NEO-GAP: A Single-Arm, Phase II Feasibility Trial of Neoadjuvant Gemcitabine, Cisplatin, and Nab-Paclitaxel for Resectable, High-Risk Intrahepatic Cholangiocarcinoma.

PURPOSE: Most patients with intrahepatic cholangiocarcinoma (IHCC) develop recurrence after resection. Adjuvant capecitabine remains the standard of care for resected IHCC. A combination of gemcitabine, cisplatin, and nab-paclitaxel (GAP) was associated with a 45% response rate and 20% conversion rate among patients with unresectable biliary tract cancers. The aim of this study was to evaluate the feasibility of delivering GAP in the neoadjuvant setting for resectable, high-risk IHCC. METHODS: A multi-institutional, single-arm, phase II trial was conducted for patients with resectable, high-risk IHCC, defined as tumor size > 5 cm, multiple tumors, presence of radiographic major vascular invasion, or lymph node involvement. Patients received preoperative GAP (gemcitabine 800 mg/m2, cisplatin 25 mg/m2, and nab-paclitaxel 100 mg/m2 on days 1 and 8 of a 21-day cycle) for a total of 4 cycles prior to an attempt at curative-intent surgical resection. The primary endpoint was completion of both preoperative chemotherapy and surgical resection. Secondary endpoints were adverse events, radiologic response, recurrence-free survival (RFS), and overall survival (OS). RESULTS: Thirty evaluable patients were enrolled. Median age was 60.5 years. Median follow-up for all patients was 17 months. Ten patients (33%) experienced grade ≥ 3 treatment-related adverse events, the most common being neutropenia and diarrhea; 50% required ≥ 1 dose reduction. The disease control rate was 90% (progressive disease: 10%, partial response: 23%, stable disease: 67%). There was zero treatment-related mortality. Twenty-two patients (73%, 90% CI 57-86; p = 0.008) completed all chemotherapy and surgery. Two patients (9%) who successfully underwent resection had minor postoperative complications. Median length of hospital stay was 4 days. Median RFS was 7.1 months. Median OS for the entire cohort was 24 months and was not reached in patients who underwent surgical resection. CONCLUSION: Neoadjuvant treatment with gemcitabine, cisplatin, and nab-paclitaxel is feasible and safe prior to resection of intrahepatic cholangiocarcinoma and does not adversely impact perioperative outcomes.

Severe Thrombocytopenia in Patients With Advanced Neuroendocrine Tumor Treated With Peptide Receptor Radioligand Therapy.

BACKGROUND: Peptide receptor radioligand therapy (PRRT) was Food and Drug Administration approved in 2018 for the treatment of unresectable somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumors (NETs) and provides an important option for patients with advanced disease. A known adverse effect of this treatment is hematologic toxicity, although usually transient. We present 3 patients with metastatic gastroenteropancreatic NETs treated with PRRT who were evaluated for severe persistent thrombocytopenia. METHODS: Three patients who commenced therapy with PRRT were known to proceed to a bone marrow (BM) biopsy for persistent severe thrombocytopenia and were included in this study. These patients were identified retrospectively and evaluated for their tumor properties, including immunohistochemical markers, treatment modalities, and clinical outcomes. RESULTS: All 3 patients had metastatic NETs that progressed on prior lines of therapy and were treated with 1 to 4 doses of 177Lu-DOTATATE 7.4 GBq (200 mCi) before developing grade 3 (25,000 to 50,000/µL) refractory thrombocytopenia. All patients had concurrent bone metastases, and 2 of the 3 had baseline grade 1 thrombocytopenia. In all 3 cases, BM biopsy documented widespread tumor infiltration. CONCLUSIONS: Severe refractory thrombocytopenia after PRRT is rare and may result from numerous known causes, including radiation-induced myelotoxicity, myelodysplastic syndrome, and tumor BM infiltration. We present 3 cases of thrombocytopenia related to persistent or progressive BM metastasis. Although known bone metastasis is not a contraindication to PRRT, thrombocytopenia may be a manifestation of tumor progression and should be considered when making decisions about continuation of therapy.

Sustained Carbohydrate Antigen 19-9 Response to Neoadjuvant Chemotherapy in Borderline Resectable Pancreatic Cancer Predicts Progression and Survival.

BACKGROUND: As neoadjuvant therapy of borderline resectable pancreatic cancer (BRPC) is becoming more widely used, better indicators of progression are needed to help guide therapeutic decisions. MATERIALS AND METHODS: A retrospective review was performed on all patients with BRPC who received 24 weeks of neoadjuvant chemotherapy. Patients with chemotoxicity or medical comorbidities limiting treatment completion and nonexpressors of carbohydrate antigen 19-9 (CA19-9) were excluded. Serum CA19-9 response was analyzed as a predictor of disease progression, recurrence, and survival. RESULTS: One hundred four patients were included; 39 (37%) progressed on treatment (18 local and 21 distant) and 65 (63%) were resected (68% R0). Multivariate logistic regression analysis determined that the percent decrease in CA19-9 from baseline to minimum value (odds ratio [OR] 0.947, p ≤ .0001) and the percent increase from minimum value to final restaging CA19-9 (OR 1.030, p ≤ .0001) were predictive of progression. A receiver operating characteristics curve analysis determined cutoff values predictive of progression, which were used to create four prognostic groups. CA19-9 responses were categorized as follows: (1) always normal (n = 6); (2) poor response (n = 31); (3) unsustained response (n = 19); and (4) sustained response (n = 48). Median overall survival for Groups 1-4 was 58, 16, 20, and 38 months, respectively (p ≤ .0001). CONCLUSION: Patients with initially elevated CA19-9 levels who do not have a decline to a sustained low level are at risk for progression, recurrence, and poor survival. Alternative treatment strategies prior to an attempt at curative resection should be considered in this cohort. IMPLICATIONS FOR PRACTICE: This study identified percent changes in carbohydrate antigen 19-9 blood levels while on chemotherapy that predict tumor growth in patients with advanced pancreas cancer. These changes could be used to better select patients who would benefit from surgical removal of their tumors and improve survival.

Palliative TACE for hepatic metastases of chromophobe renal cell carcinoma.

We describe the case of a man with chromophobe renal cell carcinoma (chRCC) and numerous metastatic lesions restricted to the liver. Despite extensive courses of various systemic targeted chemotherapies, progressive disease was noted on CT and MRI and the patient suffered from persistent abdominal pain associated with his metastatic lesions. The liver lesions and associated symptoms were effectively palliated with serial transarterial chemoembolisation (TACE). While it is unclear if TACE has impacted his overall survival, this case encourages the use of TACE for palliative intent for patients with metastatic chRCC.

Gemcitabine and Taxane Adjuvant Therapy with Chemoradiation in Resected Pancreatic Cancer: A Novel Strategy for Improved Survival?

BACKGROUND: Gemcitabine-taxane combination chemotherapy has demonstrated a survival benefit clinically in metastatic pancreatic cancer (PC). The authors present their experience with gemcitabine and docetaxel (gem/tax)-based adjuvant treatment (Rx) after surgery with curative intent. METHODS: Patients with de novo resectable PC from January 2010 to December 2015 were identified from the authors' institutional database and registry. The study included only patients who received gem/tax as their initial Rx administered exclusively at the authors' institution with or without chemoradiation (CRTx). Survival analysis was performed using Kaplan-Meier methods, and prognostic factors were investigated by Cox proportional hazard modeling. RESULTS: Of 102 patients identified, 58 met the study criteria. The median age at diagnosis was 65 years, with 55% of the patients undergoing an R1 resection (margin ≤ 1 mm). Tumor characteristics included a median tumor size of 28 mm, a poor differentiation rate of 54%, and a lymph node positivity of 67%. Most of the patients (90%, 52/58) completed 80% or more of the 24 week Rx. Of these patients, 71% received post-gem/tax CRTx Rx. Grade 3 or 4 toxicity was observed in 52% of the patients. The median follow-up period was 51.2 months, and the observed median overall survival (OS) was 52 months [95% confidence interval (CI) 27.4-not reached]. The actuarial 5-year OS was 49% (95% CI 33.7-63.4%). In the multivariate analysis, an R1 resection and American Joint Committee on Cancer (AJCC) stage 2 versus stage 1 disease were negatively associated with OS, whereas administration of CRTx was positively associated with OS. CONCLUSIONS: Adjuvant gem/tax with or without CRTx is feasible, with a favorable OS. Future prospective studies of gem/taxane-based adjuvant Rx for PC are warranted.

Role of primary tumor resection among chemotherapy-treated patients with synchronous stage IV colorectal cancer: a survival analysis.

INTRODUCTION: The benefit of an operation to remove the primary tumor among patients with synchronous stage IV colorectal cancer is controversial. This study analyzed the survival benefits associated with primary tumor resection among chemotherapy-treated stage IV colorectal cancer patients. METHODS: The study analyzed 11,716 chemotherapy-treated stage IV colorectal cancer patients in the California Cancer Registry between 1996 and 2007, with follow-up through 2009. Patients were stratified into operation and non-operation groups. Estimates of median overall and colorectal cancer-specific survival were generated. RESULTS: Patients undergoing operation compared to those who are not had higher median overall and colorectal cancer-specific survival, 21 versus 10 months (p < 0.0001) and 22 versus 12 months (p < 0.0001), respectively. Patients who were offered surgery but refused had decreased median overall and colorectal cancer-specific survival when compared to patients who underwent resection, 8 versus 21 months (p < 0.001) and 7 versus 22 months (p < 0.001), respectively. In multivariate regression models, patients who underwent resection of primary tumor had improved overall (hazard ratio (HR), 0.42; 95% confidence interval (CI) 0.40-0.44, p < 0.0001) and colorectal cancer-specific survival (HR, 0.43; 95% CI, 0.41-0.45; p < 0.0001). CONCLUSION: Primary tumor resection is associated with improved survival among stage IV chemotherapy-treated colorectal cancer patients.

Mortality risk after preoperative versus postoperative chemotherapy and radiotherapy in lymph node-positive rectal cancer.

INTRODUCTION: Persistent lymph node-positive disease after preoperative radiotherapy for rectal cancer is associated with adverse outcomes. We quantified mortality risks of persistent pathologic lymph nodes in lymph node-positive rectal cancer patients treated with preoperative versus postoperative chemoradiation. METHODS: This was a retrospective population-based analysis of 2,038 patients with stage III rectal cancer diagnosed 1994-2005 with follow-up through 2007 using data from the California Cancer Registry. Survival estimates were generated using the Kaplan-Meier method. Multivariate cancer-specific and overall mortality analyses were performed using Cox proportional hazard ratios with adjustment for age, gender, race/ethnicity, tumor grade, T stage, N stage, socioeconomic status, and time period (1994-1997, 1998-2001, and 2002-2005). RESULTS: Overall survival was higher among lymph node-positive patients receiving postoperative chemoradiation compared to lymph node-positive patients receiving preoperative chemoradiation (median overall survival = 87 versus 62 months, P = 0.0002). In adjusted analyses, patients with persistent lymph node-positive disease after preoperative chemoradiation treatment had increased overall (HR = 1.69; 95 % CI, 1.42-2.01) and CRC-specific (HR = 1.78; 95 % CI, 1.44-2.19) mortality risk compared to lymph node-positive disease after postoperative chemoradiation treatment. CONCLUSIONS: Stage III rectal cancer patients with persistent pathologic lymph nodes after preoperative chemoradiation represent a high-risk group, with higher mortality than those treated with postoperative chemoradiation.

Meat consumption, ornithine decarboxylase gene polymorphism, and outcomes after colorectal cancer diagnosis.

BACKGROUND: Dietary arginine and meat consumption are implicated in colorectal cancer (CRC) progression via polyamine-dependent processes. Polymorphism in the polyamine-regulatory gene, ornithine decarboxylase 1 (Odc1, rs2302615) is prognostic for CRC-specific mortality. Here, we examined joint effects of meat consumption and Odc1 polymorphism on CRC-specific mortality. MATERIALS AND METHODS: The analytic cohort was comprised of 329 incident stage I-III CRC cases diagnosed 1994-1996 with follow- up through March 2008. Odc1 genotyping was conducted using primers that amplify a 172-bp fragment containing the polymorphic base at +316. Dietary questionnaires were administered at cohort entry. Multivariate Cox proportional hazards regression analysis for CRC-specific mortality was stratified by tumor, node, metastasis (TNM) stage, and adjusted for clinically relevant variables, plus meat consumption (as a continuous variable, i.e., the number of medium-sized servings/week), Odc1 genotype, and a term representing the meat consumption and Odc1 genotype interaction. The primary outcome was the interaction of Odc1 and meat intake on CRC-specific mortality, as assessed by departures from multiplicative joint effects. RESULTS: Odc1 genotype distribution was 51% GG, 49% GA/AA. In the multivariate model, there was a significant interaction between meat consumption and Odc1 genotype, P-int = 0.01. Among Odc1 GA/AA CRC cases in meat consumption Quartiles 1-3, increased mortality risk was observed when compared to GG cases (adjusted hazards ratio (HR) = 7.06 [95% CI 2.34-21.28]) - a difference not found among cases in the highest dietary meat consumption Quartile 4. CONCLUSIONS: Effects of meat consumption on CRC-specific mortality risk differ based on genetic polymorphism at Odc1. These results provide further evidence that polyamine metabolism and its modulation by dietary factors such as meat may have relevance to CRC outcomes.

Role of obesity in a randomized placebo-controlled trial of difluoromethylornithine (DFMO) + sulindac for the prevention of sporadic colorectal adenomas.

BACKGROUND: Chemoprevention with the polyamine-inhibitory regimen difluoromethylornithine (DFMO) + sulindac markedly reduces risk of recurrent adenoma in colorectal adenoma patients. Obesity is associated with risk of colorectal adenoma and colorectal cancer. This study investigates how obesity influences risk of recurrent adenoma after prolonged treatment with DFMO + sulindac versus placebo. METHODS: Our analysis included subjects enrolled in the phase III colorectal adenoma prevention clinical trial investigating DFMO + sulindac versus placebo. Patients were classified by obesity (body mass index, BMI ≥ 30 kg/m(2)) status at baseline. Pearson χ(2) statistic and Mann-Whitney U test were used to compare baseline characteristics, including rectal tissue polyamine levels. Log-binomial regression analysis was used to determine the risk ratio (RR) of recurrent adenomas, adjusted for covariates and an interaction term for obesity and treatment. RESULTS: The final analytic cohort was comprised of 267 patients. In separate regression models, the risk of adenoma recurrence after treatment compared to placebo was similar for obese (RR = 0.32, 95 % CI 15-71) and non-obese patients (RR = 0.27, 95 % CI 15-49). No significant interaction was detected between obesity, treatment, and risk of colorectal adenoma in the full regression model (p (interaction) = 0.91). CONCLUSIONS: Obesity does not substantially modify the colorectal adenoma risk reduction ascribed to DFMO + sulindac versus placebo.

Population-based evaluation of adenosquamous carcinoma of the colon and rectum.

BACKGROUND: Information about adenosquamous carcinoma of the colon and rectum is scarce because of its extremely low incidence. OBJECTIVE: The aim of this study was to examine the prognostic significance of a histological diagnosis of adenosquamous carcinoma in comparison with adenocarcinoma of the colon and rectum. DESIGN: This study was retrospective in design. SETTING: California Cancer Registry data from 1994 through 2004 with follow-up through 2008 were analyzed. PATIENTS: Patients were included whose cancer of the colon and rectum, excluding the anus with a tumor histology of adenocarcinoma and adenosquamous carcinoma, was surgically treated. MAIN OUTCOME MEASURES: The primary outcomes measured were histology-specific survival analyses (with the use of the Kaplan-Meier method), and overall and colorectal-specific mortality (with the use of multivariable Cox proportional hazards regression analyses). RESULTS: A total of 111,263 adenocarcinoma and adenosquamous carcinoma of colon and rectal cancer cases were identified (adenocarcinoma, 99.91%; adenosquamous carcinoma, 0.09%). There was no significant difference in sex, age, race, and socioeconomic status between the 2 groups. The most common location of adenocarcinoma and adenosquamous carcinoma was the right and transverse colon. The adenosquamous carcinoma group was significantly associated with a higher rate of metastasis at the time of operation (adenosquamous carcinoma, 36.56% vs adenocarcinoma, 13.92%) and with poorly differentiated tumor grade (adenosquamous carcinoma, 65.96% vs adenocarcinoma, 19.74%) in comparison with the adenocarcinoma group. The median overall survival time was significantly greater in the adenocarcinoma group (82.4 months) in comparison with the adenosquamous carcinoma group (35.3 months). With the use of multivariable hazard regression analyses, adenosquamous carcinoma histology was independently associated with increased overall mortality (hazard ratio, 1.67) and colorectal-specific mortality (hazard ratio, 1.69) in comparison with adenocarcinoma. CONCLUSIONS: This is one of the largest studies of adenosquamous carcinoma of the colon and rectum to date. This uncommon colorectal cancer subtype was associated with higher overall and colorectal-specific mortality in comparison with adenocarcinoma. Among colorectal cancer cases, adenosquamous carcinoma histology should be considered a poor prognostic feature.