Sequential use of sorafenib and sunitinib in advanced renal-cell carcinoma (RCC): an Italian multicentre retrospective analysis of 189 patient cases.

OBJECTIVE: •To conduct a retrospective, multicentre, cohort analysis to assess the sequential use of the tyrosine kinase inhibitors (TKIs) sorafenib and sunitinib. PATIENTS AND METHODS: •Records of 189 patients with renal-cell carcinoma (RCC) who were treated with sorafenib and sunitinib sequentially between March 2004 and April 2009 at 12 Italian study centres were analysed. •Patients were treated under European Expanded Access Programmes or, following market approval, in general clinical practice. •Interventions were sorafenib (800 mg/day) and sunitinib (50 mg every day; 4 weeks on and 2 weeks off). •Progression-free survival (PFS) during treatment with the first and second TKI was evaluated. RESULTS: •In all, 99 patients were treated with sunitinib followed by sorafenib (SuSo) and 90 were treated with sorafenib followed by sunitinib (SoSu); 104 (55%) patients had received prior systemic therapy, mostly with cytokines. •The median (range) PFS on the first TKI was similar between treatment groups [sorafenib 8.4 (1.1-28.9) months; sunitinib 7.8 (0.5-30.4) months; hazard ratio (HR) 1.05, 95% confidence interval (CI) 0.78-1.40, P=0.758]. Multivariate analysis showed that good Memorial Sloan-Kettering Cancer Center status was associated with increased PFS. •After the second TKI, patients in the SoSu group had a longer median PFS than those in the SuSo group (7.9 months vs 4.2 months, respectively; HR 0.54, 95% CI 0.39-0.74, P<0.001). •Multivariate analysis showed only treatment and Eastern Cooperative Oncology Group performance status (and not age, gender, study centre or previous treatment) were significantly associated with duration of PFS. CONCLUSION: •Our findings suggest a limited cross-resistance between sorafenib and sunitinib and that the sequence SoSu may result in a longer combined PFS than SuSo. This is the largest retrospective study to date, though its findings are limited in part by the retrospective nature.

Maintenance versus discontinuation of androgen deprivation therapy during continuous or intermittent docetaxel administration in castration-resistant prostate cancer patients: A multicentre, randomised Phase III study by the Piemonte Oncology Network.

BACKGROUND: This study was designed to demonstrate the non-inferiority (NI) in overall survival (OS) of suspension of androgen deprivation therapy (ADT) versus maintenance and intermittent versus continuous docetaxel administration in metastatic castration-resistant prostate cancer (mCRPC) patients. PATIENTS AND METHODS: mCRPC patients were randomised to first-line docetaxel with maintenance or suspension of ADT. Patients attaining a prostate-specific antigen (PSA) response after four chemotherapy cycles underwent second randomisation to receive continuous or intermittent docetaxel therapy. Six hundred patients were to be randomised to achieve 80% statistical power to demonstrate an NI hazard ratio (HR) of 1.25 of interruption versus maintenance of ADT. RESULTS: The trial was prematurely closed when 198 participants were randomised. OS was similar in patients who continued (N = 96) versus those who interrupted (n = 102) ADT during docetaxel therapy (HR 0.98, 95% confidence interval [CI] 0.72-1.33] and those on a continuous (N = 35) versus an intermittent (N = 42) docetaxel schedule (HR 0.86, 95% CI 0.55-1.43). No difference in radiological progression-free survival, PSA response, or toxicity was observed between the study arms. The actual NI hazard margins of OS in Arms A and B patients were 1.33 and 1.43, respectively. CONCLUSIONS: This trial enrolled one-third of the planned patients; this main weakness dramatically limits the interpretation of the results. ADT discontinuation and switching to an intermittent schedule did not seem to affect docetaxel efficacy. The absence of testosterone recovery in the majority of patients could have been a contributory factor. In men with mCRPC, ADT discontinuation should only be done with regular biochemical and clinical monitoring, with the option of quickly restarting ADT at disease progression.

In vivo migration of labeled autologous natural killer cells to liver metastases in patients with colon carcinoma.

BACKGROUND: Besides being the effectors of native anti-tumor cytotoxicity, NK cells participate in T-lymphocyte responses by promoting the maturation of dendritic cells (DC). Adherent NK (A-NK) cells constitute a subset of IL-2-stimulated NK cells which show increased expression of integrins and the ability to adhere to solid surface and to migrate, infiltrate, and destroy cancer. A critical issue in therapy of metastatic disease is the optimization of NK cell migration to tumor tissues and their persistence therein. This study compares localization to liver metastases of autologous A-NK cells administered via the systemic (intravenous, i.v.) versus locoregional (intraarterial, i.a.) routes. PATIENTS AND METHODS: A-NK cells expanded ex-vivo with IL-2 and labeled with (111)In-oxine were injected i.a. in the liver of three colon carcinoma patients. After 30 days, each patient had a new preparation of (111)In-A-NK cells injected i.v. Migration of these cells to various organs was evaluated by SPET and their differential localization to normal and neoplastic liver was demonstrated after i.v. injection of 99mTc-phytate. RESULTS: A-NK cells expressed a donor-dependent CD56+ CD16+ CD3- (NK) or CD56+ CD16+ CD3+ (NKT) phenotype. When injected i.v., these cells localized to the lung before being visible in the spleen and liver. By contrast, localization of i.a. injected A-NK cells was virtually confined to the spleen and liver. Binding of A-NK cells to liver neoplastic tissues was observed only after i.a. injections. CONCLUSION: This unique study design demonstrates that A-NK cells adoptively transferred to the liver via the intraarterial route have preferential access and substantial accumulation to the tumor site.

Current therapeutic strategies for advanced pancreatic cancer: A review for clinicians.

Pancreatic cancer (PC) would become the second leading cause of cancer death in the near future, despite representing only 3% of new cancer diagnosis. Survival improvement will come from a better knowledge of risk factors, earlier diagnosis, better integration of locoregional and systemic therapies, as well as the development of more efficacious drugs rising from a deeper understanding of disease biology. For patients with unresectable, non-metastatic disease, combined strategies encompassing primary chemotherapy and radiation seems to be promising. In fit patients, new polychemotherapy regimens can lead to better outcomes in terms of slight but significant survival improvement associated with a positive impact on quality of life. The upfront use of these regimes can also increase the rate of radical resections in borderline resectable and locally advanced PC. Second line treatments showed to positively affect both overall survival and quality of life in fit patients affected by metastatic disease. At present, oxaliplatin-based regimens are the most extensively studied. Nonetheless, other promising drugs are currently under evaluation. Presently, in addition to surgery and conventional radiation therapy, new locoregional treatment techniques are emerging as alternative options in the multimodal approach to patients or diseases not suitable for radical surgery. As of today, in contrast with other types of cancer, targeted therapies failed to show relevant activity either alone or in combination with chemotherapy and, thus, current clinical practice does not include them. Up to now, despite the fact of extremely promising results in different tumors, also immunotherapy is not in the actual therapeutic armamentarium for PC. In the present paper, we provide a comprehensive review of the current state of the art of clinical practice and research in PC aiming to offer a guide for clinicians on the most relevant topics in the management of this disease.

Circulating vascular endothelial growth factor and interferon-gamma-inducible protein-10 levels in pancreatic cancer during chemotherapy.

BACKGROUND: Chemotherapeutic anticancer properties are thought to derive from apoptosis pathway activation and/or cell division arrest, but animal models have also evidenced anti-angiogenic activity in some agents. PATIENTS AND METHODS: The impact of gemcitabine, irinotecan and oxaliplatin + 5-FU upon the serum markers vascular endothelial growth factor (VEGF) (pro-angiogenic) and IFN-gamma-inducible protein (IP)-10 (anti-angiogenic) was evaluated by ELISA in locally advanced and/or metastatic cancer versus clinical efficacy and survival. RESULTS: Patients had higher serum levels of both markers versus controls. No objective response to therapy was observed and no significant difference in either marker occurred during the first month of chemotherapy; analysis by survival showed slight transient VEGF decrease in longer survivors on day 14 and slight increase on day 28 in shorter survivors, who had baseline median IP-10 levels above longer survivors, diverging on day 14 (decrease and increase, respectively). Both groups were below baseline at day 28. Changes in IP-10 were not significant. CONCLUSION: These preliminary results provide a rationale for exploring whether continuous or frequent administration of some anti-neoplastic agents may elicit a global anti-angiogenic activity, and whether different administration schedules of the same drug could have a synergistic or an antagonistic effect, which obviously would need to be taken into account in determining combinations with new agents targeting angiogenesis.

Low-molecular-weight heparin and calcium heparin in thrombosis prophylaxis in patients with percutaneous arterial and venous ports for colorectal liver metastases.

STUDY OBJECTIVE: The evaluation of low-molecular-weight heparin use to prevent arterial and venous thrombosis in patients with indwelling arterial Port-a-Cath implants. METHODS: From 1996 to March 2003 we placed 370 indwelling hepatic arterial catheters with a minimally invasive approach. The left distal subclavian artery was approached from beneath the left clavicle, then an angiographic study of the tumoral vascular district was performed and the gastroduodenal artery was occluded by an embolus. A polyurethane catheter was introduced distally into the hepatic artery and connected to a reservoir through a 3-4 cm long subcutaneous tunnel. In 90 patients a venous Port-a-Cath was placed for concurrent systemic chemotherapy. All 370 patients received regional chemotherapy and were treated with calcium heparin at a dose of 5000 IU twice a day and with low-molecular-weight heparin at prophylactic doses (dalteparin 2500 IU or nadroparin 3000 IU) during catheter permanence to prevent hepatic artery thrombosis. Intra-arterial trans-port radionuclide scans using technetium-99m-labeled micro-aggregated albumin were performed monthly to check the infusion distribution and hepatic artery patency. In the presence of anomalous patterns, thrombosis, pulmonary embolism or other complications, angiography and/or other diagnostic studies were performed to determine the cause of the vascular event and the local or systemic symptoms. The mean arterial and venous Port-a-Cath permanence times were 6 and 8 months, respectively. RESULTS: We observed episodes of hepatic artery thrombosis in 4.3% of patients. Three of these 17 patients were successfully treated by intra-arterial thrombolysis using urokinase. No venous thrombosis occurred as a consequence of regional and/or systemic chemotherapy, no episodes of arterial thrombosis were registered during arterial catheter permanence, nor did any hemorrhagic complications related to anti-coagulant therapy occur. Five patients treated with low-molecular-weight heparin required treatment suspension due to a platelet count of < 40,000/dL. CONCLUSION: Our experience suggests that low-molecular-weight heparin and/or calcium heparin at prophylactic doses could be useful in the prevention of arterial and venous thrombosis in patients with indwelling arterial catheters or venous Port-a-Cath treated with regional or systemic chemotherapy for hepatic metastases from colorectal cancer. The homogeneity of the patient group and the use of analogous chemotherapeutic drugs (fluoropyrimidines) avoided statistical contamination related to differences between kinds of cancer and between the chemotherapeutic agents used.

FOLFOX-4 regimen or single-agent gemcitabine as first-line chemotherapy in advanced biliary tract cancer.

OBJECTIVES: We conducted a retrospective cohort study to compare 2 different chemotherapy regimens for advanced biliary tract cancer (BTC). METHODS: Records of patients consecutively treated in our institution for advanced BTC from 2001 to 2006 were retrieved. Chemotherapy treatment with FOLFOX-4 regimen was routinely offered as first option; gemcitabine (GEM) as single agent was proposed as an alternative option to patients who refused central venous catheter implantation. Toxicity, overall response rate, progression-free survival (PFS), and overall survival (OS) obtained with the 2 treatments were evaluated. RESULTS: Twenty-two patients were treated with FOLFOX-4, whereas 18 patients received GEM. In the FOLFOX-4 group, the overall response rate was 13.6% (95% confidence interval [CI], 4.7-33.3), with 1 complete response and 2 partial responses, and 54.5% (95% CI, 34.7-73.1) of disease control rate (complete response+partial response+stable disease). Median OS was 14.1 months (95% CI, 9.1-18.8) and median PFS 5.44 months (95% CI, 3.2-6.3). In the GEM group, we observed no objective response, whereas 27.7% (95% CI, 12.5-50.9) obtained disease control. Median OS was 8.3 months (95% CI, 4.7-12.9) and median PFS 3.9 months (95% CI, 2.2-5.4). Toxicity, mainly hematological, was acceptable for both treatments. On a multivariable Cox model including a propensity score, only the performance status and chemotherapy regimen were confirmed as strong predictors of OS, with an hazard ratio of 0.49 (95% CI, 0.24-0.99) in favor of FOLFOX-4. CONCLUSIONS: The combination chemotherapy with oxaliplatin and 5-fluorouracil is well tolerated and seems to provide prolonged survival than GEM alone in advanced BTC treatment, but further randomized trials are warranted.

Oxaliplatin, 5-fluorouracil, and leucovorin as second-line treatment for advanced pancreatic cancer.

OBJECTIVE: A phase II study was performed to assess the activity of oxaliplatin plus 5-fluorouracil (5-FU) modulated by leucovorin, as second-line treatment in locally advanced or metastatic pancreas adenocarcinoma pretreated with gemcitabine-containing schedule. METHODS: Patients received weekly intravenous infusions of oxaliplatin 40 mg/m, 5-FU 500 mg/m, and leucovorin 250 mg/m (3 weeks on, 1 week off). RESULTS: Twenty-three patients affected with metastatic (16) or locally advanced (7) pancreas adenocarcinoma were involved in this study. A total of 148 weeks of chemotherapy was delivered (median 2 courses each patient). Among 17 assessable patients, no objective response was registered and 4 patients had stable disease, whereas 13 had tumor progression. Median duration of stable disease was 14 weeks. Median time to progression of disease (TTP) was 11.6 weeks [95% confidence interval (CI), 7.6-5.6]. Kaplan-Meier estimated median overall survival (OS) was 17.1 week (95% CI, 4.0-30.1) and 3 months survival rate was 69.6%. Seven patients experienced grade 3 to 4 toxicity. The regimen was associated with 36% clinical benefit. CONCLUSIONS: The median TTP and median OS in this population with poor prognosis suggests some activity, however, only further investigations will be able to establish the clinical value of this combination.

Activity of weekly paclitaxel in advanced hormone-refractory prostate cancer.

OBJECTIVE: We evaluated efficacy and toxicity of weekly paclitaxel in metastatic hormone-refractory prostate cancer (HRPC). MATERIALS AND METHODS: Patients received weekly paclitaxel 80 mg/m2 by 1-hour intravenous infusion. A course of therapy consisted of 6 weekly treatments and 2 weeks rest. PSA response was defined as a PSA decrease not less than 50%, maintained for 4 weeks with stable or improved performance status. RESULTS: The study enrolled 43 patients with metastatic HRPC diagnosed a median of 10.5 months before. Median age was 69 years (range, 58-86 years). Five had previous radioisotopes treatment for bone pain, 15 had previous treatment of metastatic hormone-refractory disease, mainly estramustine. The median number of weeks of therapy delivered each patient was 8 (range, 1-24 weeks; cumulative, 369 weeks). PSA response was registered in 13 patients of 36 evaluable for PSA response (36.1%; 95% confidence interval [CI], 20.8-53.8), with a median duration of 4.2 months. Among 16 patients evaluable for objective response, 5 partial responses (31.2%; 95% CI, 11.0-58.7) and 9 stable diseases were registered. Eleven (42.3%) of 26 patients presenting with cancer-related symptoms had improvement. Median survival time was 12.8 months (95% CI, 10.1-15.5) Therapy was associated with acceptable hematological toxicity (anemia grade 3, 16%; neutropenia grade 3-4, 12%) and moderate nonhematologic toxicities (thrombosis/embolism 10%; fatigue all grades, 60%). CONCLUSION: Docetaxel every 3 weeks is the standard of care for metastatic HRPC, but our results suggest some activity and an acceptable toxicity of weekly paclitaxel.

Cytoreductive surgery combined with intraperitoneal chemohyperthermia for the treatment of advanced colon cancer.

BACKGROUND: Chemohyperthermic peritoneal perfusion (CHPP) after extensive cytoreductive surgery is a possible choice as a regional treatment for peritoneal carcinomatosis (PC). The multicentric France EVOCAPE 1 study demonstrated that the median overall survival of patients with colon peritoneal carcinomatosis subjected to conventional surgical and/or chemotherapeutic treatment was 5.2 months. Historically, mitomycin C is the drug of choice in the treatment of intraperitoneal carcinomatosis from colon cancer. METHODS: Twenty-five patients affected by stage IV colon cancer with only peritoneal involvement and a prior completion of at least a partial first cycle of systemic chemotherapeutic and/or surgical treatment (24 patients) were enrolled. Immediately following extensive cytoreductive surgery, early postoperative closed abdomen CHPP was performed. RESULTS: Complete surgical cytoreduction (CC0-CC1) was obtained in 22 patients. Postoperative mortality was 1 out of 25 (4%). Major postoperative morbidity was 6 out of 25 (24%). Median overall survival estimated by Kaplan-Meier curve was 30.3 months. Locoregional progression-free survival was 17.3 months. Of all the patients 64% and 40% were alive after 1 and 2 years respectively. CONCLUSIONS: In referral centers CHPP after optimal surgical debulking is a safe procedure for peritoneal carcinomatosis from colonic cancer. Locoregional control was obtained in the majority of the pretreated patients and 1-year survival was statistically improved. A closed abdomen CHPP procedure lasting 1 hour and standard mitomycin C at a dosage of 15 mg/m(2) is probably as efficacious as other hyperthermic procedures, using higher mitomycin C dosages, with a comparable or lower number of cases of side effects. These results, as in other published phase II studies, justify future randomized trials to assess definitively the role of CHPP in the treatment of locally advanced colon neoplasms in western countries.

Cytoreductive surgery and intraperitoneal chemohyperthermia for recurrent peritoneal carcinomatosis from ovarian cancer.

Aggressive surgical cytoreduction has been shown to have a positive impact on survival of patients with ovarian cancer. After first-line chemotherapy, 47% of patients relapse within 5 years, and median survival after second line chemotherapy is 10-15 months. Adding intraperitoneal chemohyperthermia (IPCH) to surgical cytoreduction could further control ceolomic spread of disease. The aim of this study was to determine morbidity and mortality, regional relapse-free survival and, preliminarily, overall survival after combining cytoreductive surgery with IPCH for the treatment of peritoneal carcinomatosis from ovarian epithelial cancer relapsed after prior chemotherapy. Thirty women affected with such a relapse were included. Patients underwent extensive cytoreductive surgery including tumor resections and peritonectomy, followed by intraoperative IPCH with cisplatin. Complete surgical cytoreduction down to nodules less than 2.5 mm (CC0-CC1) was obtained in 23 patients (77%). One patient died postoperatively from a pulmonary embolism. Major postoperative morbidity was 5/30 (16.7%). We registered one case of anastomotic leakage, a spontaneous ileum perforation, a postoperative cholecystitis, a hydrothorax, and one patient with bone marrow toxicity. Kaplan-Meier estimates of median locoregional relapse-free survival and median overall survival were 17.1 months and 28.1 months, respectively. Patients with CC0-CC1 had locoregional relapse-free and overall survival rates of 24.4 and 37.8 months, whereas the remainder had survival rates of 4.1 and 11.0 months. We concluded that cytoreductive surgery combined with IPCH is feasible with acceptable morbidity and mortality and seems to promise good results in selected patients affected with peritoneal carcinomatosis from ovarian cancer.