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ABSTRACT: The definition and management of borderline resectability for periampullary pancreatic adenocarcinoma are evolving. In this case report, we discuss the presentation, workup, and therapeutic management of a 40-year-old man who presented with borderline resectable, periampullary pancreatic cancer and underwent a margin-negative resection following neoadjuvant chemoradiotherapy.

The definition of borderline resectability for periampullary pancreatic cancer and the treatment of this condition are evolving. In this installment of Clinical Quandaries, we present the case of a 40-year-old man with the diagnosis of borderline resectable (BR) adenocarcinoma of the pancreas, discuss his treatment course, and review the relevant literature.

A 40-year-old man presented to his primary care physician with a history of abdominal pain for several months and weight loss of 20 lb, which was 9% of his usual adult weight. Shortly before presentation, he experienced jaundice, dark urine, light-colored stools, and generalized pruritus.

The patient’s past medical history was notable only for nephrolithiasis. He was taking no medications and had no known drug allergies. He denied clinically significant alcohol intake or use of either tobacco or illicit drugs. His family history was significant for a paternal uncle with colon cancer and a maternal nephew with leukemia of unknown type. He had no family history of pancreatic cancer. On physical examination, his vital signs were stable, and his weight was 201 lb (20 lb below his baseline). Physical exam revealed significant jaundice, including scleral icterus. On abdominal exam, he had no tenderness or hepatosplenomegaly. His heart rate and rhythm were regular, and his lungs were clear to auscultation. His performance status on the Eastern Cooperative Oncology Group (ECOG) scale was 0.

Computed tomography (CT) scan of the abdomen and pelvis revealed a complex cystic mass in the head of the pancreas with ill-defined borders and biliary dilatation. A questionable right hepatic lobe lesion was of concern for metastatic disease (Figures 

). A right upper quadrant ultrasound demonstrated a 3.5 × 1.8 × 2.5 cm cystic mass in the pancreatic head, and a right liver lobe lesion measuring 1.7 cm (

The initial lab workup revealed a CA 19-9 of 83 U/mL (normal, < 37 U/mL) when he was jaundiced, but this value decreased to 33 U/mL after the jaundice resolved. His total bilirubin (7.2 mg/dL), aspartate aminotransferase (175 U/L), alanine aminotransferase (501 U/L), and alkaline phosphatase (422 U/L) were all markedly elevated at presentation. The remainder of his laboratory tests were within normal limits. Endoscopic retrograde cholangiopancreatography (ERCP) was performed and a biliary stent was placed, resulting in the resolution of the patient’s symptoms and normalization of his lab values. Brushings from the ERCP were nondiagnostic.

The patient then came to our institution for further management. An endoscopic ultrasound (EUS) visualized a 3.5 × 2.2 cm irregular cystic lobulated mass in the pancreatic head, with clear involvement of the portal vein at the confluence with the superior mesenteric vein (SMV), causing limited occlusion (

). Fine-needle aspiration (FNA) was performed during EUS and revealed well differentiated pancreatic adenocarcinoma with papillary features. The patient experienced a recrudescence of his presenting symptoms and required repeat ERCP to replace an occluded biliary stent.

The patient was also referred to an interventional radiologist to obtain a pathologic diagnosis of the suspicious liver lesion. Under ultrasound guidance, FNA of the liver lesion was performed. Cytology revealed reactive hepatocytes and fibrosis, consistent with hemangioma (

The patient was first seen by a general surgeon. Due to the involvement and limited occlusion of the SMV, upfront surgery was not recommended. The patient was referred to medical oncology and radiation oncology for consideration of neoadjuvant treatment.

Weekly gemcitabine (Gemzar) was given initially at a dose of 1,000mg/m2. The patient received four doses of gemcitabine before beginning concurrent chemoradiotherapy with reduced weekly doses of gemcitabine (750 mg/m2). Radiation was targeted to the pancreas and draining regional lymph nodes at 54 Gy in 30 fractions using a four-field, three-dimensional conformal technique. He tolerated radiotherapy well and required no treatment breaks. He experienced grade 2 nausea and vomiting, which resolved with prochlorperazine. The third dose of gemcitabine midway through the radiation course was held due to grade 3 hematologic toxicity (leukopenia), and the subsequent doses were decreased to 375 mg/m2. A repeat CT scan after the completion of neoadjuvant therapy showed shrinkage of the pancreatic head mass and reduced portal vein and SMV involvement. There was no evidence of portal vein occlusion.

Eight weeks after the completion of chemoradiotherapy the patient underwent laparotomy. Intraoperatively, tumor was found to be adherent to the posterior wall of the stomach and to the portal vein at the confluence with the SMV. A classic pancreaticoduodenectomy (Whipple procedure) with partial gastrectomy and partial portal vein resection were performed, including portal vein repair using a saphenous vein patch.

   Pathology Specimens From Whipple Procedure After Neoadjuvant Therapy 

Pathologic examination of the surgical specimen revealed residual well-differentiated adenocarcinoma, 8 mm in diameter, with surrounding fibrosis. Margins were negative, and three sampled lymph nodes were free of tumor. No venous involvement was noted (

). Postoperatively, the patient did well. He was placed on continuous venous nutrition, which was discontinued when he was able to tolerate oral intake. He was discharged 10 days after surgery.

Three months after surgery, he restarted chemotherapy, receiving an additional four cycles of gemcitabine (600 mg/m2 with a 3-week-on/1-week-off schedule). He required frequent treatment delays and dose reductions as a result of hematologic toxicity. Since the completion of adjuvant therapy, he has returned to work full-time. His most recent imaging, performed 11 months after surgery, showed no evidence of recurrent disease. His CA 19-9 level, initially elevated at presentation, has remained undetectable.

The management of pancreatic cancer is both challenging and controversial. An incidence of 37,600 cases is estimated in the United States for 2008, with 34,290 deaths related to pancreatic cancer.[1] Between 70% and 80% of pancreatic adenocarcinomas present in the periampullary region. The parity of the rates of diagnosis and death for pancreatic cancer highlights both the difficulty in treating this disease and the need for new treatment paradigms. Complete surgical resection remains the sine qua non of curative therapy, but only 20% of patients have resectable disease at presentation.[2] Furthermore, even with negative-margin resection, 5-year survival rates range from 20% to 30%, supporting the role of adjuvant treatment.[2,3] In the following section, we discuss the evidence and rationale supporting adjuvant and neoadjuvant therapy for periampullary pancreatic cancer and the relevance of these data in the management of a case with borderline resectability.

Over the past decade, technical improvements have enhanced our ability to evaluate and stage pancreatic cancer. EUS is very sensitive for detecting vascular invasion and is especially helpful when the CT findings are equivocal.[4,5] This sensitivity is valuable in determining resectability in certain situations. Additionally, EUS allows for tissue diagnosis via FNA.[6] EUS-directed FNA is preferable to CT-guided FNA because of the much lower risk of peritoneal seeding.[7] EUS is technically demanding, and operator expertise affects both sensitivity and specificity.

CA 19-9 is a sialyated Lewis A blood group antigen commonly expressed in pancreatic cancer; it also can be elevated in several other malignancies and hepatobiliary disease. Estimates of the sensitivity and specificity of CA 19-9 for pancreatic cancer range from 70% to 90%.[8] CA 19-9 can be spuriously elevated by hyperbilirubinemia, so serum levels should be repeated after the resolution of jaundice. CA 19-9 is most useful in monitoring for disease recurrence after surgery since rising levels can be a harbinger of overt relapse.[9]

If biopsy is not feasible for patients with suspected liver metastases, positron-emission tomography (PET) has been shown to be reliable in detecting liver metastases larger than 1 cm.[10]

For more than 2 decades, postoperative chemoradiotherapy has been a standard treatment for resectable pancreatic cancer in the United States. This practice was supported by the landmark Gastrointestinal Tumor Study Group (GITSG) trial which showed a dramatic survival advantage for patients receiving chemoradiotherapy with concurrent fluorouracil (5-FU) as compared to patients receiving no further therapy after surgery.[11]

A more recent European Organisation for Research and Treatment of Cancer (EORTC) trial randomized patients in a similar fashion.[12] This trial yielded survival curves that appeared very similar to the GITSG trial, but the difference in overall survival did not reach statistical significance. A recent update confirmed the absence of an advantage for the adjuvant therapy arm, although it appears that patients with cancer of the pancreatic head may have experienced a small benefit. Unfortunately, this trial lacked the statistical power to detect a difference with subset analysis, in part due to the use of a two-sided log-rank test.[13-14]

Subsequently, the Radiation Therapy Oncology Group (RTOG) 97-04 trial showed a strong trend toward a survival benefit with the addition of gemcitabine before and after adjuvant 5-FU–based chemoradiation in patients with resected tumors of the pancreatic head.[15] Current controversy regarding the role of radiotherapy in the adjuvant setting based on European Study Group for Pancreatic Cancer (ESPAC)-1 and Charit Onkologie (CONKO)-001 results is acknowledged, but is not germane to the primary focus of this report.[16-17]

Adjuvant therapy is limited by the frequent inability of upfront surgery to achieve an R0 resection. Several single-institution experiences have demonstrated that the presence of positive margins at resection is associated with significantly worse survival, approaching that of patients with inoperable disease.[3,18,19] This is of special importance in patients with BR disease. The definition of BR is controversial, but a working definition includes those tumors at high risk for having microscopic residual disease after surgical resection. To achieve a margin-negative (R0) resection in BR disease, neoadjuvant therapy has been incorporated into some treatment paradigms.

Investigation of the BR subgroup is hindered by lack of concordance of definitions of resectability between institutions. Several organizations, including the National Comprehensive Cancer Network (Table 1), have developed classification systems for pancreatic cancer resectability, but no universal standard has emerged. As a result, the available data are difficult to compare. Recently, Katz et al proposed objective CT-based anatomic criteria to classify BR disease.[20] The adoption of an objective standard definition is vital to the study of this patient subgroup.

Most series reporting on BR patients have focused on neoadjuvant treatment followed by resection. Histopathologic assessment of tumors after neoadjuvant therapy in pancreatic cancer has consistently demonstrated evidence of therapeutic effect in almost all specimens.[21,22] Katz et al found that 56% of surgery specimens had less than 50% viable tumor cells, while Ammori et al found a high degree of therapy-related fibrosis in two-thirds of patients.[20,23]

As a result of tumor shrinkage, neoadjuvant therapy appears to improve the rates of R0 resections in BR pancreatic cancer.[24] Brown et al reviewed the outcomes of BR patients who underwent neoadjuvant therapy followed by surgery and found an 85% rate of R0 resection.[25] Katz et al found that 41% of their BR patients treated with neoadjuvant therapy ultimately underwent surgery with grossly negative margins, and 94% of these had microscopic negative margins. Median survival was 40 months for patients undergoing resection, compared to 13 months for patients not receiving surgery (P < .001).[20]

Patients with clearly unresectable disease (Table 1) are rarely able to undergo margin-negative surgery even after neoadjuvant therapy, and these patients should be treated with paradigms that do not involve surgery.[26,27]

Although the neoadjuvant approach moves surgery to the last step in the treatment sequence, this modality retains its primary importance. In the past, pancreatic surgery was associated with a high mortality, causing some experts to question its utility.[28] Improvements in surgical technique and postoperative care have led to low rates of perioperative mortality with pancreaticoduodenectomy.[29] Optimally, these operations should be performed at higher-volume centers, which have lower operative morbidity and mortality rates.[30] Recent surgical advances include the involvement of vascular surgeons to assist with venous resection, reducing complications and allowing for margin-negative resection even in cases of vessel abutment.[31,32]

Based on CT and EUS findings, our patient had a high likelihood of having residual disease after upfront surgery. To address this, we treated him with neoadjuvant therapy consisting of gemcitabine, followed by chemoradiotherapy with concurrent gemcitabine. The tumor shrinkage resulting from neoadjuvant therapy aided the surgeon in obtaining microscopically negative margins. After a recovery period, we administered four cycles of adjuvant gemcitabine.

The workup and treatment of pancreatic adenocarcinoma is evolving and requires a multidisciplinary team approach. Adjuvant therapy after upfront surgery may be suboptimal for BR tumors due to the risk of an incomplete resection. Early data suggest that neoadjuvant chemoradiotherapy can increase the likelihood of a margin-negative resection for BR tumors. Randomized trials are needed to formally evaluate the efficacy of this approach. The adoption of a standard, objective definition of resectability, based on radiographic findings, would improve the ability to study this patient subgroup.

The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.

1. Jemal A, Siegel R, Ward E, et al: Cancer statistics, 2008. CA Cancer J Clin 58:71-96, 2008.
2. Li D, Xie K, Wolff R, et al: Pancreatic cancer. Lancet 363:1049-1057, 2004.
3. Yeo CJ, Abrams RA, Grochow LB, et al: Pancreaticoduodenectomy for pancreatic adenocarcinoma: Postoperative adjuvant chemoradiation improves survival. A prospective, single-institution experience. Ann Surg 225:621-633, 1997.
4. RÃ¶sch T, Dittler H, Strobel K, et al: Endoscopic ultrasound criteria for vascular invasion in the staging of cancer of the head of the pancreas: A blind reevaluation of videotapes. Gastrointest Endosc 52:469-477, 2000.
5. Snady H, Bruckner H, Siegel J, et al: Endoscopic ultrasonographic criteria of vascular invasion by potentially resectable pancreatic tumors. Gastrointest Endosc 40:326-333, 1994.
6. Raut C, Grau A, Staerkel G, et al: Diagnostic accuracy of endoscopic ultrasound-guided fine-needle aspiration in patients with presumed pancreatic cancer. J Gastrointest Surg 7:118-126, 2003.
7. Micames C, Jowell PS, White R, et al: Lower frequency of peritoneal carcinomatosis in patients with pancreatic cancer diagnosed by EUS-guided FNA vs. percutaneous FNA. Gastrointest Endosc 58:690-695, 2003.
8. Goonetilleke KS, Siriwardena AK: Systematic review of carbohydrate antigen (CA 19-9. as a biochemical marker in the diagnosis of pancreatic cancer. Eur J Surg Oncol 33:266-270, 2007.
9. Abrams RA, Grochow LB, Chakraverthy A, et al: Intensified adjuvant therapy for pancreatic and periampullary adenocarcinoma: Survival results and observations regarding patterns of failure, radiotherapy dose and CA19-9 levels. Int J Radiat Oncol Biol Phys 44:1039-1046, 1999.
10. FrÃ¶lich A, Diedrichs CG, Staib L, et al: Detection of liver metastases from pancreatic cancer using FDG PET. J Nucl Med 40:250-255, 1999.
11. Kalser M, Ellenberg S: Pancreatic cancer. Adjuvant combined radiation and chemotherapy following curative resection. Arch Surg 120:899-903, 1985.
12. Klinkenbijl J, Jeekel J, Sahmoud T, et al: Adjuvant radiotherapy and 5-fluorouracil after curative resection of cancer of the pancreas and periampullary region: Phase III trial of the EORTC gastrointestinal tract cancer cooperative group. Ann Surg 230:776-782, 1999.
13. Smeenk, van Eijck CH, Hop WC, et al: Long-term survival and metastatic pattern of pancreatic and periampullary cancer after adjuvant chemoradiation or observation: Long-term results of EORTC trial 40891. Ann Surg 246:734-740, 2007.
4. Garofalo MC, Regine WF, Tan MT: On statistical reanalysis, the EORTC trial is a positive trial for adjuvant chemoradiation in pancreatic cancer (letter to editor). Ann Surg 244:332-333, 2006. 
15. Regine W, Winter K, Abrams R, et al: Fluorouracil vs. gemcitabine chemotherapy and after fluorouracil-based chemoradiation following resection of pancreatic adenocarcinoma: A randomized controlled trial. JAMA 299:1019-1026, 2008.
16. Neoptolemos JP, Stocken DD, Friess H, et al: A randomized trial of chemoradiotherapy and chemotherapy after resection of pancreatic cancer. N Engl J Med 350:1200-1210, 2004.
17. Oettle H, Post S, Neuhaus P, et al: Adjuvant chemotherapy with gemcitabine vs observation in patients undergoing curative-intent resection of pancreatic cancer: A randomized controlled trial. JAMA 297:267-277, 2007.
18. Sohn T, Yeo C, Cameron J, et al: Resected adenocarcinoma of the pancreas-616 patients: Results, outcomes, and prognostic indicators. J Gastrointest Surg 4:567-579, 2000.
19. Trede M, Schwall G, Saeger HD: Survival after pancreatoduodenectomy. 118 consecutive resections without an operative mortality. Ann Surg 211:447-458, 1990.
20. Katz MH, Pisters PW, Evans DB, et al: Borderline resectable pancreatic cancer: The importance of this emerging stage of disease. J Am Coll Surg 206:833-846, 2008.
21. Evans DB, Rich TA, Byrd DR, et al: Preoperative chemoradiation and pancreaticoduodenectomy for adenocarcinoma of the pancreas. Arch Surg 127:1335-1339, 1992.
22. Talamonti MS, Small W, Mulcahy MF, et al: A multi-institutional phase II trial of preoperative full-dose gemcitabine and concurrent radiation for patients with potentially resectable pancreatic carcinoma. Ann Surg Oncol 13:150-158, 2006.
23. Ammori JB, Colletti LM, Zalupski MM, et al: Surgical resection following radiation therapy with concurrent gemcitabine in patients with previously unresectable adenocarcinoma of the pancreas. J Gastrointest Surg 7:766-772, 2003.
24. Pingpank JF, Hoffman JP, Ross EA, et al: Effect of preoperative chemoradiotherapy on surgical margin status of resected adenocarcinoma of the head of the pancreas. J Gastrointest Surg 5:121-130, 2001.
25. Brown KM, Siripurapu V, Davidson M, et al: Chemoradiation followed by chemotherapy before resection for borderline pancreatic adenocarcinoma. Am J Surg 195:318-321, 2008.
26. White R, Lee C, Anscher M, et al: Preoperative chemoradiation for patients with locally advanced adenocarcinoma of the pancreas. Ann Surg Oncol 6:38-45, 1999.
27. Kim H, Czischke K, Brennan MF, et al: Does neoadjuvant chemoradiation downstage locally advanced pancreatic cancer? J Gastrointest Surg 6:763-769, 2002.
28. Crile G: The advantages of bypass operations over radical pancreaticoduodenectomy in the treatment of pancreatic carcinoma. Surg Gynecol Obstet 130:1049-1053, 1970.
29. Yeo CJ, Cameron JL, Sohn TA, et al: 650 pancreaticoduodenectomies in the 1990s: Pathology, complications, and outcomes. Ann Surg 226:248-257, 1997.
30. Birkmeyer JD, Warshaw AL, Finlayson SR, et al: Relationship between hospital volume and late survival after pancreaticoduodenectomy. Surgery 126:178-183, 1999.
31. Bold RJ, Charnsangavej C, Cleary KR, et al: Major vascular resection as part of pancreaticoduodenectomy for cancer: Radiologic, intraoperative, and pathologic analysis. J Gastrointest Surg 3:233-243, 1999.
32. Fuhrman GM, Leach SD, Staley CA, et al: Rationale for en bloc vein resection in the treatment of pancreatic adenocarcinoma adherent to the superior mesenteric-portal vein confluence. Pancreatic Tumor Study Group. Ann Surg. 223:154-162, 1996.

Articles

In this case report, we discuss the presentation, workup, and therapeutic management of a 40-year-old man who presented with borderline resectable, periampullary pancreatic cancer and underwent a margin-negative resection following neoadjuvant chemoradiotherapy.

Management of a Patient With Borderline Resectable Pancreatic Cancer

ABSTRACT: The treatment of metastatic colorectal cancer (mCRC) has changed dramatically from the 1980s, when only fluorouracil (5-FU) was available for treatment and the median survival was at best 12 months, to a time when mCRC is considered more of a chronic disease in which the median survival is now reported in excess of 2 years. This review traces the evolution of treatment in this setting, including studies of single-agent vs combination treatment with 5-FU/leucovorin, irinotecan, oxaliplatin, and capecitabine, comparisons of simultaenous and sequential regimens, and the role of targeted agents such as bevacizumab, cetuximab, and panitumumab.

Colorectal cancer is the third most common cancer in the United States.[1] In 2008, an estimated 148,810 new cases of colorectal cancer will be diagnosed and nearly 50,000 people will die of the disease.[1] In the past 20 years, great advances have been made in the treatment of advanced colorectal cancer, increasing survival from 6 months to over 2 years. However, among patients diagnosed with metastatic colorectal cancer (mCRC), the 5-year survival rate is, on average, only 8%.[2] This paper will outline the progression of treatment advances in mCRC, including single and combination chemotherapeutic agents and the addition of targeted agents.

• Fluorouracil/Leucovorin-Prior to the integration of fluoropyrimidines in the management of mCRC, the median survival with best supportive care alone was a mere 6 months.[3] This improved to 10 to 12 months with the use of fluorouracil (5-FU) with or without leucovorin (LV).[3,4] 5-FU is thought to inhibit thymidylate synthase which then blocks DNA synthesis. Introduced more than 50 years ago, it was the first major breakthrough in the treatment of mCRC. The addition of LV, a reduced folate, was found preclinically to increase the intracellular concentration of reduced folates, resulting in increased binding of 5-FU to thymidylate synthase and therefore producing increased inhibition of DNA synthesis and enhanced antitumor effects.[3]

Numerous phase II and III trials assessing the dose, schedule, and method of administration of 5-FU–based chemotherapy were completed by the Groupe Cooprateur Multidisciplinaire en Oncologie (GERCOR) trials group. The GERCOR trials culminated in the French Intergroup Study comparing monthly bolus 5-FU/ LV (North Central Cancer Treatment Group [NCCTG]-Mayo regimen) with bimonthly bolus and continuous-infusion 5-FU/LV (modified LV5FU2 regimen).[5] The dose of chemotherapy given with the LV5FU2 regimen was twice that of the Mayo regimen. While there was no statistically significant difference in overall survival (OS), both response rate and progression-free survival (PFS) were improved with the modified LV5FU2 regimen. The LV5FU2 regimen also was associated with fewer grade 3/4 toxicities than were seen with the monthly regimen.[5]

Both regimens had inconveniences related to delivery. The Mayo regimen required daily bolus administration of 5-FU for 5 consecutive days on a monthly basis. By comparison, the LV5FU2 regimen consisted of a 5-FU bolus followed by a continuous infusion of 5-FU for 48 hours every 2 weeks, which involved the need for long-term venous access and an administration pump.

Subsequently, two key meta-analyses assessed the impact of the modes of delivery of 5-FU/LV on survival[6] and the relative contribution of LV to 5-FU–based chemotherapy,[7] respectively. First, a meta-analysis was performed that compared infusional vs bolus 5-FU/LV from seven phase III clinical trials, representing 1,219 patients.[6] The meta-analysis showed that infusional 5-FU was associated with an improved tumor response (22% vs 14%, P = .0002) but without a corresponding improvement in median survival (12.1 vs 11.3 months, P = .039).[6] A companion paper described the toxicity profiles and showed that bolus 5-FU was associated with increased grade 3/4 hematologic toxicity, particularly neutropenia (4% vs 31%) and mucositis, whereas higher rates of hand-foot syndrome (34% vs 13%) were observed with infusional 5-FU.[8]

Another meta-analysis assessed the impact of modulation of 5-FU by LV.[7] The tumor response rate improved from 11% to 21% with the use of 5-FU/LV vs 5-FU alone (P < .0001). Median OS improved from 10.5 to 11.7 months (P = .004). The 1-year survival rate was 43% vs 49%, but 2-year survival was identical in both groups at 17%. Prognostic factors of a good tumor response included good performance status, metastases confined to the liver, and treatment with 5-FU/LV. One-year survival was clearly worse with increasing performance status (63% vs 45% vs 20% for PS 0, 1, and 2, respectively) and was influenced by the site of metastatic disease (liver only, 50%; lung only, 57%; and other sites, 44%).[7] Overall, this analysis demonstrated a small but discernable benefit for the addition of LV to bolus 5-FU.

• Irinotecan-Irinotecan (CPT-11) was then added to the armamentarium, receiving US Food and Drug Administration (FDA) approval in 2002. Irinotecan inhibits the topoisomerase 1 enzyme. Normally, topoisomerase 1 catalyzes DNA breakage, repair, and rejoining of DNA strands, all necessary for DNA replication. Irinotecan-induced inhibition stabilizes these breaks, leaving fragmented DNA and resulting in cell death.[3]

Douillard et al[9] authored the first phase III study in which irinotecan was added to infusional 5-FU/calcium folinate compared to 5-FU/calcium folinate alone. This study demonstrated a benefit in response rate (35% vs 22%, P = .005) and median time to progression (7 vs 4 months, P = .001). The survival benefit was 3 months (17 vs 14 months, P = .031), with a 1-year survival of 69% vs 59%. Grade 3/4 toxicities were mostly limited to the irinotecan group, and consisted of diarrhea (44% vs 26%), vomiting, and leukopenia. Grade 3/4 neutropenia affected 29% of patients on irinotecan, but only 2% of all patients developed infection.[9]

At the same time, Saltz et al[10] compared three regimens: (1) weekly bolus irinotecan and 5-FU/LV (IFL); (2) 5-FU/LV (Mayo protocol); and (3) weekly single-agent irinotecan. The IFL regimen demonstrated a superior PFS compared to 5-FU/LV, increasing PFS from 4.3 to 7.0 months (P = .004) and enhanced survival from 12.6 to 14.8 months (P = .04). Survival and PFS for weekly irinotecan were similar to the 5-FU/LV regimen. However, additional toxicities of IFL included grade 3/4 diarrhea, vomiting, and infection. Mucositis was substantially increased (16.9% vs 2.2%) in the 5-FU/LV group and higher than expected by the meta-analysis data.[8]

• Oxaliplatin-Oxaliplatin (Eloxatin), a third-generation platinum derivative, demonstrated activity in mCRC in synergy with 5-FU/LV.[3] Oxaliplatin induces apoptosis by forming DNA adducts.[3] The first major study demonstrating the effectiveness of oxaliplatin when compared with the Mayo protocol (FOLFOX4 [leucovorin (folinic acid), 5-FU, oxaliplatin]) found a significant improvement in PFS from 6.2 to 9 months (P = .0001) and response rate over 5-FU/LV alone.[11] Overall survival improved from 14.7 to 16.2 months but was not statistically different between the two treatment arms, although this may have been obscured by crossover for salvage chemotherapy. Toxicity of oxaliplatin was predominantly neurosensory, overall affecting 68% of patients with grade 1 to 3 toxicity, including pharyngolaryngeal dysesthesia in almost one-quarter of the patients.[11]

• Capecitabine-Another advance in the management of mCRC was the demonstration of equivalence of 5-FU/LV and capecitabine (Xeloda). Capecitabine is an oral fluoropyrimidine that is converted enzymatically to fluorouracil, with a toxicity profile similar to infusional 5-FU [3]. Two simultaneous and identical phase III clinical trials were performed to compare the 5-FU/LV Mayo protocol with capecitabine.[12,13] One study demonstrated at least equivalence,[13] and the other demonstrated superiority of capecitabine[12] in terms of response rate. Otherwise, secondary endpoints were equivalent, including a median survival of 12 to 13 months. The toxicity profile of capecitabine demonstrated expected rates of diarrhea but more frequent hand-foot syndrome. Alopecia was less frequent and stomatitis was both less frequent and less severe with capecitabine than 5-FU.[12,13] These studies confirmed the interchangeability of 5-FU/LV and capecitabine.

Combination Comparisons and the Role of Sequential Therapies

By 2000, the optimal use of the available agents in first-line therapy, 5-FU/LV, irinotecan, and oxaliplatin, had not been determined, and capecitabine would shortly become a treatment option. Evidence was mounting for combination treatment to improve the objective response rate and time to disease progression. Irinotecan in combination with 5-FU/LV had demonstrated a benefit over 5-FU/LV or irinotecan alone,[9,10] as had oxaliplatin.[11] Second-line options were emerging, although not prespecified in trials, and the treatment options outside a clinical trial were limited. At this point, the combinations of treatments and sequencing of these agents became the focus of attention.

• N9741 Trial-In the phase III N9741 trial comparing IFL to FOLFOX and IROX (irinotecan/oxaliplatin), the superiority of FOLFOX was demonstrated in terms of improved time to progression and response rates, and an OS of 19.5 months compared to 15 months for IFL and 17.4 months for IROX (P = .0001).[14] Aside from sensory neuropathy (grade 3/4 in 18% vs 3%, P = .001), fewer and less severe toxicities were observed with FOLFOX compared to the toxicities seen with the IFL regimen. More severe vomiting and paresthesias, however, were observed with IROX as compared to IFL.[14] Based on response and survival rates, and toxicity profiles, FOLFOX was judged to be the superior regimen for mCRC, and in 2004, the FDA approved the use of FOLFOX for previously untreated mCRC.

• BICC-C Trial-The Bolus, Infusional, or Capecitabine with Camptosar-Celecoxib (BICC-C) trial was developed as a 3×2 factorial design comparing three chemotherapy options (FOLFIRI [leucovorin, 5-FU, irinotecan], modified [m]IFL, and CapeIRI [capecitabine, irinotecan]). A second randomization was performed to compare the use of celecoxib (Celebrex) or placebo with each of the chemotherapeutic regimens evaluated.[15] Due to the excessive number and severity of toxicities, the CapeIRI arm was subsequently dropped. As data emerged regarding its efficacy in CRC, bevacizumab (Avastin) was included in the trial. Patients in both the FOLFIRI and mIFL arms were subsequently randomized to receive chemotherapy plus bevacizumab or chemotherapy only. The final study design involved FOLFIRI vs mIFL with or without celecoxib, and with or without bevacizumab.

First, celecoxib did not influence therapeutic outcomes, and the randomization of celecoxib was not considered relevant to the analysis of the chemotherapeutic regimens administered either alone or in combination with bevacizumab.

Second, FOLFIRI was found to be superior to mIFL in PFS (7.6 vs 5.9 months, P = .004). Overall survival was similarly improved (23.1 vs 17.6 months, P = .09), with 1-year survival rates of 75% and 65%, respectively. CapeIRI and mIFL produced similar results for OS and PFS, but excessive toxicity was observed from CapeIRI compared to either FOLFIRI or mIFL. FOLFIRI still maintained a superior PFS over CapeIRI, even when the analysis excluded patients on the CapeIRI arm who discontinued treatment early due to significant toxicity.[15]

• XELOX vs FOLFOX-Subsequently, the NO16966 (XELOX-1) trial was designed to combine oxaliplatin with either capecitabine or 5-FU/LV.[16] Later in the trial, patients were randomized to receive XELOX and FOLFOX4 alone or with bevacizumab. The first objective of the amended protocol was to show the noninferiority of XELOX and FOLFOX4 for PFS, with or without bevacizumab. The investigators found no difference in PFS in the eligible patient population (7.9 vs 8.5 months; hazard ratio [HR] = 1.05; 97.5% confidence interval [CI] = 0.94–1.18, the upper limit being below the predefined 1.23 noninferiority margin). The median OS was also similar at 19.8 and 19.6 months, respectively. Toxicities were also similar aside from increased grade 3/4 diarrhea in the XELOX group and the increased rate of neutropenia in the FOLFOX group.[16] The interchangeability of XELOX and FOLFOX was then established.

• FOLFIRI vs FOLFOX-Colucci et al [17] reported a direct comparison of an irinotecan 5-FU combination (Douillard regimen) with FOLFOX4 (de Gramont regimen). The authors found no differences in response rate, time to progression, or survival. Almost two-thirds of patients had previously received second-line chemotherapy, mostly oxaliplatin in the FOLFIRI group and irinotecan in the FOLFOX4 group. The analysis of those patients previously treated with second-line chemotherapy demonstrated a median survival of 17 months, compared to a median survival of 10 months among patients who did not get second-line chemotherapy.[17] This confirmed the similarity in activity between the FOLFOX and the Douillard 5-FU plus irinotecan regimens in first-line chemotherapy for mCRC. The choice of an initial regimen for mCRC then became a matter of patient and physician preference and toxicity profiles rather than differential efficacy. FOLFOX caused more neutropenia and sensory neuropathy, whereas the Douillard regimen was associated with hair loss and more gastrointestinal (GI) toxicity.

• Refining the Regimens-With no new chemotherapeutic agents on the horizon, the next issue was to determine the most appropriate delivery of the agents. This was done retrospectively by Grothey et al[18] and prospectively in the FOCUS (Fluorouracil, Oxaliplatin, and CPT-11 [irinotecan] Use and Sequencing) and CAIRO (CApecitabine, IRinotecan, Oxaliplatin) trials. The variation in median survival in studies using combination chemotherapy, which ranged from 14.8 to 21.5 months, was thought to be influenced more by the choice of salvage therapies following first-line treatment, rather than explained on the basis of patient selection or other factors unrelated to the treatments.

Grothey et al[18] analyzed the impact of receiving all three active treatments (5-FU, irinotecan, and oxaliplatin) during the course of disease in a pooled analysis. Median survival was strongly correlated with the percentage of patients who received all three drugs (P = .0008). No correlation was found, however, with survival and percentage of patients who received second-line treatment (P = .19). Administration of all three drugs (combination therapy) was associated with a 3.5-month increase in median survival compared to the initial administration of only one of the three agents (monotherapy, P = .01).

This analysis brought up two important points. First, in these studies between 58% and 77% of the patients who initially received monotherapy later received second-line chemotherapy on progression. This would make a case for the early initiation of combination therapy, although the potential influence of performance status at the time of progression affecting the second-line treatment choice cannot be excluded. These patients likely had a poorer performance status at the time of initial therapy and at the time of progression that affected the administration of second-line chemotherapy. Second, because of the survival benefit gained from second-line chemotherapy, other endpoints, such as PFS and time to treatment failure, might better assess the benefit of the initial chemotherapy regimen.[18]

Subsequently, Grothey and Sargent[19] presented an updated analysis with patients from four additional trials that validated this concept. They found that the median survival correlated with the percentage of patients receiving all three chemotherapy regimens. In multivariate analyses, only first-line exposure to all three treatments was correlated with survival.[19]

• FOCUS and CAIRO Studies-The FOCUS and CAIRO trials investigated whether combination treatment was indeed required to improve overall survival, as opposed to a sequential approach that used single agents. One obvious advantage of the sequential approach would be to minimize side effects. The Medical Research Council’s FOCUS trial compared three treatment options: 5-FU/LV followed by irinotecan at treatment failure, single-agent 5-FU/LV followed by combination chemotherapy, and combination chemotherapy at the outset.[20] In the combination chemotherapy arms, patients were further randomized to 5-FU/irinotecan or 5-FU/oxaliplatin. After second-line chemotherapy, salvage chemotherapy or supportive care was instituted. Initially, salvage with 5-FU and mitomycin was the treatment of choice, but with evidence supporting the sequential use of irinotecan and oxaliplatin, these agents were later recommended (although only received by 23% of patients).[20]

Compared with single-agent 5-FU/LV, only the initial combination arm with irinotecan demonstrated an improved overall survival by 2.6 months (P = .02, adjusting for multiple comparisons). However, no differences were reported between the three groups in 2-year OS (22% vs 25% vs 28%, respectively, adjusted for multiple comparisons). A further analysis found noninferiority between the two combination strategies. Additionally, no differences in quality of life or by performance status were noted.[20] The advantage of such a study is that it demonstrates that toxicities can be balanced with the treatment options, and that treatment can be individualized without compromising survival in patients for whom curative options are not available.

A similarly aimed study, CAIRO, was published simultaneously by the Dutch Colorectal Cancer Group.[21] It used a simple two-arm study design, comparing sequential treatment (capecitabine followed by irinotecan on progression followed by CapeOX [capecitabine, oxaliplatin]) with combination treatment (CapeIRI followed by CapeOX on progression). Overall survival was not statistically different between the sequential and combination therapy groups (16.3 and 17.4 months, respectively). The 1-year survival rates were 64% and 67%, respectively (P = .38). However, multivariate analyses showed that worse survival was associated with a performance status of 2 and an abnormal lactate dehydrogenase (LDH).

Adverse effects were generally similar in the sequential and combination treatment arms except for grade 3 hand-foot syndrome, which was worse in the sequential group. Of note, both treatments were associated with grade 3/4 diarrhea (25%), nausea, vomiting, and febrile neutropenia. Quality of life was not significantly different in the two groups, aside from the incidence of diarrhea, which was worse in the combination group.[21] The diarrhea from CapeIRI, however, was less severe in this trial than in either the BICC-C or the European Organisation for Research and Treatment of Cancer (EORTC) 40015 trial, where toxicities resulted in the closure of the BICC-C trial’s CapeIRI arm and the premature closure of the EORTC 40015 trial. While possible explanations have been offered, these differences have yet to be explained.

While neither the FOCUS nor CAIRO studies used monoclonal antibody treatments, these studies were the first to determine that sequential treatment could produce similar survival as combination therapy among patients with unresectable or only potentially resectable disease. The increased median survival in the CAIRO study may be attributed to the use of all available treatments (5-FU, irinotecan, and oxaliplatin) in 36% of the sequential and 53% of the combination patients. By comparison, only 25% of the patients in the FOCUS trial received all three treatments. Clearly toxicity increased with combination treatment.

An accompanying editorial suggested that combination therapy may be most important for patients with potentially resectable disease to give the best possible chance of resection as well as for those with aggressive disease who have or are anticipated to have tumor-related symptoms or poor performance status related to disease.[22] Otherwise, the results of the FOCUS and CAIRO studies may be most appropriate for patients who do not fit into either of these two groups.[22]

• Timing-Another question relates to the sequencing of FOLFOX and FOLFIRI regimens. The C97 study by the GERCOR group compared FOLFIRI followed by FOLFOX6 at progression with the reverse sequence of regimens.[23] Performance status improved with both sequences, and the sequence of therapy had no impact on either PFS or OS. However, the sequence did influence toxicities. Grade 3/4 nausea, vomiting, and mucositis were more common with FOLFIRI, whereas neurotoxicity and neutropenia were more common with FOLFOX. Only grade 3 neurotoxicity with FOLFOX was increased when FOLFOX was used as second-line chemotherapy. Elderly patients did not experience more toxicities than younger patients.[23]

• Lower-Intensity Regimens-A previous pooled analysis in mCRC demonstrated that survival correlated with the proportion of patients receiving all three chemotherapy agents, yet did not correlate with the proportion of patients who receive second-line chemotherapy.[18] This prior analysis formed the basis of trials conducted separately by Falcone et al[24] and Souglakos et al,[25] who examined the efficacy of a modified, lower-intensity variation of the FOLFIRI regimen vs FOLFOXIRI (leucovorin, 5-FU, oxaliplatin, irinotecan) as first-line therapy. Previously, a phase II study reported a median survival of 28.4 months and a response rate of 72% with administration of FOLFOXIRI.[26]

The study by Souglakos et al[25] found that survival was not different between the groups (19.5 vs 21.5 months, P = .337), nor was time to progression (6.9 vs 8.4 months, P = .17). The dose intensity, which was only marginally higher in the mFOLFIRI group, did not explain the lack of difference. FOLFOXIRI was associated with increased diarrhea, neurosensory disorders, and severe alopecia.

In contrast, the study by Falcone et al[24] was positive. The primary endpoint was response rate, which the authors justified by the strong correlations in meta-analyses between response rate and survival, and between response rate and rate of secondary surgery on metastases. When compared with mFOLFOX, FOLFOXIRI produced an impressive response rate (66% vs 41%, P = .002), for which treatment with FOLFOXIRI was the only independent predictor in multivariate analyses. PFS improved and overall survival increased from 16.7 to 22.5 months (P = .032). As expected, FOLFOXIRI was more toxic with regard to neurotoxicity and neutropenia, although the rates of febrile neutropenia were not different. The data were insufficient for quality-of-life analyses.[24]

So how do we evaluate these discrepant results? The study by Souglakos et al used a bolus 5-FU/LV regimen, which by virtue of its side-effect profile, may have limited the dosing of irinotecan and oxaliplatin. However, both studies demonstrated significant rates of grade 3/4 diarrhea. Additionally, the patients in the Souglakos study were older and had a higher performance status. Regardless, the FOLFOXIRI regimen is not a commonly used treatment option given the alternate available regimens that include monoclonal antibodies.

• ‘Stop and Go’ Strategies-The benefits of irinotecan and oxaliplatin in overall survival for patients with mCRC have been accompanied by added toxicity. The dose-limiting factor with oxaliplatin is the neurotoxicity. Tournigand et al[27] evaluated the concept of treatment breaks (“stop and go”) by comparing continuous FOLFOX4 until progression with a regimen of higher-dose oxaliplatin (FOLFOX7) for 6 cycles, followed by 5-FU/LV for 12 cycles, followed by FOLFOX7 for 6 cycles, in the OPTIMOX1 study. With this design, duration of disease control was the primary endpoint. This was defined as PFS for the continuous group, and for the stop-and-go arm, it combined the first PFS interval with the second PFS interval if a response or stable disease was achieved with the second regimen.

Both regimens produced a similar duration of disease control (9 vs 10.6 months, P = .89), as well as overall survival (19.3 vs 21.2 months, P = .49) and PFS. In both groups, approximately 15% of patients underwent metastectomy with no difference in survival. The benefit of the stop-and-go arm was the reduced oxaliplatin-related neurotoxicity. The absolute benefit of oxaliplatin reintroduction on PFS and OS was ultimately difficult to discern because of the number of patients who never had reintroduction of oxaliplatin upon progression and the diverse reasons that the protocol-designated treatment plan was not followed.[27] For patients who experience toxicity or require breaks for various reasons, this information will help to guide clinicians in “real world” situations.

The OPTIMOX2 randomized phase II exploratory study assessed the stop-and-go strategy with oxaliplatin-based regimens, introducing the concept of chemotherapy-free intervals.[28] Randomization between the OPTIMOX1 regimen (mFOLFOX7 until progression, with adjusted oxaliplatin and 5-FU doses) vs mFOLFOX7 for six cycles and then no maintenance until progression, at which time FOLFOX7 was reintroduced. The duration of disease control was 12 and 9 months (P = .39), and PFS was 8.3 and 6.7 months in the two groups, respectively (P = .08), favoring the no-break arm. Response rates were similar in both arms. OS was 26 and 19 months (P = .0549) in favor of the no-break arm. The median chemotherapy-free interval was 17 weeks. The stop-and-go arm was better tolerated than the control arm. Although this study was underpowered to find statistically significant differences in survival unless such differences were large in magnitude, the data suggest that the OPTIMOX1 strategy (with 5-FU maintenance) is better than incorporating a chemotherapy-free interval.[28]

Single-Agent Therapy: Which Target to Inhibit and for Which Subpopulations?

Next on the market were the targeted therapies that-based on preclinical data-brought the promise of inhibition of intra- and extracellular processes, resulting in tumor suppression and cell death. While the benefits of these therapies have been realized, the gains have not been as significant as initially anticipated. To date, bevacizumab, cetuximab (Erbitux), and panitumumab (Vectibix) have demonstrated a clinical benefit in mCRC. Cetuximab is the first antibody used in mCRC for which a defined pathologic subgroup-those with K-ras wild-type (WT) as opposed to K-ras mutant tumors-derived benefit from the treatment (at least in retrospective assessments). To date, panitumumab has only demonstrated benefit in treatment refractory mCRC.

• Bevacizumab-Bevacizumab is a humanized vascular endothelial growth factor (VEGF) antibody that binds the VEGF ligand.[3] The end result is reduced angiogenesis. The serious although uncommon side effects associated with bevacizumab include gastrointestinal perforation, arterial thromboembolic events, and wound healing problems. More commonly, bevacizumab is associated with reversible proteinuria and hypertension.

The pivotal trial of bevacizumab was a phase III placebo-controled study conducted by Hurwitz et al, who combined IFL with or without bevacizumab. No crossover was permitted in the IFL group. IFL with bevacizumab increased survival from 15.6 to 20.3 months (HR = 0.66; P < .001).[29] The 1-year survival rates were 63.4% and 74.3%, in favor of the bevacizumab arm. Similarly, PFS, response rate, and duration of response were all improved. Grade 3/4 adverse events were common, occurring in 74% of patients in the IFL arm and 84.9% of those in the bevacizumab arm, mostly attributed to leukopenia, diarrhea, and hypertension. Only hypertension was more common in the bevacizumab group. Venous thromboembolic disease occurred in over 10% of patients. Bleeding was uncommon in both groups (2.5% and 3.1%, respectively). Unexpectedly, gastrointestinal perforation was seen in 1.5% of the bevacizumab patients.[29]

The impressive survival benefit seen in the Hurwitz trial was not unanimously accepted because of a perception on the part of some oncologists that bevacizumab paired with an inferior regimen (IFL) may have benefited patients more than if it had been paired with a more effective and less toxic regimen such as FOLFIRI. As oxaliplatin was not widely available at the time the Hurwitz trial was conducted, the effect of serial irinotecan- and oxaliplatin-based programs could not be assessed.

The previously described BICC-C study comparing FOLFIRI and mIFL was later amended to include bevacizumab in both arms, and 117 patients were randomized.[15] While FOLFIRI was the clear choice over mIFL in the initial evaluation, the results were mixed when bevacizumab was added. While the primary endpoint of PFS increased from 8.3 to 11.2 months with FOLFIRI, the differences were not statistically significant, nor was there a difference in the objective response rate. However, overall survival increased from 19.2 months with mIFL/bevacizumab to 28.0 months with FOLFIRI/bevacizumab (P = .037).[30] Side effects including grade 3/4 nausea and vomiting (approximately 5% vs 10%) and febrile neutropenia (1.7% vs 5.4%) were more pronounced in the FOLFIRI/bevacizumab arm. The most striking difference was a 12.5% risk of grade 3/4 hypertension with FOLFIRI/bevacizumab compared to 1.7% in the mIFL/bevacizumab arm.[15] While differences in PFS and response rate were not positive, there was a clear survival benefit that is in fact the longest survival reported in the mCRC literature.

The NO16966 (XELOX-1) trial comparison of XELOX and FOLFOX4 became a 2×2 factorial design to incorporate bevacizumab or placebo once available data supported an improvement in PFS in the first-line setting with the addition of bevacizumab to IFL.[31] In this analysis, superiority of bevacizumab over chemotherapy alone would be concluded if PFS demonstrated significance at the P ≤ .025 level. In fact, bevacizumab improved PFS from 8.0 to 9.4 months (P = .0023). There was no improvement in response rate. The survival benefit was a modest 1.4 months and not statistically significant, increasing OS from 19.9 to 21.3 months. Adverse events attributed to bevacizumab were 16% in the bevacizumab arm and 8% in the placebo arm. Of these, only venous thromboembolism and hypertension were more common in the bevacizumab-treated patients.

In exploratory analyses of NO16966, reasons for the low PFS were considered. A prespecified analysis of “on treatment PFS” was done, comparing progressive disease or death from any cause (the usual PFS definition) to that analysis adjusted so that patients in whom progressive disease or death occurred longer than 28 days from the last dose of study treatment were censored from the time of the last scan showing no progressive disease. This was intended to assess the true effect of the study drugs by censoring patients who went off treatment without progression. On treatment PFS was statistically better than for the “usual” PFS group (HR = 0.63; P = .0001), suggesting that continuation of bevacizumab may further improve PFS.

Another hypothesized reason for the negative primary outcome was related to the discontinuation of bevacizumab at the time of development of side effects. Although the study allowed continuation of both 5-FU and bevacizumab when treatment was discontinued due to oxaliplatin side effects, this rarely occurred.[31]

Further information about bevacizumab has been collected in two prospective observational cohorts of patients from Genentech-sponsored registries. In these populations, patients were treated with chemotherapy at the physician’s discretion (irinotecan-, oxaliplatin-, 5-FU–, or capecitabine-based) in combination with bevacizumab, in order to monitor the safety profile of bevacizumab. Each study registered over 1,900 patients starting in 2004, with multinational (First BEAT [Bevacizumab Expanded Access Trial]) and US-based (BriTE [Bevacizumab Regimens: Investigation of Treatment Effects and Safety]) populations.[32,33]

Colorectal cancer is the third most common cancer in the United States.[1] In 2008, an estimated 148,810 new cases of colorectal cancer will be diagnosed and nearly 50,000 people will die of the disease.

First-Line Therapeutic Strategies in Metastatic Colorectal Cancer

“If you don’t know where you are going, any road will take you there.”
-Lewis Carroll (1832–1898)

The complexity of treatment options that now exist for patients with newly diagnosed metastatic colorectal cancer has increased dramatically over the past decade. The use of these new agents has led to marked improvements in the lives of patients, with median overall survivals now exceeding 2 years. Yet as the treatment options have increased, the complexity of combining and sequencing agents has also grown. Drs. Davies and Goldberg clearly delineate the various treatment options available and their comments regarding K-

 mutational status and combined biologic therapy are of great clinical relevance. Given these complexities, it is now more important that ever to define the goals of therapy prior to selection of a first-line chemotherapy regimen.

Consistently, large series of liver metastasectomies have demonstrated 5-year survival rates of 30% to 50%,[1] and similar outcomes may be derived for patients with limited pulmonary involvement. Given such a potential benefit, identification of possible surgical candidates is the most critical component of initial chemotherapy planning. With this in mind, what is the proper endpoint with which to evaluate an appropriate first-line chemotherapy regimen?

Goal of Treatment: Resection of Limited Metastatic Disease


For patients with potentially resectable disease, other clinical endpoints besides progression-free survival may be more appropriate when selecting regimens. For example, aggressive combination chemotherapy is able to increase the rate of successful margin-negative (R0) metastasectomies. As an example, for patients with liver metastases only, FOLFOXIRI (leucovorin [folinic acid], fluorouracil [5-FU], oxaliplatin [Eloxatin], irinotecan) resulted in an R0 resection rate of 36% compared to 12% for FOLFIRI (leucovorin, 5-FU, irinotecan). Likewise, the addition of cetuximab (Erbitux) to FOLFIRI resulted in an increase in the R0 resection rate from 4.5% to 9.8% in unselected patients with liver-limited disease.[2]

In these potentially resectable patients, the added toxicities associated with these regimens may be acceptable. In addition, response rates appear to be appropriate surrogates for resection rates in a pooled analysis of trials.[3] It is in this potentially resectable subset of metastatic colorectal cancer patients where response rate is a useful endpoint in assessing a chemotherapy regimen.

One of the most useful new biomarkers for treatment selection has been the demonstration that patients with activating mutations in the K-

oncogene do not respond to anti–epidermal growth factor receptor (EGFR) therapy. By properly selecting patients, several studies have demonstrated an increased response rate to anti-EGFR therapy. In the K-

 wild type patients from the ­CRYSTAL trial, the addition of cetuximab to FOLFIRI increased response rates from 43% to 59%. Likewise, in the K-

wild type subset of the OPUS trial, response rates increased from 37% with FOLFOX (leucovorin, 5-FU, oxaliplatin [Eloxatin]) alone to 61% with the addition of cetuximab. This approach is being adopted in a planned National Surgical Adjuvant Breast and Bowel Project/American College of Surgeons Oncology Group (NSABP/ACOSOG) neoadjuvant trial, where K-

wild type patients with resectable liver metastases will be treated with perioperative or adjuvant FOLFOX and cetuximab.[4]

As noted by Davies and Goldberg, recent studies have added a word of caution to our attempts to improve outcomes by adding more agents to first-line regimens. In the Panitumumab Advanced Colorectal Cancer Evaluation (PACCE) and CApecitabine, IRinotecan, Oxaliplatin (CAIRO) II studies, the addition of anti-EGFR therapy to a bevacizumab (Avastin)/chemotherapy backbone did not improve outcomes for either the entire population or the K-

wildtype subgroup. These results have challenged our understanding of both the EGFR and vascular endothelial growth factor (VEGF) pathways and indicated that combined biologic therapy should be limited to the clinical trial setting.

For patients where palliative treatment without the possibility of surgical intervention is the goal, progression-free survival remains the best surrogate for overall survival. Equally important for this group of patients is the toxicity profile of each therapy.

Drs. Davies and Goldberg discuss the use of the OPTIMOX1 approach as one method of minimizing toxicity. Although the clinical trial dictated reintroduction of oxaliplatin at the time of disease progression, this was rarely done. Likewise, in clinical practice, reintroduction of oxaliplatin at some point in the disease course is often overlooked, even in patients with resolution of their neuropathy. This may represent a missed opportunity to treat refractory patients with an active chemothepeutic agent. Irinotecan-based therapy, such as FOLFIRI/bevacizumab, has demonstrated benefits in progression-free survival similar to those of oxaliplatin-based regimens, and given the lack of dose-limiting neurotoxicity, these strategies should also be considered viable first-line treatment options.

Given the large number of colorectal cancer patients who are older than 70 years, the applicability of aggressive combination chemotherapy to this elderly population deserves mention. A pooled analysis including 3,742 colorectal cancer patients treated with FOLFOX demonstrated equivalent benefit with regard to response rate, progression free-survival, and overall survival between those who were < 70 and those ≥ 70 years old.[5] Toxicities between the two groups were similar, with the exception of slightly higher neutropenia and thrombocytopenia in the elderly patients. A similar analysis for 2,691 patients treated with irinotecan and 5-FU demonstrated similar benefits and toxicities between the two age groups.[6] Therefore, even in a palliative setting, chronologic age alone should not dissuade the use of a first-line combination regimen.

As discussed in the review, the FOCUS (Fluorouracil, Oxaliplatin, and CPT-11 [irinotecan] Use and Sequencing) and CAIRO studies have suggested that sequential single-agent chemotherapy provides similar outcomes to a combination chemotherapy approach. However, the chemotherapy combinations used in these studies and the low utilization of second-line chemotherapy bring into question the applicability of these data. A single-agent approach should not be applied to all patients, but for whom this strategy is most appropriate is not yet clearly delineated.


We are fortunate to have a number of active agents with which to treat metastatic colorectal cancer. However, further research is needed to find better positive and negative predictive biomarkers. Clinical practitioners must be cognizant of the goals of front-line therapy and help place patients on the right road to obtaining those goals.

1. Choti MA, Sitzmann JV, Tiburi MF, et al: Trends in long-term survival following liver resection for hepatic colorectal metastases. Ann Surg 235:759-766, 2002.

2. Van Cutsem E, Nowacki M, Lang I, et al: Randomized phase III study of irinotecan and 5-FU/FA with or without cetuximab in the first-line treatment of patients with metastatic colorectal cancer (mCRC): The CRYSTAL trial (abstract 4000). J Clin Oncol 25(18S):164s, 2007.

3. Folprecht G, Cunningham D, Ross P, et al: Efficacy of 5-fluorouracil-based chemotherapy in elderly patients with metastatic colorectal cancer: A pooled analysis of clinical trials. Ann Oncol 15:1330-1338, 2004.

4. Petrelli NJ: Perioperative or adjuvant therapy for resectable colorectal hepatic metastases. J Clin Oncol 26:4862-4863, 2008.

5. Goldberg RM, Tabah-Fisch I, Bleiberg H, et al: Pooled analysis of safety and efficacy of oxaliplatin plus fluorouracil/leucovorin administered bimonthly in elderly patients with colorectal cancer. J Clin Oncol 24:4085-4091, 2006.

6. Folprecht G, Seymour MT, Saltz L, et al: Irinotecan/fluorouracil combination in first-line therapy of older and younger patients with metastatic colorectal cancer: Combined analysis of 2,691 patients in randomized controlled trials. J Clin Oncol 26:1443-1451, 2008.

Davies/Goldberg Article Reviewed.  The complexity of treatment options that now exist for patients with newly diagnosed metastatic colorectal cancer has increased dramatically over the past decade.

Picking the Right Road for Metastatic Colorectal Cancer Patients

ABSTRACT: Integrative Oncology is the synthesis of mainstream care and nonpharmacologic, evidence-based complementary therapies for the control of cancer-related physical and emotional symptoms. Herb-drug interactions and other cautions are also encompassed. This month, in the first of two installments about medicinal mushrooms, we review Coriolus versicolor, which is widely used in cancer therapies in Asia. In the November 30 issue of ONCOLOGY, this column will address the use of a second type of medicinal mushroom called maitake.

PolysaccharideK (PSK), a protein-bound polysaccharide isolated  from Coriolus versicolor, is widely used in Asia as an adjuvant agent  in the treatment of cancer. Research into the biologic mechanisms  underlying the anticancer effects of PSK is ongoing, but PSK appears  promising. More than 2 dozen human studies of PSK have been reviewed by  experts at the University of Texas M.D. Anderson Cancer Center. Almost  all of these studies were done in Japan and focused on cancers of the  esophagus, stomach, colon, or breast. Most of them found that people  with cancer were helped by PSK. People who received PSK along with other  treatments, such as surgery, chemotherapy, or radiation therapy,  generally had longer disease-free periods and increased survival rates  compared with patients who got only standard treatment. Side effects  from PSK in these studies were very mild. Smaller studies have suggested  PSK may not be as effective against liver cancer or leukemia. Adverse  effects are rare with use of medicinal mushrooms. However, because  over-the-counter Coriolus products are not standardized, and because  medicinal mushrooms may interfere with immunosuppressant medications,  patients should use caution and consult their physicians before taking  medicinal mushroom supplements.

 Coriolus versicolor, Trametes versicolor, Polyporus versicolor, Polystictus 

 PSK, PSP, VPS, turkey tail, yun zhi, kawaratake, Krestin

 Coriolus versicolor is a mushroom of the Basidiomycetes class. These are fungi with gills or pores, the group that includes the familiar edible mushrooms. Coriolus is used not as food, but as medicine ingested as capsules, as an extract, or as a tea. It was applied initially in traditional Chinese medicine as a tonic, but recent studies indicate immunostimulant and antitumor properties for which its proteoglycan constituents are responsible.

 Polysaccharide K (PSK), a proprietary product derived from Coriolus, was developed for cancer treatment in Japan. When used as an adjuvant agent, PSK enhanced immune response in vivo[1] and improved survival rates in patients with gastric[2] and colorectal cancers.[3]

Other Coriolus extracts, such as polysaccharide peptide (PSP) and versicolor polysaccharide (VPS), are available as dietary supplements. Preliminary studies show that these extracts reduce chemotherapy toxicity, increase effectiveness of chemotherapy or radiotherapy, and have antiproliferative and cytotoxic activities.[4] When used with chemotherapy, PSP may benefit patients with advanced non–small-cell lung cancer.[5]

Clinical investigations using Coriolus extract alone or in combination with other botanicals also suggest positive immunomodulatory effects.[6,7]


				1. Raghupati G, Yeung KS, Leung PC, et al: Evaluation of widely consumed botanicals as immunological adjuvants. Vaccine 26:4860-4865, 2008.
				2. Oba K, Teramukai S, Kobayashi M, et al: Efficacy of adjuvant immunochemotherapy with polysaccharide K for patients with curative resections of gastric cancer. Cancer Immunol Immunother 56:905-911, 2007.
				3. Sakamoto J, Morita S, Oba K, et al: Efficacy of adjuvant immunochemotherapy with polysaccharide K for patients with curatively resected colorectal cancer: A meta-analysis of centrally randomized controlled clinical trials. Cancer Immunol Immunother 55:404-411, 2006.
				4. Lau CB, Ho CY, Kim CF, et al: Cytotoxic activities of Coriolus versicolor (Yunzhi) extract on human leukemia and lymphoma cells by induction of apoptosis. Life Sci 75:797-808, 2004.
			  5. Tsang KW, Lam CL, Yan C, et al: Coriolus versicolor polysaccharide peptide slows progression of advanced non-small cell lung cancer. Respir Med 97:618-624, 2003.
			  6. Wong CK, Tse PS, Wong EL, et al: Immunomodulatory effects of yun zhi and danshen capsules in health subjects-a randomized, double-blind, placebo-controlled, crossover study. Int Immunopharmacol 4:201-211, 2004.
			  7. Wong CK, Bao YX, Wong EL, et al: Immunomodulatory activities of Yunzhi and Danshen in post-treatment breast cancer patients. Am J Chin Med 33:381-395, 2005. 
			  For additional information visit the Memorial Sloan-Kettering Cancer Center Integrative Medicine Service free website, “About Herbs” at 

SCIENTIFIC NAMES: Coriolus versicolor, Trametes versicolor, Polyporus versicolor, Polystictus versicolor

ONCOLOGY Vol 22 No 13 | Oncology

Management of a Patient With Borderline Resectable Pancreatic Cancer

First-Line Therapeutic Strategies in Metastatic Colorectal Cancer

Picking the Right Road for Metastatic Colorectal Cancer Patients

Coriolus versicolor