Hepatobiliary: periampullary carcinoma

LMW heparins were used more often for treatment of thromboembolism. ALLEN SILBERGLEIT, MD, PhD* EBERHARD F. MAMMEN, MD† *Department of Surgery St Joseph Mercy-Oakland Pontiac, Michigan †Wayne State University Detroit, Michigan REFERENCES 1. Mariani G, Mazzucconi MG. Factor VII congenital deficiency: clinical pictures and classification of the variants. Haemostasis 1983; 13:169 –177. 2. Mammen EF. Congenital coagulation protein disorders. In: Bick RL, editor. Hematology: clinical and laboratory practice. St Louis: Mosby, 1993. 3. Davie EW, Fujikawa K, Kisiel W. The coagulation cascade: initiation, maintenance and regulation. Biochemistry 1991;30:10363– 10370. 4. Osterud B, Rapaport SI. Activation of factor IX by the reaction product of tissue factor and factor VII. Additional pathway of initiating blood coagulation. Proc Natl Acad Sci USA 1977;74:5260 – 5264. 5. Rapaport SI, Rao LVM. The tissue factor pathway: how it has become a “prima ballerina.” Thromb Haemost 1995;74:7–17. 6. Bolton-Maggs PHB, Hill FGH. The rarer inherited coagulation disorders: a review. Blood Rev 1995;9:65–76. 7. Minnema MC, ten Cate H, Hack CE. The role of factor IX in coagulation: a matter of revision. Semin Thromb Hemost 1999;25: 419 – 428. 8. Mammen EF. Antithrombin: its physiological importance and role in DIC. Semin Thromb Hemost 1998;24:19 –25. 9. Broze CJ. The role of tissue factor pathway inhibitor in a revised model of blood coagulation. Semin Hematol 1992;29:159 –169. 10. Bajaj SP, Joist JH. New insights into how blood clots: implications for the use of APTT and PT as coagulation screening tests and in monitoring of anticoagulant therapy. Semin Thromb Hemost 1999; 25:407– 418. 11. Grady RF. Noncardiac surgery in the elderly patient with heart disease. Mt Sinai J Med 1985;52:634 – 642. 12. Katholi RE, Nolan SP, McGuire LB. Living with prosthetic heart valves: subsequent noncardiac operations and the risk of thromboembolism or hemorrhage. Am Heart J 1976;92:162–167. 13. Stein PD, Alpert JS, Copeland J, et al. Antithrombotic therapy in patients with mechanical and biological prosthetic heart valves. Chest 1995;108(suppl):371S–379S. 14. Ortin M, Olalla J-I, Marco F, et al. Low-dose vitamin K1 versus short-term withholding of acenocoumarol in the treatment of excessive anticoagulation episodes induced by acenocoumarol: a retrospective comparative study. Haemostasis 1998;28:57– 61.

15. McIntyre H. Management during dental surgery of patients on anticoagulants. Lancet 1966;2:99 –100. 16. Weismann RE, Tobin RW. Arterial embolism occurring during systemic heparin therapy. Arch Surg 1958;76:219 –227. 17. Natelson EA, Lynch EC, Alfrey CP, et al. Heparin-induced thrombocytopenia. Ann Intern Med 1969;71:1121–1125. 18. Warkentin TE, Kelton JG. Heparin-induced thrombocytopenia. Prog Hemost Thromb 1991;10:1–34. 19. Warkentin TE, Levine MN, Hirsh J, et al. Heparin-induced thrombocytopenia in patients treated with low-molecular-weight heparin or unfractionated heparin. N Engl J Med 1995;332:1330 –1335. 20. Greinacher A, Po¨tzsch B, Amiral J, et al. Heparin-associated thrombocytopenia: isolation of the antibody and characterization of a multimolecular PF4-heparin complex as the major antigen. Thromb Haemost 1994;71:247–251. 21. Amiral J, Wolf M, Fischer AM, et al. Pathogenicity of IgA and/or IgM antibodies to heparin-PF4-complexes in patients with heparininduced thrombocytopenia. Br J Haematol 1996;92:954 –959. 22. Kwaan HC, Sukarai S. Endothelial cell hyperplasia contributes to thrombosis in heparin-induced thrombocytopenia. Semin Thromb Hemost 1999;25(suppl 1):S23–S27. 23. Chong BH. Heparin-induced thrombocytopenia. Br J Haematol 1995;89:431– 439. 24. Walenga JM, Jeske WP, Fasanella AR, et al. Laboratory tests for the diagnosis of heparin-induced thrombocytopenia. Semin Thromb Hemost 1999;25(suppl 1):S43–S49. 25. Izban KF, Lietz HW, Hoppenstead DA, et al. Comparison of two PF4/heparin ELISA assays for the laboratory diagnosis of heparininduced thrombocytopenia. Semin Thromb Hemost 1999;25(suppl 1):S51–S56. 26. Raible MD. Hematologic complications of heparin-induced thrombocytopenia. Semin Thromb Hemost 1999;25(suppl 1):S17–S21. 27. Greinacher A. Antigen generation in heparin-associated thrombocytopenia: the nonimmunologic type and the immunologic type are closely linked in their pathogenesis. Semin Thromb Hemost 1995;21:106 –116. 28. Warkentin TE. Heparin-induced thrombocytopenia: IgG-mediated platelet activation, platelet microparticle generation, and altered procoagulant/anticoagulant balance in the pathogenesis of thrombosis and venous limb gangrene complicating heparin-induced thrombocytopenia. Transf Med Rev 1996;10:249 –258. 29. Walenga JM, Jeske WP, Wallis DE, et al. Clinical experience with combined treatment of thrombin inhibitors and GPIIb/IIIa inhibitors in patients with HIT. Semin Thromb Hemost 1999;25(suppl 1):S77–S81. 30. Lewis BE, Walenga JM, Wallis DE. Anticoagulation with Novastan威 (argatroban) in patients with heparin-induced thrombocytopenia and heparin-induced thrombocytopenia and thrombosis syndrome. Semin Thromb Hemost 1997;23:197–202. 31. Warkentin TE, Chong BE, Greinacher A. Heparin-induced thrombocytopenia: towards consensus. Thromb Haemost 1998;79:1–7.

Surgical Oncology

Hepatobiliary: Periampullary Carcinoma Guest Reviewer: George M. Furhman, MD REEXPLORATION FOR PERIAMPULLARY CARCINOMA: RESECTABILITY, PERIOPERATIVE RESULTS, PATHOLOGY, AND LONG-TERM OUTCOME.

Sohn TA, Lillemoe KD, Cameron JL, et al. Ann Surg 1999;229:393– 400.

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To assess outcomes of patients undergoing reexploration for periampullary carcinoma compared with patients primarily explored at a high-volume tertiary care center.

Objective

A retrospective review of a prospectively maintained data base of patients treated with periampullary malignancy.

Design

Johns Hopkins University School of Medicine, Baltimore, Maryland.

Setting

All patients explored for periampullary carcinoma with consideration for resection from November 1991 to December 1997.

Participants

Study participants were assigned to 1 of 2 groups. Patients assigned to the prior laparotomy group had undergone a prior operation for evaluation of their periampullary malignancy. Patients assigned to the primary operation group had a single surgery at Johns Hopkins to attempt resection of their malignancy. Pathologic review was standardized and included classifying the tissue of origin for all malignancies (pancreas, common bile duct, ampulla, or duodenum). Patients with pathology other than adenocarcinoma were excluded. The most common resection performed was a pylorus-preserving pancreaticoduodenectomy, but this was not standardized. When resection was impossible, palliative procedures were performed at the discretion of the operating surgeon. Perioperative morbidity, mortality, and survival were determined for all patients.

Results

The two groups had similar demographs. The rate of tumor resectability was 67% for both groups. The rationale for unresectability (metastatic disease vs visceral vessel involvement) was also similar. The only important reported difference between the preoperative characteristics of the two groups was the increased use of preoperative chemotherapy and radiotherapy in the prior laparotomy group (15% vs 1%). Morbidity (32% vs 31%), mortality (3.8% vs 2.2%), and length of stay (12.2 vs 13.8 days) were similar. In comparing perioperative factors, a slightly longer operative time was noted for the reoperative group (7.4 vs 6.6 hours), but no difference in blood transfusion or the use of superior mesenteric–portal venous resection was noted. Patients in the reoperative group had smaller tumors (2.3 vs 2.9 cm and a lower rate of lymph node involvement, 48% vs 70%). Median survival for the 2 groups was similar (23 vs 20 months). Patients undergoing reoperation for periampullary carcinoma and patients undergoing initial exploration have similar resectability, perioperative morbidity and mortality, and long-term survival rates. Finally, the authors concluded that selected patients considered to have unresectable disease should be restaged and considered for reexploration at high-volume specialized centers.

Conclusions

REVIEWER COMMENTS. The experience at Johns Hopkins demonstrates that resectability in one surgeon’s hands does not preclude resection in another’s. The very talented surgeons at Johns Hopkins have previously called attention to their outstanding results by comparing their outcomes with those of other, lower volume centers in the state of Maryland. The surgeons at Hopkins not only provided care at a reduced cost by limiting morbidity and length of stay, but also improved patient survival.1 This recent report continues to demonstrate the benefit to patients treated at high-volume tertiary care centers. It is not surprising that the Hopkins group was able to demonstrate resectability in a group of patients previously operated on for their tumor. Unfortunately, the total number of patients evaluated during the study period, which would give an estimate of the frequency of this problem, was not included. Also, to be included in the reoperative group, patients needed only to have been explored for diagnosis or palliation previously. No detailed information regarding the indications and rationale for prior laparotomy is given. In nonspecialized centers, patients are frequently operated on for jaundice or not resected because a tissue diagnosis of carcinoma cannot be achieved either preoperatively or intraoperatively. These patients would have been included in the reoperative group in this study when the intention of the referring surgeon was never to resect. The article’s conclusion that reoperative patients have resectability rates similar to those of patients initially explored at Johns Hopkins is not justified by the study design and results. It is fair to conclude that the perceived higher morbidity of pancreatic surgery associated with prior laparotomy should not preclude a patient for consideration of resection in the hands of an experienced pancreatic surgeon at a high-volume center. FACTORS PREDICTIVE OF SURVIVAL IN AMPULLARY CARCINOMA.

Howe JR, Klimstra DS, Moccia RD, Conlon KC, Brennan MF. Ann Surg 1998;229:87–94. To identify clinicopathologic factors associated with a diagnosis of carcinoma of the ampulla of Vater that impact patient survival. CURRENT SURGERY

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Objective

373

Design

Evaluation of a prospective data base including all patients presenting to a high-volume tertiary referral center with adenocarcinoma of the ampulla of Vater from October 1983 to June 1995.

Setting

Memorial Sloan-Kettering Cancer Center, New York, New York.

Participants

All patients with ampullary carcinoma evaluated during the study period participated in the study. The correlation between clinicopathologic variables and survival of ampullary carcinoma was tested by the Kaplan–Meier method and log-rank test, and Cox proportional hazards regression. Survival of patients with ampullary carcinoma was compared by the Kaplan–Meier method.

Results

In 101 of 123 eligible patients (82.1%) resection was completed. Patients whose tumors were resected with negative margins of resection and uninvolved lymph nodes enjoyed a significantly improved survival compared with patients whose tumors were not resected or those whose resections had positive nodes or margins. A 46% 5-year survival was demonstrated for all patients treated by resection regardless of margin status or nodal involvement. Survival of the resected group of patients with ampullary carcinoma was compared with that of all patients treated at the Memorial Sloan-Kettering Cancer Center during the study period with the other variants of periampullary carcinoma. Patients with ampullary and duodenal carcinoma enjoyed improved survival after resection compared with patients resected with pancreatic or common bile duct tumors. Resectability of the four subtypes of periampullary carcinoma was determined by comparing the patients whose tumors were resected with all patients evaluated at Memorial SloanKettering during the study period. The 82% resectability rate for ampullary carcinoma exceeded that of duodenal cancer (45.9%), common bile duct cancer (63.8%), and pancreas cancer (21.5%).

Conclusions

Factors predictive of survival in ampullary carcinoma were resectability and negative nodes and margins. The authors concluded that the improved survival in ampullary carcinoma was due in part to the higher rate of resectability compared with other forms of periampullary carcinoma. REVIEWER COMMENTS. This report from the group at Memorial Sloan-Kettering Cancer Center is an important contribution to the surgical literature because it sums up the largest single institution experience with an uncommon problem like ampullary carcinoma. It confirms the widely accepted opinion that the prognosis for this rare tumor is much better than that for the more common periampullary malignancy of pancreatic carcinoma.2,3 It should be pointed out that while the prognosis was improved for the ampullary carcinoma patients in this study, over half of the resected patients died within 5 years of surgery. The authors did not discuss the use of adjuvant chemotherapy or radiotherapy, additional modalities that have become standard therapies either before or after pancreaticoduodenectomy for patients with pancreatic carcinoma. A 46% 5-year survival rate leaves room for improvement and would justify adjuvant therapy based on prognosis alone. The final conclusion, where the authors attempt to explain the better outcome for patients with ampullary tumors on higher resectability rates, is not supported by the data. The best survival demonstrated is for patients with duodenal carcinoma who had a resectability rate of only 45.9%, whereas those with common bile duct carcinoma had a relatively high rate of resectability (63.8%) but a dismal 5-year median survival rate of about 20%. Instead of resectability dramatically impacting survival, it appears that there is a difference in tumor biology between duodenal and ampullary carcinomas compared with the poorer prognosis for pancreatic or common bile duct variants of periampullary malignancy. RAPID-FRACTIONATION PREOPERATIVE CHEMORADIATION, PANCREATICODUODENECTOMY, AND INTRAOPERATIVE RADIATION THERAPY FOR RESECTABLE PANCREATIC ADENOCARCINOMA.

Pisters PWT, Abbruzzese JL, Janjan NA, et al. J Clin Oncol 1998;16:3843–3850. Objective

To evaluate the toxicities, radiographic and pathologic responses, and event-free outcomes with combined modality treatment for patients with resectable pancreatic adenocarcinoma.

Design

A prospective pilot trial for patients with a preoperative diagnosis of pancreatic carcinoma, employing a short course (2 weeks) of chemoradiation and resection combined with a boost of intraoperative electron beam radiation therapy.

Setting

M. D. Anderson Cancer Center, Houston, Texas.

Participants

374

All patients with a histologic or a cytologic diagnosis of pancreatic carcinoma and radiographic evidence of a resectable tumor were eligible for the study. The criteria of resectability included an absence of extrapancreatic metastasis, a patent superior mesenteric–portal vein confluence, and no evidence of superior mesenteric arterial encasement. The preoperative chemoradiation included 2 CURRENT SURGERY

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weeks of continuous infusion of 5-fluorouracil at 300 mg/m2 for 5 days/wk and concomitant rapid fractionation radiation of 30 Gy, 3 Gy daily for 5 days/wk. Patients were restaged 4 weeks after completing chemoradiation. Patients satisfying the rigid criteria of resectability underwent pancreaticoduodenectomy with a boost of intraoperative electron beam radiation to a dose of 10 Gy if there was no evidence of tumor at the retroperitoneal resection margin or 15 Gy if tumor was evident on frozen-section assessment of this margin. A total of 35 patients were entered on the trial, and all completed the chemoradiation. A single patient required admission; the remainder completed therapy as outpatients. Three patients experienced grade III nausea and vomiting (they required intravenous hydration). All other reported toxicities of the chemoradiation were minor (grade I or II). Five of 35 patients developed radiographically apparent metastatic disease during chemoradiation. Three additional patients did not undergo surgery: 1 due to stroke, 1 due to cardiac disease, and 1 due to fatal pulmonary sepsis. Therefore, 27 of 35 patients (77%) underwent laparotomy and 20 successful resections were completed. The factors that precluded resection in the 7 patients were liver metastasis (5 patients), a single peritoneal implant (1 patient), and a locally advanced tumor (1 patient). Ten of the 20 pancreaticoduodenectomies included resections of visceral vessels (superior mesenteric vein and or superior mesenteric artery). Radiographic shrinkage of tumor in response to chemoradiation was not noted, nor did any patient demonstrate a complete pathologic response to chemoradiation. The 3-year actuarial disease-specific survival rate for patients completing all intended therapy was 33%, with only 2 patients developing recurrence in the resection field.

Results

The authors concluded that their described combined modality approach is well tolerated and achieves excellent locoregional tumor control.

Conclusions

REVIEWER COMMENTS. The Pancreatic Tumor Study Group at the high-volume, tertiary M. D. Anderson Cancer Center has evaluated the use of multimodality therapy for pancreatic carcinoma for the past decade. Multimodality therapy for pancreatic carcinoma, based on the Gastrointestinal Tumor Study Group experience, achieves improved survival compared with resection alone.4 Optimal sequencing of modalities remains unclear, and the M. D. Anderson group has outlined the rationale for their preference of using chemoradiation preoperatively. Preoperative therapy is favored because patients are assured of receiving chemoradiation instead of waiting for recovery from a pancreaticoduodenectomy before initiation of treatment. The second major reason for favoring preoperative chemoradiation is that patients with rapidly progressive disease are spared the morbidity of a useless morbid procedure like pancreaticoduodenectomy. The time it takes to deliver preoperative treatment allows for an observation period to monitor the disease. Subclinical metastatic disease that cannot be detected at the time of diagnosis may become obvious during restaging after chemoradiation. These patients are spared the morbidity of a Whipple. The authors describe the use of a rapid fractionation technique to deliver radiotherapy in 2 weeks instead of the traditional 5. Patients tolerated the therapy well. Unfortunately, maximizing the ability to treat the pancreatic bed has little impact on overall survival, as this report and others evaluating preoperative chemoradiation have not proved that it has a dramatic impact on the curability of this disease.5–7 Until better chemotherapeutic or biologic therapies are developed to deal with systemic disease, it appears that maximizing local control that minimizes the celiac pain associated with advanced locoregional disease is all we can hope for.

SUMMARY These three articles were chosen for review because they represent quality contributions to the surgical literature from three of the most active pancreatic cancer centers in the United States. Johns Hopkins, Memorial Sloan-Kettering, and M. D. Anderson have greatly contributed to the current knowledge and appreciation for the challenges in caring for patients with periampullary malignancy. The Johns Hopkins group has been a strong proponent of directing patients with periampullary malignancy to tertiary centers where large volumes of similar patients are treated. The value of a patient evaluation performed at their center is outlined by their article’s demonstration of their ability to offer hope, in the form of resection, to a group of patients considered unresectable and therefore incurable by others. The definition of a high-volume center was not clarified in this recent report and is an important issue. It is tempting for CURRENT SURGERY

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high-volume centers to define low-volume centers as any institutions that do fewer pancreatic resections than they do. Clearly, this is not an appropriate definition. Patients need help identifying quality centers for complex treatment. These centers should be defined by clinical research that evaluates treatment outcomes. The Memorial Sloan-Kettering group continues to contribute to the understanding of periampullary malignancy by reporting on their prospectively maintained data base. Their recent article on ampullary malignancy improves our understanding of the natural history of the least aggressive of the periampullary cancers and the impact of surgical treatment. The large volume of patient care delivered at Memorial Sloan-Kettering and the quality of their data management will continue to allow for answers to important future questions related to the treatment of periampullary malignancy.

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The M. D. Anderson group has investigated the addition of chemotherapy and radiotherapy to surgical resection in an attempt to improve the dismal survival rates associated with treatment for periampullary malignancies. Their strategies have been based on an appreciation of the patterns of failure after pancreaticoduodenectomy. The M. D. Anderson combined-modality approach has dramatically impacted local tumor control rates. Unfortunately, patients die from distant disease. The failure and the lack of effective systemic agents has not affected the survival rates associated with a combined-modality approach. Continued efforts to identify more effective treatments for patients with periampullary malignancy are needed, and the M. D. Anderson group’s efforts are important and valuable and should encourage cooperative group clinical trials to address the evaluation of newly proposed multimodality treatments for periampullary malignancy. GEORGE M. FUHRMAN, MD Department of Surgery Ochsner Clinic and Alton Ochsner Medical Foundation New Orleans, Louisiana

REFERENCES 1. Gordon TA, Burleyson GP, Tielsch JM, Cameron JL. The effects of regionalization on cost and outcome for one general high-risk surgical procedure. Ann Surg 1995;221:43– 49. 2. Talamini MA, Moesinger RC, Pitt HA, et al. Adenocarcinoma of the ampulla of Vater. A 28-year experience. Ann Surg 1997;225:590 – 600. 3. Martin FM, Rossi RL, Dorrucci V, Silverman ML, Braasch JW. Clinical and pathologic correlations in patients with periampullary tumors. Arch Surg 1990;125:723–726. 4. Gastrointestinal Tumor Study Group. Further evidence of effective adjuvant combined radiation and chemotherapy following curative resection of pancreatic cancer. Cancer 1987;59:2006 –2010. 5. Evans DB, Rich TA, Byrd DR, et al. Preoperative chemoradiation and pancreaticoduodenectomy for adenocarcinoma of the pancreas. Arch Surg 1992;127:1335–1339. 6. Staley CA, Lee JE, Cleary KR, et al. Preoperative chemoradiation, pancreaticoduodenectomy, and intraoperative radiation therapy for adenocarcinoma of the pancreatic head. Am J Surg 1996;171:118 – 124. 7. Evans DB, Pister PWT, Lee JE. Multimodality therapy for adenocarcinoma of the pancreas: the M. D. Anderson experience. Probl Gen Surg 1997;14:117–124.

Surgical Oncology

Medullary Carcinoma Update Guest Reviewers: James H. North, Jr, MD, FACS, and Dominic R. Gallo, MD A NATIONAL CANCER DATA BASE REPORT ON 53,856 CASES OF THYROID CARCINOMA TREATED IN THE U.S., 1985–1995.

Hundahl SA, Fleming ID, Fremgen AM, Menck HR. Cancer 1998;83:2638 –2648. Objective

376

To summarize the National Cancer Data Base (NCDB) findings concerning thyroid carcinoma in the United States in the period 1985 to 1995.

Design

Analysis of the NCDB.

Setting

Cancer Department, American College of Surgeons, Chicago, Illinois.

Participants

Using standardized definitions and uniform reporting formats, the NCDB collects data annually from hospitals throughout the United States. Approximately 21,000 hospitals were involved during this data collection period. In addition, central and state registries were queried. Cancers were staged according to the third and fourth editions of the American Joint Committee for Cancer’s Manual for Staging of Cancer.1,2

Results

During the period 1985 to 1995, 53,856 cases of thyroid carcinoma were reported to the NCDB. Of these, 1928 cases (3.6%) were medullary cancers. Stage I and stage II tumors accounted for 16.5% and 29.6% of medullary carcinoma, respectively, whereas 26.8% of cases were stage III. Eleven percent of cases were stage IV and 16% were unknown. Surgery was the preferred form of treatment. Treatment was unknown in 11.4% of cases. A thyroid lobectomy (8.9% of cases) or near total thyroidectomy (6.8% of cases) was performed in the minority of cases. A total thyroidectomy without a lymph node dissection (LND) was performed in 24.2% of cases. Total thyroidectomy with a limited LND was performed in 17.6% of cases, whereas a total thyroidectomy and radical or modified radical LND was performed in 19.2% of cases. The treatment was defined as “other” (surgery or radiation plus chemotherapy) in 11.9% of cases. CURRENT SURGERY

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