Jinru Shia

Cetuximab Shows Activity in Colorectal Cancer Patients With Tumors That Do Not Express the Epidermal Growth Factor Receptor by Immunohistochemistry

PURPOSE To establish evidence of activity, or lack thereof, of cetuximab-based therapy in patients with refractory colorectal cancer with tumors that do not demonstrate epidermal growth factor receptor (EGFR) expression by immunohistochemistry (IHC). PATIENTS AND METHODS Pharmacy computer records were reviewed to identify all patients who received cetuximab at Memorial Sloan-Kettering Cancer Center in a nonstudy setting during the first 3 months of cetuximabs commercial availability. Medical records of these patients were then reviewed to identify colorectal cancer patients who had experienced failure with a prior irinotecan-based regimen and who had a pathology report indicating an EGFR-negative tumor by IHC. Pathology slides from these patients were reviewed by a reference pathologist to confirm EGFR negativity, and computed tomography scans during cetuximab-based therapy were reviewed by a reference radiologist. Response rates were reported using WHO criteria. RESULTS Sixteen chemotherapy-refractory, EGFR-negative colorectal cancer patients who received cetuximab in a nonstudy setting were identified. Fourteen of these patients received cetuximab plus irinotecan, and two received cetuximab monotherapy. In the 16 patients, four major objective responses were seen (response rate, 25%; 95% CI, 4% to 46%). CONCLUSION Colorectal cancer patients with EGFR-negative tumors have the potential to respond to cetuximab-based therapies. EGFR analysis by current IHC techniques does not seem to have predictive value, and selection or exclusion of patients for cetuximab therapy on the basis of currently available EGFR IHC does not seem warranted.

Long-term oncologic outcome following preoperative combined modality therapy and total mesorectal excision of locally advanced rectal cancer

Objective:Our aims were to (1) determine the long-term oncologic outcome for patients with rectal cancer treated with preoperative combined modality therapy (CMT) followed by total mesorectal excision (TME), (2) identify factors predictive of oncologic outcome, and (3) determine the oncologic significance of the extent of pathologic tumor response. Summary Background Data:Locally advanced (T3–4 and/or N1) rectal adenocarcinoma is commonly treated with preoperative CMT and TME. However, the long-term oncologic results of this approach and factors predictive of a durable outcome remain largely unknown. Methods:Two hundred ninety-seven consecutive patients with locally advanced rectal adenocarcinoma at a median distance of 6cm from the anal verge (range 0–15 cm) were treated with preoperative CMT (radiation: 5040 centi-Gray (cGy) and 5-fluorouracil (5-FU)-based chemotherapy) followed by TME from 1988 to 2002. A prospectively collected database was queried for long-term oncologic outcome and predictive clinicopathologic factors. Results:With a median follow-up of 44 months, the estimated 10-year overall survival (OS) was 58% and 10 year recurrence-free survival (RFS) was 62%. On multivariate analysis, pathologic response >95%, lymphovascular invasion and/or perineural invasion (PNI), and positive lymph nodes were significantly associated with OS and RFS. Patients with a >95% pathologic response had a significantly improved OS (P = 0.003) and RFS (P = 0.002). Conclusions:Treatment of locally advanced rectal cancer with preoperative CMT followed by TME can provide for a durable 10-year OS of 58% and RFS of 62%. Patients who achieve a >95% response to preoperative CMT have an improved long-term oncologic outcome, a novel finding that deserves further study.

Long-term Survival Following Treatment of Pseudomyxoma Peritonei: An Analysis of Surgical Therapy

Summary Background Data:Pseudomyxoma peritonei (PMP) is a clinical syndrome with a poorly defined natural history. Relative contributions of tumor biology, patient selection, and the extent of treatment on ultimate outcome are not well characterized. Methods:Patients treated at the Memorial Sloan-Kettering Cancer Center between 1980 and 2002 with a diagnosis of PMP were identified. Patient characteristics, pathologic features, and details of treatment were analyzed retrospectively. Results:The 97 patients included in this study underwent a mean 2.2 ± 0.1 operations (range, 1–6). Although complete cytoreduction was achieved in 55% (53/97), disease recurred in 91% (48/53) of patients. The median disease-free interval after complete cytoreduction was 24 months. The median overall survival was 9.8 years and was independently associated with low-grade pathologic subtype (P < 0.001) and the ability to achieve complete cytoreduction (P < 0.001). Ten-year survival was attained in 21% (20/97) of the patients, of which 90% (18/20) had low-grade pathologic features. At the time of death or completion of follow-up, only 12% (12/97) of the patients were disease free. Conclusions:Outcome in patients with PMP is strongly associated with tumor biology. Although improved survival is associated with low-grade pathology and tumors amenable to complete cytoreduction, recurrence of PMP is common. Treatment may be beneficial, particularly in controlling symptoms, but absolute cure, defined as a prolonged disease-free state, is uncommon.

Neuroendocrine carcinomas of the colon and rectum.

PURPOSE: This study was designed to review experience with neuroendocrine carcinomas of the colon and rectum at a single institution, with emphasis on the pathology and clinical characteristics of this uncommon malignancy. METHODS: A study group of patients was identified from a prospective colorectal service database. Pathology was reviewed and neuroendocrine tumors were classified by a single pathologist. Medical records were retrospectively reviewed. RESULTS: From March 1975 to September 1998, 38 patients with neuroendocrine carcinomas were identified from the colorectal service database comprising 6495 patients (0.6 percent). These neuroendocrine carcinomas did not include carcinoid tumors. Average patient age was 57 years (range, 29–86 years). There were 17 males (44.7 percent) and 21 females (55.3 percent). Tumors were located as follows: 17 colon, 14 rectum, 6 anal canal, and 1 appendix. The diagnosis of neuroendocrine carcinoma was suggested preoperatively from tissue biopsy in 59.3 percent (16/27) of patients evaluable. Pathology was reviewed and tumors were categorized as small cell carcinoma (n = 22) or large cell neuroendocrine carcinoma (n = 16). Most tumors (20/25 evaluable, 80 percent) stained positive by means of immunohistochemistry for neuroendocrine markers, including chromogranin (18/19), synaptophysin (10/15), and/or neuron-specific enolase (14/15). Metastatic disease was detected at the time of diagnosis in 69.4 percent of the patients (25/36). Tumors were advanced at the time of diagnosis, with American Joint Committee on Cancer (AJCC) Stage I (n = 6), Stage III (n = 7), and Stage IV (n = 25) tumors. As a group, these tumors had a poor prognosis, with a median survival of 10.4 months. One-year, two-year, and three-year survival was 46 percent, 26 percent, and 13 percent, respectively. There was no significant difference in survival based on pathologic subtypes. Median follow-up time was 9.4 months (range, 0.6–263.7 months). CONCLUSIONS: Neuroendocrine carcinomas of the colon and rectum are uncommon, comprising less than 1 percent of colon and rectal cancers. Pathologically, these tumors are poorly differentiated carcinomas with distinctive cytoarchitectural features and are often immunoreactive for markers of neuroendocrine differentiation. The prognosis for highgrade neuroendocrine carcinomas is poor, as most patients have metastatic disease at the time of diagnosis.

Operative Blood Loss Independently Predicts Recurrence and Survival After Resection of Hepatocellular Carcinoma

Objective:To determine if the degree of blood loss during resection of hepatocellular carcinoma (HCC) is predictive of recurrence and long-term survival. Background:Several studies have addressed the impact of blood transfusion on survival and recurrence after liver resection for HCC. However, the independent effect of intraoperative estimated blood loss (EBL) on oncologic outcome is unclear. Methods:From our prospective database, we identified 192 patients who had a partial hepatectomy for HCC from 1985 to 2002. Clinicopathologic predictors of EBL were identified using logistic regression. Overall survival (OS), disease-specific survival (DSS), and recurrence free survival (RFS) were assessed using the Kaplan-Meier and Cox regression methods. Results:The median patient age was 64 (range, 19–86) and 66% were men. All patients had histologically proven HCC. The median follow-up time was 34 months (range, 1–297). Factors associated with increased EBL on multivariate analysis were male gender, vascular invasion, extent of hepatectomy, and operative time (P < 0.01). EBL and vascular invasion were independent predictors of OS and DSS. Only EBL was significantly associated with RFS on multivariate analysis (P = 0.02). Additionally, we found a significant inverse correlation between increasing levels of EBL and length of DSS (P = 0.01). Conclusions:The magnitude of EBL during HCC resection is related to biologic characteristics of the tumor as well as the extent of surgery. Increased intraoperative blood loss during HCC resection is an independent prognostic factor for tumor recurrence and death.

Relationship of Gene Expression and Chromosomal Abnormalities in Colorectal Cancer

Several studies have verified the existence of multiple chromosomal abnormalities in colon cancer. However, the relationships between DNA copy number and gene expression have not been adequately explored nor globally monitored during the progression of the disease. In this work, three types of array-generated data (expression, single nucleotide polymorphism, and comparative genomic hybridization) were collected from a large set of colon cancer patients at various stages of the disease. Probes were annotated to specific chromosomal locations and coordinated alterations in DNA copy number and transcription levels were revealed at specific positions. We show that across many large regions of the genome, changes in expression level are correlated with alterations in DNA content. Often, large chromosomal segments, containing multiple genes, are transcriptionally affected in a coordinated way, and we show that the underlying mechanism is a corresponding change in DNA content. This implies that whereas specific chromosomal abnormalities may arise stochastically, the associated changes in expression of some or all of the affected genes are responsible for selecting cells bearing these abnormalities for clonal expansion. Indeed, particular chromosomal regions are frequently gained and overexpressed (e.g., 7p, 8q, 13q, and 20q) or lost and underexpressed (e.g., 1p, 4, 5q, 8p, 14q, 15q, and 18) in primary colon tumors, making it likely that these changes favor tumorigenicity. Furthermore, we show that these aberrations are absent in normal colon mucosa, appear in benign adenomas (albeit only in a small fraction of the samples), become more frequent as disease advances, and are found in the majority of metastatic samples.

Rate of Pathologic Complete Response with Increased Interval between Preoperative Combined Modality Therapy and Rectal Cancer Resection

INTRODUCTIONRecent data suggest a favorable prognosis for rectal cancer patients with a pathologic complete response to preoperative combined modality therapy. Prolongation of the interval between preoperative combined modality therapy and surgery (RT-surgery interval) as a means of increasing pathologic complete response rate has not been fully examined.METHODSOne hundred and fifty-five rectal cancer patients undergoing preoperative pelvic external beam radiation therapy and 5-fluorouracil-based chemotherapy followed by rectal resection were identified. All patients had endorectal ultrasound prior to combined modality therapy. Final pathology reports were reviewed for ypT and ypN stage and margin status. Medical records were reviewed for sphincter preservation, operative time, estimated blood loss, hospital stay, and morbidity (overall, anastomotic, and perineal).RESULTSA pathologic complete response (ypT0N0) occurred in 24 patients (15 percent). Median RT-surgery interval was 44 (range, 15-206) days. A pathologic complete response occurred in 19 percent of patients with an interval >44 days, vs. 12 percent in those with an interval ≤44 days (P = 0.27). Downstaging by three stages occurred more frequently in the long-interval group (15 percent vs. 6 percent, P = 0.11). The rates of sphincter preservation, positive margins, estimated blood loss, and operative time were not significantly different. Overall morbidity was similar between groups.CONCLUSIONSOur results demonstrate a trend toward increased pathologic complete response rate and downstaging with increased RT-surgery interval. However, sphincter preservation is not increased. Until prospective analyses are conducted assessing the impact of prolonged RT-surgery interval on long-term outcome, the benefit of a prolonged interval between the completion of preoperative combined modality therapy and surgery remains unclear.

Neoadjuvant Chemotherapy Without Routine Use of Radiation Therapy for Patients With Locally Advanced Rectal Cancer: A Pilot Trial

PURPOSE Although neoadjuvant chemoradiotherapy achieves low local recurrence rates in clinical stages II to III rectal cancer, it delays administration of optimal chemotherapy. We evaluated preoperative infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX)/bevacizumab with selective rather than consistent use of chemoradiotherapy. PATIENTS AND METHODS Thirty-two patients with clinical stages II to III rectal cancer participated in this single-center phase II trial. All were candidates for low anterior resection with total mesorectal excision (TME). Patients were to receive six cycles of FOLFOX, with bevacizumab included for cycles 1 to 4. Patients with stable/progressive disease were to have radiation before TME, whereas responders were to have immediate TME. Postoperative radiation was planned if R0 resection was not achieved. Postoperative FOLFOX × 6 was recommended, but adjuvant regimens were left to clinician discretion. The primary outcome was R0 resection rate. RESULTS Between April 2007 and December 2008, 32 (100%) of 32 study participants had R0 resections. Two did not complete preoperative chemotherapy secondary to cardiovascular toxicity. Both had preoperative chemoradiotherapy and then R0 resections. Of 30 patients completing preoperative chemotherapy, all had tumor regression and TME without preoperative chemoradiotherapy. The pathologic complete response rate to chemotherapy alone was 8 of 32 (25%; 95% CI, 11% to 43%). The 4-year local recurrence rate was 0% (95% CI, 0% to 11%); the 4-year disease-free survival was 84% (95% CI, 67% to 94%). CONCLUSION For selected patients with clinical stages II to III rectal cancer, neoadjuvant chemotherapy and selective radiation does not seem to compromise outcomes. Preoperative Radiation or Selective Preoperative Radiation and Evaluation Before Chemotherapy and TME (PROSPECT), a randomized phase III trial to validate this experience, is now open in the US cooperative group network.

Resection of Hepatocellular Carcinoma in Patients Otherwise Eligible for Transplantation

Introduction The incidence of hepatocellular carcinoma (HCC) in the United States has increased 75% in the last decade. Liver transplantation is gaining acceptance for the treatment of early HCC, even in patients with adequate liver function. The objective of this study was to determine the long-term outcome of patients with early HCC who would have been candidates for transplantation but were treated instead with partial hepatectomy. Methods From August 1989 to November 2001, 611 patients with HCC were evaluated at our institution and entered into a prospective database. There were 180 (29%) patients who underwent partial hepatectomy, of whom 36 (20%) satisfied the currently accepted criteria for transplantation: 2 or 3 lesions each ≤ 3 cm in size or a solitary tumor ≤ 5 cm. Survival was determined by Kaplan-Meier analysis. Results Median tumor size was 3.5 (range, 1.8–5) cm and the median number of lesions was 1 (range, 1–3). Patients had pathologically confirmed cirrhosis of the liver in 78% (28/36) of cases, and 86% had normal liver function (Child class A). Perioperative morbidity was 25%, the median length of hospital stay was 8 (range, 4–24) days, and there was 1 (2.8%) perioperative death. At a median follow-up of 35 months for survivors, the 1-, 3-, and 5-year overall survival was 85%, 74%, and 69%, respectively, with a median survival of 71 months. The 5-year disease-free survival was 48% with a median of 52 months. Conclusions Partial hepatectomy in patients with early HCC who are otherwise eligible for transplantation can be performed with minimal morbidity and can achieve comparable 5-year survival to that reported for liver transplantation. Resection should be considered the standard therapy for patients with HCC who have adequate liver reserve.

Pathologic stage is most prognostic of disease‐free survival in locally advanced rectal cancer patients after preoperative chemoradiation

Preoperative chemoradiation is the standard treatment for locally advanced rectal cancer. However, it is uncertain whether pretreatment clinical stage, degree of response to neoadjuvant treatment, or pathologic stage is the most reliable predictor of outcome. This study compared various staging elements and treatment‐related variables to identify which factors or combination of factors reliably prognosticates disease‐free survival in rectal cancer patients receiving neoadjuvant combined modality therapy.