Validation of the Survival Benefits of Metformin in Middle Eastern Patients With Type II Diabetes Mellitus and Colorectal Cancer.

Purpose Epidemiologic data from several populations suggest that metformin may decrease cancer risk and mortality in patients with colorectal cancer (CRC) and type II diabetes mellitus (DM). Although type II DM and CRC are major health problems in the Middle East, no investigations have been performed to test the effect metformin has on the outcome of patients with type II DM and CRC who are also treated with metformin. Materials and Methods We retrospectively reviewed the medical records of 1,902 patients diagnosed with CRC at King Hussein Cancer Center between January 2004 and December 2012, and identified 349 patients (18%) with type II DM; we censored the data of 28 patients because their antidiabetic medications were unknown. We then categorized these 321 patients into two groups: 192 patients treated with metformin (group A) and 129 patients treated with other antidiabetic medications (group B). Results Group A patients had significantly longer overall survival (89 months; 95% CI, 66 to 112 months) and progression-free survival (47 months; 95% CI, 15 to 79 months) than group B patients (overall survival: 36 months; 95% CI, 24 to 48 months; P ≤ .001; progression-free survival: 21 months; 95% CI, 13 to 29 months; P = .016). After adjustment for age, sex, body mass index, aspirin use, anticholesterol treatment, and CRC stage, group A patients had a 40% reduction in mortality (hazard ratio, 0.58; 95% CI, 0.4% to 0.85%; P = .005). Conclusion Our results support findings from other populations that patients with diabetes and CRC who are also treated with metformin have better outcomes than those treated with other antidiabetic medications.

Identification and characterization of RET fusions in advanced colorectal cancer.

There is an unmet clinical need for molecularly directed therapies available for metastatic colorectal cancer. Comprehensive genomic profiling has the potential to identify actionable genomic alterations in colorectal cancer. Through comprehensive genomic profiling we prospectively identified 6 RET fusion kinases, including two novel fusions of CCDC6-RET and NCOA4-RET, in metastatic colorectal cancer (CRC) patients. RET fusion kinases represent a novel class of oncogenic driver in CRC and occurred at a 0.2% frequency without concurrent driver mutations, including KRAS, NRAS, BRAF, PIK3CA or other fusion tyrosine kinases. Multiple RET kinase inhibitors were cytotoxic to RET fusion kinase positive cancer cells and not RET fusion kinase negative CRC cells. The presence of a RET fusion kinase may identify a subset of metastatic CRC patients with a high response rate to RET kinase inhibition. This is the first characterization of RET fusions in CRC patients and highlights the therapeutic significance of prospective comprehensive genomic profiling in advanced CRC.

Phase I study of everolimus, cetuximab and irinotecan as second-line therapy in metastatic colorectal cancer.

AIM: To evaluate feasible doses of weekly everolimus and irinotecan given with cetuximab for previously treated metastatic colorectal cancer (mCRC). PATIENTS AND METHODS: Adults with mCRC that progressed after 5-fluorouracil or capecitabine-plus-oxaliplatin were treated using a sequential dose escalation scheme. Dosing decisions were based on the probability of experiencing a dose-limiting toxicity (DLT) during the first two 21-day treatment cycles. RESULTS: Patients received everolimus 30 mg/week plus irinotecan 350 mg/m2 q3w (n=5; dose A1) or everolimus 30 mg/week plus irinotecan 250 mg/m2 q3w (n=14; dose B1). Among patients evaluable for the maximum tolerated dose, two out of four in A1 and one out of eight in B1 experienced four DLTs. The trial was terminated early based on changes in clinical practice and emerging data on everolimus dosing. CONCLUSION: The feasible doses of everolimus and irinotecan administered with cetuximab as second-line therapy in mCRC were 30 mg/week and 250 mg/m2, respectively.

Antitumor activity in RAS-driven tumors by blocking AKT and MEK.

PURPOSE: KRAS is the most commonly mutated oncogene in human tumors. KRAS-mutant cells may exhibit resistance to the allosteric MEK1/2 inhibitor selumetinib (AZD6244; ARRY-142886) and allosteric AKT inhibitors (such as MK-2206), the combination of which may overcome resistance to both monotherapies. EXPERIMENTAL DESIGN: We conducted a dose/schedule-finding study evaluating MK-2206 and selumetinib in patients with advanced treatment-refractory solid tumors. Recommended dosing schedules were defined as MK-2206 at 135 mg weekly and selumetinib at 100 mg once daily. RESULTS: Grade 3 rash was the most common dose-limiting toxicity (DLT); other DLTs included grade 4 lipase increase, grade 3 stomatitis, diarrhea, and fatigue, and grade 3 and grade 2 retinal pigment epithelium detachment. There were no meaningful pharmacokinetic drug-drug interactions. Clinical antitumor activity included RECIST 1.0-confirmed partial responses in non-small cell lung cancer and low-grade ovarian carcinoma. CONCLUSION: Responses in KRAS-mutant cancers were generally durable. Clinical cotargeting of MEK and AKT signaling may be an important therapeutic strategy in KRAS-driven human malignancies (Trial NCT number NCT01021748).

Impact of non-steroidal anti-inflammatory drugs on gastrointestinal cancers: current state-of-the science.

Growing evidence from epidemiologic and preclinical studies suggests that nonsteroidal anti-inflammatory drugs (NSAIDs) reduce the risk of gastrointestinal (GI) cancers, including esophageal, gastric, pancreatic, colorectal cancer, and hepatocellular carcinoma. However, there is also evidence indicating the absence of this benefit. The exact mechanism of NSAIDs' action on GI tumors is not known. Although some studies have suggested inhibition of carcinogenesis by NSAIDs through suppression effect on inflammation-associated cyclooxygenase-2 (COX-2) expression, other studies have suggested COX-2-independent mechanisms. Herein, we summarize the current state of-the-science regarding NSAID benefit for patients with GI cancers.

Preoperative radiation therapy with concurrent capecitabine, bevacizumab, and erlotinib for rectal cancer: a phase 1 trial.

PURPOSE: The goal of this phase 1 trial was to determine the maximum tolerated dose (MTD) of concurrent capecitabine, bevacizumab, and erlotinib with preoperative radiation therapy for rectal cancer. METHODS AND MATERIALS: Patients with clinical stage II to III rectal adenocarcinoma, within 12 cm from the anal verge, were treated in 4 escalating dose levels, using the continual reassessment method. Patients received preoperative radiation therapy with concurrent bevacizumab (5 mg/kg intravenously every 2 weeks), erlotinib, and capecitabine. Capecitabine dose was increased from 650 mg/m(2) to 825 mg/m(2) orally twice daily on the days of radiation therapy; erlotinib dose was increased from 50 mg orally daily in weeks 1 to 3, to 50 mg daily in weeks 1 to 6, to 100 mg daily in weeks 1 to 6. Patients underwent surgery at least 9 weeks after the last dose of bevacizumab. RESULTS: A total of 19 patients were enrolled, and 18 patients were considered evaluable. No patient had grade 4 acute toxicity, and 1 patient had grade 3 acute toxicity (hypertension). The MTD was not reached. All 18 evaluable patients underwent surgery, with low anterior resection in 7 (39%), proctectomy with coloanal anastomosis in 4 patients (22%), posterior pelvic exenteration in 1 (6%), and abdominoperineal resection in 6 (33%). Of the 18 patients, 8 (44%) had pathologic complete response, and 1 had complete response of the primary tumor with positive nodes. Three patients (17%) had grade 3 postoperative complications (ileus, small bowel obstruction, and infection). With a median follow-up of 34 months, 1 patient developed distant metastasis, and no patient had local recurrence or died. The 3-year disease-free survival was 94%. CONCLUSIONS: The combination of preoperative radiation therapy with concurrent capecitabine, bevacizumab, and erlotinib was well tolerated. The pathologic complete response rate appears promising and may warrant further investigation.

High prevalence of recurrent thrombosis in subsets of cancer patients with isolated gonadal vein thrombosis: a single center retrospective study.

PURPOSE: Cancer patients are a high-risk population for venous thromboembolism (VTE); the natural history of gonadal vein thrombosis (GVT) occurring in cancer patients is not well described in the medical literature. METHODS: Utilizing a software program the computerized tomographic scan reports of patients at a single cancer center from January 1, 2004 to June 30, 2011 were searched for the term GVT. Patients included in this analysis had a diagnosis of cancer, an isolated GVT (i.e. no evidence of thrombosis at another site), no symptoms referable to the GVT, and at least six months of follow-up information. All subsequent recurrent VTE events were confirmed by imaging studies. RESULTS: 196 cancer patients with GVT were identified. The majority of patients in this analysis had metastatic disease (118, 61.2%) as well as active cancer (167, 85.2%). Twenty patients (10.8%) developed recurrent VTE (median follow-up 14.5 months); median time to recurrent VTEs was 5.5 months (range 0-19 months). When considering only patients with without a recent history of gynecologic surgery, VTE recurrence rates were 14.3%. Active cancer was the only risk factor significantly associated with recurrent VTE (P=0.047). CONCLUSIONS: Based upon the patient's risk factors for VTE, treatment of an incidentally detected GVT in cancer patients with anticoagulation, as per guidelines for other VTE sites, may be indicated in certain high risk subgroups, especially those patients with active cancer who have not had prior pelvic surgery.

Metformin use and improved response to therapy in rectal cancer.

Locally advanced rectal cancer is commonly treated with chemoradiation prior to total mesorectal excision (TME). Studies suggest that metformin may be an effective chemopreventive agent in this disease as well as a possible adjunct to current therapy. In this study, we examined the effect of metformin use on pathologic complete response (pCR) rates and outcomes in rectal cancer. The charts of 482 patients with locally advanced rectal adenocarcinoma treated from 1996 to 2009 with chemoradiation and TME were reviewed. Median radiation dose was 50.4 Gy (range 19.8-63). Nearly, all patients were treated with concurrent 5-fluorouracil-based chemotherapy (98%) followed by adjuvant chemotherapy (81.3%). Patients were categorized as nondiabetic (422), diabetic not taking metformin (40), or diabetic taking metformin (20). No significant differences between groups were found in clinical tumor classification, nodal classification, tumor distance from the anal verge or circumferential extent, pretreatment carcinoembryonic antigen level, or pathologic differentiation. pCR rates were 16.6% for nondiabetics, 7.5% for diabetics not using metformin, and 35% for diabetics taking metformin, with metformin users having significantly higher pCR rates than either nondiabetics (P = 0.03) or diabetics not using metformin (P = 0.007). Metformin use was significantly associated with pCR rate on univariate (P = 0.05) and multivariate (P = 0.01) analyses. Furthermore, patients taking metformin had significantly increased disease-free (P = 0.013) and overall survival (P = 0.008) compared with other diabetic patients. Metformin use is associated with significantly higher pCR rates as well as improved survival. These promising data warrant further prospective study.

Randomized phase 2 study of pegylated SN-38 (EZN-2208) or irinotecan plus cetuximab in patients with advanced colorectal cancer.

BACKGROUND: Irinotecan is cytotoxic in patients with advanced colorectal cancer (CRC). SN-38 (10-hydroxy-7-ethyl-camptothecin) is the active metabolite of irinotecan. Attachment of polyethylene glycol (PEG) polymer chains (pegylation) to SN-38 (EZN-2208) increases the solubility, exposure, and half-life of SN-38. Preclinical studies demonstrated superior in vitro efficacy of EZN-2208 when it was tested in irinotecan-refractory human CRC cell lines. METHODS: Patients with metastatic or locally recurrent CRC who had previously received 5-flurouracil (5-FU), oxaliplatin, and irinotecan were assigned to receive EZN-2208 monotherapy (9 mg/m(2) on days 1, 8, and 15 every 28 days for patients with KRAS-mutant tumors only [arm A]), and patients with KRAS wild-type tumors were randomized (2:1) to receive either EZN-2208 plus cetuximab (400 mg/m(2) loading dose on day 1 followed by 250 mg/m(2) weekly starting on day 8 [arm B]) or irinotecan 125 mg/m(2) on days 1 and 8 every 21 days plus cetuximab at the same doses indicated above (arm C). RESULTS: The overall response rate and progression-free survival were 0% and 1.8 months, respectively, in arm A; 10.7% and 4.9 months (95% confidence interval [CI], 3.2-5.8 months), respectively, in arm B; and 14.3% and 3.7 months (95% CI, 2.1-5.8 months), respectively, in arm C. EZN-2208 was well tolerated in combination with cetuximab. No statistically significant difference in survival was observed between arm B (9.8 months; 95% CI, 7.2-11.2 months) and arm C (9.1 months; 95% CI, 6.0-13.0 months). CONCLUSIONS: EZN-2208, either as monotherapy or in combination with cetuximab, was well tolerated in patients with refractory CRC. Overall survival and progression-free survival were similar in the cetuximab plus irinotecan arm and the EZN-2208 arm.

Rare Though Not Mutually Exclusive: A Report of Three Cases of Concomitant KRAS and BRAF Mutation and a Review of the Literature.

KRAS mutations occur frequently in colorectal cancers (CRC) and predict lack of response to anti-epidermal growth factor receptor (EGFR) monoclonal antibody therapy. CRC BRAF mutations, most commonly at V600E, occur less than 10% of the time, and occur usually in KRAS wild-type tumors, and more frequently in microsatellite instable tumors. Concomitant KRAS and BRAF mutant CRCs are rare (occurring in 0.001%); BRAF mutations should not be routinely tested in patients with KRAS mutant tumors, unless the patients is participating in a clinical trial enriching for the presence of a KRAS or BRAF tumor. Clinical trials treating patients with either KRAS or BRAF mutant tumors should address eligibility of patients with concomitant KRAS and BRAF mutations.

A Primer on the Current State-of-the-Science Neoadjuvant and Adjuvant Therapy for Patients with Locally Advanced Rectal Adenocarcinomas.

Patients with rectal cancers, due to the unique location of the tumor, have a recurrence pattern distinct from colon cancers. Advances in adjuvant therapy over the last three decades have played an important role in improving patient outcomes. This article serves to review the clinical studies that lay the basis for our current standard-of-care treatment of patients with locally advanced rectal cancer, as well as touch upon future ongoing experimental clinical trials of adjuvant chemoradiation therapy.

Complete longitudinal analyses of the randomized, placebo-controlled, phase III trial of sunitinib in patients with gastrointestinal stromal tumor following imatinib failure.

PURPOSE: To analyze final long-term survival and clinical outcomes from the randomized phase III study of sunitinib in gastrointestinal stromal tumor patients after imatinib failure; to assess correlative angiogenesis biomarkers with patient outcomes. EXPERIMENTAL DESIGN: Blinded sunitinib or placebo was given daily on a 4-week-on/2-week-off treatment schedule. Placebo-assigned patients could cross over to sunitinib at disease progression/study unblinding. Overall survival (OS) was analyzed using conventional statistical methods and the rank-preserving structural failure time (RPSFT) method to explore cross-over impact. Circulating levels of angiogenesis biomarkers were analyzed. RESULTS: In total, 243 patients were randomized to receive sunitinib and 118 to placebo, 103 of whom crossed over to open-label sunitinib. Conventional statistical analysis showed that OS converged in the sunitinib and placebo arms (median 72.7 vs. 64.9 weeks; HR, 0.876; P = 0.306) as expected, given the cross-over design. RPSFT analysis estimated median OS for placebo of 39.0 weeks (HR, 0.505, 95% CI, 0.262-1.134; P = 0.306). No new safety concerns emerged with extended sunitinib treatment. No consistent associations were found between the pharmacodynamics of angiogenesis-related plasma proteins during sunitinib treatment and clinical outcome. CONCLUSIONS: The cross-over design provided evidence of sunitinib clinical benefit based on prolonged time to tumor progression during the double-blind phase of this trial. As expected, following cross-over, there was no statistical difference in OS. RPSFT analysis modeled the absence of cross-over, estimating a substantial sunitinib OS benefit relative to placebo. Long-term sunitinib treatment was tolerated without new adverse events.

Survival benefit associated with surgical oophorectomy in patients with colorectal cancer metastatic to the ovary.

BACKGROUND AND OBJECTIVES: The purpose of this study was to determine the outcome of patients with colorectal cancer metastatic to the ovary and the impact of surgical oophorectomy on the outcome. METHODS: We conducted a retrospective evaluation of patients with metastatic colorectal cancer to the ovary. Of 3776 female patients with colorectal cancer seen at MD Anderson from 2001-2008, 110 (2.9%) were identified as having metastases to the ovary. The Kaplan-Meier method and log-rank test were used to examine the survival functions. RESULTS: Seventy-one patients (64.5%) had disease metastatic to the ovary at the time of initial presentation; in 39 patients (35.5%) the ovaries were a site of relapse after previous curative colorectal surgical resection. Patients who presented with ovarian relapse after previous colorectal surgery and who underwent oophorectomy had a median survival of 50 months compared with 12 months for those who did not (P < .0001). Patients with metastatic disease at the time of presentation who underwent oophorectomy had a median survival of 39.4 months vs. 18.2 months for those who did not. CONCLUSIONS: This retrospective analysis suggests that women with metastatic colorectal cancer metastatic to the ovary may derive a survival benefit from palliative oophorectomy.

Cetuximab in the treatment of patients with colorectal cancer.

INTRODUCTION: Cetuximab is a chimeric mAb with avidity for the EGFR higher than that of the natural ligands of the receptor. Preclinical studies showed that cetuximab demonstrated synergy with topoisomerase I inhibitors in the treatment of human colorectal cancer (CRC) cell lines in vivo. Subsequent clinical trials have shown that cetuximab can reverse resistance to topoisomerase I inhibitors in addition to having modest monotherapy activity. These studies led to accelerated provisional FDA approval of the drug for the treatment of patients with irinotecan-refractory metastatic CRC. Its clinical utility has been improved with the discovery of negative predictive biomarkers; these have shown that there is a lack of cetuximab benefit for patients whose tumors generally harbor a KRAS mutation, thus sparing these patients the toxicity of the agent which would not be of treatment benefit. AREAS COVERED: This review covers the last decade of clinical trials that have determined the toxicity and efficacy of cetuximab when given to patients with CRC, as well as some of the molecular subgroups tumors from patients with CRC who appear to not derive benefit from this mAb. EXPERT OPINION: Cetuximab has modest single-agent efficacy in the treatment of patients with metastatic CRC whose tumors do not harbor a KRAS mutation. In combination with irinotecan, it is associated with an overall survival (OS) and progression-free survival (PFS) advantage in first-line therapy in patients with KRAS non mutant metastatic CRC; it can be combined with irinotecan to overcome resistance in patients with KRAS non mutant CRC who have previously progressed on prior irinotecan chemotherapy. Future studies of putative biomarkers are likely to give additional information to clearly define which patients with metastatic CRC receive therapeutic benefit from cetuximab and other monoclonal anti-EGFR therapies.

Is resection of colorectal liver metastases after a second-line chemotherapy regimen justified?

BACKGROUND: Patient outcomes following resection of colorectal liver metastases (CLM) after second-line chemotherapy regimen is unknown. METHODS: From August 1998 to June 2009, data from 1099 patients with CLM were collected prospectively. We retrospectively analyzed outcomes of patients who underwent resection of CLM after second-line (2 or more) chemotherapy regimens. RESULTS: Sixty patients underwent resection of CLM after 2 or more chemotherapy regimens. Patients had advanced CLM (mean number of CLM ± standard deviation, 4 ± 3.5; mean maximum size of CLM, 5 ± 3.2 cm) and had received 17 ± 8 cycles of preoperative chemotherapy. In 54 (90%) patients, the switch from the first regimen to another regimen was motivated by tumor progression or suboptimal radiographic response. All patients received irinotecan or oxaliplatin, and the majority (42/60 [70%]) received a monoclonal antibody (bevacizumab or cetuximab) as part of the last preoperative regimen. Postoperative morbidity and mortality rates were 33% and 3%, respectively. At a median follow-up of 32 months, 1-year, 3-year, and 5-year overall survival rates were 83%, 41%, and 22%, respectively. Median chemotherapy-free survival after resection or completion of additional chemotherapy administered after resection was 9 months (95% confidence interval, 4-14 months). Synchronous (vs metachronous) CLM and minor (vs major) pathologic response were independently associated with worse survival. CONCLUSIONS: Resection of CLM after a second-line chemotherapy regimen was found to be safe and was associated with a modest hope for definitive cure. This approach represents a viable option in patients with advanced CLM.

High survival rate after two-stage resection of advanced colorectal liver metastases: response-based selection and complete resection define outcome.

PURPOSE: Prolonged survival after two-stage resection (TSR) of advanced colorectal liver metastases (CLM) may be the result of selection of best responders to chemotherapy. The impact of complete resection in this well-selected group is controversial. PATIENTS AND METHODS: Data on 890 patients undergoing resection and 879 patients who received only chemotherapy for CLM were collected prospectively. We used intent-to-treat analysis to evaluate the survival of patients who underwent TSR. Additionally, we evaluated a cohort of nonsurgically treated patients selected to mirror the TSR population: colorectal metastases with liver-only disease, objective response to chemotherapy, and alive 1 year after chemotherapy initiation. RESULTS: Sixty-five patients underwent the first stage of TSR; 62 patients fulfilled the inclusion criteria for the medical group. TSR patients had a mean of 6.7 ± 3.4 CLM with mean size of 4.5 ± 3.1 cm. Nonsurgical patients had a mean of 5.9 ± 2.9 CLM with mean size of 5.4 ± 3.4 cm (not significant). Forty-seven TSR patients (72%) completed the second stage. Progression between stages was the main cause of noncompletion of the second stage (61%). After 50 months median follow-up, the 5-year survival rate was 51% in the TSR group and 15% in the medical group (P = .005). In patients who underwent TSR, noncompletion of TSR and major postoperative complications were independently associated with worse survival. CONCLUSION: TSR is associated with excellent outcome in patients with advanced CLM as a result of both selection by chemotherapy and complete resection of metastatic disease.

Phase I pharmacokinetic and pharmacodynamic study of triciribine phosphate monohydrate, a small-molecule inhibitor of AKT phosphorylation, in adult subjects with solid tumors containing activated AKT.

PURPOSE: Triciribine phosphate is a potent, small-molecule inhibitor of activation of all three isoforms of AKT in vitro. AKT is an intracellular protein that, when activated, leads to cellular division; it is dysregulated in a large number of malignancies, and constitutively activating AKT mutations are present in a minority of cancers. PATIENTS AND METHODS: In this phase I study triciribine phosphate monohydrate (TCN-PM) was administered to subjects whose tumors displayed evidence of increased AKT phosphorylation (p-AKT) as measured by immunohistochemical analysis (IHC). TCN-PM was administered over 30 min on days 1, 8 and 15 of a 28-day cycle. Tumor biopsy specimens, collected before treatment and on day +15, were assessed for p-AKT by IHC and western blot analyses. RESULTS: Nineteen subjects were enrolled; 13 received at least one cycle of therapy, and a total of 34 complete cycles were delivered. One subject was treated at the 45 mg/m(2) dose before the study was closed due to its primary objective having been met. No dose-limiting toxic effects were observed. Modest decreases in tumor p-AKT following therapy with TCN-PM were observed at the 35 mg/m(2) and 45 mg/m(2) dose levels, although definitive conclusions were limited by the small sample size. CONCLUSIONS: These preliminary data suggest that treatment with TCN-PM inhibits tumor p-AKT at doses that were tolerable. Although single agent activity was not observed in this enriched population, further combination studies of TCN-PM with other signal transduction pathway inhibitors in solid tumors is warranted.

Reirradiation to the abdomen for gastrointestinal malignancies.

BACKGROUND: Reirradiation to the abdomen could potentially play a role in palliation of symptoms or local control in patients with gastrointestinal malignancies. Our goal was to retrospectively determine rates of toxicity, freedom from local progression and overall survival in gastrointestinal cancer patients treated with reirradiation to the abdomen. METHODS: Between November 2002 and September 2008, 13 patients with a prior history of abdominal radiotherapy (median dose 45 Gy) were treated with reirradiation for recurrent or metastatic gastrointestinal malignancies. The median interval between the two courses of radiotherapy was 26 months. Patients were treated with a hyperfractionated accelerated regimen, using 1.5 Gy fractions twice daily, with a median dose of 30 Gy (range 24-48 Gy). Concurrent chemotherapy was administered to 8 (62%) patients. RESULTS: The 1-year rate of freedom from local progression was 50%, and the median duration of freedom from local progression was 14 months. The 1-year rate of overall survival was 62%, and the median duration of overall survival was 14 months. One patient developed grade 3 acute toxicity (abdominal pain and gastrointestinal bleeding), requiring hospitalization during radiotherapy; subsequently, that patient experienced a grade 4 late toxicity (gastrointestinal bleeding). No other patients developed grade 3-4 acute or late toxicity or required hospitalization during radiotherapy. CONCLUSION: Hyperfractionated accelerated reirradiation to the abdomen was well-tolerated with low rates of acute and late toxicity. Reirradiation could play a role in providing a limited duration of local control in gastrointestinal cancer patients with a history of prior abdominal radiotherapy.

Circulating levels of soluble KIT serve as a biomarker for clinical outcome in gastrointestinal stromal tumor patients receiving sunitinib following imatinib failure.

PURPOSE: To evaluate changes in circulating levels of soluble KIT (sKIT) extracellular domain as a potential biomarker for clinical outcome in gastrointestinal stromal tumor patients treated with the multitargeted tyrosine kinase inhibitor sunitinib following imatinib failure in a previously reported phase III study. EXPERIMENTAL DESIGN: Patients received sunitinib 50 mg/d (n = 243) or placebo (n = 118) daily in 6-week cycles (4 weeks on, 2 weeks off treatment). Plasma sKIT levels were sampled every 2 weeks in cycle 1 and on days 1 and 28 of subsequent cycles; analyzed by ELISA; and evaluated using Prentice criteria, Cox proportional hazards models, and proportion of treatment effect (PTE) analysis. RESULTS: From 4 weeks on treatment and onward, significant differences were shown between treatment groups (P < 0.0001) in sKIT level changes from baseline (median levels decreased with sunitinib and increased with placebo). Decreases in sKIT levels were a significant predictor of longer time to tumor progression (TTP). Patients with reduced levels at the end of cycle 2 had a median TTP of 34.3 weeks versus 16.0 weeks for patients with increased levels [hazard ratio, 0.71; 95% confidence interval (95% CI), 0.61-0.83; P < 0.0001], and changes in sKIT levels replaced treatment as a stronger predictor of TTP (PTE, 0.80; 95% CI, 0.34-3.70), showing even greater surrogacy on cycle 3 day 1 (PTE, 0.98; 95% CI, 0.39-3.40). CONCLUSIONS: The results suggest that circulating plasma sKIT levels seem to function as a surrogate marker for TTP in gastrointestinal stromal tumor patients. Additional studies are warranted to confirm and expand these findings.

Phase I and pharmacokinetic study of YM155, a small-molecule inhibitor of survivin.

PURPOSE: To determine the maximum-tolerated dose (MTD) and assess the safety, pharmacokinetics, and preliminary evidence of antitumor activity of YM155, a small-molecule inhibitor of survivin. PATIENTS AND METHODS: Patients with advanced solid malignancies or lymphoma were treated with escalating doses of YM155 administered by 168-hour continuous intravenous infusion (CIVI). Plasma and urine samples were assayed to determine pharmacokinetic parameters and excretion. RESULTS: Forty-one patients received 127 cycles of YM155 at doses ranging from 1.8 to 6.0 mg/m(2)/d by 168-hour CIVI every 3 weeks. Overall, the most common grade 1 to 2 toxicities were stomatitis, pyrexia, and nausea, whereas grade 3 and 4 toxicities were rare. Reversible elevation in serum creatinine in two patients, with one developing acute tubular necrosis, was dose-limiting at 6.0 mg/m(2). The MTD was 4.8 mg/m(2). At the MTD, the mean steady-state concentration, clearance, volume of distribution at steady-state, and terminal elimination half-life were 7.7 ng/mL, 47.7 L/h, 1,763 L, and 26 hours, respectively. One complete and two partial responses lasting 8, 24+ and 48+ months occurred in three patients with non-Hodgkin's lymphoma, two patients with hormone- and docetaxel-refractory prostate cancer had prostate-specific antigen responses, and one patient with non-small-cell lung cancer had a minor response. CONCLUSION YM155 can be administered safely at 4.8 mg/m(2)/d 168 hours CIVI every 3 weeks. The absence of severe toxicities, attainment of plasma concentrations active in preclinical models, and compelling antitumor activity warrant further disease-directed studies of this agent alone and in combination with chemotherapy in a broad array of tumors.