Larissa K. Temple

Outcome of Primary Tumor in Patients With Synchronous Stage IV Colorectal Cancer Receiving Combination Chemotherapy Without Surgery As Initial Treatment

CRA4030 The full, final text of this abstract will be available in Part II of the 2009 ASCO Annual Meeting Proceedings, distributed onsite at the Meeting on May 30, 2009, and as a supplement to the June 20, 2009, issue of the Journal of Clinical Oncology. [Table: see text].PURPOSE The purpose of this study was to describe the frequency of interventions necessary to palliate the intact primary tumor in patients who present with synchronous, stage IV colorectal cancer (CRC) and who receive up-front modern combination chemotherapy without prophylactic surgery. PATIENTS AND METHODS By using a prospective institutional database, we identified 233 consecutive patients from 2000 through 2006 with synchronous metastatic CRC and an unresected primary tumor who received oxaliplatin- or irinotecan-based, triple-drug chemotherapy (infusional fluorouracil, leucovorin, and oxaliplatin; bolus fluorouracil, leucovorin, and irinotecan; or fluorouracil, leucovorin, and irinotecan) with or without bevacizumab as their initial treatment. The incidence of subsequent use of surgery, radiotherapy, and/or endoluminal stenting to manage primary tumor complications was recorded. RESULTS Of 233 patients, 217 (93%) never required surgical palliation of their primary tumor. Sixteen patients (7%) required emergent surgery for primary tumor obstruction or perforation, 10 patients (4%) required nonoperative intervention (ie, stent or radiotherapy), and 213 (89%) never required any direct symptomatic management for their intact primary tumor. Of those 213 patients, 47 patients (20%) ultimately underwent elective colon resection at the time of metastasectomy, and eight patients (3%) underwent this resection during laparotomy for hepatic artery infusion pump placement. Use of bevacizumab, location of the primary tumor in the rectum, and metastatic disease burden were not associated with increased intervention rate. CONCLUSION Most patients with synchronous, stage IV CRC who receive up-front modern combination chemotherapy never require palliative surgery for their intact primary tumor. These data support the use of chemotherapy, without routine prophylactic resection, as the appropriate standard practice for patients with neither obstructed nor hemorrhaging primary colorectal tumors in the setting of metastatic disease.

Immunohistochemistry for hMLH1 and hMSH2: a practical test for DNA mismatch repair-deficient tumors.

Inactivation of deoxyribonucleic acid (DNA) mismatch repair genes, most commonly human mutL homologue 1 (hMLH1) or human mutS homologue 2 (hMSH2), is a recently described alternate pathway in cancer development and progression. The resulting genetic instability is characterized by widespread somatic mutations in tumor DNA, and is termed high-frequency microsatellite instability (MSI-H). Although described in a variety of tumors, mismatch repair deficiency has been studied predominantly in colorectal carcinoma. Most MSI-H colorectal carcinomas are sporadic, but some occur in patients with hereditary nonpolyposis colorectal cancer (HNPCC), and are associated with germline mutations in mismatch repair genes. Until now, the identification of MSI-H cancers has required molecular testing. To evaluate the role of immunohistochemistry as a new screening tool for mismatch repair-deficient neoplasms, the authors studied the expression of hMLH1 and hMSH2, using commercially available monoclonal antibodies, in 72 formalin-fixed, paraffin-embedded tumors that had been tested previously for microsatellite instability. They compared immunohistochemical patterns of 38 MSI-H neoplasms, including 16 cases from HNPCC patients with known germline mutations in hMLH1 or hMSH2, with 34 neoplasms that did not show microsatellite instability. Thirty-seven of 38 MSI-H neoplasms were predicted to have a mismatch repair gene defect, as demonstrated by the absence of hMLH1 and/or hMSH2 expression. This included correspondence with all 16 cases with germline mutations. All 34 microsatellite-stable cancers had intact staining with both antibodies. These findings clearly demonstrate that immunohistochemistry can discriminate accurately between MSI-H and microsatellite-stable tumors, providing a practical new technique with important clinical and research applications.

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.

T1 Adenocarcinoma of the Rectum: Transanal Excision or Radical Surgery?

Background:Recent studies suggest local excision may be acceptable treatment of T1 adenocarcinoma of the rectum, but there is little comparative data with radical surgery to assess outcomes and quantify risk. We performed a retrospective evaluation of patients with T1 rectal cancers treated by either transanal excision or radical resection at our institution to assess patient selection, cancer recurrence, and survival. Methods:All patients who underwent surgery for T1 adenocarcinomas of the rectum (0–15 cm from anal verge) by either transanal excision (TAE) or radical resection (RAD) between January 1987 and January 2004 were identified from a prospective database. Data were analyzed using Fisher exact test, Kaplan-Meier method, and log-rank test. Results:Three hundred nineteen consecutive patients with T1 lesions were treated by transanal excision (n = 151) or radical surgery (n = 168) over the 17-year period. RAD surgery was associated with higher tumor location in the rectum, slightly larger tumor size, a similar rate of adverse histology, and a lymph node metastasis rate of 18%. Despite these features, patients who underwent RAD surgery had fewer local recurrences, fewer distant recurrences, and significantly better recurrence-free survival (P = 0.0001). Overall and disease-specific survival was similar for RAD and TAE groups. Conclusion:Despite a similar risk profile in the 2 surgical groups, patients with T1 rectal cancer treated by local excision were observed to have a 3- to 5-fold higher risk of tumor recurrence compared with patients treated by radical surgery. Local excision should be reserved for low-risk cancers in patients who will accept an increased risk of tumor recurrence, prolonged surveillance, and possible need for aggressive salvage surgery. Radical resection is the more definitive surgical treatment of T1 rectal cancers.

Nonoperative management of rectal cancer with complete clinical response after neoadjuvant therapy.

Introduction:Nonoperative management (NOM) of rectal cancer after a complete clinical response (cCR) to neoadjuvant therapy is controversial. In this article, we retrospectively reviewed the outcomes of patients managed with selective NOM after a cCR to neoadjuvant treatment and compared these with patients who underwent standard rectal resection with a pathological complete response (pCR). Methods:Patients completing neoadjuvant chemoradiotherapy (CRT) for stage I to III rectal cancer between January 2006 and August 2010 were retrospectively reviewed. Median follow-up was calculated in months after completion of CRT. Results:Thirty-two patients (median follow-up 28 months) were treated by NOM after a cCR. Among 265 treated by CRT and rectal resection, 57 patients (22%) had a pCR and formed the control group (median follow-up 43 months). Factors associated with selective use of NOM included lower pretreatment stage, older age, and distal tumor location (P < 0.05). In the NOM group, 6 recurred locally (median 11 months, range 7–14), 3 of whom also had concurrent distant recurrence. All 6 local failures were controlled by salvage rectal resection with no further local recurrence of disease (median follow-up 17 months). In the rectal resection/pCR group, there were no local failures. The 2-year distant disease-free survival (88% vs 98%, P = 0.27) and overall survival (96% vs 100%, P = 0.56) were similar for NOM and rectal resection/pCR groups. Conclusions:Rectal resection was successfully avoided in 81% of patients selected for NOM. When combined with salvage surgery, NOM appears to achieve similar local and distant disease control compared with patients with a pCR treated by rectal resection. Longer follow-up and prospective trials are warranted to evaluate this promising treatment option.

Use of Surgery Among Elderly Patients With Stage IV Colorectal Cancer

PURPOSE The role of surgery to remove the primary tumor among patients with stage IV colorectal cancer (CRC) is controversial. The purpose of this study was to evaluate surgical practice patterns for patients > or = 65 years of age with stage IV CRC in a US population-based cohort. PATIENTS AND METHODS We used the Surveillance, Epidemiology, and End Results-Medicare-linked database to evaluate the patterns of cancer treatment for 9,011 Medicare beneficiaries presenting with stage IV CRC from 1991 to 1999. Patients were categorized according to whether they had primary-cancer-directed surgery (CDS) or no CDS within 4 months of diagnosis. The use of other treatment modalities, including metastasectomy, chemotherapy, and radiation, was evaluated in relationship to whether patients belonged to the CDS or no CDS group. RESULTS Seventy-two percent (6,469 of 9,011) of patients received CDS, and their 30-day postoperative mortality was 10%. Patients with left-sided or rectal lesions, patients older than age 75 years, blacks, and those of lower socioeconomic status were less likely to undergo CDS; but even among those older than age 75, the CDS rate was 69% (3,378 of 4,909). In contrast, chemotherapy use was less common (47% for patients who had CDS and 31% for those who did not). Metastasectomy was rare; only 3.9% of patients underwent these operations at any point from diagnosis to death. CONCLUSION Palliative resection of the primary tumor is often performed for elderly US patients with stage IV colorectal cancer. This practice pattern merits re-evaluation, given the improvement in the efficacy of systemic chemotherapy.

Pathologic Classification and Clinical Behavior of the Spectrum of Goblet Cell Carcinoid Tumors of the Appendix

Appendiceal tumors exhibiting both neuroendocrine and glandular differentiation are uncommon and have caused difficulty in pathologic classification, prediction of prognosis, and clinical management. Previously, such lesions have been variously designated as adenocarcinoid, goblet cell carcinoid (GCC), and mixed adenocarcinoma carcinoid. In this study, we undertook a retrospective investigation of 63 such cases and classified them as typical GCC (group A) and adenocarcinoma ex GCC on the basis of the histologic features of the tumor at the primary site. The adenocarcinoma ex GCC group was further divided into signet ring cell type (group B) and poorly differentiated adenocarcinoma type (group C). The clinical characteristics and prognosis were compared within these groups and with conventional de novo appendiceal adenocarcinomas. Both groups A and B tumors shared a similar immunoprofile, which included generally focal immunoreactivity for neuroendocrine markers, and a normal intestinal type mucin glycoprotein profile (negative MUC1 expression and preserved MUC2 immunoreactivity). The proliferative index was relatively low in these tumors and slightly increased from groups A to B tumors (11% to 16%). Both β-catenin and E-cadherin exhibited a normal membranous staining pattern in groups A and B tumors. The poorly differentiated adenocarcinomas ex GCC (group C) demonstrated abnormal p53 and β-catenin immunoreactivity. The mean follow-up time was 49±5 (SE) months. The overall disease-specific survival for all subtypes was 77%, with 46% of patients without evidence of disease and 31% alive with disease. The mean survival was 43±7 months. All the patients with clinical stage of I or IIA disease had a favorable outcome after appropriate surgery with or without chemotherapy. Although most patients (63%) with GCC presented at an advanced clinical stage, their clinical outcome could be differentiated by subclassification of tumors. The stage IV-matched 5-year survival was 100%, 38%, and 0% for groups A, B, and C, respectively. In conclusion, GCC is a distinctive appendiceal neoplasm that exhibits unique pathologic features and clinical behavior. They display a spectrum of histologic features and possess the potential to transform to an adenocarcinoma phenotype of either signet ring cell or poorly differentiated adenocarcinoma types. Careful evaluation of the morphologic features of GCCs and appropriate pathologic classification are crucial for clinical management and prediction of outcome. Surgical management with right hemicolectomy is recommended after appendectomy for most cases, particularly those with an adenocarcinoma component (groups B and C).

The Development of a Validated Instrument to Evaluate Bowel Function After Sphincter-Preserving Surgery for Rectal Cancer

PURPOSESphincter-preserving surgery is technically feasible for many rectal cancers, but functional results are not well understood. Therefore, the purpose of this study was to develop an instrument to evaluate bowel function after sphincter-preserving surgery.METHODSA 41-item bowel function survey was developed from a literature review, expert opinions, and 59 patient interviews. An additional 184 patients who underwent sphincter-preserving surgery between 1997 and 2001 were asked to complete the survey and quality-of-life instruments (Fecal Incontinence Quality of Life, European Organization for Research and Treatment of Cancer QLQ 30/Colorectal Cancer 38). A factor analysis of variance was performed. Test–retest reliability was evaluated, with 20 patients completing two surveys within a mean of 11 days. Validity testing was done with clinical variables (gender, age, radiation, length of time from surgery), surgical variables (procedure: local excision, low anterior resection, coloanal anastomosis), reconstruction (J-pouch, straight), anastomosis (handsewn, stapled), and quality-of-life instruments.RESULTSThe survey response rate was 70.1 percent (129/184). Among the 127 patients with usable data, 67 percent were male, the median age was 64 (range, 38–87) years, and the mean time for restoration of bowel continuity after sphincter-preserving surgery was 22.9 months. Patients had a median of 3.5 stools/day (range, 0–30), and 37 percent were dissatisfied with their bowel function. Patients experienced a median of 22 symptoms (range, 7–32), with 27 percent reported as severe, 37 percent as moderate, and 36 percent as mild. The five most common symptoms were incomplete evacuation (96.8 percent), clustering (94.4 percent), food affecting frequency (93.2 percent), unformed stool (92.8 percent), and gas incontinence (91.8 percent). The factor analysis identified 14 items that collapsed into three subscales: FREQUENCY (α = 0.75), DIETARY (α = 0.78), and SOILAGE (α = 0.79), with acceptable test–retest reliability for the three subscales and total score (0.62–0.87). The instrument detected differences between patients with preoperative radiation (n = 67) vs. postoperative radiation (n = 15) vs. no radiation (n = 45) (P = 0.02); local excision (n = 10) vs. low anterior resection (n = 55) vs. coloanal anastomosis (n = 62) (P = 0.002); and handsewn (n = 18) vs. stapled anastomosis (n = 99) (P = 0.006). The total score correlated with 4 of 4 Fecal Incontinence Quality of Life (P < 0.01) and 9 of 17 European Organization for Research and Treatment of Cancer subscales (all P < 0.01).CONCLUSIONSPatients undergoing sphincter-preserving surgery for rectal cancer have impaired bowel function, and those treated with radiation, coloanal anastomoses, or handsewn anastomoses have significantly worse function. This reliable and valid instrument should be used to prospectively evaluate bowel function after sphincter-preserving surgery in patients undergoing rectal cancer therapy.

Sphincter preservation in low rectal cancer is facilitated by preoperative chemoradiation and intersphincteric dissection.

Objective:The aim of this study was to evaluate oncologic outcome in patients with locally advanced distal rectal cancer treated with preoperative chemoradiation followed by low anterior resection (LAR)/stapled coloanal anastomosis, LAR/intersphincteric dissection/hand-sewn coloanal anastomosis, or abdominoperineal resection (APR). Summary Background Data:Distal rectal cancer presents a surgical challenge, and the goals of treatment often include tumor eradication without sacrifice of the anal sphincters. The technique of intersphincteric resection removes the internal anal sphincter to gain additional distal rectal margin in hopes of avoiding a permanent stoma. Methods:We analyzed 148 patients with stage II and III rectal cancers (endorectal ultrasound staged uT3–4 and/or uN1) located ≤6 cm from the anal verge, treated by preoperative chemoradiation and total mesorectal excision from 1998 to 2004. Eighty-five patients (57%) had sphincter-preserving resection (41, LAR/stapled coloanal anastomosis; 44, LAR/intersphincteric resection/hand-sewn coloanal anastomosis); 63 patients had APR. Results:Patients undergoing APR were older, with more poorly differentiated tumors evidencing less response to chemoradiation and more likely to require extended resection. Complete resection with negative histologic margins was achieved in 92%; circumferential margins were positive in 2 (5%) of 44 in the intersphincteric resection group and 8 (13%) of 63 in the APR group. Distal margins were positive in 2 (5%) of 44 in the intersphincteric resection group. With median follow-up of 47 months, there were a total of 7 local recurrences (5%): 1, 0, and 6 in the stapled anastomosis, intersphincteric resection, and APR groups, respectively. Estimated 5-year recurrence-free survival for the stapled anastomosis, intersphincteric resection, and APR groups were 85%, 83%, and 47% respectively (P = 0.001). Conclusions:In low rectal cancer, sphincter preservation is facilitated by a significant response to preoperative chemoradiation and intersphincteric resection, without compromise of margins or outcome. In those who have a less favorable response, abdominoperineal resection is more likely to be required and is associated with poorer outcome.