John P. Hoffman

Fluorouracil vs Gemcitabine Chemotherapy Before and After Fluorouracil-Based Chemoradiation Following Resection of Pancreatic Adenocarcinoma: A Randomized Controlled Trial

CONTEXT Among patients with locally advanced metastatic pancreatic adenocarcinoma, gemcitabine has been shown to improve outcomes compared with fluorouracil. OBJECTIVE To determine if the addition of gemcitabine to adjuvant fluorouracil chemoradiation (chemotherapy plus radiation) improves survival for patients with resected pancreatic adenocarcinoma. DESIGN, SETTING, AND PARTICIPANTS Randomized controlled phase 3 trial of patients with complete gross total resection of pancreatic adenocarcinoma and no prior radiation or chemotherapy enrolled between July 1998 and July 2002 with follow-up through August 18, 2006, at 164 US and Canadian institutions. INTERVENTION Chemotherapy with either fluorouracil (continuous infusion of 250 mg/m2 per day; n = 230) or gemcitabine (30-minute infusion of 1000 mg/m2 once per week; n = 221) for 3 weeks prior to chemoradiation therapy and for 12 weeks after chemoradiation therapy. Chemoradiation with a continuous infusion of fluorouracil (250 mg/m2 per day) was the same for all patients (50.4 Gy). MAIN OUTCOME MEASURES Survival for all patients and survival for patients with pancreatic head tumors were the primary end points. Secondary end points included toxicity. RESULTS A total of 451 patients were randomized, eligible, and analyzable. Patients with pancreatic head tumors (n = 388) had a median survival of 20.5 months and a 3-year survival of 31% in the gemcitabine group vs a median survival of 16.9 months and a 3-year survival of 22% in the fluorouracil group (hazard ratio, 0.82 [95% confidence interval, 0.65-1.03]; P = .09). The treatment effect was strengthened on multivariate analysis (hazard ratio, 0.80 [95% confidence interval, 0.63-1.00]; P = .05). Grade 4 hematologic toxicity was 1% in the fluorouracil group and 14% in the gemcitabine group (P < .001) without a difference in febrile neutropenia or infection. There were no differences in the ability to complete chemotherapy or radiation therapy (>85%). CONCLUSIONS The addition of gemcitabine to adjuvant fluorouracil-based chemoradiation was associated with a survival benefit for patients with resected pancreatic cancer, although this improvement was not statistically significant. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00003216.

Phase II trial of preoperative radiation therapy and chemotherapy for patients with localized, resectable adenocarcinoma of the pancreas: an Eastern Cooperative Oncology Group Study.

PURPOSE A prospective, multiinstitutional trial was initiated in 1991 to examine the tolerance to and efficacy of a program of preoperative chemoradiotherapy (CTRT) and surgical resection for patients with localized adenocarcinoma of the pancreas. PATIENTS AND METHODS Fifty-three patients were assessable for analysis, with a median follow-up of 52 months for survivors. Radiation therapy (RT) totaling 5,040 cGy in 180 cGy fractions with mitomycin 10 mg/m2 day 2 and fluorouracil (5-FU) 1,000 mg/m2/d continuous infusion days 2 through 5 and 29 through 32 were given as preoperative adjuvant therapy. Twelve patients did not proceed to surgery (one death, one toxicity, three local progression, six distant metastases, one intercurrent illness), whereas 41 patients underwent surgery. Of these, 17 patients did not have resection (11, hepatic and/or peritoneal metastases and six local extension that precluded resection). Twenty-four patients had tumor resection (19 Whipple, four total pancreatectomy, one distal pancreatectomy). RESULTS Treatment toxicity was primarily hematologic, although a comparable number suffered biliary tract complications, either from obstruction or cholangitis as a result of an occluded stent or the primary tumor. There was one postoperative death. Median survival for the entire group and for the 24 patients with resection was 9.7 and 15.7 months. This survival rate reflected the advanced state of most resected cancers (positive peritoneal cytology, three patients; margins within 2 mm, 13 patients; involved lymph nodes, four patients; and need for superior mesenteric vein (SMV) resection, four patients). Tumor progression was most frequent at metastatic sites. CONCLUSION This preoperative CTRT protocol was feasible and safe in a cooperative group setting. Entry of patients with advanced tumors probably accounted for the suboptimal resectability and survival results.

Phase II trial of neoadjuvant/adjuvant imatinib mesylate (IM) for advanced primary and metastatic/recurrent operable gastrointestinal stromal tumor (GIST): early results of RTOG 0132/ACRIN 6665.

Therapy for gastrointestinal stromal tumors (GIST) has changed significantly with the use of imatinib mesylate (IM). Despite the success of this drug in metastatic GIST, disease progression remains a perplexing clinical issue suggesting the need for multimodality management. There have been no prospective studies either evaluating the neoadjuvant use of IM in primary GIST or as a preoperative cytoreduction agent for metastatic GIST.

Patients with early stage invasive cancer with close or positive margins treated with conservative surgery and radiation have an increased risk of breast recurrence that is delayed by adjuvant systemic therapy.

PURPOSE The association between a positive resection margin and the risk of ipsilateral breast tumor recurrence (IBTR) after conservative surgery and radiation is controversial. The width of the resection margin that minimizes the risk of IBTR is unknown. While adjuvant systemic therapy may decrease the risk of an IBTR in all patients, its impact on patients with positive or close margins is largely unknown. This study examines the interaction between margin status, margin width, and adjuvant systemic therapy on the 5- and 10-year risk of IBTR after conservative surgery and radiation. METHODS AND MATERIALS A series of 1,262 patients with clinical Stage I or II breast cancer were treated by breast-conserving surgery, axillary node dissection, and radiation between March 1979 and December 1992. The median follow-up was 6.3 years (range 0.1-15.6). The median age was 55 years (range 24-89). Clinical size was T1 in 66% and T2 in 34%. Seventy-three percent of patients were node-negative. Only 5 % of patients had tumors that were EIC-positive. Forty-one percent had a single excision, and 59% had a reexcision. The final margins were negative in 77%, positive in 12%, and close (< or = 2 mm) in 11%. The median total dose to the tumor bed was 60 Gy with negative margins, 64 Gy with close margins, and 66 Gy with positive margins. Chemotherapy +/- tamoxifen was used in 28%, tamoxifen alone in 20%, and no adjuvant systemic therapy in 52%. RESULTS The 5-year cumulative incidence (CI) of IBTR was not significantly different between patients with negative (4%), positive (5%), or close (7%) margins. However, by 10 years, a significant difference in IBTR became apparent (negative 7%, positive 12%, close 14%, p = 0.04). There was no significant difference in IBTR when a close or positive margin was involved by invasive tumor or DCIS. Reexcision diminished the IBTR rate to 7% at 10 years if the final margin was negative; however, the highest risk was observed in patients with persistently positive (13%) or close (21%) (p = 0.02) margins. The median interval to failure was 3.7 years after no adjuvant systemic therapy, 5.0 years after chemotherapy +/- tamoxifen, and 6.7 years after tamoxifen alone. This delay to IBTR was observed in patients with close or positive margins, with little impact on the time to failure in patients with negative margins. The 5-year CI of IBTR in patients with close or positive margins was 1% with adjuvant systemic therapy and 13% with no adjuvant therapy. However, by 10 years, the CI of IBTR was similar (18% vs. 14%) due to more late failures in the patients who received adjuvant systemic therapy. CONCLUSION A negative margin (> 2 mm) identifies patients with a very low risk of IBTR (7% at 10 years) after conservative surgery and radiation. Patients with a close margin (< or = 2 mm) are at an equal or greater risk of IBTR as with a positive margin, especially following a reexcision. A margin involved by DCIS or invasive tumor has the same increased risk of IBTR. A reexcision of an initially close or positive margin that results in a negative final margin reduces the risk of IBTR to that of an initially negative margin. A close or positive margin is associated with an increased risk of IBTR even in patients who are EIC-negative or receiving higher boost doses of radiation. The median time to IBTR is delayed; however, the CI is not significantly decreased by adjuvant systemic therapy in patients with close or positive margins-the 5 year results in these patients underestimate their ultimate risk of recurrence.

Postresection CA 19-9 Predicts Overall Survival in Patients With Pancreatic Cancer Treated With Adjuvant Chemoradiation: A Prospective Validation by RTOG 9704

PURPOSE CA 19-9 is an important tumor marker in patients with pancreatic adenocarcinoma. A secondary end point of Radiation Therapy Oncology Group trial 9704 was prospective evaluation of the ability of postresectional CA 19-9 to predict survival. METHODS CA 19-9 expression was analyzed as a dichotomized variable (< 180 v > or = 180) or (< or = 90 v > 90). Cox proportional hazards models were utilized to identify the impact of CA 19-9 expression on overall survival (OS). Actuarial estimates for OS were calculated using Kaplan-Meier methods. RESULTS Three hundred eighty-five patients patients had assessable CA 19-9 levels. The majority had a CA 19-9 level lower than 180 or < or = 90 (n = 220 and 200, respectively), while 34% were Lewis Antigen negative and 33 (9%) and 53 (14%) patients had levels higher than 180 and higher than 90. When CA 19-9 was analyzed as a dichotomized variable, there was a significant survival difference favoring patients with CA 19-9 lower than 180 (hazard ratio [HR], 3.53; P < .0001). This corresponds to a 72% reduction in the risk of death for patients with a CA 19-9 lower than 180. This was also true for patients with CA 19-9 < or = 90 (HR, 3.4; P < .0001). Multivariate analyses confirmed that CA 19-9, when analyzed as both a continuous and a dichotomized variable, is a highly significant predictor of OS in patients with resected pancreatic cancer. CONCLUSION To our knowledge, this is the first phase III trial to perform prospective analysis of CA 19-9 levels in patients treated with adjuvant chemoradiotherapy. It definitively confirms the prognostic importance of postresectional CA 19-9 levels after surgery with curative intent in patients with pancreatic cancer.

A multi-institutional phase II trial of preoperative full-dose gemcitabine and concurrent radiation for patients with potentially resectable pancreatic carcinoma

BackgroundWe report the results of a multi-institutional phase II trial that used preoperative full-dose gemcitabine and radiotherapy for patients with potentially resectable pancreatic carcinoma.MethodsPatients were treated before surgery with three cycles of full-dose gemcitabine (1000 mg/m2 intravenously), with radiation during the second cycle (36 Gy in daily 2.4-Gy fractions). Patients underwent surgery 4 to 6 weeks after the last gemcitabine infusion.ResultsThere were 10 men and 10 women, with a median age of 58 years (range, 50–80 years). Nineteen patients (95%) completed therapy without interruption, and one experienced grade 3 gastrointestinal toxicity. The mean weight loss after therapy was 4.0%. Of 20 patients taken to surgery, 17 (85%) underwent resections (16 pancreaticoduodenectomies and 1 distal pancreatectomy). The complication rate was 24%, with an average length of stay of 13.5 days. There were no operative deaths. Pathologic analysis revealed clear margins in 16 (94%) of 17 and uninvolved lymph nodes in 11 (65%) of 17 specimens. One specimen contained no residual tumor, and three specimens revealed only microscopic foci of residual disease. With a median follow-up of 18 months, 7 (41%) of the 17 patients with resected disease are alive with no recurrence, 3 (18%) are alive with distant metastases, and 7 (41%) have died.ConclusionsPreoperative gemcitabine/radiotherapy is well tolerated and safe when delivered in a multi-institutional setting. This protocol had a high rate of subsequent resection, with acceptable morbidity. The high rate of negative margins and uninvolved nodes suggests a significant tumor response. Preliminary survival data are encouraging. This regimen should be considered in future neoadjuvant trials for pancreatic cancer.

Anal sphincter conservation for patients with adenocarcinoma of the distal rectum: long-term results of radiation therapy oncology group protocol 89-02

PURPOSE To assess the outcome of a multi-institutional, national cooperative group study attempting functional preservation of the anorectum for patients with limited, distal rectal cancer. METHODS AND MATERIALS Between September 21, 1989 and November 1, 1992, a Phase II trial of sphincter-sparing therapy was conducted for patients with clinically mobile rectal cancers located below the pelvic peritoneal reflection. Protocol treatment was designed for patients who were, in the judgement of their attending surgeon, unsuitable for anal sphincter conservation in the context of anterior resection, and would have required abdominoperineal resection (APR) as conventional surgical therapy. Primary cancers were estimated to be 4 cm or less in largest clinical diameter, and occupied 40% or less of the rectal circumference. Chest radiography and computerized axial tomography (CT) of the abdomen and pelvis excluded patients with overt lymphatic or hematogenous metastases. Protocol surgery was intended to remove the primary cancer by en-bloc, transmural excision of an ellipse of rectal wall by transanal, transcoccygeal, or trans-sacral technique, while conserving the anal sphincter. Based on tumor size, T classification, grade, and adequacy of surgical margins, patients were allocated to one of three treatment assignments: observation, or adjuvant treatment with 5-fluorouracil (5-FU) and one of two different dose levels of local-regional radiation. After completion of protocol therapy, patients were observed with follow-up that included periodic general physical and rectal examination, determinations of CEA, abdominopelvic CT, chest radiography, and surveillance endoscopy. Sixty-five eligible and analyzable patients were registered. RESULTS With minimum follow-up of 5 years and median follow-up of 6.1 years, 11 patients have failed: 3 patients recurred local-regionally only, 3 patients had distant failure alone, and 5 patients manifested local-regional and distant failure. Eight patients died of intercurrent illness. Local-regional failure correlated with T-category revealed: T1 1/27 (4%), T2 4/25 (16%), and T3 3/13 (23%). Local-regional failure escalated with percentage involvement of the rectal circumference: 2/31 (6%) among patients with cancers involving 20% or less of the rectal circumference, and 6/34 (18%) among patients with cancers involving 21-40% of the circumference. Distant dissemination rose with T-category with 1/27 (4%) T1, 3/25 (12%) T2, and 4/13 (31%) T3 patients manifesting hematogenous spread. Eight patients (12%) required temporary or permanent colostomy. Five of 8 patients with local-regional recurrence achieved local-regional control with management including surgery, although 4 of these patients subsequently developed distant dissemination. Three patients (5%) had persistent, uncontrolled, local disease. Actuarial freedom from pelvic relapse at 5 years is 88% based on the entire study population, and 86% for the less favorable patients treated with adjuvant radiation and 5-FU. CONCLUSION Conservative, sphincter-sparing therapy is a feasible alternative treatment for selected patients with limited cancer involving the middle and lower rectum. Risk of both local and distant failure appears to escalate with increasing T-category (depth of invasion). Results achieved in the multi-institutional, cooperative group setting approximate results reported from single institutions.

En Bloc Resection for Locally Advanced Cancer of the Pancreas ☆: Is It Worthwhile?

The benefit of radical surgical resection of contiguously involved structures for locally advanced pancreatic cancer is unclear. The aim of this study was to examine patient outcome after extended pancreatic resection for locally advanced tumors and to determine if any subset of extended resection affected outcome. We retrospectively reviewed the records of 116 patients with adenocarcinoma of the pancreas, who underwent extirpative pancreatic surgery between 1987 and 2000. Of the 116 patients, 37 (32%) required resection of surrounding structures (group I), and 79 patients (68%) underwent standard pancreatic resections (group II). In all cases, all macroscopic disease was excised. In group I a total of 46 contiguously involved structures were resected: vascular in 25 patients (54%), mesocolon in 16 (35%) (colic vessels in 3, colon in 13), adrenal in three (7%), liver in one (2%), stomach in one (2%) (for a tumor in the tail of the pancreas), and multiple structures in four. Excision of regional blood vessels included the superior mesenteric vein and/or portal vein in 16, hepatic artery in five, and celiac axis in four. No differences between groups I and II were detected for any of the following parameters: age, sex, history of previous operation, estimated blood loss, or hospital stay. For the entire cohort the morbidity and mortality were 38% and 1.7%, respectively, and these rates were similar in the two groups. Adjuvant therapy was administered to more than 90% of patients in both groups. However, patients in group I were more likely to have received neoadjuvant therapy (76% vs. 42%, P = 0.001). Total pancreatectomy and distal pancreatectomy were more often performed in group I (P = 0.005). Additionally, the median operative time was longer (8.5 hours compared to 6.9 hours (P = 0.0004)). Both groups had similar rates of microscopically positive margins and involved lymph nodes, as well as total number of lymph nodes removed. The median survival was 26 months for patients in group I and 16 months for patients in group II (P = 0.08). The median disease-free survival for groups I and II was 16 months and 14 months, respectively (P = 0.88). In comparing patients in group I, who underwent vascular resection vs. mesocolon (colon or middle colic vessels) resection, the median survival was 26 months and 19 months, respectively (P = 0.12). We were unable to detect a difference in outcome for patients with locally advanced cancers requiring extended pancreatic resections compared to patients with standard resections. En bloc resection of involved surrounding structures, to completely extirpate all macroscopic disease, may be of benefit in selected patients with locally advanced disease, particularly when combined with preoperative chemoradiation therapy.

Effect of preoperative chemoradiotherapy on surgical margin status of resected adenocarcinoma of the head of the pancreas

We examined the effect of preoperative chemoradiotherapy on the ability to obtain pathologically negative resection margins in patients undergoing pancreaticoduodenectomy for adenocarcinoma of the head of the pancreas. Between 1987 and 2000, 100 patients underwent Whipple resection with curative intent for primary adenocarcinoma of the head of the pancreas. Pathologic assessment of six margins (proximal and distal superior mesenteric artery, proximal and distal superior mesenteric vein, pancreas, retroperkoneum, common bile duct, and hepatic artery) was undertaken by either frozen section (pancreas and common duct) or permanent section. A margin was considered positive if tumor was present less than 1 mm from the inked specimen. Margins noted to be positive on frozen section were resected when-ever possible. Of the 100 patients treated, 47 (47%) underwent postoperative radiation and chemotherapy (group I) and 53 (53%) received preoperative chemoradiotherapy (group II) with either 5-fluorouracil (32 patients) or gemcitabine (21 patients). Patient demographics and operative parameters were similar in the two groups, with the exception of preoperative tumor size (CT scan), which was greater in group II (P <0.001), and number of previous operations, which was greater in group II (P <0.0001). Statistical analysis of the number of negative surgical margins clear of tumor was performed using Fisher’s exact test. All patients (100%) had six margins assessed for microscopic involvement with tumor. In the preoperative therapy group, 5 (7.5%) of 53 patients had more than one positive margin, whereas 21 (44.7%) of 47 patients without preoperative therapy had more than one margin with disease extension (P < 0.001). Additionally, only 11 (25.6%) of the 47 patients without preoperative therapy had six negative margins vs. 27 (50.9%) of 53 in the group receiving preoperative therapy (P = 0.013). Survival analysis reveals a significant increase in survival in margin-negative patients (P = 0.02). Similarly, a strong trend toward improved disease-free and overall survival is seen in patients with a single positive margin vs. multiple margins. Overall, we find a negative impact on survival with an increasing number of positive margins (P = 0.025, hazard ratio 1.3). When stratified for individual margin status, survival was decreased in patients with positive superior mesenteric artery (P = 0.06) and vein (P = 0.04) margins. However, this has not yet resulted in a significant increase in disease-free or overall survival for patients receiving preoperative therapy (P = 0.07).

Outcome of Patients Receiving Radiation for Cancer of the Esophagus: Results of the 1992-1994 Patterns of Care Study

PURPOSE A Patterns of Care Study examined the records of patients with esophageal cancer (EC) treated with radiation in 1992 through 1994 to determine the national practice processes of care and outcomes and to compare the results with those of clinical trials. PATIENTS AND METHODS A national survey of 63 institutions was conducted using two-stage cluster sampling, and specific information was collected on 400 patients with squamous cell (62%) or adenocarcinoma (37%) of the thoracic esophagus who received radiation therapy (RT) as part of primary or adjuvant treatment. Patients were staged according to a modified 1983 American Joint Committee on Cancer staging system. Fifteen percent of patients had clinical stage (CS) I disease, 40% had CS II disease, and 30% had CS III disease. Twenty-six percent of patients underwent esophagectomy. Seventy-five percent of patients received chemotherapy; 84% of these received concurrent chemotherapy and radiation (CRT). RESULTS Significant variables for overall survival in multivariate analysis include the use of esophagectomy (risk ratio [RR] = 0.62), the use of chemotherapy (RR = 0.63), Karnofsky performance status (KPS) greater than 80 (RR = 0.61), CS I or II disease (RR = 0.66), and facility type (RR = 0.72). Age, sex, and histology were not significant. Preoperative CRT resulted in a nonsignificantly higher 2-year survival rate compared with definitive CRT alone (63% v 39%; P =.11), whereas 2-year survival by planned treatment rather than treatment given was 47.7% for preoperative CRT and 35.4% for definitive CRT (P =.23). Definitive CRT compared with definitive RT alone resulted in significantly higher 2-year survival (39% v 20.6%; P =.027) and lower 2-year local regional failure (30% v 57.9%; P =. 0031). CONCLUSION This study confirms the value of CRT in EC treatment. It indicates that the results obtained in practice settings nationwide are similar to those obtained in clinical trials and that KPS and the 1983 clinical staging system are useful prognostic indicators. The suggested value of esophagectomy and superiority of preoperative CRT over CRT alone in this study should be tested in a randomized trial.