Michael G. Haddock

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.

Fluorouracil, Mitomycin, and Radiotherapy vs Fluorouracil, Cisplatin, and Radiotherapy for Carcinoma of the Anal Canal: A Randomized Controlled Trial

CONTEXT Chemoradiation as definitive therapy is the preferred primary therapy for patients with anal canal carcinoma; however, the 5-year disease-free survival rate from concurrent fluorouracil/mitomycin and radiation is only approximately 65%. OBJECTIVE To compare the efficacy of cisplatin-based (experimental) therapy vs mitomycin-based (standard) therapy in treatment of anal canal carcinoma. DESIGN, SETTING, AND PARTICIPANTS US Gastrointestinal Intergroup trial RTOG 98-11, a multicenter, phase 3, randomized controlled trial comparing treatment with fluorouracil plus mitomycin and radiotherapy vs treatment with fluorouracil plus cisplatin and radiotherapy in 682 patients with anal canal carcinoma enrolled between October 31, 1998, and June 27, 2005. Stratifications included sex, clinical nodal status, and tumor diameter. INTERVENTION Participants were randomly assigned to 1 of 2 intervention groups: (1) the mitomycin-based group (n = 341), who received fluorouracil (1000 mg/m2 on days 1-4 and 29-32) plus mitomycin (10 mg/m2 on days 1 and 29) and radiotherapy (45-59 Gy) or (2) the cisplatin-based group (n = 341), who received fluorouracil (1000 mg/m2 on days 1-4, 29-32, 57-60, and 85-88) plus cisplatin (75 mg/m2 on days 1, 29, 57, and 85) and radiotherapy (45-59 Gy; start day = day 57). MAIN OUTCOME MEASURES The primary end point was 5-year disease-free survival; secondary end points were overall survival and time to relapse. RESULTS A total of 644 patients were assessable. The median follow-up for all patients was 2.51 years. Median age was 55 years, 69% were women, 27% had a tumor diameter greater than 5 cm, and 26% had clinically positive nodes. The 5-year disease-free survival rate was 60% (95% confidence interval [CI], 53%-67%) in the mitomycin-based group and 54% (95% CI, 46%-60%) in the cisplatin-based group (P = .17). The 5-year overall survival rate was 75% (95% CI, 67%-81%) in the mitomycin-based group and 70% (95% CI, 63%-76%) in the cisplatin-based group (P = .10). The 5-year local-regional recurrence and distant metastasis rates were 25% (95% CI, 20%-30%) and 15% (95% CI, 10%-20%), respectively, for mitomycin-based treatment and 33% (95% CI, 27%-40%) and 19% (95% CI, 14%-24%), respectively, for cisplatin-based treatment. The cumulative rate of colostomy was significantly better for mitomycin-based than cisplatin-based treatment (10% vs 19%; P = .02). Severe hematologic toxicity was worse with mitomycin-based treatment (P < .001). CONCLUSIONS In this population of patients with anal canal carcinoma, cisplatin-based therapy failed to improve disease-free-survival compared with mitomycin-based therapy, but cisplatin-based therapy resulted in a significantly worse colostomy rate. These findings do not support the use of cisplatin in place of mitomycin in combination with fluorouracil and radiotherapy in the treatment of anal canal carcinoma. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00003596.

Liver Transplantation with Neoadjuvant Chemoradiation is More Effective than Resection for Hilar Cholangiocarcinoma

Objective:Compare survival after neoadjuvant therapy and liver transplantation with survival after resection for patients with hilar CCA. Summary Background Data:We developed a protocol combining neoadjuvant radiotherapy, chemosensitization, and orthotopic liver transplantation for patients with operatively confirmed stage I and II hilar CCA in 1993. Since then, patients with unresectable CCA or CCA arising in the setting of PSC have been enrolled in the transplant protocol. Patients with tumors amenable to resection have undergone excision of the extrahepatic duct with lymphadenectomy and liver resection. Methods:We reviewed our experience between January 1993 and August 2004 and compared patient survival between the treatment groups. Results:Seventy-one patients entered the transplant treatment protocol and 38 underwent liver transplantation. Fifty-four patients were explored for resection. Twenty-six (48%) underwent resection, and 28 (52%) had unresectable disease. One-, 3-, and 5-year patient survival were 92%, 82%, and 82% after transplantation and 82%, 48%, and 21% after resection (P = 0.022). There were fewer recurrences in the transplant patients (13% versus 27%). Conclusions:Liver transplantation with neoadjuvant chemoradiation achieved better survival with less recurrence than conventional resection and should be considered as an alternative to resection for patients with localized, node-negative hilar CCA.

RTOG 0529: A Phase 2 Evaluation of Dose-Painted Intensity Modulated Radiation Therapy in Combination With 5-Fluorouracil and Mitomycin-C for the Reduction of Acute Morbidity in Carcinoma of the Anal Canal

PURPOSE A multi-institutional phase 2 trial assessed the utility of dose-painted intensity modulated radiation therapy (DP-IMRT) in reducing grade 2+ combined acute gastrointestinal and genitourinary adverse events (AEs) of 5-fluorouracil (5FU) and mitomycin-C (MMC) chemoradiation for anal cancer by at least 15% compared with the conventional radiation/5FU/MMC arm from RTOG 9811. METHODS AND MATERIALS T2-4N0-3M0 anal cancer patients received 5FU and MMC on days 1 and 29 of DP-IMRT, prescribed per stage: T2N0, 42 Gy elective nodal and 50.4 Gy anal tumor planning target volumes (PTVs) in 28 fractions; T3-4N0-3, 45 Gy elective nodal, 50.4 Gy ≤ 3 cm or 54 Gy >3 cm metastatic nodal and 54 Gy anal tumor PTVs in 30 fractions. The primary endpoint is described above. Planned secondary endpoints assessed all AEs and the investigators ability to perform DP-IMRT. RESULTS Of 63 accrued patients, 52 were evaluable. Tumor stage included 54% II, 25% IIIA, and 21% IIIB. In primary endpoint analysis, 77% experienced grade 2+ gastrointestinal/genitourinary acute AEs (9811 77%). There was, however, a significant reduction in acute grade 2+ hematologic, 73% (9811 85%, P=.032), grade 3+ gastrointestinal, 21% (9811 36%, P=.0082), and grade 3+ dermatologic AEs 23% (9811 49%, P<.0001) with DP-IMRT. On initial pretreatment review, 81% required DP-IMRT replanning, and final review revealed only 3 cases with normal tissue major deviations. CONCLUSIONS Although the primary endpoint was not met, DP-IMRT was associated with significant sparing of acute grade 2+ hematologic and grade 3+ dermatologic and gastrointestinal toxicity. Although DP-IMRT proved feasible, the high pretreatment planning revision rate emphasizes the importance of real-time radiation quality assurance for IMRT trials.

Curative Potential of Multimodality Therapy for Locally Recurrent Rectal Cancer

ObjectiveTo assess the results of multimodality therapy for patients with recurrent rectal cancer and to analyze factors predictive of curative resection and prognostic for overall survival. Summary Background DataLocally recurrent rectal cancer is a difficult clinical problem, and radical treatment options with curative intent are not generally accepted. MethodsA total of 394 patients underwent surgical exploration for recurrent rectal cancer. Ninety were found to have unresectable local or extrapelvic disease and 304 underwent resection of the recurrence. The latter patients were prospectively followed to determine long-term survival and factors influencing survival. ResultsOverall 5-year survival was 25%. Curative, negative resection margins were obtained in 45% of patients; in these patients a 5-year survival of 37% was achieved, compared to 16% (P < .001) in patients with either microscopic or gross residual disease. In a logistic regression analysis, initial surgery with end-colostomy and symptomatic pain (both univariate) and increasing number of sites of the recurrent tumor fixation in the pelvis (multivariate) were associated with palliative surgery. Overall survival was significantly decreased for symptomatic pain (P < .001) and more than one fixation (P = .029). Survival following extended resection of adjacent organs was not different from limited resection (28% vs. 21%, P = .11). Patient demographics and factors related to the initial rectal cancer did not affect outcome. Perioperative mortality was only 0.3%, but significant morbidity occurred in 26% of patients, with pelvic abscess being the most common complication. ConclusionsThis study demonstrates that many patients with locally recurrent rectal cancer can be resected with negative margins. Long-term survival can be achieved, especially for patients with no symptoms and minimal fixation of the recurrence in the pelvis, provided no gross residual disease remains.

Long-Term Update of US GI Intergroup RTOG 98-11 Phase III Trial for Anal Carcinoma: Survival, Relapse, and Colostomy Failure With Concurrent Chemoradiation Involving Fluorouracil/Mitomycin Versus Fluorouracil/Cisplatin

PURPOSE On initial publication of GI Intergroup Radiation Therapy Oncology Group (RTOG) 98-11 [A Phase III Randomized Study of 5-Fluorouracil (5-FU), Mitomycin, and Radiotherapy Versus 5-Fluorouracil, Cisplatin and Radiotherapy in Carcinoma of the Anal Canal], concurrent chemoradiation (CCR) with fluorouracil (FU) plus mitomycin (MMC) decreased colostomy failure (CF) when compared with induction plus concurrent FU plus cisplatin (CDDP), but did not significantly impact disease-free survival (DFS) or overall survival (OS) for anal canal carcinoma. The intent of the updated analysis was to determine the long-term impact of treatment on survival (DFS, OS, colostomy-free survival [CFS]), CF, and relapse (locoregional failure [LRF], distant metastasis) in this patient group. PATIENTS AND METHODS Stratification factors included sex, clinical node status, and primary size. DFS and OS were estimated univariately by the Kaplan-Meier method, and treatment arms were compared by log-rank test. Time to relapse and CF were estimated by the cumulative incidence method and treatment arms were compared by using Grays test. Multivariate analyses used Cox proportional hazard models to test for treatment differences after adjusting for stratification factors. RESULTS Of 682 patients accrued, 649 were analyzable for outcomes. DFS and OS were statistically better for RT + FU/MMC versus RT + FU/CDDP (5-year DFS, 67.8% v 57.8%; P = .006; 5-year OS, 78.3% v 70.7%; P = .026). There was a trend toward statistical significance for CFS (P = .05), LRF (P = .087), and CF (P = .074). Multivariate analysis was statistically significant for treatment and clinical node status for both DFS and OS, for tumor diameter for DFS, and for sex for OS. CONCLUSION CCR with FU/MMC has a statistically significant, clinically meaningful impact on DFS and OS versus induction plus concurrent FU/CDDP, and it has borderline significance for CFS, CF, and LRF. Therefore, RT + FU/MMC remains the preferred standard of care.

Predictors of Disease Recurrence Following Neoadjuvant Chemoradiotherapy and Liver Transplantation for Unresectable Perihilar Cholangiocarcinoma

Background. Sixty-five patients with unresectable hilar cholangiocarcinoma (CCA) have undergone orthotopic liver transplantation (OLT) after neoadjuvant chemoradiotherapy per a clinical care protocol developed in 1993. We reviewed our experience with the aim to identify clinicopathological predictors of disease recurrence. Methods. All patients with CCA that underwent OLT at our institution between 1993 and January 1, 2006 were treated in accord with our published protocol. We analyzed multiple clinical and explant pathologic factors using Cox regression analysis. Results. Sixty-five patients with CCA underwent OLT. Four patients died within six months due to postoperative complications. At last follow-up, 11 patients (17%) had developed recurrence seven to 64 months after OLT. Mean time to recurrence was 29 months, and eight patients had died from recurrent disease. Patient and disease-free survival were 76% and 60% five years after OLT. Predictors of recurrence were older age, pretransplant cancer antigen (CA) 19-9 >100 U/ml, prior cholecystectomy, mass on cross-sectional imaging, residual tumor in explant >2 cm, tumor grade and perineural invasion in explant. Underlying primary sclerosing cholangitis, percutaneous biliary intubation, gender, and other time points for CA 19-9 were not associated with recurrence. Prolonged staging-to-OLT intervals for patients transplanted after implementation of model for end-stage liver disease (MELD) showed a trend toward increased recurrence. Conclusions. Older patients and those with high CA-19.9 levels, and larger tumors are more likely to develop recurrent disease. Prolonged waiting time may emerge as a significant risk factor with longer follow-up. These findings may guide patient selection, applicability of live donor transplantation and MELD score exceptions for this aggressive protocol.

USE OF INTRAOPERATIVE ELECTRON BEAM RADIOTHERAPY IN THE MANAGEMENT OF RETROPERITONEAL SOFT TISSUE SARCOMAS

PURPOSE To evaluate the disease control, survival results, and tolerance of intraoperative electron beam radiotherapy (IOERT) as a component of treatment for retroperitoneal soft tissue sarcomas. METHODS AND MATERIALS Between March 1981 and September 1995, 87 patients with primary (n = 43) or recurrent (n = 44) retroperitoneal or intrapelvic sarcomas received IOERT as a component of treatment at the Mayo Clinic. The tumors were high grade in 54 patients (62%) and low grade in 33 (38%). The median tumor size was 10 cm (range 2-36). All patients underwent maximal surgical resection with IOERT; in 72 patients, only microscopic or no residual tumor remained. The IOERT doses ranged from 8.75 to 30 Gy (median 15). All primary tumors received external beam irradiation (EBRT) with a median dose of 48.6 Gy. Thirty-four of the 44 recurrent tumors received EBRT to a median dose of 45 Gy. All patients were followed prospectively for outcome and toxicity evaluation. RESULTS The median follow-up, based on 46 patients (53%) currently alive, was 3.5 years. The overall estimated 5-year survival was 47%. For patients with tumors > or = 10 cm, the 5-year overall survival was significantly poorer (28%) than for those with smaller lesions (60%) (p = 0.01). Neither primary vs. recurrent status nor tumor grade had a significant impact on survival. Patients with gross residual tumor had a marginally significantly poorer survival compared with patients with microscopic or no residual tumor, with a 5-year survival rate of 37% and 52%, respectively (p = 0.08). A total of 49 patients (56%) experienced failure, including 20 local recurrences (23%). The median time to failure was 2.3 years. Four recurrences were within the IOERT field, 3 within the IOERT and EBRT field, and 13 within the EBRT field alone. The 3- and 5-year estimated local control rate was 77% and 59%, respectively. Local control was marginally significantly affected by the amount of residual tumor, with a 5-year local control rate of 41% for those with gross residual tumor, 60% for those with microscopic residual tumor, and 100% for those with no residual tumor (p = 0.09). Gastrointestinal complications were recorded in 12 incidences (Grade 3 or higher toxicity). These complications were believed to be secondary to surgery and/or EBRT in 10 of the 12 cases. Seven patients had fistula formation, and 3 experienced severe proctitis. Grade 3 peripheral neurologic toxicities occurred in 9 patients (10%), but none had pain as a component of their neuropathy. CONCLUSION Retroperitoneal soft tissue sarcomas can be treated with an aggressive combined approach of EBRT, surgery, and IOERT, with acceptable toxicity. Local control in primary disease appears to be improved in this retrospective series with this approach. Distant disease control and options for recurrent disease needs further definition.

Locally advanced primary colorectal cancer: intraoperative electron and external beam irradiation +/- 5-FU.

PURPOSE For locally advanced primary colorectal cancer, our institution has combined intraoperative electron irradiation (IOERT) with external beam irradiation (EBRT) +/- 5-fluorouracil (5-FU) and surgical resection. Disease control and survival were compared with the current IOERT and prior non-IOERT regimens. METHODS AND MATERIALS From April 1981 through August 1995, 61 patients received an IOERT dose of 10-20 Gy, usually combined with 45-55 Gy of fractionated EBRT; 56 had minimum follow-up of 18 months. The amount of residual disease remaining at IOERT after exploration and maximal resection in the 56 patients was gross in 16, < or = microscopic in 39, and unresected in 1. RESULTS Survival (SR) and disease control were analyzed as a function of potential prognostic factors. Factors that achieved statistical significance for improved overall survival included treatment sequence of preop EBRT + 5-FU (vs. postoperative EBRT + 5-FU, p = 0.003) and < or = microscopic residual disease after maximal resection (vs. gross residual, p = 0.005). Those that appeared to favorably impact disease-free survival included EBRT + 5-FU (vs. EBRT alone, p = 0.01), < or = microscopic residual (vs. gross, p = 0.0014), and colon site of primary (vs. rectum, p = 0.009). Failures within an irradiation field have occurred in 4 of 16 patients (25%) who presented with gross residual after partial resection vs. 2 of 39 (5%) with < or = microscopic residual after gross total resection (p = 0.01). The significant prognostic factors for a decrease in distant metastases were the same as for disease-free SR with respective p-values of 0.013 (EBRT + 5-FU), 0.008 (microscopic residual), and 0.03 (colon primary). The current data suggests a relationship between IOERT dose and incidence of Grade 2 or 3 neuropathy (< or = 12.5 Gy--1 of 29 or 3%, > or = 15 Gy--6 of 26 or 23%, p = 0.03). CONCLUSIONS Both overall survival and disease control appear to be improved with the addition of IOERT to standard treatment. More routine use of systemic therapy is indicated as a component of IOERT containing treatment regimens because the incidence of distant metastases was 50% of patients at risk.

Intraoperative electron and external beam irradiation with or without 5-fluorouracil and maximum surgical resection for previously unirradiated, locally recurrent colorectal cancer

PURPOSE/OBJECTIVE: 1) Disease control and survival will be evaluated for treatment regimens containing intraoperative electron irradiation (IOERT) for locally recurrent, previously unirradiated colorectal cancers. 2) Various prognostic factors will be evaluated to determine whether they have an impact on disease control or survival. MATERIALS AND METHODS: From April 1981 through August 1995, 123 patients with previously unirradiated locally recurrent colorectal cancers received IOERT at our institution, usually as a supplement to external beam irradiation (EBRT) and maximum resection. All received EBRT with or without concomitant 5-fluorouracil-based chemotherapy. Forty-five Gy in 25 fractions was given to the tumor or tumor bed plus 3-cm to 5-cm margins in 121 of 123 patients and a boost of 5.4 to 9 Gy in 3 to 5 fractions to the tumor plus 2-cm margins. Maximum resection was performed before or after EBRT. IOERT doses ranged from 10 to 20 Gy in 119 of 123 patients, with dose dependent on resection margins (130 fields in 123 patients). Maintenance chemotherapy was given to only two patients. RESULTS: Disease relapse and survival were evaluated. Central failure (within the IOERT field) was documented in 13 of 123 patients (11 percent) with a five-year actuarial rate of 26 percent. Local relapse (in EBRT field) occurred in 24 patients (20 percent); five-year rate was 37 percent. Distant metastases occurred in 66 patients (54 percent); five-year rate was 72 percent. Median survival was 28 months, with overall survival at two, three, and five years of 62, 39, and 20 percent, respectively. Tolerance data suggest a relationship between IOERT dose and incidence of Grade 2 or 3 neuropathy (≤12.5 Gy, 2 of 29 or 7 percent; ≥15 Gy, 19 of 101 or 19 percent;P=0.12). Survival and disease control were analyzed as a function of potential prognostic factors. None of the prognostic factors had a significant impact on disease control or survival. Although there was a trend for reduction in local relapse rates with gross totalvs. partial resection, this neither achieved statistical significance nor translated into improved survival. Patients with gross residual disease after maximum resection had three-year and five-year survival rates of 36 and 18 percent, respectively, which paralleled results for patients with gross total resection at 41 and 24 percent, respectively. CONCLUSION: Encouraging trends for improved local control with or without survival exist in separate locally recurrent colorectal IOERT analyses from our institution and other institutions. Therefore, continued evaluation of IOERT approaches seems warranted. Disease control within the IOERT and external fields is decreased when the surgeon is unable to accomplish a gross total resection. Therefore, it is reasonable to consistently add 5-fluorouracil or other dose modifiers during EBRT and to evaluate the use of dose modifiers in conjunction with IOERT (sensitizers and hyperthermia). In view of high systemic failure rates of >50 percent in patients with locally recurrent disease, more routine use of systemic therapy is indicated as a component of IOERT-containing treatment regimens (use existent chemotherapy and/or develop effective immunotherapy and gene transfer therapy). Even with locally recurrent lesions, the aggressive multimodality approaches including IOERT have resulted in improved local control and long-term survival rates of 20 percentvs. an expected 5 percent with conventional techniques.