Hepatic arterial infusion chemotherapy

15. Aston SJ, Rees TD. Breast reduction and mastopexy. In: Rees TD, ed. Aesthetic

Plastic Surgery. Philadelphia, Pa: WB Saunders Co, 1980:903-953. 16. Harris JR, Levene MB, Svenson G, et al. Analysis of cosmetic results following

primary radiation therapy for stage I and stage II carcinoma of the breast. Int J Radiat Oncol Biol Phys. 1979;5:257-261. 17. Beadle GF, Silver B, Botnick L, et al. Cosmetic results following primary radia-

tion therapy for early breast cancer. Cancer. 1984;54:2911-2918. 18. Rose MA, Olivotto I, Cady B, et al. Conservative surgery and radiation therapy

for early breast cancer: long-term cosmetic results. Arch Surg. 1989;124:153-157. 19. Pickrell KL, Puckett CL, Given KS. Subpectoral augmentation mammaplasty

Plast Reconstr Surg. 1977;60:325-336. 20. Mahler DM, Hauben DJ. Retromammary versus retropectoral breast augmenta-

tion—a comparative study. Ann Plast Surg. 1982;8:370-374. 21. Pearl RM, Wisnicki J. Breast reconstruction following lumpectomy and irradia-

tion. Plast Reconstr Surg. 1985;76:83-86. 22. Noguchi M, Earashi M, Ohta N, et al. Mastectomy with and without immediate

breast reconstruction using a musculocutaneous flap. Am J Surg. 1993;166:279283. 23. O’Brien W, Hasselgren PO, Hummel RP, et al. Comparison of postoperative

wound complications and early cancer recurrence between patients undergoing mastectomy with or without immediate breast reconstruction. Am J Surg. 1993; 166:1-5. 24. Noone RB, Frazier TG, Noone GC, Blanchet NP, Murphy JB, Rose D. Recur-

rence of breast carcinoma following immediate breast reconstruction: a 13 year review. Plast Reconstr Surg. 1984;93:96-106.

Surgical Oncology Hepatic Arterial Infusion Chemotherapy Guest Reviewers: Ran S. Kim, MD, Robert D. Riether, MD, and Herbert C. Hoover, Jr, MD HEPATIC ARTERIAL INFUSION OF CHEMOTHERAPY AFTER RESECTION OF HEPATIC METASTASES FROM COLORECTAL CANCER. Kemeny N, Huang Y, Cohen AM, et al. N Engl J Med. 1999;341:2039-2048. Objective: To determine the outcomes of patients after postoperative combination treatment of hepatic arterial infusion chemotherapy (HAIC) plus systemic chemotherapy, compared with the use of systemic chemotherapy alone. Design: A prospectively randomized, stratified study in patients who underwent

complete resection of hepatic metastases from colorectal cancer. Setting: Memorial Sloan-Kettering Cancer Center, New York, New York. Participants: One hundred fifty-six patients with hepatic metastases from colorectal

cancer who met the eligibility criteria. CURRENT SURGERY • Volume 58/Number 2 • March/April 2001

REVIEWER COMMENTS

This paper from Memorial Sloan-Kettering Cancer Center followed 156 patients after complete resection of hepatic metastases with regional and systemic chemotherapy for a mean period of 62.7 months. The beneficial effect of resection of hepatic metastases on survival has been shown in the past.1 In other randomized trials that compared HAIC with systemic therapy in patients with unresectable hepatic disease, those patients who received HAIC also showed higher rates of partial 155

REVIEWER COMMENTS (Con’t) 2,3

response. Although this paper shows the improvement in the control of local disease and 2-year overall survival, more adverse effects occur with HAIC than with systemic chemotherapy. As this study shows, more prospectively randomized studies are needed to clearly see the benefits of HAIC compared with systemic chemotherapy. Hepatic arterial infusion chemotherapy cost-effectiveness and quality-of-life issues need to be further investigated.

Results: Study participants were randomly assigned to 1 of 2 groups at the time of

resection. They were stratified depending on previous chemotherapy treatments and the number of liver metastases identified at operation. The combined therapy group received 6 cycles of hepatic arterial infusion with floxuridine and dexamethasone plus intravenous fluorouracil, with or without leucovorin. The monotherapy group received a higher dose of intravenous fluorouracil, but the same dose of leucovorin. All patients who were randomly assigned to receive combined therapy received an implantable pump. The adequacy of perfusion was assessed by infusing human serum albumin macroaggregated with technetium-99m through the side port of the pump postoperatively. At 2 years, the actuarial rate of survival (86%), the median survival (72.2 months), the rates of survival free of hepatic recurrence (90%), and the rates of progression-free survival (57%) were all higher in the combined therapy group compared with 72%, 59.3 months, 60%, and 42% in the monotherapy group. The toxic effects of chemotherapy were similar in both groups, except that more patients in the combined therapy group had diarrhea and adverse hepatic effects. The complications related to the pump or the catheter used for hepatic arterial infusion included a pump pocket infection, arterial thromboses, catheter dislodgement, intra-abdominal hemorrhage, and a pseudoaneurysm of the hepatic artery. No significant differences existed between the 2 groups with respect to baseline characteristics. Conclusions: Use of regional hepatic chemotherapy significantly improves the control of local disease in patients who undergo resection of liver metastases from colorectal cancer. The authors concluded that the use of HAIC plus systemic chemotherapy not only decreased the rate of hepatic recurrence, but also improved 2-year overall survival, compared with the use of systemic therapy alone.

REVIEWER COMMENTS

This paper from Germany reports the investigation of 3 treatment regimens of regional and systemic chemotherapy in patients with nonresectable hepatic metastases from colorectal cancer. Despite the fact that HAI 5-FU/LV was superior to IV 5-FU/LV in terms of response, the overall effect of HAI was disappointing. The doubling of the response rate did not result in a significant increase in time to progression or survival, except in the 35% of patients with an intrahepatic tumor burden of less than 25%. This discrepancy may be explained by the higher mortality rate observed among patients who underwent intra-arterial port implantation than among those who received intravenous port implantation. It would be interesting to study whether results can be improved by using improved 5-FU regimens or by increasing the sensitivity of preoperative diagnostic techniques.

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RANDOMIZED, MULTICENTER TRIAL OF FLUOROURACIL PLUS LEUCOVORIN ADMINISTERED EITHER VIA HEPATIC ARTERIAL OR INTRAVENOUS INFUSION VERSUS FLUORODEOXYURIDINE ADMINISTERED VIA HEPATIC ARTERIAL INFUSION IN PATIENTS WITH NONRESECTABLE LIVER METASTASES FROM COLORECTAL CARCINOMA. Lorenz M, Muller H-H, and the German Cooperative Group on Liver Metastases. J Clin Oncol. 2000;18:243-254. Objective: To compare the efficacy and tolerability between hepatic arterial infusion

(HAI) of fluorodeoxyuridine (FUDR) versus 5-FU plus leucovorin administered via either HAI or intravenous infusion. Design: A prospectively randomized, multicenter phase III study of patients with nonresectable liver metastases for adenocarcinoma of the colon or rectum between April 1991 and June 1995. Setting: Johann Wolfgang Goethe-Universita¨t, Frankfurt am Main, and the Insti-

tute for Medical Biometry and Epidemiology, Philips-Universita¨t, Marburg, Germany. Participants: One hundred sixty-eight patients at 25 treatment centers with docu-

mented adenocarcinoma of the colon or rectum who had undergone complete resection of primary tumor and had nonresectable liver metastases that did not exceed 75% of the liver volume. Results: Of the 168 patients enrolled in the study, 57 patients were randomized to

receive 5-FU/LV via HAI, 54 were randomized to receive FUDR via HAI, and 57 were randomized to receive 5-FU/LV via IV infusion. No significant difference existed in the median time to disease progression between treatment groups between patients with an intrahepatic tumor burden greater than 25%. However, a nearly 2-fold increase occurred in the time to progression among patients with an intrahepatic tumor CURRENT SURGERY • Volume 58/Number 2 • March/April 2001

burden less than 25%, who were treated with HAI 5-FU/LV. No clinically significant differences existed between treatment groups in survival among patients with an intrahepatic tumor burden greater than 25%, but a survival benefit existed among patients with an intrahepatic tumor burden less than 25%, who were treated with HAI 5-FU/LV. An increase in intrahepatic response occurred among patients with HAI 5-FU/LV and HAI FUDR compared with those who received IV 5-FU/LV. On the other hand, extrahepatic tumor suppression was significant among patients who were treated with either HAI or IV 5-FU/LV when compared with those who received HAI FUDR. Lastly, more severe toxicity was seen in patients who were treated with HAI 5-FU/LV than in those who received either IV 5-FU/LV or HAI FUDR. Conclusions: Although the use of HAI 5-FU/LV in treating liver metastases after

resection of colorectal carcinoma cannot be recommended as a standard course of treatment, it is associated with the most favorable clinical outcome, especially in patients with an intrahepatic tumor burden less than 25%. Further investigation is warranted, especially using improved 5-FU regimens.

ECONOMIC IMPLICATIONS OF HEPATIC ARTERIAL INFUSION VERSUS INTRAVENOUS CHEMOTHERAPY OR SYMPTOM PALLIATION IN THE TREATMENT OF NONRESECTABLE COLORECTAL LIVER METASTASES. Durand-Zaleski I, Roche B, Buyse M, et al. Crit Rev Oncol/Hematol. 1999;32:125-131. Objective: To analyze the cost-effectiveness of HAIC versus intravenous chemo-

therapy in the treatment of nonresectable colorectal liver metastases. Design: A sensitivity analysis provided a range of cost-effectiveness ratios to evaluate

whether the additional costs of intra-arterial infusion were justified in view of the expected clinical benefits. Setting: The valuation method used health care (hospital and ambulatory) costs standardized in 1 European Center (Hospital Henri Mondor, Creteil, France) and 1 North American Center (Stanford University Medical Center, Palo Alto, California). Participants: The patient population was drawn from 7 randomized clinical trials

included in the meta-analysis. Individual data from each of the 654 patients were available.

REVIEWER COMMENTS

Several limitations to this study exist. For instance, the authors point out that it is important to note that the costs used in this economic analysis are not those of the actual patients included in the original trial, but the costs of patients recently or currently treated at the 2 sites. However, it is not clear how this information can facilitate prospective decision making based on current medical practice. The computational and accounting analysis models they used to extrapolate their findings to the cost-effectiveness of localized chemotherapy for nonresectable colorectal liver metastases were difficult to follow. Further prospective studies should examine medical and financial costs to society and the patients’ quality of life.

Results: Using survival and tumor response as the measure of efficacy, health care

costs (in 1995 USD) were computed over the duration of patient follow-up, derived from actual costs in the 2 centers. The total gain in life expectancy in the hepatic arterial infusion group compared with the control group was 3.2 months (SE ⫽ 0.7 month). The additional costs of hepatic arterial infusion over control treatment were $19,636 in France and $19,280 in California. The cost-effectiveness with respect to survival of hepatic arterial infusion patients compared with control patients was $73,635 per life-year in France and $72,300 per life-year in California. Conclusions: The author concluded that this meta-analysis and economic evalua-

tion suggest that the cost-effectiveness of HAI for colorectal liver metastases is within the range of accepted treatments for other severe medical conditions. CURRENT SURGERY • Volume 58/Number 2 • March/April 2001

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REVIEWER COMMENTS

As more data are accumulating, it seems that in patients with extensive hepatic disease (40% to 60% liver involvement) who can tolerate surgery, HAIC as the first treatment may be preferred. In patients with less than 20% hepatic involvement, time to start with systemic chemotherapy may exist; if the tumor fails to respond, the patient can be switched to regional infusion. However, the current Cancer and Leukemia Group B may define the role of regional therapy in patients with colorectal cancer confined to the liver as this study is randomizing patients to HAI versus systemic therapy without a crossover to demonstrate if HAI improves survival or quality of life in addition to response rates.

HEPATIC ARTERIAL CHEMOTHERAPY IN METASTATIC COLORECTAL PATIENTS. Kemeny NE, Ron IG. Semin Oncol. 1999;26:524-535. Objective: To review the literature on the therapeutic benefit of HAIC in colorectal

cancer patients with inoperable liver metastases. Design: A review article comparing studies on HAIC versus systemic therapy. Setting: Gastrointestinal Oncology Service, Solid Tumor Division, Department of

Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York. Conclusions: Although HAIC is only applicable to a minority of metastatic colorectal patients and has some associated complications; it is probably the best available therapy for selected patients.

REVIEWER SUMMARY These 4 papers were selected because they represent major oncologic centers with large patient experience with HAIC. Kemeny and associates examine the role of HAIC in patients with resected hepatic metastases from colorectal cancer. Lorenz and associates evaluate the role of chemotherapeutic agents in patients with nonresectable liver metastases from colorectal carcinoma. Durand-Zaleski and associates discuss the economic implication of chemotherapy in treating patients with inoperable colorectal liver metastases. Finally, Kemeny and Ron present a review article on HAIC in colorectal cancer patients with inoperable liver metastases. The rationale for treatment of colorectal liver metastases with HAIC is that liver metastases derive about 95% of their blood supply from the hepatic artery.4 Resection in most of these patients with colorectal liver metastases may not be possible. Tumor response rate to systemic chemotherapy in these patients, on the other hand, is 20% at best. Therefore, HAIC is a treatment modality that has a sound theoretical basis in patients with colorectal liver metastases. Patients who are candidates for HAIC should have unresectable hepatic metastases and no evidence of extrahepatic metastatic disease. They should be of satisfactory operative risk especially with liver reserve. Preoperative evaluation should include a computed tomography scan of the pelvic, chest, and abdomen; colonoscopy, if not done within the preceding 6 to 9 months; and laboratory studies for estimates of nutrition and liver reserve. Visceral angiography is also obtained to define the hepatic arterial anatomy and evaluate the patency of the portal vein. Although current studies show improved short-term response rates with HAIC compared with systemic chemotherapy, survival has not been shown to be better in most studies. Crossover from systemic treatment to HAIC has made survival data unreliable. The chemotherapy-related complications are more virulent than are technical/ surgical complications of HAIC, with biliary sclerosis being the major dose-limiting complication of HAIC using FUDR. It occurred in 15% to 25% of patients in earlier 158

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studies, but appears to be less with more recent approaches. Although its mechanism is not clearly understood, it is exacerbated by continuous FUDR infusion and the coadministration of leucovorin and may be decreased by concomitant administration of dexamethasone. However, intra-arterial 5-FU appears to have less biliary toxicity. Currently, HAIC is not the standard of care in the United States. The data in Europe suggest a survival benefit and that it may be cost-effective.5 However, so far the long-term benefit is not as great as had been expected. This is partially because of significant problems with adverse hepatic toxicities that develop in these patients with hepatic arterial chemotherapy infusion.6,7 The use of adjuvant HAIC in resectable liver metastases in colorectal cancer patients is an interesting concept that is encouraging as seen in the paper by Kemeny and associates. Hopefully, more data are forthcoming in that important area. This approach, using hepatic intraarterial perfusion for the therapy of hepatic metastases, needs considerable further investigation to determine the best combination and sequence of chemotherapy drugs.

RAN S. KIM, MD ROBERT D. RIETHER, MD HERBERT C. HOOVER, JR, MD Department of Surgery Lehigh Valley Hospital Allentown, Pennsylvania S0149-7944(00)00372-X

REFERENCES 1. Wagman LD, Kemeny MM, Leong L, et al. A prospective, randomized evaluation

of the treatment of colorectal cancer metastatic to the liver. J Clin Oncol. 1990;8: 1885-1893. 2. Allen-Mersh TG, Earlam S, Fordy C, Abrams K, Houghton J. Quality of life and

survival with continuous hepatic-artery floxuridine infusion for colorectal liver metastases. Lancet. 1994;344:1255-1260. 3. Rougier P, Laplanche A, Huguier M, et al. Hepatic arterial infusion of floxuridine

in patients with liver metastases from colorectal carcinoma: long-term results of a prospective randomized trial. J Clin Oncol. 1992;10:1112-1118. 4. Knol JA. Colorectal cancer metastatic to the liver: hepatic arterial infusion chemo-

therapy. In: Cameron JL, ed. Current Surgical Therapy. 6th ed. St. Louis, Mo: Mosby; 1998:355-361. 5. Durand-Zaleski I, Earlam S, Fordy C, Davies M, Allen-Mersh TG. Cost-effective-

ness of systemic and regional chemotherapy for the treatment of patients with unresectable colorectal liver metastases. Cancer. 1998;83:882-888. 6. Riether RD, Khubchandani IT, Sheets JA, Stasik JJ, Rosen L. A prospective study

of continuous hepatic perfusion with implantable pump. Dis Colon Rectum. 1985; 28:24-26. 7. Trivisionno DP, Riether RD, Sheets JA, et al. Follow-up on a prospective study of

continuous hepatic perfusion with implantable pump. Dis Colon Rectum. 1986;29: 691-693.

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