Michael J. Overman

Improved Survival in Metastatic Colorectal Cancer Is Associated With Adoption of Hepatic Resection and Improved Chemotherapy

PURPOSE Fluorouracil/leucovorin as the sole therapy for metastatic colorectal cancer (CRC) provides an overall survival of 8 to 12 months. With an increase in surgical resections of metastatic disease and development of new chemotherapies, indirect evidence suggests that outcomes for patients are improving in the general population, although the incremental gain has not yet been quantified. METHODS We performed a retrospective review of patients newly diagnosed with metastatic CRC treated at two academic centers from 1990 through 2006. Landmark analysis evaluated the association of diagnosis year and liver resection with overall survival. Additional survival analysis of the Surveillance Epidemiology and End Results (SEER) database evaluated a similar population from 1990 through 2005. RESULTS Two thousand four hundred seventy patients with metastatic CRC at diagnosis received their primary treatment at the two institutions during this time period. Median overall survival for those patients diagnosed from 1990 to 1997 was 14.2 months, which increased to 18.0, 18.6, and 29.3 months for patients diagnosed in 1998 to 2000, 2001 to 2003, and 2004 to 2006, respectively. Likewise, 5-year overall survival increased from 9.1% in the earliest time period to 19.2% in 2001 to 2003. Improved outcomes from 1998 to 2004 were a result of an increase in hepatic resection, which was performed in 20% of the patients. Improvements from 2004 to 2006 were temporally associated with increased utilization of new chemotherapeutics. In the SEER registry, overall survival for the 49,459 identified patients also increased in the most recent time period. CONCLUSION Profound improvements in outcome in metastatic CRC seem to be associated with the sequential increase in the use of hepatic resection in selected patients (1998 to 2006) and advancements in medical therapy (2004 to 2006).

Pathologic Response to Preoperative Chemotherapy: A New Outcome End Point After Resection of Hepatic Colorectal Metastases

PURPOSE The primary goal of this study was to evaluate whether pathologic response to chemotherapy predicts patient survival after preoperative chemotherapy and resection of colorectal liver metastases (CLM). The secondary goal of the study was to identify the clinical predictors of pathologic response. PATIENTS AND METHODS A retrospective review was performed of 305 patients who underwent preoperative irinotecan- or oxaliplatin-based chemotherapy, followed by resection of CLM. Pathologic response was systematically evaluated and reported as the mean of the percentage of cancer cells remaining within each tumor. Univariate and multivariate analyses were performed to identify the predictors of pathologic response and survival. RESULTS Cumulative 5-year overall survival rates by pathologic response status were as follows: 75% complete response (no residual cancer cells), 56% major response (1% to 49% residual cancer cells), and 33% minor response (> or = 50% residual cancer cells; complete v major response, P = .037; major v minor response, P = .028). Multivariate analysis revealed that only surgical margin status (P = .050; hazard ratio [HR], 1.77) and pathologic response (major response: P = .034; HR, 4.80; minor response: P = .007; HR, 6.93) were independent predictors of survival. Multivariate analysis of the predictors of pathologic response revealed that carcinoembryonic antigen level < or = 5 ng/mL, tumor size < or = 3 cm, and chemotherapy with fluoropyrimidine plus oxaliplatin and bevacizumab were independent predictors of pathologic response. CONCLUSION Pathologic response predicts survival after preoperative chemotherapy and resection of CLM. Degree of pathologic response represents a new outcome end point for prognosis after resection of CLM.

Phase II Trial of Infusional Fluorouracil, Irinotecan, and Bevacizumab for Metastatic Colorectal Cancer: Efficacy and Circulating Angiogenic Biomarkers Associated With Therapeutic Resistance

PURPOSE We investigated the efficacy of fluorouracil (FU), leucovorin, irinotecan, and bevacizumab (FOLFIRI + B) in a phase II trial in patients previously untreated for metastatic colorectal cancer (mCRC), and changes during treatment in plasma cytokines and angiogenic factors (CAFs) as potential markers of treatment response and therapeutic resistance. PATIENTS AND METHODS We conducted a phase II, two-institution trial of FOLFIRI + B. Each 14-day cycle consisted of bevacizumab (5 mg/kg), irinotecan (180 mg/m(2)), bolus FU (400 mg/m(2)), and leucovorin (400 mg/m(2)) followed by a 46-hour infusion of FU (2,400 mg/m(2)). Levels of 37 CAFs were assessed using multiplex-bead assays and enzyme-linked immunosorbent assay at baseline, during treatment, and at the time of progressive disease (PD). RESULTS Forty-three patients were enrolled. Median progression-free survival (PFS), the primary end point of the study, was 12.8 months. Median overall survival was 31.3 months, with a response rate of 65%. Elevated interleukin-8 at baseline was associated with a shorter PFS (11 v 15.1 months, P = .03). Before the radiographic development of PD, several CAFs associated with angiogenesis and myeloid recruitment increased compared to baseline, including basic fibroblast growth factor (P = .046), hepatocyte growth factor (P = .046), placental growth factor (P < .001), stromal-derived factor-1 (P = .04), and macrophage chemoattractant protein-3 (P < .001). CONCLUSION Efficacy and tolerability of FOLFIRI + B appeared favorable to historical controls in this single arm study. Before radiographic progression, there was a shift in balance of CAFs, with a rise in alternate pro-angiogenic cytokines and myeloid recruitment factors in subsets of patients that may represent mechanisms of resistance.

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.

Surgical Strategies for Synchronous Colorectal Liver Metastases in 156 Consecutive Patients: Classic, Combined or Reverse Strategy?

BACKGROUND An increasing number of patients with synchronous colorectal liver metastases (CLM) are candidates for resection. The optimal treatment sequence in these patients has not been defined. STUDY DESIGN Data on 156 consecutive patients with synchronous resectable CLM and intact primary were reviewed. Surgical strategies were defined as combined (combined resection of primary and liver), classic (primary before liver), and reverse (liver before primary) after preoperative chemotherapy. Postoperative morbidity and mortality rates and overall survival were analyzed. RESULTS One hundred forty-two patients (83%) had resection of all disease. Seventy-two patients underwent classic, 43 combined, and 27 reverse strategies. Median numbers of CLMs per patient were 1 in the combined, 3 in the classic, and 4 in the reverse strategy group (p = 0.01 classic vs reverse; p < 0.001 reverse vs combined). Postoperative mortality rates in the combined, classic, and reverse strategies were 5%, 3%, and 0%, respectively (p = NS), and postoperative cumulative morbidity rates were 47%, 51%, and 31%, respectively (p = NS). Three-year and 5-year overall survival rates were, respectively, 65% and 55% in the combined, 58% and 48% in the classic, and 79% and 39% in the reverse strategy (NS). On multivariate analysis, liver tumor size >3 cm (hazard ratio [HR] 2.72, 95% CI 1.52 to 4.88) and cumulative postoperative morbidity (HR 1.8, 95% CI 1.03 to 3.19) were independently associated with overall survival after surgery. CONCLUSIONS The classic, combined, or reverse surgical strategies in patients with synchronous presentation of CLM are associated with similar outcomes. The reverse strategy can be considered as an alternative option in patients with advanced CLM and an asymptomatic primary.

Beyond VEGF: Inhibition of the fibroblast growth factor pathway and antiangiogenesis

Fibroblast growth factor (FGF) signaling regulates cell proliferation, differentiation, survival, angiogenesis, and wound healing. Compelling evidence for deregulated FGF signaling in tumorigenesis continues to emerge, and a growing body of research suggests that FGF may also play an integral role in the resistance to anti-VEGF therapy. Although agents targeting FGF signaling are early in development, the potential to target both the VEGF and FGF pathways may translate into improvements in the clinical care of cancer patients. Clin Cancer Res; 17(19); 6130–9. ©2011 AACR.

Nivolumab in patients with metastatic DNA mismatch repair-deficient or microsatellite instability-high colorectal cancer (CheckMate 142): an open-label, multicentre, phase 2 study

BACKGROUND Metastatic DNA mismatch repair-deficient (dMMR)/microsatellite instability-high (MSI-H) colorectal cancer has a poor prognosis after treatment with conventional chemotherapy and exhibits high levels of tumour neoantigens, tumour-infiltrating lymphocytes, and checkpoint regulators. All of these features are associated with the response to PD-1 blockade in other tumour types. Therefore, we aimed to study nivolumab, a PD-1 immune checkpoint inhibitor, in patients with dMMR/MSI-H metastatic colorectal cancer. METHODS In this ongoing, multicentre, open-label, phase 2 trial, we enrolled adults (aged ≥18 years) with histologically confirmed recurrent or metastatic colorectal cancer locally assessed as dMMR/MSI-H from 31 sites (academic centres and hospitals) in eight countries (Australia, Belgium, Canada, France, Ireland, Italy, Spain, and the USA). Eligible patients had progressed on or after, or been intolerant of, at least one previous line of treatment, including a fluoropyrimidine and oxaliplatin or irinotecan. Patients were given 3 mg/kg nivolumab every 2 weeks until disease progression, death, unacceptable toxic effects, or withdrawal from study. The primary endpoint was investigator-assessed objective response as per Response Evaluation Criteria in Solid Tumors (version 1.1). All patients who received at least one dose of study drug were included in all analyses. This trial is registered with ClinicalTrials.gov, number NCT02060188. FINDINGS Of the 74 patients who were enrolled between March 12, 2014, and March 16, 2016, 40 (54%) had received three or more previous treatments. At a median follow-up of 12·0 months (IQR 8·6-18·0), 23 (31·1%, 95% CI 20·8-42·9) of 74 patients achieved an investigator-assessed objective response and 51 (69%, 57-79) patients had disease control for 12 weeks or longer. Median duration of response was not yet reached; all responders were alive, and eight had responses lasting 12 months or longer (Kaplan-Meier 12-month estimate 86%, 95% CI 62-95). The most common grade 3 or 4 drug-related adverse events were increased concentrations of lipase (six [8%]) and amylase (two [3%]). 23 (31%) patients died during the study; none of these deaths were deemed to be treatment related by the investigator. INTERPRETATION Nivolumab provided durable responses and disease control in pre-treated patients with dMMR/MSI-H metastatic colorectal cancer, and could be a new treatment option for these patients. FUNDING Bristol-Myers Squibb.

Phase II Study of Capecitabine and Oxaliplatin for Advanced Adenocarcinoma of the Small Bowel and Ampulla of Vater

PURPOSE Adenocarcinomas of the small bowel and ampulla of Vater represent rare cancers that have limited data regarding first-line therapy. We conducted a phase II trial to evaluate the benefit of capecitabine in combination with oxaliplatin (CAPOX) in patients with advanced adenocarcinoma of small bowel or ampullary origin. PATIENTS AND METHODS Eligible patients with metastatic or unresectable tumors and no prior systemic chemotherapy for advanced disease participated in this phase II trial. CAPOX was administered as a 21-day cycle with oxaliplatin 130 mg/m(2) on day 1 and capecitabine 750 mg/m(2) twice a day on days 1 through 14. The primary end point was overall response rate as assessed by Response Evaluation Criteria in Solid Tumors. RESULTS Thirty-one patients were enrolled onto the study, and 30 patients received study treatment. The confirmed overall response rate was 50%; three patients with metastatic disease achieved complete responses. The median time to progression (TTP) was 11.3 months, and the median overall survival (OS) was 20.4 months. Subset analysis of patients with metastatic disease only (n = 25) revealed a median TTP of 9.4 months and median OS of 15.5 months. The most common grades 3 or 4 toxicities included fatigue (30%), peripheral neuropathy (10%), vomiting (10%), diarrhea (10%), and neutropenia (10%). CONCLUSION When administered to patients with good performance status, CAPOX is well tolerated and produces a superior response rate and longer OS compared with other regimens in the literature. CAPOX should be considered a new standard regimen for advanced small bowel and ampullary adenocarcinomas.

Oxaliplatin-Mediated Increase in Spleen Size As a Biomarker for the Development of Hepatic Sinusoidal Injury

PURPOSE Oxaliplatin-based chemotherapy can cause hepatic sinusoidal injury, with resultant sinusoidal damage and portal hypertension. We sought to explore the relationship between oxaliplatin induced hepatic sinusoidal injury, increases in spleen size, and the subsequent development of thrombocytopenia. PATIENTS AND METHODS We retrospectively assessed the relationship between chemotherapy exposure, changes in spleen size (determined by volumetric measurements), and platelet counts in 136 patients treated with adjuvant fluorouracil and oxaliplatin (FOLFOX) or fluoropyrimidine for stage II or III colorectal adenocarcinoma. Hepatic sinusoidal injury and changes in spleen size were graded in a separate population of 63 patients with metastatic colorectal cancer receiving fluoropyrimidine and oxaliplatin before liver resection. RESULTS Spleen size increased in 86% of patients treated with adjuvant FOLFOX (P < .001), with a > or = 50% increase in 24% of patients. Spleen size did not significantly increase in patients treated with adjuvant fluoropyrimidine. Increases in spleen size correlated with cumulative oxaliplatin dose (P = .003). Patients with splenic enlargement > or = 50% had higher rates of thrombocytopenia in the first year after completion of chemotherapy (27% v 5%; P = .003). In patients with hepatic metastases treated with preoperative fluoropyrimidine and oxaliplatin, increases in spleen size was a predictor of higher histologic grades of sinusoidal injury in both univariate (P = .03) and multivariate (P = .02) analyses. CONCLUSION Increases in spleen size correlate with increasing grade of hepatic sinusoidal injury and can serve as a simple method for identifying patients at risk for this toxicity. Oxaliplatin-induced increases in spleen size should be recognized as a potential etiology of persistent thrombocytopenia after oxaliplatin treatment.

Use of Research Biopsies in Clinical Trials: Are Risks and Benefits Adequately Discussed?

PURPOSE Although the incorporation of research biopsies into clinical trials is increasing, limited information is available about how study protocols and informed consents integrate and describe their use. METHODS All therapeutic clinical trials in which image-guided research biopsies were performed from January 1, 2005, to October 1, 2010, were identified from an interventional radiology database. Data from study protocols and informed consents were extracted and analyzed. Procedural complications were recorded. RESULTS A total of 57 clinical trials were identified, of which 38 (67%) contained at least one mandatory biopsy. The analysis of the research biopsy tumor tissue was a study end point in 95% of trials. The primary indication for a research biopsy was for integral biomarker analysis in 32% and for correlative science in 68% of trials. A statistical analytic plan for the correlative science research biopsy tumor tissue was mentioned in 26%, described as exploratory in 51%, and not mentioned in 23% of trials. For studies with mandatory biopsies, biopsy was an eligibility criterion in 71% of trials, and a statistical justification for the research biopsy sample size was present in 50% of trials. A total of 745 research biopsies were performed on 576 patients. Overall and major complication rates were 5.2% (39 of 745 biopsies) and 0.8% (six of 745 biopsies), respectively. Complication rates for intrathoracic and abdominal/pelvic solid organ biopsies were 17.1% (36 of 211 biopsies) and 1.6% (three of 189 biopsies), respectively. Site-stratified research biopsy-related risks were discussed in five consents. CONCLUSION A better representation of the risks and benefits of research biopsies in study protocols and informed consents is needed.