Efficacy Of Combination Chemotherapy Research Articles

Abstract 2557: Efficacy of combination chemotherapy using a novel oral chemotherapeutic agent, TAS-102, with oxaliplatin on human colorectal or gastric cancers and 5-FU-resistant gastric cancer xenografts

Abstract Background: TAS-102 is a novel oral nucleoside antitumor agent composed of trifluridine (FTD) and tipiracil hydrochloride (TPI) at a molar ratio 1:0.5. FTD is the active antitumor component of TAS-102 and its triphosphate form is incorporated into DNA in tumor cells. TPI is a potent inhibitor of thymidine phosphorylase, an enzyme that degrades FTD, allowing adequate plasma concentrations of orally administered FTD to be maintained and potentiating the antitumor activity of FTD. In a recent international multicenter randomized double blind Phase III study (RECOURSE), use of TAS-102 was shown to significantly improve overall survival, progression-free survival and had a favorable safety profile in comparison to the placebo in patients with metastatic colorectal cancer refractory to standard chemotherapies. In this study, we evaluated the antitumor effects of TAS-102 in combination with oxaliplatin on gastrointestinal tumor xenografts, including a 5-FU-resistant subline, in a nude mouse model. Method: The human colorectal cell lines HCT-116 and SW48 and gastric cancer cell lines SC-2, MKN74 and MKN74/5-FU, a 5-FU-resistant cell line derived from MKN74, were implanted into nude mice subcutaneously. TAS-102 (150 mg/kg/day) was orally administered twice daily from days 1 to 14 and oxaliplatin (7 or 13 mg/kg/day) was administered intravenously on days 1 and 8. Growth inhibitory activity was evaluated by assessing tumor volume and the growth delay period, estimated based on the period required to reach a tumor volume five times greater than the initial volume (RTV5). Results: TAS-102 and oxaliplatin monotherapy were effective on all the evaluated colorectal and gastric cancers, even for a 5-FU-resistant gastric cancer cell line. The tumor growth inhibitory activity and RTV5 of the group receiving TAS-102 with oxaliplatin were significantly superior to those receiving either monotherapy for all evaluated cancers (P<0.05). Tumor growth inhibition in the combination treatment group was more than 70%. Furthermore, the RTV values on day 29 were less than 5 for SC-2, MKN74 and MKN74/5FU xenografts. These results demonstrate that combination therapy with TAS-102 and oxaliplatin is significantly more effective than either monotherapy in colorectal and gastric cancer xenografts, including a 5-FU-resistant xenograft, when evaluated by tumor growth inhibition and growth delay period. This combination appeared to be well-tolerated, as drug-related death or a reduction in body weight of more than 20% was not observed. Conclusion: The present preclinical findings indicate that combination therapy of TAS-102 and oxaliplatin is a promising treatment option for colorectal or gastric cancer, not only for chemo-naïve tumors, but also for recurrent tumors after 5-FU-based chemotherapy. Citation Format: Mamoru Nukatsuka, Fumio Nakagawa, Kazuaki Matsuoka, Hiroshi Tsukihara, Teiji Takechi. Efficacy of combination chemotherapy using a novel oral chemotherapeutic agent, TAS-102, with oxaliplatin on human colorectal or gastric cancers and 5-FU-resistant gastric cancer xenografts. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2557. doi:10.1158/1538-7445.AM2015-2557

Efficacy of combination chemotherapy with itraconazole for treating metastatic pancreatic cancer in the second-line setting.

e15255 Background: The treatment of progressive pancreatic cancer after front-line chemotherapy is under investigation. Pretreated tumors express cancer stem cell markers and P-glycoprotein. Itraconazole, a common antifungal agent, is a potent inhibitor of the Hedgehog pathway, P-glycoprotein, and angiogenesis. We aimed to evaluate the efficacy and feasibility of chemotherapy with itraconazole for treating progressive pancreatic cancer. Methods: We retrospectively reviewed the medical charts of histologically diagnosed pancreatic cancer patients who had received one or more lines of chemotherapy and subsequent chemotherapy with itraconazole. The efficacy of itraconazole was evaluated according to the Response Evaluation Criteria in Solid Tumors, version 1.1 by considering the survival after chemotherapy with itraconazole. Results: Between 2008 and 2013, we enrolled 38 recurrent patients. All the patients were referred to our institution from tertiary care hospitals; they received docetaxel (35 mg/m2), gem...

Efficacy of combination chemotherapy using a novel oral chemotherapeutic agent, TAS-102, together with bevacizumab, cetuximab, or panitumumab on human colorectal cancer xenografts.

TAS-102 is a novel oral nucleoside antitumor agent that consists of trifluridine (FTD) and tipiracil hydrochloride (TPI) at a molecular ratio of 1:0.5, and was approved in Japan in March 2014 for the treatment of patients with unresectable advanced or recurrent colorectal cancer that is refractory to standard therapies. In the present study, we used colorectal cancer xenografts to assess whether the efficacy of TAS-102 could be improved by combining it with bevacizumab, cetuximab or panitumumab. TAS-102 was orally administered twice a day from day 1 to 14, and bevacizumab, cetuximab and panitumumab were administered intraperitoneally twice a week for 2 weeks. Growth inhibitory activity was evaluated based on the relative tumor volume (RTV) after 2 weeks of drug administration and time taken for the relative tumor volume to increase five-fold (RTV5). Tumor growth inhibition and RTV5 with TAS-102 and bevacizumab combination treatment were significantly better than those with TAS-102 or bevacizumab alone in the SW48 and HCT116 tumor models, and the concentration of phosphorylated FTD in tumors determined by liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis was higher in the TAS-102 and bevacizumab combination group than in the TAS-102 monotherapy group. The combination of TAS-102 and cetuximab or panitumumab was also significantly more effective than either monotherapy in the SW48 tumor model. There was no significant difference in the body weight between the mice treated with TAS-102 monotherapy and any of the combination therapies on day 29. Our preclinical findings indicate that the combination therapy of TAS-102, bevacizumab and cetuximab or panitumumab is a promising treatment option for colorectal cancer.

Abstract 3486: Efficacy of neoadjuvant chemotherapy in combination with fluorescence-guided surgery on a pancreatic cancer patient-derived orthotopic xenograft (PDOX)

Abstract The aim of this study is to determine the efficacy of neoadjuvant chemotherapy (NAC) in combination with fluorescence-guided surgery (FGS) on pancreatic cancer patient derived orthotopic xenograft (PDOX). We established the PDOX from the patient suffering from metastatic CA19-9-positive pancreatic cancer. Forty nude mice were implanted with tumor using surgical orthotopic implantation (SOI) on the nude mouse pancreas. Four weeks after implantation, the mice with tumor were randomized into 4 treatment groups: (1) bright-light surgery (BLS) only; (2) FGS; (3) NAC-BLS; (4) NAC-FGS. Gemcitabine (80 mg/kg, ip, weekly, 3 weeks) was used for NAC. Seven weeks after implantation, BLS was performed on all tumor-bearing mice. A monoclonal anti-human CA19-9 antibody conjugated with Dylight 650 was delivered to tumor-bearing mice in the FGS groups as a single intravenous dose 24 hours before BLS. Postoperatively, the surgical resection bed of FGS mice were imaged with the OV100 fluorescence imaging system to detect fluorescent residual tumors. The fluorescent residual tumors of FGS groups were then resected under fluorescence navigation. The average resected tumor weight of each group was as follows: (1) BLS, 188.5 ± 50.0 mg; (2) FGS, 278.0 ± 111.4 mg; (3) NAC-BLS, 84.5 ± 48.7 mg; (4) NAC-FGS, 141.8 ± 48.9 mg. The average resected tumor weight of NAC groups was significantly less than the non-NAC groups (113.1 ± 57.0 mg and 235.6 ± 94.3 mg, respectively; p>0.001). The average resected tumor weight of the FGS groups was significantly larger than the BLS groups (213.4 ± 107.1 mg and 136.5 ± 73.8 mg, respectively; p=0.016). Eight weeks after resection, we performed laparotomy to examine recurrence. The recurrence rate of each group was as follows: (1) BLS, 9 / 9 (100%); (2) FGS, 4 / 8 (50%); (3) NAC-BLS, 6 / 9 (66.7%); (4) NAC-FGS, 2 / 8 (25%). The recurrence rate of FGS groups was significantly lower than BLS groups (6 /16; 37.5% and 15 / 18; 83.3%, respectively; p=0.012), whereas there was no significant difference between FGS and NAC-FGS groups (p=0.608). There was no significant difference in the total recurrence rate between NAC and non-NAC groups (p=0.157). However NAC significantly reduced peritoneal recurrence (29.4 % and 0%, respectively; p=0.044). The results indicate that NAC in combination with FGS might reduce or even eliminate the peritoneal recurrence of pancreatic cancer. Citation Format: Yukihiko Hiroshima, Ali Maawy, Yong Zhang, Sho Sato, Takashi Murakami, Mako Yamamoto, Fuminari Uehara, Shinji Miwa, Shuya Yano, Masashi Momiyama, Takashi Chishima, Kuniya Tanaka, Michael Bouvet, Itaru Endo, Robert M. Hoffman. Efficacy of neoadjuvant chemotherapy in combination with fluorescence-guided surgery on a pancreatic cancer patient-derived orthotopic xenograft (PDOX). [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3486. doi:10.1158/1538-7445.AM2014-3486

Efficacy and feasibility of gemcitabine and carboplatin as first-line chemotherapy in elderly patients with advanced non-small cell lung cancer

Background Although platinum-based chemotherapy is a standard first-line treatment in advanced non-small cell lung cancer (NSCLC), further research for the safety and efficacy of combination chemotherapy in elderly patients has been required. The purpose of this study was to evaluate the efficacy and safety of gemcitabine and carboplatin as first-line treatment in elderly patients with advanced NSCLC and to evaluate the prognostic factors. Methods Eligibility included: (1) age of 70 years or more, (2) histologically confirmed NSCLC, (3) chemotherapy-naïve, (4) advanced disease with stage IIIB or IV, (5) Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-2, (6) adequate organ function. Patients received intravenous carboplatin (area under curve (AUC)=5) on day 1 and gemcitabine (1000 mg/m2) on days 1 and 8, every 3 weeks. Results The medical records of forty patients were reviewed retrospectively. Median age was 73.9 years (range, 70-84.6), and there were 27 men (67.5%). Thirty-seven patients (92.5%) had ECOG PS 0-1. Adenocarcinoma was found in 57.5%. Median cycles were administrated with 4.5 per person (range: 1-6). Best responses were partial response in 22 (55.0%) patients and stable disease (SD) in 13 (32.5%). The median progression free survival (PFS) and overall survival (OS) were 5.9 months (95% CI: 4.5-7.3 months) and 9.6 months (95% CI: 8.2-11.0 months), respectively. Grade 4 hematologic toxicities for neutropenia (7.5%), thrombocytopenia (7.5%) and anemia (5.0%) were observed. Histology was significant prognostic factor for PFS (P=0.024). Conclusion Gemcitabine and carboplatin combination chemotherapy is an effective and manageable treatment option in elderly advanced NSCLC patients with good performance status.

Comparison of efficacy and toxicity of bevacizumab in combination with chemotherapy in the first, second, and third or higher line of treatment for metastatic colorectal carcinoma (mCRC): Data from the Czech multi-institutional registry.

e14622 Background: Data from the Czech national registry of patients treated with targeted therapies for mCRC were analyzed retrospectively to compare treatment outcomes for bevacizumab in combination with chemotherapy in the 1st, 2nd and 3rd line of treatment. Methods: The database was launched in 2005 as a clinical registry of patients with mCRC treated with bevacizumab. Epidemiological and clinical data are entered by all Czech comprehensive cancer centers administering targeted therapy. In total, 4487 mCRC patients who received bevacizumab combined with chemotherapy in either 1st line (n=3990, 88.9%), 2nd line (n=386, 8.6%), or 3rd and higher line (n=111, 2.5%) had evaluable data and were included in the present analysis. Survival was calculated using the Kaplan-Meier method, and the differences were assessed using the log-rank test. Results: Statistically significant differences were observed in the efficacy of combination chemotherapy with bevacizumab between the treatment lines. The objective response rate (ORR) in the 1st, 2nd, and 3rd/higher line was 42.9%, 34.0% and 8.3%; (p<0.001) respectively. Similarly, in the 1st, 2nd, and 3rd/higher line median progression free survival (mPFS) was 11.3 months (95% CI 11.0-11.7 months), 9.5 months (95% CI 8.2-10.9 months) , and 7.3 months (95% CI 5.9-8.7 months; p<0.001), and median overall survival (mOS) was 28.4 months (95% CI 27.1-29.8 months), 25.9 months (95% CI 19.4-32.4 months), and 15.0 months (95% CI 10.7-19.3 months; p<0.001), respectively. The spectrum of the most common adverse events was comparable in the 1st, 2nd, or 3rd/higher line, and incidence of adverse events was similar at 11.6%, 8.8% and 8.1%, respectively. Conclusions: The efficacy of bevacizumab in combination with chemotherapy decreased when administered in later lines of treatment for mCRC while the incidence and spectrum of toxicities remains unchanged.

IS7-1 - Treatment of NSCLC Patients with EGFR Mutation

ABSTRACT Advanced non-small-cell lung cancer (NSCLC) patients may benefit from several chemotherapeutic or targeted agents. However, patients respond differently to the same treatment in terms of anticancer efficacy or side-effects. As the choices for patients increase over the time along with advances in clinical research, selecting the right agents that provide patients with best chance of anticancer activity and lowest possibility of toxicity is the main theme in future research and clinical practice. Gene expressions in tumor cells may be good biomarkers for selecting treatment. Somatic gene expression may indirectly affect tumor gene and also determine the toxicity to various treatment. Several biomarkers were found to be correlated well with efficacy of drug treatment. For example, mutations in the exon 21 (L858R) and deletion in exon 19 of epidermal growth factor receptor (EGFR) were found to be correlated well with responsiveness to EGFR tyrosine kinase inhibitors such as gefitinib or erlotinib. The discovery of EML4-ALK or a ROS1 translocation predicted good response to ALK inhibitor crizotinib. The above-mentioned predictive factors for drug responsiveness were also prognostic factors for survival time. For example, activating mutation of EGFR may be a good prognostic factor for advanced NSCLC patients in addition to its role as a good predictive factor for EGFR-TKI treatment response. The results of Iressa Pan-Asian Survival Study (IPASS) have shown that patients whose tumor samples have tested positive for EGFR mutations may receive gefitinib as first-line treatment. The progression-free survival for those patients receiving gefitinib was longer than those receiving paclitaxel and carboplatin. The response rate of gefitinib for patients with EGFR mutation was 70% and that of wild-type patients was only 1%. In the updated final overall survival analysis, IPASS showed that overall survival was similar, with no significant difference, between gefitinib and carboplatin/paclitaxel in between treatment arms for OS in the subgroups defined by EGFR mutation status: EGFR mutation-positive patients (HR = 1.00, 95% CI 0.76–1.33, median OS 21.6 versus 21.9 months). The equalization of OS in overall population and in EGFR mutation positive or negative patients after significant difference in PFS in the first-line period is probably due to the extensive crossing over treatment patients received after they progressed on first-line treatment. Several phase III studies selecting treatment-naive patients with EGFR mutations and randomize to gefitinib versus docetaxel cisplatin (WJOG3405), gefitinib versus paclitaxel carboplatin (NEJ002), erlotinib versus gemcitabine carboplatin (OPTIMAL), erlotinib versus cisplatin regimen (EURTAC) all demonstrated same results of small molecule EGFR TKI superiority over combination chemotherapy on response rate, PFS and quality of life. It is advisable to send tumor for the EGFR mutation test in all adenocarcinoma lung patients and select EGFR-TKI if the test result turns out to be positive. However, small fraction of EGFR mutation positive patients does not respond well to gefitinib or erlotinib. In addition, patients responded to gefitinib or erlotinib with limited period of time. Second-generation EGFR TKIs such as afatinib or dacomitinib are irreversible EGFR inhibitors. They have the potential to inhibit the proliferation of resistant exon 20 T790M mutation in the EGFR mutation-positive tumor cells. Afatinib was tested in 129 EGFR mutation-positive patients. The PFS of patients with del 19 and L858R were 13.7 months with independent review. The phase III study of afatinib versus pemetrexed cisplatin was recently presented in ASCO. The long of independent reviewed PFS of afatinib in these studies will be confirmed in a randomized study comparing afatinib to gefitinib. Salvage treatment after EGFR-TKI failure has become an important issue recently when EGFR-TKI become a standard treatment of these patients. When EGFR-TKI was given as the first-line treatment, the salvage treatment of patients after EGFR-TKI is usually combination chemotherapy. However, there are limited publications on the efficacy of combination chemotherapy after failure of EGFR-TKI as first-line treatment. The response rates and progression-free survival time for EGFR-TKI-treated patients may not be the same as EGFR-TKI-naive patients. Therefore, more prospective study in this area should be carried out. Another unsolved question is whether patients with EGFR mutations are still addicted to EGFR pathways when they fail EGFR-TKI treatment and that whether continuing EGFR-TKI treatment even in combination with chemotherapy is necessary. Further randomized study should be considered in this aspect. For slow or minimal progression patients, it may be helpful for patients to stay on EGFR-TKI treatment beyond progression rather than switching to chemotherapy. Studies such as IMPRESS will address such questions. The emergence additional EGFR T790M mutation and/or cMET amplifcation was shown to be the predominant resistance mechanism in EGFR-TKI-acquired resistance patients. Novel agents that act on these resistance mechanisms such as irreversible EGFR-TKI or cMET inhibitors may play some role in the future as salvage treatment of EGFR mutation-positive patients who fail EGFR-TKI.

P2-026 - The Combination Chemotherapy of Gemcitabine and Carboplatin–Bevacizumab in Patients with Advanced Non-Small-Cell Lung Cancer

ABSTRACT Background The addition of bevacizumab–paclitaxel and carboplatin showed significant benefits in progression-free survival and overall survival in patients with advanced non-small-cell lung cancer. We are conducting a prospective study about safety and efficacy of combination chemotherapy with gemcitabine and carboplatin–bevacizumab (GC + BV) in previously untreated patients with advanced or metastatic NSCLC. Methods Between April 2010 and January 2012, a total of 35 patients with recurrent or advanced NSCLC (stage IIIB or IV) were treated with the GC + BV regimen. The regimen consists of gemcitabine of 1000 mg/m2 on days 1 and 8, carboplatin of AUC 5 and bevacizumab of 15 mg/kg on day 1. Treatment repeats every 3 weeks up to six cycles, followed by bevacizumab until disease progression or intolerable toxicity. Results Thirty-four patients were male. The median age of patients was 68 (55–79) years. Twenty-six patients were stage IV or recurrent disesase and 9 were IIIB. Fifteen (69%) patients were adenocarcinoma (12, squamous cell carcinoma; 8, others). Twenty-four (68%) patients had ECOG PS of 0–1. The overall response rate was 46% with no complete response and 16 partial responses. Grade 3 and 4 neutropenia were 16 and 1%, respectively. Clinically significant hemorrhagic events were not identified till now. There was one treatment-related death (septic shock with neutropenia during the first cycle). Non-hematologic toxicities were mild and manageable, but two patients complained grade 3 general weakness and one patient experienced grade 4 pneumonia. The median PFS was 5.7 months (95% CI, 3.69–6.45 months). Conclusions The addition of bevacizumab–gemcitabine and carboplatin in the treatment of selected patients is effective and tolerable in NSCLC including squamous cell carcinoma. This is ongoing study and we present preliminary results.

A Phase I Study of Infusional 5-Fluorouracil, Leucovorin, Oxaliplatin and Irinotecan in Japanese Patients with Advanced Colorectal Cancer Who Harbor UGT1A1*1/*1,*1/*6 or *1/*28

Objective: To evaluate the safety and efficacy of combination chemotherapy with 5-fluorouracil (5-FU), leucovorin, irinotecan and oxaliplatin (FOLFOXIRI) in Japanese patients with advanced colorectal cancer. Methods: This phase I dose-finding study was designed to determine the maximum tolerated dose (MTD), recommended dose (RD) or both of FOLFOXIRI. Patients with UDP-glucuronosyltransferase (UGT) 1A1*6/*6, *28/*28 and *6/*28 genotypes were excluded, because these UGT1A1 genotypes are linked to severe neutropenia in Japanese. Results: A total of 10 Japanese patients with advanced colorectal cancer were studied. The MTD of FOLFOXIRI in these Japanese patients was 165 mg/m² irinotecan, 85 mg/m² oxaliplatin and 2,400 mg/m² 5-FU. Accordingly, the RD of FOLFOXIRI was determined to be 150 mg/m² irinotecan, 85 mg/m² oxaliplatin and 2,400 mg/m² 5-FU. Toxic effects, evaluated until the completion of 4 cycles, were manageable. Grade 3–4 neutropenia occurred in 27% of cycles, but there was no febrile neutropenia. Among the 9 assessable patients, the objective response rate was 89%. Conclusions: We thus determined the RD of FOLFOXIRI in Japanese patients with advanced colorectal cancer who do not have UGT1A1*28/*28, *6/*6 or *6/*28 genotypes. Our results indicate that FOLFOXIRI is a well-tolerated regimen for these Japanese patients.

Fluoropyrimidine plus cisplatin for patients with advanced or recurrent gastric cancer with peritoneal metastasis

There are few data on the efficacy of combination chemotherapy with a fluoropyrimidine plus cisplatin for patients with advanced or recurrent gastric cancer (AGC) complicated by peritoneal metastasis, especially massive ascites. We retrospectively evaluated the efficacy and safety of a fluoropyrimidine (S-1 or capecitabine) plus cisplatin as first-line chemotherapy in 120 patients with AGC and peritoneal metastasis. Ascites was detected in 50 patients, with 11 patients having massive ascites. Median progression-free survival (PFS) and overall survival (OS) of all patients was 6.1 and 15.9months, respectively. The PFS and OS were shorter in patients with massive ascites (n=11; 3.7 and 9.5months) compared with patients with small or moderate ascites (n=39; 5.8 and 13.5months) or patients without ascites (n=70; 6.9 and 18.1months). The objective response in terms of ascites was similar whether ascites was massive (4 of 11 patients; 36.4%) or small or moderate (16 of 39 patients; 41%). The frequencies of grade 3 or higher toxicity or treatment discontinuation due to toxicity are relatively similar across ascites groups. Fluoropyrimidine plus cisplatin appears to be tolerated in selected patients with peritoneal metastasis.

Electroporation increases antitumoral efficacy of the bcl-2 antisense G3139 and chemotherapy in a human melanoma xenograft

BackgroundNucleic acids designed to modulate the expression of target proteins remain a promising therapeutic strategy in several diseases, including cancer. However, clinical success is limited by the lack of efficient intracellular delivery. In this study we evaluated whether electroporation could increase the delivery of antisense oligodeoxynucleotides against bcl-2 (G3139) as well as the efficacy of combination chemotherapy in human melanoma xenografts.MethodsMelanoma-bearing nude mice were treated i.v. with G3139 and/or cisplatin (DDP) followed by the application of trains of electric pulses to tumors. Western blot, immunohistochemistry and real-time PCR were performed to analyze protein and mRNA expression. The effect of electroporation on muscles was determined by histology, while tumor apoptosis and the proliferation index were analyzed by immunohistochemistry. Antisense oligodeoxynucleotides tumor accumulation was measured by FACS and confocal microscopy.ResultsThe G3139/Electroporation combined therapy produced a significant inhibition of tumor growth (TWI, more than 50%) accompanied by a marked tumor re-growth delay (TRD, about 20 days). The efficacy of this treatment was due to the higher G3139 uptake in tumor cells which led to a marked down-regulation of bcl-2 protein expression. Moreover, the G3139/EP combination treatment resulted in an enhanced apoptotic index and a decreased proliferation rate of tumors. Finally, an increased tumor response was observed after treatment with the triple combination G3139/DDP/EP, showing a TWI of about 75% and TRD of 30 days.ConclusionsThese results demonstrate that electroporation is an effective strategy to improve the delivery of antisense oligodeoxynucleotides within tumor cells in vivo and it may be instrumental in optimizing the response of melanoma to chemotherapy. The high response rate observed in this study suggest to apply this strategy for the treatment of melanoma patients.

Single-agent irinotecan or 5-fluorouracil and leucovorin (FOLFIRI) as second-line chemotherapy for advanced colorectal cancer; results of a randomised phase II study (DaVINCI) and meta-analysis

BackgroundSecond-line treatment with irinotecan for advanced or metastatic colorectal cancer prolongs survival. It is uncertain whether irinotecan is better administered with 5-fluorouracil or alone in patients previously treated with a fluoropyrimidine. We compared toxicity (particularly diarrhoea), quality of life, and efficacy of combination chemotherapy and irinotecan in these patients. MethodsIn DaVINCI, a randomised phase II trial, patients with advanced colorectal cancer were randomly allocated to: Combination therapy (FOLFIRI), irinotecan (180mg/m2 IV over 90min, day 1), 5-fluorouracil (400mg/m2 IV bolus and 2400mg/m2 by 46-hour infusion from day 1) and folinic acid (20mg/m2 IV bolus, day 1), 2-weekly; or Single-agent, irinotecan (350mg/m2 IV over 90min), 3-weekly. Toxicity was evaluated every treatment cycle; QOL and response 6-weekly. Analysis was by intention to treat. The trial, amended from a larger factorial design, was terminated early due to slow recruitment. Results were also combined with other second-line irinotecan trials. FindingsWe randomised 44 patients to combination and 45 to single agent. Eight patients in the irinotecan arm and 4 in the combination arm had grade 3/4 diarrhoea (P=0.24). Treatment groups did not differ significantly in overall QOL changes, response rate or progression free or overall-survival. In a systematic review of 29 trials of second-line irinotecan-based treatment, single-agent irinotecan was associated with more diarrhoea and alopecia than the combination but efficacy was similar. InterpretationCombination treatment compared with single-agent irinotecan reduces alopecia and diarrhoea without compromising efficacy on clinical outcomes. Both regimens remain as reasonable treatment options. FundingResearch grant (Pfizer).

My Cancer Genome: Web-based clinical decision support for genome-directed lung cancer treatment.

7576 Background: Lung cancer has traditionally been treated according to histologic subtype with a plateau in the efficacy of combination chemotherapy. Recent advances have identified oncogenic ‘dr...

Phase II study of combination chemotherapy with biweekly cetuximab and irinotecan for wild-type KRAS metastatic colorectal cancer refractory to irinotecan, oxaliplatin, and fluoropyrimidines.

561 Background: Weekly cetuximab and irinotecan is a standard regimen in heavily pretreated patients with metastatic colorectal cancer (MCRC). The aim of this study was to prospectively evaluate the efficacy of combination chemotherapy with biweekly cetuximab and irinotecan in patients with pretreated MCRC harboring wild-type KRAS. Methods: Patients with wild- type KRAS MCRC that had progressed after chemotherapy with irinotecan, oxaliplatin, and fluoropyrimidine were included in this study. Cetuximab was administered at 500 mg/m2 biweekly with irinotecan. The primary endpoint was response rate. The secondary endpoints included adverse events, progression-free survival, and overall survival. The pharmacokinetics of cetuximab was also evaluated in five patients. Results: From May, 2009 to February, 2010, a total of 31 patients were enrolled from five institutions. One patient was not eligible. Among the 30 assessable patients, ECOG PS was 0 in 12, 1 in 16, and 2 in two patients. The objective response rate was 30.0% (95% confidence interval [CI], 14.7-49.4), and the disease control rate (complete response, partial response, or stable disease) was 76.7% (95%CI, 61.4-92.3). The median progression-free survival was 5.3 months (95%CI, 3.4-7.3). Grade 3 skin toxicity was observed in 3 patients (10%), and treatment related death due to pneumonia occurred in one patient. Conclusions: The efficacy data are similar to those of standard dose of cetuximab plus irinotecan. Combination chemotherapy with biweekly cetuximab and irinotecan is effective for pretreated metastatic wild-type KRAS MCRC. No significant financial relationships to disclose.

Exemestane and Chemotherapy as First-line Treatment of Metastatic Breast Cancer: Results of a Phase II Study

Background Metastatic breast cancer remains largely incurable. Strategies involving the combination of the selective estrogen receptor modulator tamoxifen and chemotherapy have been abandoned in view of unacceptable toxicity because of thromboembolic events. The aim of this study was to investigate the safety and efficacy of the third-generation steroidal aromatase inhibitor exemestane plus chemotherapy. Patients and Methods Postmenopausal women with advanced breast cancer received 6 cycles of intravenous chemotherapy (5-fluorouracil [5-FU], epirubicin, and cyclophosphamide) and exemestane 25 mg/day that was continued after chemotherapy was completed. The primary efficacy endpoint was time to progression (TTP), and response rates were also assessed. Safety was assessed from adverse events. Results Twenty-three patients (median age, 62 years) were included in this study. Twenty patients completed 6 chemotherapy cycles. Median TTP was 13.7 months. Overall response was achieved by 20 patients (73.9%), and the clinical benefit rate was 87%. During the chemotherapy plus exemestane treatments, 50 adverse events were reported in 14 of the 23 patients (60.9%). As expected, the incidence of adverse events decreased during the phase of exemestane treatment alone (19 adverse events in 10 of 20 patients [50%]). There were 2 grade 4 events reported, pulmonary embolism and pneumonia, although pneumonia was not considered to be related. Conclusion Although a small number of patients were included, the combination of exemestane and chemotherapy was well tolerated and only 1 thromboembolic event was reported. Response rates were similar to other comparable series and may encourage further studies to confirm the efficacy of chemotherapy in combination with an aromatase inhibitor.

The efficacy of combination chemotherapy with oxaliplatin for advanced colorectal cancer

Objective To observe the efficacy and toxicity of oxaliplatin (L-OHP) combined with 5-fluorouracil (5-FU) and leucovorin (LV) for advanced colorectal cancer, and to compare the clinical value of 2 week- or 3 week-regimen. Methods According to the chronology, 95 patients with advanced colorectal cancer were randomly divided into: ① treatment group 1 (47 cases): L-OHP 85 mg/m2, intravenous drip 2h for day 1; LV, intravenous drip 2 h for days 1 and 2; 5-fluorouracil (5-Fu) 400 mg/m2 were injected after LV,followed by 5-Fu 600 mg/m2, continuous intravenous drip 22 h, d1 、d2, repeated every 2w, at least 6 cycles. ②treatment group 2 (48 cases): L-OHP 130 mg/m2, intravenous drip 2 h, d1; LV 200 mg/m2, intravenous drip 2h,followed by 5-Fu 500 rag/d, intravenous drip 4 h for days 1 to 5, repeated every 3 weeks, at least 4 cycles. The two groups were injected Tropisetron 100 mg 30 min or Azasetron 10 mg for oral administration in order to prevent vomiting before, chemotherapy.Results The efficacy was similar in the two groups, the total efficacy achieved 46.8% and 41.6% (P>0.05); The incidence of adverse reactions were similar in the two groups. The main adverse reactions were gastrointestinal reactions, myclosuppression, neurological toxicity, and alopecia (P>0.05); CEA and CA-199 were significantly decreased after treatment (P 0.05). The median survival and median progression-free survival were significantly different (P<0.01). Conclusions L-OHP combined with LV and 5-FU is a relatively effective, less toxic regimen in the treatment of advanced colorectal cancer, and it is suggested to choose the standard 2 week-regime first. Key words: Oxaliplatin; 5-Fluorouracil ; Leucovorin; Advanced colorectal cancer; Combinationchemotherapy

Phase II Study of Combination Chemotherapy with Biweekly Cetuximab and Irinotecan for Pre-treated Metastatic Colorectal Cancer Harboring Wild-type KRAS

Standard weekly cetuximab and irinotecan is an effective regimen in heavily pre-treated patients with metastatic colorectal cancer. The aim of this study is to prospectively evaluate the efficacy of combination chemotherapy with biweekly cetuximab and irinotecan in patients with pre-treated metastatic colorectal cancer harboring wild-type KRAS. A total of 30 patients will be enrolled at four medical institutions. The primary endpoint is response rate. The secondary endpoints include adverse events, progression-free survival and overall survival. The pharmacokinetics of cetuximab will also be evaluated in five patients.

Update on management of seminoma

Testicular germ cell tumors and, in particular, seminomas are exquisitely radiation and chemotherapy-sensitive and most presentations are highly curable. In recent years the management focus has been on reducing late sequelae of treatment. For Stage I disease surveillance and adjuvant carboplatin, chemotherapy has become an option. The efficacy of combination chemotherapy has been established for advanced metastatic disease. Through a review of the available literature this article outlines the recent changes in the management of seminoma.

Evaluation of combined docetaxel and nedaplatin chemotherapy for recurrent esophageal cancer compared with conventional chemotherapy using cisplatin and 5-fluorouracil: a retrospective study

This retrospective study evaluated the safety and efficacy of combination chemotherapy using docetaxel and nedaplatin in an outpatient setting compared with those of chemotherapy using cisplatin (CDDP) and 5-Fu under hospitalization. Subjects comprised 21 patients who had been diagnosed with recurrent esophageal squamous cell carcinoma (ESCC), with 10 patients receiving combination chemotherapy comprising CDDP and 5-fluorouracil (5-Fu) under hospitalization (FP group; n = 10), and 11 patients receiving combination chemotherapy comprising docetaxel and nedaplatin in an outpatient setting (Doc/Ned group; n = 11). In the Doc/Ned group, patients received 30 mg/m(2) of docetaxel over a 1-h infusion on day 1, followed by 40 mg/m(2) of nedaplatin over a 2-h infusion on day 1 in an outpatient setting. In the Doc/Ned group, complete response was observed in two patients (18.1%), one with liver metastasis and one with abdominal lymph node metastasis, and two (18.1%) achieved partial response. In contrast, no complete responses were obtained in the FP group, and partial response was observed in only one patient (10.0%) with local recurrence. Response rates were thus 36.3% for the Doc/Ned group and 10.0% for the FP group. With a median follow-up of 234 days in the Doc/Ned group and 279 days in the FP group, median survival time (MST) was 234 days in the Doc/Ned group and 378 days in the FP group. No significant differences in MST were identified between groups. Thus regimen based on docetaxel and nedaplatin allows administration on an outpatient basis and appears feasible for recurrent ESCC as a second-line chemotherapy.

Incidence and Management of Colorectal Cancer in Liver Transplant Recipients

Liver transplant recipients are at an increased risk of developing de novo malignancies because of the prolonged immunosuppression necessary to avoid acute and chronic rejections. Skin cancers and lymphoproliferative diseases are the most common malignancies, but the overall incidence of colon cancer in this patient population does differ from that of the general population. Therefore, colorectal cancer (CRC) is a major health concern in liver transplant recipients. Furthermore, there are unique subsets of liver transplant recipients, such as those with primary sclerosing cholangitis and inflammatory bowel disease, who are at an increased risk for developing CRC after liver transplantation and might require special screening/surveillance strategies. The similar principles for management of colon cancer can be applied to transplant recipients if the adjustment to maintain the need for the long-term immunosuppression is made. Colectomy can be performed safely during the posttransplantation period. Prophylactic colectomy at the time of liver transplantation has been performed in some patients at high risk or with known premalignant conditions. Chemotherapy with 5- fluorouracil and oxaliplatin has been used in transplant recipients for the treatment of metastatic CRC; however, further research is required to examine the safety, tolerability, and efficacy of combination chemotherapy and biologic agents in this patient population. This review summarizes the incidence, risk factors, diagnosis, and management of de novo CRC in liver transplant recipients.