John H. Donohue

Oxaliplatin, Fluorouracil, and Leucovorin for Patients With Unresectable Liver-Only Metastases From Colorectal Cancer: A North Central Cancer Treatment Group Phase II Study

PURPOSE Surgical resection of liver-only metastases from colorectal cancer has undergone extensive evaluation and review. The use of neoadjuvant chemotherapy to improve the likelihood of resection in disease that is not optimally resectable has not been as well studied. PATIENTS AND METHODS Patients with liver-only metastases from colorectal cancer deemed not optimally resectable by a surgeon with expertise in liver surgery received fluorouracil, leucovorin, and oxaliplatin (FOLFOX4). Patients were periodically reassessed for resectability. Surgical response was classified as completely resectable (S-CR), partially resectable (S-PR), or unresectable (S-UR). Study design specified the accrual of 39 patients, with two or more S-CRs considered evidence of promising activity with respect to increasing the S-CR rate. RESULTS Forty-two of 44 patients were assessable for this analysis. Twenty-five patients (60%) had tumor reduction by serial imaging. Seventeen patients (40%) underwent surgery (S-CR, n = 14; S-PR, n = 1; and S-UR, n = 2) after a median of 6 months of chemotherapy. With a median postsurgical follow-up of 22 months (range, 13 to 32 months), 11 recurrences have occurred in the 15 S-CR and S-PR patients. Median survival time was 26 months. CONCLUSION Our data suggest that FOLFOX4 has a high response rate (complete response, partial response, or reduction) in patients with liver-only metastases from colorectal cancer, allowing for successful resection of disease in a portion of patients initially not judged to be optimally resectable. However, a high recurrence rate after surgery was observed, which, in 73% of patients, involved the liver. Further trials are indicated based on the promising results observed in this trial.

Prospectively randomized trial of postoperative adjuvant chemotherapy in patients with high-risk colon cancer.

PURPOSE This study had two major goals: (1) to assess the effectiveness of a regimen of fluorouracil (5-FU) plus levamisole plus leucovorin as postoperative surgical adjuvant therapy for patients with high-risk colon cancer, and (2) to evaluate 6 months versus 12 months of chemotherapy. PATIENTS AND METHODS Patients with poor-prognosis stage II or III colon cancer were randomly assigned to receive adjuvant chemotherapy with either intensive-course 5-FU and leucovorin combined with levamisole, or a standard regimen of 5-FU plus levamisole. Patients were also randomly assigned to receive either 12 months or 6 months of chemotherapy, which resulted in four treatment groups. RESULTS Eight hundred ninety-one of 915 patients entered (97.4%) were eligible. The median follow-up duration is 5.1 years for patients still alive. There was a difference among the four treatment groups with respect to patient survival, and a significant duration-by-regimen interaction was observed. Specifically, standard 5-FU plus levamisole was inferior to 5-FU plus leucovorin plus levamisole when treatment was given for 6 months (5-year survival rate, 60% v 70%; P < .01). CONCLUSION There was no significant improvement in patient survival when chemotherapy was given for 12 months compared with 6 months. When chemotherapy was given for 6 months, standard 5-FU plus levamisole was associated with inferior patient survival compared with intensive-course 5-FU plus leucovorin plus levamisole. These data suggest that 5-FU plus levamisole for 6 months should not be used in clinical practice, whereas 6 months of treatment with 5-FU plus leucovorin plus levamisole is effective.

Long-term survival after pancreatoduodenectomy for pancreatic adenocarcinoma: is cure possible?

Objective:To determine long-term survival after pancreatoduodenectomy for pancreatic ductal adenocarcinoma and to identify clinical factors associated with long-term survival. Summary Background Data:The prognosis for long-term survival even after potentially curative resection for pancreatic adenocarcinoma is thought to be poor. Clinical factors determining short-term survival after pancreatic resection are well studied, but prognostic factors predicting long-term survival with a potential for cure are poorly understood. Methods:A case-control study was conducted of 357 patients who underwent pancreatoduodenectomy for pancreatic ductal adenocarcinoma between 1981 and 2001. Histologic specimens were reanalyzed to confirm diagnosis. Follow-up was at least 5 years or until death. Results:There was an improved survival throughout the observation period (P = 0.004). We found 62 actual 5-year survivors of whom 21 patients survived greater than 10 years, for a 5- and 10-year survival rate of 18% and 13%, respectively. Cohort analysis comparing patients with short-term (<5 years, n = 295) and long-term (≥5 years, n = 62) survival showed that more advanced disease (greatest tumor diameter, lymph node metastasis) and decreased serum albumin concentration were unfavorable for long-term survival (all P < 0.05). In contrast, the extent of resection and more aggressive histologic features did not correlate with long-term survival (all P > 0.05). En-bloc resection (P = 0.005) but not resection margin status (P > 0.05) was associated with long-term survival. Adjuvant chemoradiation therapy did not significantly influence long-term survival. Multivariate analysis identified lymph node status (OR 0.36, 95% CI 0.14–0.89, P = 0.03) as a prognostic factor for long-term survival. Five-year survival was no guarantee of cure because 16% of this subset died of pancreatic cancer up to 7.8 years after operation. Conclusion:Pancreatoduodenectomy for adenocarcinoma in the head of pancreas can provide long-term survival in a subset of patients, particularly in the absence of lymph node metastasis. One of 8 patients can achieve 10-year survival with a potential for cure.

Development and validation of a prognostic nomogram for recurrence-free survival after complete surgical resection of localised primary gastrointestinal stromal tumour: a retrospective analysis.

BACKGROUND Adjuvant imatinib mesylate prolongs recurrence-free survival (RFS) after resection of localised primary gastrointestinal stromal tumours (GIST). We aimed to develop a nomogram to predict RFS after surgery in the absence of adjuvant therapy to help guide patient selection for adjuvant imatinib therapy. METHODS A nomogram to predict RFS based on tumour size (cm), location (stomach, small intestine, colon/rectum, or other), and mitotic index (<5 or > or =5 mitoses per 50 high-power fields) was developed from 127 patients treated at Memorial Sloan-Kettering Cancer Center (MSKCC), New York, NY, USA. The nomogram was tested in patients from the Spanish Group for Research on Sarcomas (GEIS; n=212) and the Mayo Clinic, Rochester, MN, USA (Mayo; n=148). The nomogram was assessed by calculating concordance probabilities and testing calibration of predicted RFS with observed RFS. Concordance probabilities were also compared with those of three commonly used staging systems. FINDINGS The nomogram had a concordance probability of 0.78 (SE 0.02) in the MSKCC dataset, and 0.76 (0.03) and 0.80 (0.02) in the validation cohorts. Nomogram predictions were well calibrated. Inclusion of tyrosine kinase mutation status in the nomogram did not improve its discriminatory ability. Concordance probabilities of the nomogram were better than those of the two NIH staging systems (0.76 [0.03] vs 0.70 [0.04, p=0.04] and 0.66 [0.04, p=0.01] in the GEIS validation cohort; 0.80 [0.02] vs 0.74 [0.02, p=0.04] and 0.78 [0.02, p=0.05] in the Mayo cohort) and similar to those of the AFIP-Miettinen staging system (0.76 [0.03] vs 0.73 [0.004, p=0.28] in the GEIS cohort; 0.80 [0.02] vs 0.76 [0.003, p=0.09] in the Mayo cohort). Nomogram predictions of RFS seemed better calibrated than predictions made with the AFIP-Miettinen system. INTERPRETATION The nomogram accurately predicts RFS after resection of localised primary GIST and could be used to select patients for adjuvant imatinib therapy.

Phase II Trial of Preoperative Chemoradiation in Patients With Localized Gastric Adenocarcinoma (RTOG 9904): Quality of Combined Modality Therapy and Pathologic Response

PURPOSE Preoperative therapy for localized gastric cancer has considerable appeal. We hypothesized that, in a cooperative group setting, preoperative chemoradiotherapy would induce a 20% pathologic complete response (pathCR) rate. Combined-modality therapy quality, survival, and safety were secondary end points. PATIENTS AND METHODS Patients with localized gastric adenocarcinoma were eligible. A negative laparoscopic evaluation was required. Patients received two cycles of induction fluorouracil, leucovorin, and cisplatin followed by concurrent radiation and chemotherapy (infusional fluorouracil and weekly paclitaxel). Resection was attempted 5 to 6 weeks after chemoradiotherapy was completed. Quality of therapy was assessed with other end points. RESULTS Twenty institutions participated. Forty-nine patients were entered and 43 were assessable (12% stage IB; 37% stage II; and 52% stage III). The pathCR and R0 resection rates were 26% and 77%, respectively. At 1 year, more patients with pathCR (82%) are living than those with less than pathCR (69%). Grade 4 toxicity occurred in 21% of patients. Chemotherapy, radiotherapy, and surgery per protocol (including acceptable variations) occurred in 98%, 44%, and 63% of patients, respectively. A D2 dissection was performed in 50% of patients. Of 18 major radiotherapy variations, 17 were due to the lack of inclusion of the L3-4 vertebral interphase as prespecified. CONCLUSION For localized gastric cancer, preoperative chemoradiotherapy strategy achieved a pathCR rate of more than 20% in a cooperative group setting. The quality of surgery improved (50% with D2 dissection) possibly because surgery was part of this trial. With some refinements, this preoperative chemoradiotherapy strategy is poised for a randomized comparison with postoperative adjuvant chemoradiotherapy in patients with gastric cancer.

Efficacy of Contralateral Prophylactic Mastectomy in Women With a Personal and Family History of Breast Cancer

PURPOSE To estimate the efficacy of contralateral prophylactic mastectomy in women with a personal and family history of breast cancer. PATIENTS AND METHODS We followed the course of 745 women with a first breast cancer and a family history of breast and/or ovarian cancer who underwent contralateral prophylactic mastectomy at the Mayo Clinic between 1960 and 1993. Family history information and cancer follow-up information were obtained from the medical record, a study-specific questionnaire, and telephone follow-up. Life-tables for contralateral breast cancers, which consider age at first breast cancer, current age, and type of family history, were used to calculate the number of breast cancers expected in our cohort had they not had a prophylactic mastectomy. RESULTS Of the 745 women in our cohort, 388 were premenopausal (age < 50 years) and 357 were post- menopausal. Eight women developed a contralateral breast cancer. Six events were observed among the premenopausal women, compared with 106.2 predicted, resulting in a risk reduction of 94.4% (95% confidence interval [CI], 87.7% to 97.9%). For the 357 postmenopausal women, 50.3 contralateral breast cancers were predicted, whereas only two were observed, representing a 96.0% risk reduction (95% CI, 85.6% to 99.5%). CONCLUSION The incidence of contralateral breast cancer seems to be reduced significantly after contralateral prophylactic mastectomy in women with a personal and family history of breast cancer.

Hepatic Resection for Colorectal Metastases: Value for Risk Scoring Systems?

Introduction:Predictors of outcome in patients with metastatic colorectal cancer remain inconsistent. We aimed to identify predictors of outcome in these patients, to develop a prognostic scoring system, and to assess the general applicability of the current major risk scoring systems. Materials and Methods:Following IRB approval, medical records of 662 consecutive patients undergoing resection of colorectal metastases to the liver during 1960 to 1995 were reviewed. Clinicopathologic and outcome data were assessed from records and mailed questionnaire. Clinicopathologic variables were tested using univariate and multivariate analyses; best-fit models were then generated to study the effect of each independent risk factor on outcome. To validate existing scoring models, our independent data set was applied to those scores. The relative concordance probability estimates were calculated for these models and compared with that of the proposed Mayo model. Results:The overall and disease-specific 5-year survival rates were 37% and 42%, respectively. The probability of recurrence at any site was 65% at 5 years. Perioperative blood transfusion and positive hepatoduodenal nodes were the major determinants of survival and recurrence. To assess the general applicability of the proposed risk scoring systems, we imported the data from our patient population into 3 other scoring systems. Neither survival nor recurrence among our patients was stratified discretely by any of the scoring systems. Based on probability estimates, all models were only marginally better than chance alone in predicting outcome. Conclusion:Broad application of risk scoring systems for patients with metastatic colorectal cancer has limited clinical value and refinement and external validation should be undertaken before utilization.

Hepatic Resection of Hepatocellular Carcinoma in Patients With Cirrhosis: Model of End-Stage Liver Disease (MELD) Score Predicts Perioperative Mortality

Hepatic resection for hepatocellular carcinoma (HCC) in patients with cirrhosis is generally recommended for patients with Child-Turcotte-Pugh (CTP) Class A liver disease and early tumor stage. The Model for End-Stage Liver Disease (MELD) has been shown to accurately predict survival in patients with cirrhosis, but whether MELD is useful for selection of patients with cirrhosis for hepatic resection is unknown. We examined whether MELD was predictive of perioperative mortality and correlated MELD with other potential clinicopathologic factors to overall survival in patients with cirrhosis undergoing hepatic resection for HCC. A retrospective chart review was undertaken of patients with HCC and cirrhosis undergoing hepatic resection between 1993 and 2003. Eighty-two patients (62 men, 20 women; mean age, 62 years) were identified. Forty-five patients had MELD score ≥9 (range, 9–15) and CTP score ranged from 5 to 9 points. Fifty-nine patients underwent minor (<3 segments) hepatic resections (MELD ≤8, n = 29; MELD ≥9, n = 30) and 23 underwent major (≥3 segments) hepatic resections (MELD ≤8, n = 8; MELD ≥9, n = 15). Perioperative mortality rate was 16%. MELD score ≤8 was associated with no perioperative mortality versus 29% for patients with an MELD score ≥9 (P < 0.01). Multivariate analysis demonstrated that MELD score ≥9 (P < 0.01), clinical tumor symptoms (P < 0.01), and ASA score (P = 0.046) are independent predictors of perioperative mortality. Multivariate analysis showed MELD ≥9 (P < 0.01), tumor size >5 cm(P < 0.01), high tumor grade (P = 0.03), and absence of tumor capsule (P < 0.01) as independent predictors of decreased long-term survival. MELD score was a strong predictor of both perioperative mortality and long-term survival in patients with cirrhosis undergoing hepatic resection for HCC. In patients with cirrhosis, hepatic resection (minor or major) for HCC is recommended if the MELD score is ≤8. In patients with MELD score ≥9, other treatment modalities should be considered.

Characteristics of biliary tract complications during laparoscopic cholecystectomy: A multi-institutional study

We collected the records of 81 patients with biliary tract injuries occurring during laparoscopic cholecystectomy (LC) who were referred to 3 referral centers during a 33-month (May 1990 to March 1993) period. All records were reviewed to provide data concerning the anatomy of the lesion induced, method of injury, timing of injury detection, role of intraoperative cholangiography (IOC), methods of treatment, and outcome of these injuries. Injuries were classified by our own method as follows: (1) cystic duct leaks (n = 15), (2) bile leaks and/or ductal strictures (n = 27), and (3) ductal transections or excisions (n = 39). Peak occurrence by quarter of the year was 4th quarter, 1990 (Lahey), and 3rd quarter, 1991 (Mason), and 1st quarter, 1992 (Mayo). The majority (62%) of the injuries were recognized after LC. At the time of LC, 31 of 81 (38%) injuries were recognized and converted to open procedures. Data regarding IOC were available in 63 of 81 (78%) cases. In patients in whom IOC was not performed, 14 of 38 (37%) operations were converted; if an IOC was obtained and interpreted correctly, 13 of 21 (62%) operations were converted. Primary repair was attempted in 11 leaks and/or strictures, but 36% required additional treatment. Primary repair was used in six transections or excisions, and 17% have required further intervention. In patients who had biliary-enteric bypass (BEB) performed outside (17) versus at the referral institution (29), 94% (16 patients) versus 0%, respectively, required additional operative (e.g., revision of a hepaticojejunostomy) or nonoperative (e.g., radiologic or endoscopic stenting or balloon dilation) procedures. When used as initial therapy or after a primary ductal repair, stents (with or without balloon dilation) resolved 100% of simple cystic duct leaks and 91% of leaks and/or strictures. In conclusion, the peak incidence of LC-related biliary injuries appears to have passed. A completed and correctly interpreted IOC increases the chance of detection of biliary injuries intraoperatively and should assist surgeons who use routine IOC. Nonsurgical techniques allow treatment of most simple cystic duct leaks, major ductal leaks and/or strictures, and postoperative BEB strictures, although follow-up is limited. The poor results of pre-referral BEB is not surprising since all of these patients were selected for referral because their treatments had not been successful.

Satisfaction After Contralateral Prophylactic Mastectomy: The Significance of Mastectomy Type, Reconstructive Complications, and Body Appearance

PURPOSE Contralateral prophylactic mastectomy (CPM) is one option for reducing the risk of a second breast cancer in women with a personal and family history of breast cancer. Few data are available regarding satisfaction, psychological, and social function after CPM. The purpose of this research is to evaluate womens long-term satisfaction with CPM, factors influencing satisfaction, and psychological and social function after CPM. PATIENTS AND METHODS This was a descriptive study of all women with a family history of breast cancer, known to be alive, who elected CPM at Mayo Clinic (Rochester, MN) between 1960 and 1993 (n = 621). Ninety-four percent of the women (n = 583) completed a study-specific questionnaire. RESULTS A mean of 10.3 years after the procedure, the majority of women (83%) were satisfied with their CPM. A smaller number were neutral (8%) or dissatisfied (9%). Women who had a subcutaneous mastectomy had more problems with reconstruction, and fewer of these women were satisfied than women with simple mastectomy. Decreased satisfaction with CPM was associated with decreased satisfaction with appearance, complications with reconstruction, reconstruction after CPM, and increased level of stress in life. The majority of women experienced no change or favorable effects in self-esteem (83%), level of stress in life (83%), and emotional stability (88%). Satisfaction with body appearance, feelings of femininity, and sexual relationships were the most adversely affected with 33%, 26%, and 23% of the women responding negatively. CONCLUSION Although most women are satisfied with CPM, each woman should weigh the benefits alongside the potential adverse effects.