Evaluation of Circulating Tumor DNA for Methylated BCAT1 and IKZF1 to Detect Recurrence of Stage II/Stage III Colorectal Cancer (CRC).

BACKGROUND: Most recurrences of early-stage colorectal cancer detected with current surveillance measures are widespread and incurable. Circulating tumor DNA (ctDNA) may facilitate earlier diagnosis of recurrent colorectal cancer and improve cancer-related outcomes. METHODS: Plasma from patients undergoing standard surveillance after definitive treatment for stage II/III colorectal cancer was assayed with COLVERA and carcinoembryonic antigen (CEA) at a single time point. Results were correlated with radiographic imaging. Assay performance, including sensitivity and specificity for recurrence, were compared. Impact of potentially confounding variables was also explored. RESULTS: 322 patients were included in the final analysis, and 27 recurrences were documented over a median follow-up period of 15 months. Sensitivity for recurrence was 63% [confidence interval (CI), 42.4-80.6] and 48% (CI, 28.7-68.1) for COLVERA and CEA (≥5 ng/mL), respectively (P = 0.046), while specificity was 91.5% (CI, 87.7-94.4) and 96.3% (CI, 93.4-98.1), respectively (P = 0.016). Smoking and age were independent predictors of CEA but not COLVERA positivity. CONCLUSIONS: COLVERA was more sensitive but less specific than CEA in detecting recurrent colorectal cancer. Short median follow-up may have been responsible for apparent false positives in COLVERA. Studies with serial sampling and longer follow-up are needed to assess whether earlier detection of colorectal cancer recurrence translates into clinical benefit. IMPACT: This prospective study showed that COLVERA (a two-gene ctDNA assay) was more sensitive for detection of recurrence in a cohort of patients undergoing surveillance after definitive therapy for stages II and III colorectal cancer.

Four Synchronous Primary Malignancies of the Breast, Lung, Colon and Esophagus.

The literature contains few reports of patients with four more or more synchronous primary malignancies. We report the case of a 74-year-old woman who presented with synchronous primary malignant neoplasms of the breast (metaplastic carcinoma), lung (squamous cell carcinoma), esophagus (adenocarcinoma), and colon (adenocarcinoma). She was treated with multimodality therapy and demonstrated a favorable response at early follow-up. To our knowledge, this combination of synchronous primary malignancies has not been previously reported. The management of patients with multiple synchronous primary malignancies introduces a number of unique challenges which necessitate highly individualized treatment plans that may not strictly adhere to standard practices in the setting of a single malignancy.

Radiographic staging practices of newly diagnosed colorectal cancer vary according to medical specialty.

BACKGROUND: Since 2008, multiple guidelines have endorsed incorporation of chest CT in the radiographic staging assessment of newly diagnosed colorectal cancer (CRC). Radiographic staging practices performed after CRC is detected have not been studied. OBJECTIVE: To evaluate radiographic staging practices for newly diagnosed CRC between gastroenterologists versus non-gastroenterologists. DESIGN: Observational cohort study. SETTING: Single, tertiary-care referral center. PATIENTS: Patients newly diagnosed with a T1 or higher stage CRC at time of colonoscopy between 2008 and 2013. INTERVENTIONS: Radiographic staging. MAIN OUTCOME MEASUREMENTS: Radiographic preoperative staging examinations ordered by gastroenterologists in comparison to those ordered by non-gastroenterology specialists. RESULTS: This study included 277 patients with CRC newly diagnosed by colonoscopy. There were 141 total ordering physicians (68 gastroenterologists and 73 non-gastroenterologists). The majority of preoperative radiographic staging was performed by gastroenterologists (59.2% of patients, n = 164). Colorectal surgeons managed staging in 28.7% of patients (n = 47). Gastroenterologists were more likely to omit a staging chest CT than were non-gastroenterologists (64.6% vs 46.9%; P < .001). Physician practice setting, rectal location of tumor, and advanced endoscopic appearance of tumors were predictors of chest CT inclusion. LIMITATIONS: Single center, moderate sample size of both providers and patients. CONCLUSION: Gastroenterologists more frequently ordered the initial radiographic staging studies in newly diagnosed CRC patients. However, gastroenterologists were less likely to include chest CT in the initial staging of CRC despite current guideline recommendations to do so. If confirmed with further studies, educational efforts to improve compliance and standardization may be needed.

A phase I study of the biomodulation of capecitabine by docetaxel and gemcitabine (mGTX) in previously untreated patients with metastatic adenocarcinoma of the pancreas.

BACKGROUND: Pancreas cancer remains a formidable challenge. We report the first prospective analysis of the 3-drug combination of gemcitabine (G), docetaxel (T) and capecitabine (X) (mGTX) with schedule modification to maximize biomodulation of X. METHODS: We conducted a dose escalation study of mGTX in first-line treatment of metastatic pancreas cancer using three dose levels (DL 1-3). Patients received docetaxel on days 1 and 8, gemcitabine on days 8 and 15, and capecitabine on days 8 through 21. Gemcitabine dose was fixed at 750 mg/m² over 75 min, capecitabine was given twice daily and escalated from 500 to 650 mg/m² at DL2 and docetaxel increased from 30 to 36 mg/m² at DL3. RESULTS: Twenty-one patients (18 evaluable) were enrolled in the study. MTD was reached at DL3 and one DLT was observed at DL2 (prolonged neutropenia). The most common grade 3/4 toxicities were leukopenia (29%) and neutropenia (29%) and fatigue (25%). Tumor growth control rate was 80% (11% PR; 69% SD lasting at least 3 months). Median progression-free-survival was 5.8 months (95% CI 2.7, 10.6) and median overall survival was 7.4 months (95% CI 3.8 16.8). CA 19-9 decreased by at least 50% from baseline in half the patients. CONCLUSION: mGTX demonstrates acceptable tolerability with interesting activity in patients with pancreatic cancer. The recommended doses for phase II studies are docetaxel 36 mg/m² days 1 and 8, gemcitabine 750 mg/m² over 75 min days 8 and 15, and capecitabine 625 mg/m² twice daily days 8 through 21.

A phase I dose escalation study of a pharmacobiologically based scheduling of capecitabine and mitomycin C in patients with gastrointestinal malignancies.

BACKGROUND: Mitomycin C (MMC) produces significant upregulation of thymidine phosphorylase, a principal determinant of the therapeutic index of capecitabine-based treatment, starting 4-6 days after treatment. On the basis of the time-dependency of this upregulation, we performed a phase I dose escalation study of capecitabine and MMC in patients with gastrointestinal malignancies. METHODS: A total of 29 patients with advanced gastrointestinal malignancies received MMC at 6 mg/m2 on day 1 and capecitabine escalated in four successive patient cohorts of doses 500-1,000 mg/m2/day twice daily on days 8-21, every 28 days. MMC was capped at 36 mg/m2. RESULTS: A total of 29 patients were enrolled and 90% had at least one prior treatment in the metastatic setting. There was one DLT, grade 3 hand and foot syndrome, at dose level four. The most common toxicity was fatigue (61%). No patients experienced grade 4 toxicities. Nine patients experienced prolonged stability of disease. CONCLUSION: Capecitabine in combination with MMC in the proposed schedule is well-tolerated with evidence of preliminary activity. The recommended dose for phase II studies are MMC at 6 mg/m2 on day 1 of a 28-day cycle with the dose capped at 36 mg/m2, in combination with capecitabine at 1,000 mg/m2 twice daily on days 8-21.