and RCC. Sunitinib demonstrates a high level of efficacy with acceptable tolerability using either the 50 mg daily oral dosing for 4 weeks every 6 weeks or a continuous daily administration schedule at a lower dose. Hypertension and asthenia appear to be the most common adverse effects with sunitinib. Diarrhoea, anorexia, disgeusia, stomatitis and skin toxicity are other clinically relevant toxicities. Fatigue may, at least in part, be related to the development of hypothyroidism during sunitinib therapy. Skin toxicity consists of bullous lesion in the soles and palms that may require treatment discontinuation for a few days and/or dose reduction. Thyroid hormone levels should be monitored during treatment with sunitinib, with the occurrence of clinical signs of hypothyroidism needing treatment with levothyroxine sodium. Hypertension usually requires standard antihypertensive therapy and treatment discontinuation is less frequently necessary. Mild neutropenia and thrombocytopenia usually require no intervention. A decrease in left ventricular ejection fraction is a rare but potentially life-threatening complication. Although usually well tolerated, sunitinib needs to be administered cautiously with medical follow-up in patients with cancer to prevent, avoid and treat adverse effects in order to improve patient compliance. Its established antitumor activity requires attempting to maintain the highest tolerable dose in individual patients. Current oral formulations allow physicians to modulate dosages (between 25 and 50 mg/day) and/or schedules (4 weeks on, 2 weeks off or continuous administration) to optimize the benefit-risk profile of sunitinib in individual patients.

Pure and mixed fibrolamellar hepatocellular carcinomas differ in natural history and prognosis after complete surgical resection

The purpose of the current study was to describe pure and mixed fibrolamellar hepatocellular carcinoma (FL‐HCC).

Gemcitabine in elderly patients with advanced pancreatic cancer

AIM To assess feasibility, tolerability and efficacy of gemcitabine-based chemotherapy in patients ≥ 75 years old with advanced pancreatic cancer. METHODS All consecutive patients ≥ 75 years old with advanced pancreatic adenocarcinoma were included in this retrospective study. Necessary criteria to receive chemotherapy were: performance status 0-2, adequate biological parameters and no serious comorbidities. Other patients received best supportive care (BSC). RESULTS Thirty-eight patients (53% women, median age 78 years, range 75-84) with pancreatic cancer (metastatic: n = 20, locally advanced: n = 18) were studied. Among them, 30 (79%) were able to receive chemotherapy [median number: 9 infusions (1-45)]. Six patients (23%) had at least one episode of grade 3 neutropenia and one patient developed a grade 3 hemolytic-uremic syndrome. No toxic death occurred. Three patients (11%) had a partial tumor response, 13 (46%) had a stable disease and 12 (43%) had a tumor progression. Median survival was 9.1 mo (metastatic: 6.9 mo, locally advanced: 11.4 mo). CONCLUSION Tolerance and efficacy of gemcitabine-based chemotherapy is acceptable in elderly patients in good condition, with similar results to younger patients.