Issues Relating to Cytotoxic and Biologic Agents in Liver-Limited Disease

August 16, 2009

About the ActivityThis activity is based on a brief article developed as part of the E-Update Series and posted on the Web. It was developed from an identified educational need for information about practical management issues in the practice of medical, surgical, and radiation oncology. This activity has been developed and approved under the direction of CME LLC.

Table of Contents

CONTINUING MEDICAL EDUCATION

Activity Release Date: August 15, 2009 Activity Expiration Date: August 15, 2010

About the Activity
This activity is based on a brief article developed as part of the E-Update Series and posted on the Web. It was developed from an identified educational need for information about practical management issues in the practice of medical, surgical, and radiation oncology. This activity has been developed and approved under the direction of CME LLC.

Activity Learning Objectives
After reading this article, participants should be able to:

  • Appraise and assimilate the surgical issues in liver-limited disease;

  • Demonstrate an understanding of the correct usage of all chemotherapy and biologic agents for liver-limited disease;

  • Incorporate into practice knowledge of toxicity issues in liver-limited disease;

  • Develop and use a multidisciplinary team relationship (oncologist, surgeon, and radiologist) to maximize patient care

 

Target Audience
This activity targets physicians in the fields of oncology and hematology.

Accreditation
CME LLC is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

Continuing Education Credit
AMA PRA Category 1 Credit
CME LLC designates this educational activity for a maximum of 2 AMA PRA Category 1 Credits™ . Physicians should only claim credit commensurate with the extent of their participation in the activity.

Compliance Statement

This activity is an independent educational activity under the direction of CME LLC. The activity was planned and implemented in accordance with the Essential Areas and policies of the ACCME, the Ethical Opinions/Guidelines of the AMA, the FDA, the OIG, and the PhRMA Code on Interactions with Healthcare Professionals, thus assuring the highest degree of independence, fair balance, scientific rigor, and objectivity.

However, CME LLC, the Grantor, and CMPMedica shall in no way be liable for the currency of information or for any errors, omissions, or inaccuracies in the activity. Discussions concerning drugs, dosages, and procedures may reflect the clinical experience of the author(s) or may be derived from the professional literature or other sources and may suggest uses that are investigational in nature and not approved labeling or indications. Activity participants are encouraged to refer to primary references or full prescribing information resources. The opinions and recommendations presented herein are those of the author(s) and do not necessarily reflect the views of the provider or producer.

Financial Disclosures
Dr. Chu serves as a consultant for Bristol-Myers Squibb Company, Eli Lilly and Company, Hoffmann-La Roche Inc., and ImClone Systems. Dr. Alberts receives research support from Bristol-Myers Squibb Company.

Copyright
Copyright owned by CME LLC. Copyright 2009, all rights reserved.

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Issues Relating to Cytotoxic and Biologic Agents in Liver-Limited Disease
Steven R. Alberts, MD, MPH

Professor of Medicine and Pharmacology
Mayo Clinic College of Medicine
Consultant, Division of Oncology
Medical Director, Cancer Center Clinical Research Office
Rochester, Minnesota

A Word From the Editor

Dear Clinical Colleague:

We are pleased to introduce the first of two E-Updates, in a series entitled Liver-Limited Metastatic Colorectal Cancer.

When you click on the link below you will find Dr. Steven Alberts's introductory installment to the series: "Issues Relating to Cytotoxic and Biologic Agents in Liver-Limited Disase." Dr. Alberts is a leading expert in this area of clinical research, as he has been actively involved in developing combination regimens that incorporate cytotoxic chemotherapy plus biologic agents. In this E-Update, he reviews the clinical data on the role of neoadjuvant and/or conversion therapy in patients who present with metastatic disease that is confined solely to the liver. In addition, he gives a nice overview of the potential limitations and complications associated with this approach.

The next update in this series will focus on the surgical management of patients with liver-limited disease, and we have the good fortune of having as our author Dr. Michael Choti, one of the leading surgical oncologists in this field. In particular, he will highlight the absolute requirement for close interaction and communication between the medical oncologist and the surgical oncologist in determining the optimal time for liver-directed surgery and in optimizing clinical outcome.

Patients with liver-limited disease are potentially curable with 3 to 5 year survival rates in the 30% to 50% range, and without question, the success of treating this particular group of patients stems from the highly interactive, multidisciplinary team-based approach that involves medical oncologists, surgical oncologists, pathologists, and radiologists. I believe that these E-Updates will be most helpful to the practicing clinicians, as they approach colorectal cancer patients with liver-limited disease.

Sincerely,

 

Edward Chu, MD
Professor of Medicine and Pharmacology
Chief, Section of Medical Oncology
Deputy Director, Yale Cancer Center
Yale University School of Medicine

Introduction

It is estimated that approximately 147,000 new cases of colorectal cancer (CRC) are diagnosed in the United States each year.[1] The majority of these patients will have potentially resectable disease at the time of diagnosis. For patients with surgically resected stage I to III disease, the overall rate of recurrence ranges from 9% for stage I to 56% for stage III at 5 years.[2]

When CRC recurs, the liver is one of the most frequent sites of recurrence. In patients developing distant recurrence after a potentially curative surgery for stage I to III CRC (metachronous metastases), metastatic disease is confined to the liver in 44% of patients.[2] In patients presenting with stage IV disease, 77% will have metastases confined to the liver (synchronous metastases) at the time of diagnosis.[3] The large proportion of patients presenting with liver-only involvement has led to a long-standing focus on therapeutic approaches to the treatment of liver metastases from CRC.

Given that a large proportion of patients will have liver-limited disease, current clinical approaches focus on methods of eradicating the metastases. At initial presentation, approximately 20% to 25% of patients will have disease that is potentially resectable, while an additional 10% to 15% will have disease that may become resectable with the initial use of chemotherapy.[4,5] It is estimated that eventually 30% to 40% of patients undergoing surgery will become long-term survivors based on 5-year overall survival rates.[6]

Timing and Sequence of Chemotherapy

Achieving the best outcome requires the coordinated efforts of a multidisciplinary team that includes the medical oncologist, the surgeon, and the radiologist. The timing and sequence of any chemotherapy must be coordinated with surgery to provide the optimal chance of eradicating the metastases while avoiding excessive toxicity that may hinder the ability to perform surgery.

Chemotherapy, with or without a biologic agent, is frequently administered to patients with liver-only metastases. In this setting, chemotherapy may be given:

  • as adjuvant therapy, following a complete resection of all metastases (R0 surgical resection) and with the intent of preventing recurrence;

  • as neoadjuvant therapy for patients with potentially resectable disease to help reduce the risk of recurrence; or

  • as conversion therapy for patients with initially unresectable disease.

In many cases, a combination of these approaches is used in the form of perioperative therapy.

Preoperative Chemotherapy

An increasing number of patients are receiving preoperative chemotherapy for liver metastases. When using this approach, it is important to recognize the potential benefits as well as limitations associated with this type of treatment.

Conversion Therapy

When liver-only metastases from CRC are determined to have progressed beyond the point of an R0 resection, the use of chemotherapy (conversion therapy) may allow the metastases to be downsized to a point where they may become resectable. Initial evidence for this approach came from retrospective, single center patient series.[7-9]

The largest of these series was originally reported and subsequently updated by Bismuth and Adam from the Hspital Paul Brousse in Paris.[7,10] (See Table 1.) In this series, 701 patients with initially unresectable liver metastases, as determined by expert surgical review, were given oxaliplatin (Eloxatin), chronomodulated fluorouracil (5-FU), and leucovorin on a 3-week treatment cycle. The use of preoperative chemotherapy permitted surgery to be performed in 14% of the patients. With 5 years of follow-up after surgery, 34 patients were still alive, with 19 patients (22%) having no evidence of residual or recurrent disease.

Beyond the information obtained from retrospective studies, limited information is currently available from prospective clinical trials. (See Table 1.) All of the trials reported to-date have been phase II trials, and they have generally included both high risk, but potentially resectable patients, as well as initially unresectable patients. In a phase II trial conducted by the North Central Cancer Treatment Group (NCCTG), 42 eligible patients received FOLFOX4 (5-FU, leucovorin, oxaliplatin) until their liver metastases became potentially resectable.[11] A clinical response rate of 52% was observed, and ultimately 17 of the 42 patients underwent attempted resection. Fourteen of the patients (33%) had complete resection of their metastases. The median overall survival for patients undergoing resection was 35 months.

In a similar trial using FOLFIRI (5-FU, leucovorin, irinotecan [CPT-11, Camptosar]) with 40 patients at a single institution, Pozzo et al reported a 47.5% conversion rate that allowed surgical resection to be performed in 13 patients.[12,13] In this trial, the median disease-free interval following surgery was 52.5 months, while the median time to progression in patients not able to undergo surgery was 5.2 months.

The potential role of conversion therapy has also been suggested from several retrospective analyses of trials that have attempted to enhance clinical efficacy and overall response rates with novel chemotherapy regimens. Folprecht et al identified a strong correlation between response rates of treatment regimens and the resection rate, suggesting that a focus on regimens with the highest response rate was likely to be of greatest benefit.[14]

It has been further noted that the degree of response, as determined by evaluation of the resected metastasis, correlates with survival.[15] One approach has been to maximize the potential benefit of FOLFOX and FOLFIRI by combining 5-FU, leucovorin, oxaliplatin, and irinotecan into one integrated regimen that has been termed FOLFIXIRI This regimen was assessed in a randomized phase III trial for patients with metastatic colorectal cancer (mCRC) using FOLFIRI as the comparator arm.[16] In this trial, a planned secondary analysis of the rate of R0 resection was performed. Of the 244 patients enrolled in the trial, 33% had liver-only metastases. The rate of R0 resection following chemotherapy was 36% in the FOLFOXIRI arm compared to 12% in the FOLFIRI arm (P = .017). While patients in this trial were not randomized based on the presence of liver-only metastases, the increased ability for patients to undergo R0 surgical resection suggests potential benefit to this regimen. In general, the combination of FOLFOXIRI was well tolerated, with neutropenia, diarrhea, and neurotoxicity being the main toxicities. Only 9% of patients treated with FOLFOXIRI required treatment interruption secondary to toxicity. The 60-day mortality rate, all due to rapidly progressive disease, was 1.6%.

In a phase II trial of FOLFOXIRI for patients with initially unresectable liver-only metastases, a 70.6% radiologic response rate was seen in 34 of the evaluable patients.[17] (See Table 1.) This response permitted 28 patients to undergo an attempt at surgery, although an R0 resection was possible in only 9 patients. With a median follow-up of 31 months, 8 of the 9 patients relapsed. The median relapse-free survival was 31 months, with 7 of the 8 relapses occurring in the liver.

Neoadjuvant Therapy

The use of neoadjuvant therapy for potentially resectable liver metastases has been assessed as part of perioperative therapy in a randomized phase III trial of perioperative FOLFOX4 and surgery vs surgery alone. Patients randomized to chemotherapy received six cycles of chemotherapy before surgery and six cycles after surgery.[18] A partial or complete response was seen in 43% of patients receiving chemotherapy. A nonsignificant increase in progression-free survival also was seen in patients receiving chemotherapy. Of the 171 patients given preoperative chemotherapy, only 115 were able to be treated with postoperative chemotherapy and only 80 of these were able to complete all six cycles of postoperative chemotherapy.

Potential Limitations and Toxicities of Chemotherapy

The primary intent of neoadjuvant therapy or conversion therapy is to optimize resectability. However, the use of neoadjuvant chemotherapy has several potential disadvantages. Perhaps one of the most serious concerns is that this approach may lead to a radiologic complete response. With a radiologic complete response, it may no longer be possible for the surgeon to determine the exact location of the disease within the liver, which would then either prevent surgery from being successfully performed and/or require that more extensive surgery is performed in order to confidently achieve a complete resection. In addition, retrospective series have shown that a complete clinical response does not directly correlate with eradication of the tumor.[19] Therefore, a mixed partial and complete response may disrupt surgical planning for the complete resection or ablation of the originally identified lesions and result in a high rate of recurrence.

In addition to the recognition of the potential limitations caused by a complete response, there is now a growing recognition of chemotherapy-associated liver injury when neoadjuvant or conversion therapy is used. Both nonalcoholic fatty liver disease and sinusoidal injury have been reported.

Nonalcoholic liver disease associated with chemotherapy ranges from the development of steatosis to chemotherapy-associated steatohepatitis (CASH).[20] Steatosis of any cause has been shown to cause a higher rate of complications following hepatic resection.[21] However, the development of steatohepatitis resulting from chemotherapy is of greater concern. Histologically, CASH appears as severe steatosis, lobular inflammation, and ballooning.[22, 23] While the initial reports of CASH showed an association with the use of either irinotecan or oxaliplatin,[22] there is now growing evidence that CASH is more closely associated with the use of irinotecan chemotherapy.[23] Moreover, this liver toxicity appears to occur more frequently in patients with higher body mass index.[24]

The development of CASH has been associated with a higher postoperative mortality rate related primarily to postoperative liver failure. In a series of 248 patients who had received chemotherapy prior to surgery compared to 158 who had not received any chemotherapy, 20.2% of patients receiving irinotecan had evidence of steatohepatitis in nontumor bearing liver, compared to 6.3% of patients who had received oxaliplatin, and 4.4% of those who had not received any chemotherapy.[23] The 90-day mortality rate in those with evidence of steatohepatitis was 14.7%, compared to 1.6% for those who did not have evidence of steatohepatitis.

Chemotherapy may also lead to sinusoidal injury within the liver, and this form of liver toxicity is most commonly associated with the use of oxaliplatin.[23,25] Histologically, this toxicity presents as sinusoidal dilation with erythrocyte congestion, and in more severe cases, it may evolve to perisinusoidal fibrosis and sinusoidal obstruction, similar to what is observed with veno-occlusive disease.

The development of sinusoidal dilation does not appear to have an increased risk of postoperative mortality. In a cohort of 303 patients who had undergone surgery for liver metastases, 92 were randomly selected for a detailed pathologic analysis of the resected liver.[26] Among these 92 patients, 23 had received 5-FU and leucovorin alone, 52 had received FOLFOX, and 17 had received no chemotherapy prior to surgery. Vascular lesions in the nontumor bearing liver were commonly seen in patients who had received chemotherapy compared to those who had not (52% vs 18%). This included higher rates of sinusoidal dilatation and congestion, peliosis, hemorrhagic centrilobular necrosis, and regenerative nodular hyperplasia. However, no veno-occlusive disease was seen. The perioperative morbidity and mortality rates were similar in both groups.

Biologic Agents

Currently, biologic agents are primarily used in patients with mCRC to enhance the clinical efficacy of cytotoxic chemotherapy regimens. The two main approaches have focused on developing inhibitors that target the epidermal growth factor receptor (EGFR) and the vascular endothelial growth factor (VEGF).

Epidermal Growth Factor Receptor Inhibitors

Cetuximab (Erbitux) and panitumumab (Vectibix) are the two anti-EGFR inhibiting antibodies that currently are approved for use in mCRC based on their activity in patients with disease refractory to standard chemotherapy.[27,28] A randomized phase III trial demonstrated an increased response rate, from 10.8% to 22.9%, by adding cetuximab to irinotecan compared to cetuximab alone.[29] Subsequent evidence of clinical benefit has been seen in first-line and second-line trials with cetuximab combined with cytotoxic chemotherapy,[30-32] and there are now several clinical studies investigating the use of panitumumab in combination with various chemotherapy regimens.

While the trials using EGFR inhibitors have shown significant evidence of benefit, as measured in terms of progression-free survival and response rate, the benefit is restricted to patients with tumors expressing wild-type K-ras.[33] Overall, approximately 60% of patients with mCRC will have wild-type K-ras, while 40% of patients will have tumors with mutant K-ras. K-ras mutations occur early in the development of CRC, and in nearly all cases involve codons 12 or 13.[34] Of note, a high concordance in the K-ras status has been observed between the primary tumor and metastases.[34] In a trial assessing the added benefit of cetuximab to FOLFOX, the response rate for patients with tumors containing wild-type K-ras was 61% with the addition of cetuximab, compared to 37% for FOLFOX alone.[30] A decline in benefit was observed with the addition of cetuximab in those with a mutated K-ras (49% vs 33%).

The potential benefit of cetuximab in patients with liver metastases has been shown in several phase II trials. In the CELIM-trial, a total of 111 patients with initially unresectable liver-only metastases from CRC were randomized to cetuximab added to either FOLFOX or FOLFIRI.[35] The interim results of this study were presented at this year's American Society of Clinical Oncology (ASCO) Gastrointestinal Cancers Symposium in San Francisco. The overall response rate was 63%, but when patients were stratified based on K-ras status, the overall response rate was 70% in patients with wild type K-ras vs 43% for those with mutant K-ras. The rate of R0 resection for patients treated with FOLFOX/FOLFIRI plus cetuximab was 35%, and the median time to surgical resection was 5 months.

In a separate phase II trial, patients with initially unresectable liver metastases with or without extrahepatic metastases were treated with the combination of FOLFIRI and cetuximab.[36] The overall radiologic response rate was 39%, with 30% of patients able to undergo resection of their liver metastases. Unfortunately, K-ras status was not assessed in this trial.

Additional information on the potential benefit of cetuximab plus chemotherapy comes from secondary analyses of trials for patients with mCRC. In a phase II trial of FOLFOX and cetuximab, 37 of the 43 patients enrolled had liver involvement, including 17 with the liver as the only site of metastatic disease.[37] Among the 34 patients (79%) having an objective response, 10 underwent surgical resection of their metastases, including 8 patients with liver metastases.

However, the results of a similar trial of cetuximab in combination with FOLFOX resulted in only a 17% R0 resection rate.[38] In a retrospective series of 151 patients with liver metastases refractory to conventional chemotherapy receiving cetuximab, 27 patients (18%) had a clinical response allowing resection.[39] The most common toxicities associated with the use of EGFR inhibitors include skin changes (papulopustular rash, growth of facial hair and eyelashes, periungual inflammation), hypomagnesemia, and in the case of cetuximab, infusion reactions.[40]

Antiangiogenic Agents

Bevacizumab (Avastin) is a humanized antibody against vascular endothelial growth factor (VEGF), and it has become an integral component of treatment regimens for mCRC.[41-43] In a pivotal phase III trial, the addition of bevacizumab to IFL (irinotecan, 5-FU, leucovorin) increased response rate (44.8 vs 34.8%, P = .004), progression-free survival (10.6 vs 6.2 months, P < .001), and overall survival (20.3 vs 15.6 months, P < .001) over IFL alone.[42] In a separate trial of bevacizumab added to oxaliplatin-based regimens (FOLFOX4 or capecitabine [Xeloda] and oxaliplatin), the median progression-free survival was significantly improved over chemotherapy alone (9.4 vs 8.0 months, P = .0023).[43] (See Table 2.)

Evaluation of the potential benefit of bevacizumab in patients with liver metastases from CRC has been obtained mainly through secondary analyses of trials for patients with metastatic CRC. In a randomized phase III clinical trial evaluating the addition of bevacizumab to either FOLFOX4 or to capecitabine and oxaliplatin vs these chemotherapy regimens alone, a higher attempt at a curative metastasectomy occurred in those receiving bevacizumab (8.4%), compared to those receiving chemotherapy alone (6.1%).[43] (See Table 2.)

To date, only limited data exists on the use of bevacizumab in patients with liver-only metastases from CRC. In a phase II trial of 53 patients recieving FOLFOX and bevacizumab for mCRC, a clinical response rate of 67.9% was achieved.[44] Six of 34 patients with liver involvement in this trial had a response allowing a surgical resection and with a median follow-up of 10 months, all of the 6 were still alive. Two of those six patients, however, developed recurrence, one at 11 months and the other at 13 months. (See Table 2.)

A more recent trial, specifically focused on patients with potentially resectable liver metastases, investigated neoadjuvant therapy with bevacizumab, capecitabine, and oxaliplatin.[45] Fifty-six patients received six cycles of therapy prior to proceeding to surgery. Based on preoperative assessment, an objective response rate of 73% was observed. Of those 56 patients, 52 were able to undergo R0 surgical resection, with complete pathologic response occurring in 5 patients (8.9%). Only three patients had evidence of progressive disease. (See Table 2.)

Given the concerns over the potential risks for bleeding and/or wound healing complications, bevacizumab was not given with the last cycle of chemotherapy prior to surgery. No increased intraoperative bleeding or wound-healing complications were observed, and normal liver regeneration occurred in all but one patient.

Reddy and colleagues conducted a retrospective review of 39 of 96 patients who had received bevacizumab concurrently with chemotherapy prior to surgical resection of their liver metastases.[46] No increase in overall complications, bleeding, wound-healing complications, or liver regeneration was observed in patients receiving bevacizumab compared to those receiving chemotherapy alone. However, a nonsignificant increase in complications for patients receiving bevacizumab within 8 weeks of surgery was noted, emphasizing the need to stop bevacizumab at least 6 to 8 weeks prior to surgery. Similar results were described by the MD Anderson group in a separate retrospective analysis of 59 patients.[47]

Conclusions

The use of chemotherapy and more recently the addition of biologic therapy as part of preoperative therapy for patients with liver metastases from CRC have shown promising results. Following initial evidence of benefit from retrospective or planned subset analysis in trials for metastatic CRC, prospective trials also have shown promising results. However, much of the current information on the use of bevacizumab or cetuximab comes from relatively small phase II trials. The added benefit of incorporating a biologic agent with cytotoxic chemotherapy will need to be determined through prospective randomized trials. In a similar manner, the use of a biologic agent with chemotherapy as part of neoadjuvant therapy, has only been reported as part of a single-arm phase II trial.

At this point in time, biologic agents are believed to enhance response to chemotherapy and therefore permit a greater number of patients with initially unresectable disease to undergo surgery. Based on the mCRC clinical trials as a whole, the addition of biologic agents also provides meaningful increases in survival. A similar benefit would therefore be expected in patients with liver-only metastases from CRC.

While promising results have been observed, it is also important to consider the potential limitations and complications associated with neoadjuvant and/or conversion therapy. Significant liver injury may occur with the use of preoperative therapy. Careful monitoring of liver function is needed to ensure that surgery, if possible, may be safely performed. The goal of preoperative therapy continues to be to enhance the likelihood of a successful resection and not to achieve a complete radiologic response that may limit the ability to perform surgery.

The promising results of the trials reported thus far provide significant hope that further clinical benefit may be seen with the new generation of biologic agents currently under development. It is likely that some of these agents will have a meaningful role in further enhancing the treatment of patients with liver-only metastases. Given the common occurrence of liver-only metastases in patients with CRC, there continues to be a need to support clinical trials to refine the treatment strategies for this particular group of patients.

 

 

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Disclosures:

Dr. Chu serves as a consultant for Bristol-Myers Squibb Company, Eli Lilly and Company, Hoffmann-La Roche Inc., and ImClone Systems. Dr. Alberts receives research support from Bristol-Myers Squibb Company.