Alfred M. Cohen

Liver resection for colorectal metastases.

PURPOSE More than 50,000 patients in the United States will present each year with liver metastases from colorectal cancers. The current study was performed to determine if liver resection for colorectal metastases is safe and effective and to evaluate predictors of outcome. MATERIALS AND METHODS Data for 456 consecutive resections performed between July 1985 and December 1991 in a tertiary referral center were analyzed. RESULTS The perioperative mortality rate was 2.8%, with a mortality rate of 4.6% for resections that involved a lobectomy or more. The median hospital stay was 12 days and only 9% of patients were admitted to the intensive care unit. The 5-year survival rate is 38%, with a median survival duration of 46 months. By univariate analysis, nodal status of the primary lesion, short disease-free interval before detection of liver metastases, carcinoembryonic antigen (CEA) level greater than 200 ng/mL, multiple liver tumors, extrahepatic disease, large tumors, or positive resection margin was predictive of poorer outcome. Sex, age greater than 70 years, site of primary tumor, or perioperative transfusion was not predictive of outcome. By multivariate analysis, positive margin, size greater than 10 cm, disease-free interval less than 12 months, multiple tumors, and extrahepatic disease were independent predictors of poorer outcome. Short disease-free interval or multiple tumors were nevertheless associated with a 5-year survival rate greater than 24%. CONCLUSION Liver resection for colorectal metastases is safe and effective therapy and currently represents the only potentially curative therapy for metastatic colorectal cancer. The only absolute contraindication to resection is extrahepatic disease. A randomized trial to examine efficacy of surgical resection cannot ethically be performed. Liver resection should be considered standard therapy for all fit patients with colorectal metastases isolated to the liver.

American Society of Clinical Oncology Recommendations on Adjuvant Chemotherapy for Stage II Colon Cancer

PURPOSE To address whether all medically fit patients with curatively resected stage II colon cancer should be offered adjuvant chemotherapy as part of routine clinical practice, to identify patients with poor prognosis characteristics, and to describe strategies for oncologists to use to discuss adjuvant chemotherapy in practice. METHODS An American Society of Clinical Oncology Panel, in collaboration with the Cancer Care Ontario Practice Guideline Initiative, reviewed pertinent information from the literature through May 2003. RESULTS A literature-based meta-analysis found no evidence of a statistically significant survival benefit of adjuvant chemotherapy for stage II patients. Recommendations The routine use of adjuvant chemotherapy for medically fit patients with stage II colon cancer is not recommended. However, there are populations of patients with stage II disease that could be considered for adjuvant therapy, including patients with inadequately sampled nodes, T4 lesions, perforation, or poorly differentiated histology. CONCLUSION Direct evidence from randomized controlled trials does not support the routine use of adjuvant chemotherapy for patients with stage II colon cancer. Patients and oncologists who accept the relative benefit in stage III disease as adequate indirect evidence of benefit for stage II disease are justified in considering the use of adjuvant chemotherapy, particularly for those patients with high-risk stage II disease. The ultimate clinical decision should be based on discussions with the patient about the nature of the evidence supporting treatment, the anticipated morbidity of treatment, the presence of high-risk prognostic features on individual prognosis, and patient preferences. Patients with stage II disease should be encouraged to participate in randomized trials.

Hepatic arterial infusion of chemotherapy after resection of hepatic metastases from colorectal cancer.

BACKGROUND Two years after undergoing resection of liver metastases from colorectal cancer, about 65 percent of patients are alive and 25 percent are free of detectable disease. We tried to improve these outcomes by treating patients with hepatic arterial infusion of floxuridine plus systemic fluorouracil after liver resection. METHODS We randomly assigned 156 patients at the time of resection of hepatic metastases from colorectal cancer to receive six cycles of hepatic arterial infusion with floxuridine and dexamethasone plus intravenous fluorouracil, with or without leucovorin, or six weeks of similar systemic therapy alone. Patients were stratified according to previous treatment and the number of liver metastases identified at operation. The study end points were overall survival, survival without recurrence of hepatic metastases, and survival without any metastases at two years. RESULTS The actuarial rate of overall survival at two years was 86 percent in the group treated with local plus systemic chemotherapy and 72 percent in the group given systemic therapy alone (P=0.03). The median survival was 72.2 months in the combined-therapy group and 59.3 months in the monotherapy group, with a median follow-up of 62.7 months. After two years, the rates of survival free of hepatic recurrence were 90 percent in the monotherapy group and 60 percent in the monotherapy group (P<0.001), and the respective rates of progression-free survival were 57 percent and 42 percent (P=0.07). At two years, the risk ratio for death was 2.34 among patients treated with systemic therapy alone, as compared with patients who received combined therapy (95 percent confidence interval, 1.10 to 4.98; P=0.027), after adjustment for important variables. The rates of adverse effects of at least moderate severity were similar in the two groups, except for a higher frequency of diarrhea and hepatic effects in the combined-therapy group. CONCLUSIONS For patients who undergo resection of liver metastases from colorectal cancer, postoperative treatment with a combination of hepatic arterial infusion of floxuridine and intravenous fluorouracil improves the outcome at two years.

Simultaneous liver and colorectal resections are safe for synchronous colorectal liver metastasis

BACKGROUND The optimal surgical strategy for the treatment of synchronous resectable colorectal liver metastasis has not been defined. The aims of this study were to review our experience with synchronous colorectal metastasis and to define the safety of simultaneous versus staged resection of the colon and liver. STUDY DESIGN From September 1984 through November 2001, 240 patients were treated surgically for primary adenocarcinoma of the large bowel and synchronous hepatic metastasis. Clinicopathologic, operative, and perioperative data were reviewed to evaluate selection criteria, operative methods, and perioperative outcomes. RESULTS One hundred thirty-four patients underwent simultaneous resection of a colorectal primary and hepatic metastasis in a single operation (Group I), and 106 patients underwent staged operations (Group II). Simultaneous resections tend to be performed for right colon primaries (p < 0.001), smaller (p < 0.01) and fewer (p < 0.001) liver metastases, and less extensive liver resection (p < 0.001). Complications were less common in the simultaneous resection group, with 65 patients (49%) sustaining 142 complications, compared with 71 patients (67%) sustaining 197 complications for both hospitalizations in the staged resection group (p < 0.003). Patients having simultaneous resection required fewer days in the hospital (median 10 days versus 18 days, p = 0.001). Perioperative mortality was similar (simultaneous, n = 3; staged, n = 3). CONCLUSIONS Simultaneous colon and liver resection is safe and efficient in the treatment of patients with colorectal cancer and synchronous liver metastasis. By avoiding a second laparotomy, the overall complication rate is reduced, with no change in operative mortality. Given its reduced morbidity, shorter treatment time, and similar cancer outcomes, simultaneous resection should be considered a safe option in patients with resectable synchronous colorectal metastasis.

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.

Assessing the predictive value of clinical complete response to neoadjuvant therapy for rectal cancer: an analysis of 488 patients

BACKGROUND Patients with transmural or node-positive rectal cancer benefit from the addition of chemoradiation to surgical resection. Administration of the chemoradiation (combined modality therapy) preoperatively has gained popularity in recent years. Some patients undergo apparent complete tumor regression after preoperative combined modality therapy, and controversy exists about the proper management of these patients. Some investigators have proposed that such patients should simply be observed and not undergo resection. STUDY DESIGN The purpose of this study was to determine the significance of clinical complete response to preoperative combined modality therapy. Specifically, we have attempted to determine the frequency with which a clinical complete response (based on the absence of detectable tumor on preoperative digital rectal examination and proctoscopy) correlates with a pathologic complete response (based on the absence of cancer cells in the resected specimen). A retrospective review of the clinical and pathologic characteristics of 488 patients from the Memorial Sloan-Kettering prospective colorectal database who received preoperative chemoradiation followed by resection for primary rectal cancer was performed. The indications for preoperative therapy included clinical or ultrasound T3 or T4 tumors or node-positive disease. RESULTS The clinical complete response rate to preoperative therapy was 19%. All patients underwent resection subsequent to preoperative therapy regardless of response. The pathologic complete response rate among all patients was 10%. The pathologic complete response rate among clinical complete responders was 25%. Clinical complete response was a significant predictive factor for pathologic complete response, but the majority (75%) of clinical complete responders had persistent foci of tumor that were not detectable on preoperative examination or proctoscopy. CONCLUSIONS Clinical complete response to preoperative therapy as determined by preoperative digital rectal examination and proctoscopy or EUA is not an accurate predictor of pathologic complete response. A significant percentage of clinical complete responders have persistent deep tumors or nodal involvement. We do not recommend making treatment decisions based solely on the absence of clinically palpable or visible tumor after chemoradiation. Our data suggest that all acceptable-risk patients with a diagnosis of primary rectal cancer should undergo resection, regardless of their response to preoperative therapy.

Long-term results of local excision for rectal cancer

ObjectiveTo review the authors’ experience with local excision of early rectal cancers to assess the effectiveness of initial treatment and of salvage surgery. Summary Background DataLocal excision for rectal cancer is appealing for its low morbidity and excellent functional results. However, its use is limited by inability to assess regional lymph nodes and uncertainty of oncologic outcome. MethodsPatients with T1 and T2 adenocarcinomas of the rectum treated by local excision as definitive surgery between 1969 to 1996 at the authors’ institution were reviewed. Pathology slides were reviewed. Among 125 assessable patients, 74 were T1 and 51 were T2. Thirty-one patients (25%) were selected to receive adjuvant radiation therapy. Fifteen of these 31 patients received adjuvant radiation in combination with 5-fluorouracil chemotherapy. Median follow-up was 6.7 years. One hundred fifteen patients (92%) were followed until death or for greater than 5 years, and 69 patients (55%) were followed until death or for greater than 10 years. Recurrence was recorded as local, distant, and overall. Survival was disease-specific. ResultsTen-year local recurrence and survival rates were 17% and 74% for T1 rectal cancers and 26% and 72% for T2 cancers. Median time to relapse was 1.4 years (range 0.4–7.0) for local recurrence and 2.5 years (0.8–7.5) for distant recurrence. In patients receiving radiotherapy, local recurrence was delayed (median 2.1 years vs. 1.1 years), but overall rates of local and overall recurrence and survival rates were similar to patients not receiving radiotherapy. Among 26 cancer deaths, 8 (28%) occurred more than 5 years after local excision. On multivariate analysis, no clinical or pathologic features were predictive of local recurrence. Intratumoral vascular invasion was the only significant predictor of survival. Among 34 patients who developed tumor recurrence, the pattern of first clinical recurrence was predominantly local: 50% local only, 18% local and distant, and 32% distant only. Among the 17 patients with isolated local recurrence, 14 underwent salvage resection. Actuarial survival among these surgically salvaged patients was 30% at 6 years after salvage. ConclusionsThe long-term risk of recurrence after local excision of T1 and T2 rectal cancers is substantial. Two thirds of patients with tumor recurrence have local failure, implicating inadequate resection in treatment failure. In this study, neither adjuvant radiotherapy nor salvage surgery was reliable in preventing or controlling local recurrence. The postoperative interval to cancer death is as long as 10 years, raising concern that cancer mortality may be higher than is generally appreciated. Additional treatment strategies are needed to improve the outcome of local excision.

Utility of 18F-FDG positron emission tomography scanning on selection of patients for resection of hepatic colorectal metastases

BACKGROUND Hepatectomy represents a standard and potentially curative therapy for hepatic colorectal metastases. However, up to two thirds of patients explored for resection are found to have unsuspected disease, which precludes resection. METHODS In order to determine if 18F-FDG positron emission tomography (PET) scanning may prevent unnecessary surgery, a group of 40 patients being considered for hepatic resection but at high risk for unresectable disease by clinical criteria were subjected to whole body 18F-FDG-PET scanning. Effect on clinical outcome was evaluated. In addition, PET findings in the 25 patients who underwent resection of hepatic metastases were directly compared with the resected specimen to determine the sensitivity of 18F-FDG PET scanning in the liver. RESULTS Findings on 18F-FDG-PET scanning influenced the clinical management in 16 patients (40%) and directly altered management in 9 cases (23%). Six patients were spared laparotomy, and 3 others had PET-directed surgery that found extrahepatic tumor and spared the patient unwarranted liver resection. In 3 cases PET missed peritoneal metastases found on laparotomy. In these cases all missed tumors were less than 1 cm in size. Out of 52 resected hepatic lesions, 18F-FDG-PET detected 37. Within the liver, sensitivity of detection was also related to size. Only 25% of hepatic lesions smaller than 1 cm were detected by PET, while 85% of lesions larger than 1 cm were detected. CONCLUSIONS FDG-PET is best for detecting extrahepatic disease. There are few false positives, and surgeons should carefully evaluate and biopsy extrahepatic positive sites. This test should be used for patients at high risk for extrahepatic disease and should be evaluated prospectively for all patients under consideration for liver resection.

Enhancement of radiation-induced downstaging of rectal cancer by fluorouracil and high-dose leucovorin chemotherapy.

PURPOSE To determine if fluorouracil (5-FU) plus high-dose leucovorin (LV) enhances local response in patients receiving preoperative radiation therapy (RT) for adenocarcinoma of the rectum, we compared the degree of downstaging in patients receiving preoperative RT with or without chemotherapy. PATIENTS AND METHODS For this comparison, three groups of patients who were treated with identical doses and techniques of preoperative pelvic RT (total dose of 5,040 cGy) were examined. Group 1 included 20 patients with unresectable disease who received combined RT and LV/5-FU. Group 2 included 11 patients with unresectable disease who received preoperative RT. Group 3 included 21 patients with invasive, resectable, primary disease who received preoperative RT. RESULTS Patients with unresectable disease who received LV/5-FU had a higher rate of pathologic complete response (20% v 0%) and a lower incidence of positive nodes (30% v 64%) compared with those who did not receive chemotherapy. Even when the most favorable group of patients was included (group 3), patients who received LV/5-FU still had a higher complete response rate (20% v 6%) and a lower incidence of positive nodes (30% v 53%) compared with those who received RT without LV/5-FU. Of those patients with initially unresectable disease, the resectability rate was higher in those who received LV/5-FU compared with those who did not receive LV/5-FU (90% v 64%). Patients who received LV/5-FU experienced slightly more grade 1 to 2 fatigue, stomatitis, nausea, and grade 3 diarrhea, tenesmus, and dysuria. CONCLUSIONS Despite the fact that patients who received chemotherapy (group 1) had more advanced disease compared with those with resectable disease (group 3), the addition of LV/5-FU increased the resectability and downstaging rates. The ultimate impact of a complete response as well as a decrease in the incidence of pelvic nodes on local control and survival remains to be determined. However, given the enhancement of down-staging in patients with unresectable rectal cancer, we are encouraged by the combined modality approach.

Failure patterns following curative resection of colonic carcinoma.

To identify patterns of failure following curative resection of colonic (nonrectal) carcinoma, the medical records of 533 patients undergoing resection with curative intent were reviewed. The overall local failure rate was 19% (102/533 patients) with 32 patients having local failure alone and 70 patients having concurrent local failure and distant metastases. The incidence of local failure rose with advancing stage of disease. Tumors staged B3, C2, and C3 had local failure rates in excess of 30%. Local failures occurred predominantly in tumor bed and adjoining structures (82%) and not by regional nodal failure (18%). One hundred thirty-one patients (25%) developed distant metastases. One hundred ten patients (84%) failed in the abdomen-liver, peritoneal seeding, para-aortic, or portahepatic lymph nodes. Patients with Stage B3, C2, and C3 tumors were found to have abdominal failure rates (excluding local failure) of greater than 20%. The highest failure rates in the liver were in Stage C2 and C3 patients in which the subsequent development of liver metastases was 29% and 31%, respectively. In Stage C3, peritoneal seeding and abdominal lymph node failure occurred in 18% and 14% of the patients, respectively.