Survival Advantage of Yttrium-90 Radioembolization to Systemic Therapy in Patients with Hepatic Metastases from Colorectal Cancer in the Salvage Setting: Results of a Matched Pair Study.

RATIONALE AND OBJECTIVES: Patients with hepatic metastases from colorectal cancer have a poor prognosis in the salvage setting. This study assessed the survival benefit of adding transarterial 90Y radioembolization in the salvage setting to systemic therapy. MATERIALS AND METHODS: In this retrospective, matched-pair study, 21 patients who underwent radioembolization plus systemic therapy were matched with a cohort of 173 patients who received systemic chemotherapy alone in the salvage setting, defined as progression on at least two different regimens of systemic chemotherapy. Patients were matched one-to-one on Eastern Cooperative Oncology Group Performance Status, presence of extrahepatic disease, and presence of tumor KRAS mutation. Radioembolization patients underwent treatment using standard dosimetry to either a hepatic lobe or the whole liver. Survival data was analyzed using Kaplan-Meier analysis. RESULTS: Patients who underwent radioembolization plus systemic therapy vs. those who had systemic therapy alone had similar demographics and exposure to prior systemic chemotherapies. Median survival from the date of primary diagnosis was 38 (95% CI 26 to 50) v 25 (95% CI 15 to 35) months in radioembolization with systemic therapy vs. systemic therapy alone (p = 0.17). Median survival from the date of hepatic metastases was 31 (95% CI 23.8 to 38.2) v 20 months (95% CI 10.2 to 29.8) in radioembolization with systemic therapy vs. systemic therapy alone (p = 0.03). CONCLUSION: The addition of radioembolization to systemic therapy in patients with metastatic colorectal cancer to the liver may improve survival in the salvage setting.

Talimogene laherparepvec: review of its mechanism of action and clinical efficacy and safety.

Intratumoral immunotherapy inhibits tumor growth by killing injected tumor cells, thus initiating local and systemic immune responses. Oncolytic viruses are a novel class of intratumoral immunotherapies that show promise for treating solid tumors. Talimogene laherparepvec is a first-in-class, genetically modified, herpes simplex virus type 1-based oncolytic immunotherapy approved for the local treatment of unresectable cutaneous, subcutaneous and nodal lesions in patients with melanoma recurrent after initial surgery. This review highlights the dual mechanism of action for talimogene laherparepvec (direct tumor cell lysis and stimulation of local response in tumor microenvironment and systemic immune response in distant metastases), summarizes key preclinical and clinical trials evaluating efficacy and safety of talimogene laherparepvec in melanoma, and describes studies ongoing in other solid tumors.

Personalizing Survival Predictions in Advanced Colorectal Cancer: The ARCAD Nomogram Project.

Background: Estimating prognosis on the basis of clinicopathologic factors can inform clinical practice and improve risk stratification for clinical trials. We constructed prognostic nomograms for one-year overall survival and six-month progression-free survival in metastatic colorectal carcinoma by using the ARCAD database. Methods: Data from 22 674 patients in 26 randomized phase III clinical trials since 1997 were used to construct and validate Cox models, stratified by treatment arm within each study. Candidate variables included baseline age, sex, body mass index, performance status, colon vs rectal cancer, prior chemotherapy, number and location of metastatic sites, tumor mutation status (BRAF, KRAS), bilirubin, albumin, white blood cell count, hemoglobin, platelets, absolute neutrophil count, and derived neutrophil-to-lymphocyte ratio. Missing data (<11%) were imputed, continuous variables modeled with splines, and clinically relevant pairwise interactions tested if P values were less than .001. Final models were internally validated via bootstrapping to obtain optimism-corrected calibration and discrimination C-indices, and externally validated on a 10% holdout sample from each trial (n = 2257). Results: In final models, all included variables were associated with overall survival except for lung metastases, and all but total white cell count associated with progression-free survival. No clinically relevant pairwise interactions were identified. Final nomogram calibration was good (C = 0.68 for overall and C = 0.62 for progression-free survival), as was external validity (concordance between predicted >50% vs < 50% probability) and actual (yes/no) survival (72.8% and 68.2% concordance, respectively, for one-year overall and six-month progression-free survival, between predicted [>50% vs < 50% probability] and actual [yes/no] overall and progression-free survival). Median survival predictions fell within the actual 95% Kaplan-Meier confidence intervals. Conclusions: The nomograms are well calibrated and internally and externally valid. They have the potential to aid prognostication and patient-physician communication and balance risk in colorectal cancer trials.

Phase II Pilot Study of Vemurafenib in Patients With Metastatic BRAF-Mutated Colorectal Cancer.

PURPOSE: BRAF V600E mutation is seen in 5% to 8% of patients with metastatic colorectal cancer (CRC) and is associated with poor prognosis. Vemurafenib, an oral BRAF V600 inhibitor, has pronounced activity in patients with metastatic melanoma, but its activity in patients with BRAF V600E-positive metastatic CRC was unknown. PATIENTS AND METHODS: In this multi-institutional, open-label study, patients with metastatic CRC with BRAF V600 mutations were recruited to an expansion cohort at the previously determined maximum-tolerated dose of 960 mg orally twice a day. RESULTS: Twenty-one patients were enrolled, of whom 20 had received at least one prior metastatic chemotherapy regimen. Grade 3 toxicities included keratoacanthomas, rash, fatigue, and arthralgia. Of the 21 patients treated, one patient had a confirmed partial response (5%; 95% CI, 1% to 24%) and seven other patients had stable disease by RECIST criteria. Median progression-free survival was 2.1 months. Patterns of concurrent mutations, microsatellite instability status, CpG island methylation status, PTEN loss, EGFR expression, and copy number alterations were not associated with clinical benefit. In contrast to prior expectations, concurrent KRAS and NRAS mutations were detected at low allele frequency in a subset of the patients' tumors (median, 0.21% allele frequency) and were apparent mechanisms of acquired resistance in vemurafenib-sensitive patient-derived xenograft models. CONCLUSION: In marked contrast to the results seen in patients with BRAF V600E-mutant melanoma, single-agent vemurafenib did not show meaningful clinical activity in patients with BRAF V600E mutant CRC. Combination strategies are now under development and may be informed by the presence of intratumor heterogeneity of KRAS and NRAS mutations.

Individual patient data analysis of progression-free survival versus overall survival as a first-line end point for metastatic colorectal cancer in modern randomized trials: findings from the analysis and research in cancers of the digestive system database.

PURPOSE: Progression-free survival (PFS) has previously been established as a surrogate for overall survival (OS) for first-line metastatic colorectal cancer (mCRC). Because mCRC treatment has advanced in the last decade with extended OS, this surrogacy requires re-examination. METHODS: Individual patient data from 16,762 patients were available from 22 first-line mCRC studies conducted from 1997 to 2006; 12 of those studies tested antiangiogenic and/or anti-epidermal growth factor receptor agents. The relationship between PFS (first event of progression or death) and OS was evaluated by using R(2) statistics (the closer the value is to 1, the stronger the correlation) from weighted least squares regression of trial-specific hazard ratios estimated by using Cox and Copula models. RESULTS: Forty-four percent of patients received a regimen that included biologic agents. Median first-line PFS was 8.3 months, and median OS was 18.2 months. The correlation between PFS and OS was modest (R(2), 0.45 to 0.69). Analyses limited to trials that tested treatments with biologic agents, nonstrategy trials, or superiority trials did not improve surrogacy. CONCLUSION: In modern mCRC trials, in which survival after the first progression exceeds time to first progression, a positive but modest correlation was observed between OS and PFS at both the patient and trial levels. This finding demonstrates the substantial variability in OS introduced by the number of lines of therapy and types of effective subsequent treatments and the associated challenge to the use of OS as an end point to assess the benefit attributable to a single line of therapy. PFS remains an appropriate primary end point for first-line mCRC trials to detect the direct treatment effect of new agents.

Improved imaging and the clinician: the role of positron emission tomography in the management of colorectal cancer.

Colorectal cancer is the second most common cause of cancer death in the United States and Western Europe. Positron emission tomography (PET) has been shown to be a valuable tool for the evaluation of malignancies of the breast, lung, and gastrointestinal tract. Potential areas of utility in patients with colorectal cancer include early detection, improved staging at the time of initial diagnosis, the detection and staging of recurrent disease, and early determination of treatment response. Despite continued advancement in the technical aspects of PET, the true measure of its worth is how well it assists the clinician in the care of the patient. To best use the information provided by PET, the nuclear medicine physician and oncologist must both understand the treatment choices available for patients at various stages in the disease.

Randomized, phase II study of the insulin-like growth factor-1 receptor inhibitor IMC-A12, with or without cetuximab, in patients with cetuximab- or panitumumab-refractory metastatic colorectal cancer.

PURPOSE: To evaluate the safety and efficacy of IMC-A12, a human monoclonal antibody (mAb) that blocks insulin-like growth factor receptor-1 (IGF-1R), as monotherapy or in combination with cetuximab in patients with metastatic refractory anti-epidermal growth factor receptor (EGFR) mAb colorectal cancer. METHODS: A randomized, phase II study was performed in which patients in arm A received IMC-A12 10 mg/kg intravenously (IV) every 2 weeks, while patients in arm B received this same dose of IMC-A12 plus cetuximab 500 mg/m(2) IV every 2 weeks. Subsequently, arm C (same combination treatment as arm B) was added to include patients who had disease control on a prior anti-EGFR mAb and wild-type KRAS tumors. Archived pretreatment tumor tissue was obtained when possible for KRAS, PIK3CA, and BRAF genotyping, and immunohistochemistry was obtained for pAKT as well as IGF-1R. RESULTS: Overall, 64 patients were treated (median age, 61 years; range, 40 to 84 years): 23 patients in arm A, 21 in arm B, and 20 in arm C. No antitumor activity was seen in the 23 patients treated with IMC-A12 monotherapy. Of the 21 patients randomly assigned to IMC-A12 plus cetuximab, one patient (with KRAS wild type) achieved a partial response, with disease control lasting 6.5 months. Arm C (all patients with KRAS wild type), however, showed no additional antitumor activity. Serious adverse events thought possibly related to IMC-A12 included a grade 2 infusion-related reaction (2%; one of 64 patients), thrombocytopenia (2%; one of 64 patients), grade 3 hyperglycemia (2%; one of 64 patients), and grade 1 pyrexia (2%, one of 64 patients). CONCLUSION: IMC-A12 alone or in combination with cetuximab was insufficient to warrant additional study in patients with colorectal cancer refractory to EGFR inhibitors.