/STRU^NI RAD 616.348/.351-006.06:616.36.089 Multimodal Treatment of Metastatic Colorectal Cancer... Irene Kuehrer University Clinic of Surgery, General Hospital of Vienna Background: Metastases to the liver is the leading cause of death in patients with colorectal cancer. Methods: The authors review the data on diagnosis and management of this clinical problem, and they discuss management options that can be considered. Results: Complete surgical resection of metastases from colorectal cancer that are localized to the liver results in 5-year survival rates ranging from 26% to 40%. Conclusions: By adding modalities such as targeted systemic therapy and other "local" treatments for liver metastases, further gains in survival are anticipated Key words: liver metasases, surgical resection, neoadjuvant chemotherapy, extrahepatic disease, survival benefit rezime INTRODUCTION Colorectal cancer is the third most common cancer in both men and women. About 50% of patients diagnosed with CRC will die from their disease, accounting for about 10% of all cancer deaths. Tremendous strides are made regularly in the prevention, diagnosis, and treatment of colorectal cancer, posing a challenge to the clinician who must stay abreast of the most recent advances. In the 1970s, treatment options for patients with advanced colorectal cancer were limited to the fluoropyrimidine 5-fluorouracil (5-FU). Since that time, newer cytotoxic agents, such as capecitabine, irinotecan, and oxaliplatin, have been introduced, extending survival, facilitating administration, and permitting better tailoring of treatment regimens to individual patients. The last 3 years have seen yet further advances with the approval of biologic agents such as bevacizumab in front-line therapy and cetuximab in second- and third-line therapy. The more aggressive chemotherapy regimens can not only control the disease, but also render some advanced metastatic disease into a resectable stage. BACKGROUND: The natural history of colorectal cancer metastasis in the majority of patients is dismal. Historically, the median survival is 6 to 12 months if untreated. Even with newer therapeutics such as irinotecan or oxaliplatin, the 5-year survival rate with nonsurgically treated hepatic metastases is low. In contrast, those who undergo a complete resection have 5-year survival rates of 25% to 40%. It can be argued that the patients who undergo resection are selected and may have better outcomes because they have less virulent disease. A trial designed to compare resection vs systemic therapy is unlikely until more efficacious systemic therapy regimens are discovered. Currently, the survival rates reported after curative hepatic resections are 25% to 39% for 5 years and 22% to 23% for 10 years. RESECTION OF EXTRAHEPATIC COLORECTAL ME- TASTASES Once suspected, colorectal liver metastases are staged by spiral CT, CT portography and MRI, which have similar overall accuracies. Mortality following liver resection is less than 5% in major centres, with a morbidity rate of 20% to 50%. Prognostic scoring systems can be used to predict the likely cure rate with resection. Pulmonary metastases occur in 10-25% of patients with resected colorectal cancer, but are limited to the lung in only 2% of cases. In these selected cases surgery provides long-term survival in 20-40%, and repeat lung resection has shown similar rates. The presence of thoracic lymph node involvement and elevated carcinoembryonic antigen level before pulmonary resection are associated with reduced survival. For patients with unresectable disease, chemotherapy and ablation techniques have been demonstrated to prolong survival, although chemotherapy alone has been shown to improve quality of life.
52 I. Kuehrer ACI Vol. LIII LIVER RESECTION FOR COLORECTAL METASTASES Surgical resection is associated with the best chance for cure of colorectal cancer when complete resection of the tumor-bearing liver can be accomplished. However, historically, only 10% to 20% of patients with colorectal liver metastases have been eligible for resection with radical intent. Recent improvements in preoperative imaging techniques, patient selection, and surgical techniques, as well as the introduction of new cytotoxic and biologic agents for preoperative and postoperative chemotherapy have improved the resectability rate and almost doubled the 5-year survival rate for patients with colorectal liver metastases, from about 30% two decades ago to nearly 60%.Moreover, in patients with nonresectable metastases, modern chemotherapy alone extends median survival to 2 years or more, and 20% of patients with nonresectable metastases are still alive 4 years after detection of nonoperable liver disease. In summary, the care of patients with hepatic colorectal metastases has rapidly changed. Novel chemotherapeutic regimens combining 5-FU, folinic acid, and oxaliplatin and/or irinotecan have been associated with improved response rates (approximately 50%), allowing 10% to 30% of the patients with initially unresectable disease to be successfully treated with liver surgery. In addition, early results from trials evaluating novel biologic agents that target angiogenesis and the epidermal growth factor receptor, bevacizumab and cetuximab, suggest that even more patients with initially unresectable disease may respond to primary treatment with combinations of systemic therapies (response rates up to 70%). NEOADJUVANT THERAPY Most patients with colorectal liver metastases will present with unresectable disease. Beginning in the 1990s, Bismuth et al reported on a small percentage of patients who had a significant downsizing of their hepatic lesion with neoadjuvant chemotherapy. These patients were then brought to surgery for an attempted R0 resection. The 5- year survival rate was 40%, similar to those resected de novo. These results have been reproduced multiple times. Therefore, those patients initially determined to be unresectable should be reevaluated for resectability after neoadjuvant therapy for resectability. More recently, newer effective chemotherapeutic combinations, including FOL- FOX or FOLFIRI with bevacizumab, have had more consistent results in downsizing liver metastases from colorectal adenocarcinoma. There is no evidence to support pretreatment with neoadjuvant chemotherapy in patients with respectable disease also response might be a surrogate maker for curative resection and studies will shoe the impact of adjuvant therapy after liver resection. 20% will progress while on chemotherapy and will have no benefit from subsequent liver resection. RECURRENCE FOLLOWING LIVER RESECTION Approximately 60% to 70% of patients treated with resection will recur. Of those who recur, 30% of recurrences will be isolated to the liver. The liver parenchyma will regenerate or hypertrophy to presurgical size in 3 to 6 months, and significant resection can be performed a second time if the patient s physical status will allow repeat procedures. Several studies have demonstrated similar morbidity and mortality compared to primary resection. The overall 5-year survival is similar to that of the initial resections and the timetable is reset from the time of the second resection. A recent retrospective study by Petrowsky et al demonstrated similar morbidity and mortality rates compared to primary resection, with a 34% actuarial 5-year survival rate and 15% actual 5-year survivors at the time of follow-up. These results are similar to those published for primary resections and suggest that reintervention is of benefit.the recent emergence of molecularly targeted monoclonal antibody therapiewith proven efficacy in metastatic colorectal cancer, provides a significant improvement in the outcomes for patients, but also presenting challenges for clinicians in selecting the most appropriate combination of therapy for their patients after liver resection. FOLLOW-UP AFTER RESECTION: Postoperative surveillance evaluates the efficacy of treatment as well as screening for recurrence. According to the 2006 National Comprehensive Cancer Network guidelines, follow-up includes a physical examination, a CEA measurement, and a CT scan of the chest and abdomen every 3 months for 2 to 3 years, then every 6 months for 5 years. Some clinicians limit the use of CT scan until a measurable CEA level is noted. Most recurrences are identified within the first 2 years of operation. The surveillance begins again if a patient has had a re-resection of a liver lesion. A recurrence beyond 5 years of intervention is rare; therefore, routine imaging and laboratory followup other than screening colonoscopy are unnecessary CONCLUSIONS With the addition of newer chemotherapeutics, survival has improved in patients treated both medically and surgically for metastatic colorectal cancer. The role of neoadjuvant chemotherapy is being clarified. The current approach is upfront surgery unless a lesion is considered unresectable. Neoadjuvant therapy may soon be recommended more frequently, however, as more predictable responses from the intervention occur. During the preoperative evaluation, attention needs to be focused on considering sufficient liver parenchyma and assessment for extrahepatic disease. Survival benefits in patients undergoing a second liver resection have similar outcomes as those undergoing a primary resection. Regardless of the surgical resection, patients benefit most when tumor-free margins greater than 1 cm are achieved. If the margins are close, RFA or cryotherapy can be added to ensure an adequate depth. SUMMARY Hepatic metastases occur in 60% of patients following resection for colorectal cancer. Liver resection is the only curative option, with one third of resected patients alive at five years. In those developing recurrence in the liver fol-
Br. 2 Multimodal treatment of metastatic colorectal cancer 53 lowing resection, further liver surgery may be curative, with similar 5 years survival rates of about 30%. Until recently surgery was feasible in only 15-25% of patients with colorectal liver metastases. New strategies, such as downstaging chemotherapy, portal vein embolization and two-stage hepatectomy, may increase the resectability rate by 15%. Earlier detection of liver metastases would increase resectability, although good follow-up trials are lacking. SUMMARY MULTIMODALNO LE^ENJE METASTATSKOG KOLOREKTALNOG KARCINOMA Uvod: Metastatska bolest jetre je vode}i uzrok smrti bolesnika sa kolorektalnim karcinomom. Materijal i metode: Autori analiziraju podatke iz literature u vezi sa dijagnozom i le~enjem metastatske bolesti jetre i diskutuju o mogu}im na~inima le~enja. Rezultati: Radikalna hirur{ka resekcija metastaza u jetri poreklom od kolorektalnog karcinoma omogu}ava petogodi{nje pre ivljavanje u 26 do 40% bolesnika. Zaklju~ak: Dodavanjem drugih modaliteta le~enja kao {to su ciljana sistemska hemioterapija i drugi vidovi lokalne terapije metastaza, mogu se posti}i bolji rezultati u le~enju metastatske bolesti jetre. Klju~ne re~i: metastaze u jetri, hirur{ka resekcija, neoadjuvantna hemoterapija, ekstrahepati~na bolest, pre ivljavanje REFERENCES 1. Adam R, Pascal G, Castaing D, et al. Tumor progression while on chemotherapy: a contraindication to liver resection for multiple colorectal metastases? Ann Surg. 2004;240:1052-1061. 2. Andre T, Boni C, Mounedji-Boudiaf L, et al. Oxaliplatin, fluorouracil and leucovorin as adjuvant treatment for colon cancer. N Engl J Med. 2004;350:2343-2351. 3. Bentrem DJ, Dematteo RP, Blumgart LH. Surgical therapy for metastatic disease to the liver. Annu Rev Med. 2005;56:139-156. 4. Bismuth H, Adam R, Levi F, et al. Resection of nonresectable liver metastases from colorectal cancer after neoadjuvant chemotherapy. Ann Surg. 1996;224:509-520; discussion 520-522. 5. Bolton JS, Fuhrman GM. Survival after resection of multiple bilobar hepatic metastases from colorectal carcinoma. Ann Surg. 2000;231:743-751. 6. Bozzetti F, Bignami P, Montalto F, et al. Repeated hepatic resection for recurrent metastases from colorectal cancer. Br J Surg. 1992;79:146-148. 7. Choti MA, Sitzmann JV, Tiburi MF, et al. Trends in long-term survival following liver resection for hepatic colorectal metastases. Ann Surg. 2002; 235:759-766. 8. Cunningham D, Humblett Y, Siena S, et al. Cetuximab (C225) alone or in combination with irinotecan (CPT-11) in patients with epidermal growth factor receptor (EGFR)-positive, irinotecan-refractory metastatic colorectal cancer (MCRC). Proc Am Soc Clin Oncol. 2003;22:252. Abstract 1012 9. Delaunoit T, Alberts SR, Sargent DJ, et al. Chemotherapy permits resection of metastatic colorectal cancer: experience from Intergroup N9741. Ann Oncol. 2005;16:425-429. Epub 2005 Jan 27. 10. DeMatteo RP, Palese C, Jarnagin WR, et al. Anatomic segmental hepatic resection is superior to wedge resection as an oncologic operation for colorectal liver metastases. J Gastrointest Surg. 2000;4:178-184. 11. Desch CE. Post-treatment surveillance for colorectal cancer. American Society of Clinical Oncology Educational Book; 2006:175-178. 12. Fernandez-Trigo V, Shamsa F, Sugarbaker PH. Repeat liver resections from colorectal metastasis. Repeat Hepatic Metastases Registry. Surgery. 1995;117:296-304. 13. Fong Y, Cohen AM, Fortner JG, et al. Liver resection for colorectal metastases. J Clin Oncol. 1997;15:938-946. 14. Fong Y, Fortner J, Sun RL, et al. Clinical score for predicting recurrence after hepatic resection for metastatic colorectal cancer: analysis of 1001 consecutive cases. Ann Surg. 1999;230:309-321. 15. Fuchs C, Marshall J, Mitchell E, et al. A randomized trial of first-line irinotecan/fluoropyrimidine combinations with or without celecoxib in metastatic colorectal cancer (BICC-C). Proc Am Soc Clin Oncol. 2006;24:147s. Abstract 3506. 16. Fujita S, Akasu T, Moriya Y. Resection of synchronous liver metastases from colorectal cancer. Jpn J Clin Oncol. 2000;30:7-11. 17. Giacchetti S, Itzhaki M, Gruia G, et al. Long-term survival of patients with unresectable colorectal cancer liver metastases following infusional chemotherapy with 5-fluorouracil, leucovorin, oxaliplatin and surgery. Ann Oncol. 1999;10:663-669. 18. Goldberg RM, Sargent DJ, Morton RF, et al. A randomized controlled trial of fluorouracil plus leucovorin, irinotecan, and oxaliplatin combinations in patients with previously untreated metastatic colorectal cancer. J Clin Oncol. 2004;22:23-30. Epub 2003 Dec 9. 19. Heslin MJ, Medina-Franco H, Parker M, et al. Colorectal hepatic metastases: resection, local ablation, and hepatic artery infusion pump are associated with prolonged survival. Arch Surg. 2001;136:318-323. Erratum in: Arch Surg. 2001;136:809. 20. Hochster HS, Hart LL, Ramanathan RK, et al. Safety and efficacy of oxaliplatin/fluoropyrimidine regimens with or without bevacizumab as first-line treatment of metastatic colorectal cancer (mcrc): final analysis of the TREE-Study. Proc Am Soc Clin Oncol. 2006;24:148s. Abstract 3510. 21. Hohenberger P, Schlag P, Schwarz V, et al. Tumor recurrence and options for further treatment after resection of liver metastases in patients with colorectal cancer. J Surg Oncol. 1990;44:245-251. 22. Hurwitz H, Fehrenbacher L, Novotny W, et al. Bevacizumab plus irinotecan, fluorouracil,
54 I. Kuehrer ACI Vol. LIII 23. Jaffe BM, Donegan WL, Watson F, et al. Factors influencing survival in patients with untreated hepatic metastases. Surg Gynecol Obstet. 1968; 127:1-11. 24. Jenkins LT, Millikan KW, Bines SD, et al. Hepatic resection for metastatic colorectal cancer. Am Surg. 1997;63:605-610. 25. Kamel IR, Bluemke DA. MR imaging of liver tumors. Radiol Clin North Am. 2003;41:51-65. 26. Kato T, Yasui K, Hirai T, et al. Therapeutic results for hepatic metastasis of colorectal cancer with special reference to effectiveness of hepatectomy: analysis of prognostic factors for 763 cases recorded at 18 institutions. Dis Colon Rectum. 2003;46:S22-S31. 27. Kemeny N, Jarnagin W, Gonen M, et al. Phase I/II study of hepatic arterial therapy with floxuridine and dexamethasone in combination with intravenous irinotecan as adjuvant treatment after resection of hepatic metastases from colorectal cancer. J Clin Oncol. 2003;21:3303-3309. 28. Lahr CJ, Soong SJ, Cloud G, et al. A multifactorial analysis of prognostic factors in patients with liver metastases from colorectal carcinoma. J Clin Oncol. 1983;1:720-726. 29. Leonard GD, Brenner B, Kemeny NE, et al. Neoadjuvant chemotherapy before liver resection for patients with unresectable liver metastases from colorectal carcinoma. J Clin Oncol. 2005;23:2038-2048. 30. Lorenz M, Staib-Sebler E, Hochmuth K, et al. Surgical resection of liver metastases of colorectal carcinoma: short and long-term results. Semin Oncol. 2000;27(5 Suppl 10):112-119. 31. Lyass S, Zamir G, Matot I, et al. Combined colon and hepatic resection for synchronous colorectal liver metastases. J Surg Oncol. 2001;78:17-21. 32. Martin R, Paty P, Fong Y, et al. Simultaneous liver and colorectal resections are safe for synchronous colorectal liver metastasis. J Am Coll Surg. 2003;197:233-242. 33. Metcalfe M, Mann C, Mullin E, et al. Detecting curable disease following hepatectomy for colorectal metastases. ANZ J Surg. 2005;75:524-527. 34. Moertel CG, Gunderson LL, Mailliard JA, et al. Early evaluation of combined fluorouracil and leucovorin as a radiation enhancer for locally unresectable, residual, or recurrent gastrointestinal carcinoma. The North Central Cancer Treatment Group. J Clin Oncol. 1994;12:21-27. 35. Morris DL. Surgery for liver metastases: how many? ANZ J Surg. 2002;72:2. 36. Nordlinger B, Guiguet M, Vaillant JC, et al. Surgical resection of colorectal carcinoma metastases to the liver. A prognostic scoring system to improve case selection, based on 1568 patients. Association Francaise de Chirurgie. Cancer. 1996;77:1254-1262. 37. Nordlinger B, Peschaud F, Malafosse R. Resection of liver metastases from colorectal cancer: how can we improve results? Colorectal Dis. 2003;5:515-517. 38. Okano K, Yamamoto J, Okabayashi T, et al. CT imaging of intrabiliary growth of colorectal liver metastases: a comparison of pathological findings of resected specimens. Br J Radiol. 2002;75:497-501. 39. Parkin DM, Bray F, Ferlay J, et al. Global cancer statistics, 2002. CA Cancer J Clin. 2005;55:74-108. 40. Petrowsky H, Gonen M, Jarnagin W, et al. Second liver resections are safe and effective treatment for recurrent hepatic metastases from colorectal cancer: a bi-institutional analysis. Ann Surg. 2002;235:863-871. 41. Pfister DG, Benson AB 3rd, Somerfield MR. Clinical practice. Surveillance strategies after curative treatment of colorectal cancer. N Engl J Med. 2004;350:2375-2382. 42. Poston GJ, Adam R, Alberts S, et al. OncoSurge: a strategy for improving resectability with curative intent in metastatic colorectal cancer. J Clin Oncol. 2005;23:7125-7134. 43. Poston GJ. Surgical strategies for colorectal liver metastases. Surg Oncol. 2004;13:125-136. 44. Pozzo C, Basso M, Cassano A, et al. Neoadjuvant treatment of unresectable liver disease with irinotecan and 5-fluorouracil plus folinic acid in colorectal cancer patients. Ann Oncol. 2004;15:933-939. 45. Pozzo C, Basso M, Cassano A, et al. Neoadjuvant treatment of unresectable liver disease with irinotecan and 5-fluorouracil plus folinic acid in colorectal cancer patients. Ann Oncol. 2004;15:933-939. 46. Rosen CB, Nagorney DM, Taswell HF, et al. Perioperative blood transfusion and determinants of survival after liver resection for metastatic colorectal carcinoma. Ann Surg. 1992;216:493-505. 47. Ruers T, Bleichrodt RP. Treatment of liver metastases, an update on the possibilities and results. Eur J Cancer. 2002;38:1023-1033. 48. Sahani DV, Kalva SP. Imaging the liver. Oncologist. 2004;9:385-397. 49. Saini S. Imaging of the hepatobiliary tract. N Engl J Med. 1997;336: 1889-1894. 50. Scheele J, Altendorf-Hofmann A, Grube T, et al. Resection of colorectal liver metastases: what prognostic factors determine patient selection? [in German] Chirurg. 2001;72:547-560. 51. Scheele J, Stang R, Altendorf-Hofmann A, et al. Resection of colorectal liver metastases. World J Surg. 1995;19:59-71. 52. Stangl R, Altendorf-Hofmann A, Charnley RM, et al. Factors influencing the natural history of colorectal liver metastases. Lancet. 1994;343:1405-1410. 53. Tournigand C, Andre T, Achille E, et al. FOLFIRI follo wed by FOL-FOX6 or the reverse sequence in advanced colorectal cancer: a randomized GERCOR study. J Clin Oncol. 2004;22:229-237. Epub 2003 Dec 2. 54. Valls C, Andia E, Sanchez A, et al. Hepatic metastases from colorectal cancer: preoperative detection and assessment of resectability with helical CT. Radiology.. 55. Wagner JS, Adson MA, Van Heerden JA, et al. The natural history of hepatic metastases from colorectal cancer: a comparison with resective treatment. Ann Surg. 1984;199:502-508. 56. Wein A, Riedel C, Kockerling F, et al. Impact of surgery on survival in palliative patients with metastatic colorectal cancer after first line treatment with weekly 24-
Br. 2 Multimodal treatment of metastatic colorectal cancer 55 hour infusion of high-dose 5-fluorouracil and folinic acid. Ann Oncol. 2001;12:1721-1727. 57. Wong SL, Edwards MJ, Chao C, et al. Radiofrequency ablation for unresectable hepatic tumors. Am J Surg. 2001;182:552-557. 58. Wray CJ, Lowy AM, Mathews JB, et al. The significance and clinical factors associated with a subcentimeter resection of colorectal liver metastases. Ann Surg Oncol. 2005;12:374-380. Epub 2005 Mar 29. 59. Yamaguchi J, Yamamoto M, Komuta K, et al. Hepatic resections for bilobar liver metastases from colorectal cancer. J Hepatobiliary Pancreat Surg. 2000;7:404-409.