Prognostic value of the combination of circulating tumor cells plus KRAS in patients with metastatic colorectal cancer treated with chemotherapy plus bevacizumab.

OBJECTIVE: Circulating tumor cells (CTCs) and v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) status were identified as prognostic factors for progression-free survival (PFS) and overall survival (OS) in patients with metastatic colorectal cancer treated with chemotherapy and bevacizumab in analyses of the MACRO (Maintenance Treatment in Advanced Colorectal Cancer) trial. In this post hoc analysis of the MACRO trial, the potential additive effect of these 2 factors on patient outcomes was explored. METHODS: A total of 158 of the 480 patients involved in the MACRO trial were included in the biological marker substudy. CTC isolation and enumeration were centralized and performed using the CellSearch System (Veridex LLC, Raritan, NJ) in 7.5 mL of whole blood. Evaluation of KRAS status was performed retrospectively by the standard method used at each center. PFS and OS were analyzed by the Kaplan-Meier method according to CTC count and KRAS status. RESULTS: Patients with < 3 CTC per 7.5 mL blood at baseline and KRAS wild-type tumors had a median PFS of 14.2 months compared with 6.2 months in patients with ≥ 3 CTCs and KRAS mutated tumors (P < .0001; hazard ratio, 3.0; 95% confidence interval, 1.8-5.2). Similar findings were observed for OS (28.9 and 13.7 months, respectively, P = .0004; hazard ratio 2.8; 95% confidence interval, 1.6-4.9). Multivariate analyses showed that CTC count ≥ 3 and KRAS status were the only independent prognostic factors for both PFS and OS. CONCLUSIONS: This post hoc analysis showed that CTC count and KRAS status were independent prognostic factors for outcomes in patients with metastatic colorectal cancer treated with bevacizumab ± chemotherapy. These factors should be taken into account in the design of future phase III trials.

Time from (clinical or certainty) diagnosis to treatment onset in cancer patients: the choice of diagnostic date strongly influences differences in therapeutic delay by tumor site and stage.

OBJECTIVES: To analyze whether differences between the interval from suspicion or clinical diagnosis to treatment onset (IClinDT) and the interval from certainty diagnosis to treatment onset (ICertDT) varied by tumor site, stage, and mode of hospital admission. STUDY DESIGN AND SETTING: From our hospital cancer registry, we selected all 8,814 patients with breast, colorectal, lung, prostate, or cervical cancer diagnosed between 1992 and 2006. We compared IClinDT and ICertDT with density plots and logistic regression. RESULTS: IClinDT was up to three times higher than ICertDT. There were very large differences among stages and within each stage in IClinDT and ICertDT. Tumor stage significantly influenced the difference between the two intervals in three of the five locations (breast, lung, and prostate cancer); as stage worsened, the difference between IClinDT and ICertDT became smaller. In all tumor sites, the difference was larger in scheduled than in emergency admissions. Overall, therapeutic delays--even when measured by ICertDT--were disturbingly common for important subgroups of patients. CONCLUSION: The difference between IClinDT and ICertDT varied highly by tumor site, stage, and mode of hospital admission. More standardized definitions and procedures to calculate time intervals between cancer diagnosis and treatment onset are needed.

Colorectal cancer survival: results from a hospital-based cancer registry / Supervivencia del cáncer colorrectal: resultados de un registro hospitalario

Introduction: colorectal cancer is one of the most common malignancies in developed countries. Data on specific and 10-year survival are scarce. This study analyzes overall and disease-specific survival for patients with colorectal cancer and assesses the value of clinical factors on disease-specific survival. Methods: a retrospective cohort study of newly diagnosed invasive colorectal cancer cases diagnosed from 1992 to 2007 were identified through the Hospital del Mar Cancer Registry. Five- and 10-year survival functions were estimated using Kaplan-Meier method. Cox proportional hazard models were used to assess prognostic factors. Results: a total of 2,080 patients with colorectal cancer were identified. The median age at diagnosis was 72 years and 58.5% were men. By the end of the follow-up period (December 2008), ,225 patients had died and 68.4% of deaths were due to colorectal cancer. The 5- and 10-year cancer-specific survival rates were 55.5% (95%CI 53.9-57.9%) and 48.5% (95%CI 45.6-51.3%), respectively. The 5-year specific survival rate improved in the last period (2003- 2007) (60.4%, 95%CI 55.4-65.0) compared with 1992-1997 (53.4%; 95%CI 49.2-57.4) and 1998-2002 (52.0%; 95%CI 47.8- 56.2). Various factors were independently associated with excess CRC mortality: male sex (HR 1.21), age at diagnosis > 75 years (HR 1.97), rectal location (HR 1.33), more advanced stages (stage IV: HR 18.54), poorly differentiated/undifferentiated tumors (HR 1.80), and admission through the emergency department (HR 1.52). Conclusions: cancer-specific survival improved from 1992 to 2007. This improvement could be due to more effective treatment, since changes in stage distribution or age at diagnosis were not observed during the study period. Overall survival rates should notably improve with the implementation of a population-based colorectal cancer screening program in Spain(AU)

Circulating tumor cell count is a prognostic factor in metastatic colorectal cancer patients receiving first-line chemotherapy plus bevacizumab: a Spanish Cooperative Group for the Treatment of Digestive Tumors study.

BACKGROUND: The Maintenance in Colorectal Cancer trial was a phase III study to assess maintenance therapy with single-agent bevacizumab versus bevacizumab plus chemotherapy in patients with metastatic colorectal cancer. An ancillary study was conducted to evaluate the circulating tumor cell (CTC) count as a prognostic and/or predictive marker for efficacy endpoints. PATIENTS AND METHODS: One hundred eighty patients were included. Blood samples were obtained at baseline and after three cycles. CTC enumeration was carried out using the CellSearch® System (Veridex LLC, Raritan, NJ). Computed tomography scans were performed at cycle 3 and 6 and every 12 weeks thereafter for tumor response assessment. RESULTS: The median progression-free survival (PFS) interval for patients with a CTC count ≥3 at baseline was 7.8 months, versus the 12.0 months achieved by patients with a CTC count <3 (p = .0002). The median overall survival (OS) time was 17.7 months for patients with a CTC count ≥3, compared with 25.1 months for patients with a lower count (p = .0059). After three cycles, the median PFS interval for patients with a low CTC count was 10.8 months, significantly longer than the 7.5 months for patients with a high CTC count (p = .005). The median OS time for patients with a CTC count <3 was significantly longer than for patients with a CTC count ≥3, 25.1 months versus 16.2 months, respectively (p = .0095). CONCLUSIONS: The CTC count is a strong prognostic factor for PFS and OS outcomes in metastatic colorectal cancer patients.

Cisplatin and gemcitabine administered every two weeks in patients with locally advanced or metastatic urothelial carcinoma and impaired renal function.

BACKGROUND: Cisplatin-based combination chemotherapy is the mainstay of treatment for locally advanced or metastatic urothelial carcinoma. However, standard dose schedule of cisplatin cannot be used in patients with impaired renal function. We evaluated the safety and efficacy of gemcitabine and a split dose administration of cisplatin in patients with renal dysfunction. PATIENTS AND METHODS: Patients with locally advanced or metastatic urothelial carcinoma with creatinine clearance between 35 and 59 ml/min received gemcitabine 2500 mg/m(2) and cisplatin 35 mg/m(2) on day 1 and day 15 for an every 28 day schedule. RESULTS: Between March 2004 and November 2009, 38 patients were treated. Median creatinine clearance was 49 ml/min. Median number of cycles per patient was 3 (1-7). There were 15 partial responses (39%) and 12 patients had stable disease (31%). Median progression free survival and overall survival were 3.5 and 8.5 months (mo), respectively. Grade 3-4 haematological toxicities were: neutropenia 9%, anaemia 6% and thrombocytopenia 16%. No patient developed renal toxicity. CONCLUSIONS: Biweekly gemcitabine and cisplatin is an active and feasible regimen in this subset of patients and could be an option for unfit patients. However, results seem not to be superior to those obtained with carboplatin based regimens in this population of patients.

First-line XELOX plus bevacizumab followed by XELOX plus bevacizumab or single-agent bevacizumab as maintenance therapy in patients with metastatic colorectal cancer: the phase III MACRO TTD study.

PURPOSE: The aim of this phase III trial was to compare the efficacy and safety of bevacizumab alone with those of bevacizumab and capecitabine plus oxaliplatin (XELOX) as maintenance treatment following induction chemotherapy with XELOX plus bevacizumab in the first-line treatment of patients with metastatic colorectal cancer (mCRC). PATIENTS AND METHODS: Patients were randomly assigned to receive six cycles of bevacizumab, capecitabine, and oxaliplatin every 3 weeks followed by XELOX plus bevacizumab or bevacizumab alone until progression. The primary endpoint was the progression-free survival (PFS) interval; secondary endpoints were the overall survival (OS) time, objective response rate (RR), time to response, duration of response, and safety. RESULTS: The intent-to-treat population comprised 480 patients (XELOX plus bevacizumab, n = 239; bevacizumab, n = 241); there were no significant differences in baseline characteristics. The median follow-up was 29.0 months (range, 0-53.2 months). There were no statistically significant differences in the median PFS or OS times or in the RR between the two arms. The most common grade 3 or 4 toxicities in the XELOX plus bevacizumab versus bevacizumab arms were diarrhea, hand-foot syndrome, and neuropathy. CONCLUSION: Although the noninferiority of bevacizumab versus XELOX plus bevacizumab cannot be confirmed, we can reliably exclude a median PFS detriment >3 weeks. This study suggests that maintenance therapy with single-agent bevacizumab may be an appropriate option following induction XELOX plus bevacizumab in mCRC patients.

Identification of a mutation in the extracellular domain of the Epidermal Growth Factor Receptor conferring cetuximab resistance in colorectal cancer.

Antibodies against epidermal growth factor receptor (EGFR)--cetuximab and panitumumab--are widely used to treat colorectal cancer. Unfortunately, patients eventually develop resistance to these agents. We describe an acquired EGFR ectodomain mutation (S492R) that prevents cetuximab binding and confers resistance to cetuximab. Cells with this mutation, however, retain binding to and are growth inhibited by panitumumab. Two of ten subjects studied here with disease progression after cetuximab treatment acquired this mutation. A subject with cetuximab resistance harboring the S492R mutation responded to treatment with panitumumab.

Colorectal cancer survival: results from a hospital-based cancer registry.

INTRODUCTION: colorectal cancer is one of the most common malignancies in developed countries. Data on specific and 10-year survival are scarce. This study analyzes overall and disease-specific survival for patients with colorectal cancer and assesses the value of clinical factors on disease-specific survival. METHODS: a retrospective cohort study of newly diagnosed invasive colorectal cancer cases diagnosed from 1992 to 2007 were identified through the Hospital del Mar Cancer Registry. Five-and 10-year survival functions were estimated using Kaplan-Meier method. Cox proportional hazard models were used to assess prognostic factors. RESULTS: a total of 2,080 patients with colorectal cancer were identified. The median age at diagnosis was 72 years and 58.5%were men. By the end of the follow-up period (December 2008), 1,225 patients had died and 68.4% of deaths were due to colorectal cancer. The 5- and 10-year cancer-specific survival rates were 55.5% (95%CI 53.9-57.9%) and 48.5% (95%CI 45.6-51.3%), respectively. The 5-year specific survival rate improved in the last period (2003-2007) (60.4%, 95%CI 55.4-65.0) compared with 1992-1997(53.4%; 95%CI 49.2-57.4) and 1998-2002 (52.0%; 95%CI 47.8-56.2). Various factors were independently associated with excess CRC mortality: male sex (HR 1.21), age at diagnosis > 75 years(HR 1.97), rectal location (HR 1.33), more advanced stages (stage IV: HR 18.54), poorly differentiated/undifferentiated tumors (HR 1.80), and admission through the emergency department (HR 1.52). CONCLUSIONS: cancer-specific survival improved from 1992 to 2007. This improvement could be due to more effective treatment, since changes in stage distribution or age at diagnosis were not observed during the study period. Overall survival rates should notably improve with the implementation of a population-based colorectal cancer screening program in Spain.

Phase II, randomized study of concomitant chemoradiotherapy followed by surgery and adjuvant capecitabine plus oxaliplatin (CAPOX) compared with induction CAPOX followed by concomitant chemoradiotherapy and surgery in magnetic resonance imaging-defined, locally advanced rectal cancer: Grupo cancer de recto 3 study.

PURPOSE The optimal therapeutic sequence of the adjuvant chemotherapy component of preoperative chemoradiotherapy (CRT) for patients with locally advanced rectal cancer is controversial. Induction chemotherapy before preoperative CRT may be associated with better efficacy and compliance. PATIENTS AND METHODS A total of 108 patients with locally advanced rectal cancer were randomly assigned to arm A-preoperative CRT with capecitabine, oxaliplatin, and concurrent radiation followed by surgery and four cycles of postoperative adjuvant capecitabine and oxaliplatin (CAPOX)-or arm B-induction CAPOX followed by CRT and surgery. The primary end point was pathologic complete response rate (pCR). Results On an intention-to-treat basis, the pCR for arms A and B were 13.5% (95% CI, 5.6% to 25.8%) and 14.3% (95% CI, 6.4% to 26.2%), respectively. There were no statistically significant differences in other end points, including downstaging, tumor regression, and R0 resection. Overall, chemotherapy treatment exposure was higher in arm B than in arm A for both oxaliplatin (P < .0001) and capecitabine (P < .0001). During CRT, grades 3 to 4 adverse events were similar in both arms but were significantly higher in arm A during postoperative adjuvant CT than with induction CT in arm B. There were three deaths in each arm during the treatment period. CONCLUSION Compared with postoperative adjuvant CAPOX, induction CAPOX before CRT had similar pCR and complete resection rates. It did achieve more favorable compliance and toxicity profiles. On the basis of these findings, a phase III study to definitively test the induction strategy is warranted.

Symptom-to-diagnosis interval and survival in cancers of the digestive tract.

The objective was to identify the main correlates of the symptom-to-diagnosis interval (SDI) and to analyze their influence upon the survival in patients with cancers of the digestive tract. Two hundred forty-eight symptomatic patients with cancer of the esophagus (N = 31), stomach (N = 70), colon (N = 84), and rectum (N = 66) were interviewed and prospectively followed (median follow-up of 77 months). Cox's regression was used to assess the relative risk (RR) of death according to SDI. The median SDI was about 4 months, with nonsignificant differences by sex, age, social class, family history of cancer, or tumor site. The RR of death varied significantly by age (P = 0.012), tumor site (P < 0.01), tumor stage (P < 0.01), and type of hospital admission (P < 0.01). After adjustment for known and potential predictors of survival and as compared to an SDI < 2.5 months, the RR of death was 0.89 (95% CI: 0.61-1.32) for an SDI of 2.5-6 months, 0.78 (95% CI: 0.49-1.26) for SDI > 6-12 months, and 0.81 (95% CI: 0.44-1.49) for SDI > 12 months. These results do not imply that specific actions to hasten diagnosis must of necessity be ineffective, but underscore what a challenging task the secondary prevention of cancer remains.