Integrating Targeted Agents into Therapeutic Regimens for Patients with Resectable Colorectal Cancer John L. Marshall Abstract New surgical techniques and new systemic treatments have come together to increase the number of patients with metastatic colorectal cancer who have been cured. There is great hope that new targeted agents will further increase our success, both through improved therapeutic outcomes and better selection of patients for this more invasive and aggressive approach. A summary of this current clinical data is presented herein to establish our current standards and to guide us toward our future goals. We are increasingly managing patients with a multidisciplinary approach, a critical element in our success. Biologic therapies will continue to play an important role in the management of these patients. Clinical Colorectal Cancer, Vol. 7, Suppl. 2, S63-S66, 2008; DOI: 10.3816/CCC.2008.n.010 Keywords: Bevacizumab, Cetuximab, FOLFOX4, K-ras, Panitumumab
Introduction Only a few short years ago, the concept of resecting patients’ metastatic disease was fundamentally against our understanding of tumor biology. The assumption was that if patients had metastatic lesions from colon cancer or any other cancer, in fact, then the lesions we were detecting on imaging were merely the first of what would be many. Therefore, the role of resecting visible detectable metastasis was deemed inappropriate because the risks of surgery were high and the gain was minimal. It was not until the past decade or so that the concept of resecting metastatic lesions with curative intent emerged as a standard of care. The earliest data were, in fact, with colorectal cancer (CRC). Patients who were undergoing resections for their primary tumor who, at the time of intraoperative examination, were found to have isolated metastasis on their liver were the first subjects in this “experiment.”1 These patients underwent resections of their liver, which contained the metastasis. Although the majority of these patients had recurrent disease and eventually died of their metastatic colon cancer, there was clearly a group of patients who enjoyed long-term survival and, in fact, experienced long-term disease-free intervals, which equated with cure. With these observations, the world of surgical intervention for resection of hepatic metastasis was born.
The Age of Surgical Resection for Metastatic Disease Of course, hepatic resections have expanded dramatically over the past decade. With both the advent of better surgical techniques in Division of Hematology/Oncology, Georgetown University Hospital, Lombardi Comprehensive Cancer Center, Washington, DC Submitted: Jul 10, 2008; Revised: Aug 6, 2008; Accepted: Aug 11, 2008 Address for correspondence: John L. Marshall, MD, Division of Hematology/ Oncology, Georgetown University Hospital, Lombardi Comprehensive Cancer Center, 3800 Reservoir Road NW, Washington DC, 20007 Fax: 202-444-1229; e-mail: [email protected]
specialized centers, which dramatically improved outcomes by reducing the surgical morbidity and mortality, and an improvement in systemic chemotherapy options for patients with metastatic colon cancer, more patients are enjoying prolonged disease-free survival and even cures, whereas before, only palliative options were available to them. In addition, although not covered in this article, there has been an increasing use of surgery for extrahepatic disease.2 The effect of chemotherapy and newer targeted agents on liver resections is not well established. Very few dedicated clinical trials have been performed in this patient population,3 and, in fact, the majority of the data we do have today come from clinical trials testing systemic chemotherapeutic options for patients. Out of these trials has come a consistent subgroup of patients who have undergone hepatic resections with curative intent, and it is from this data set that we base most of our current recommendations for therapy.4 Resectable metastatic colon cancer falls into 2 primary categories. First, there are the patients who are immediately resectable for cure. This definition of “immediately resectable” is typically made by hepatic surgeons and is based on the distribution of the metastases, the number of metastases, and their location.5,6 This group of patients remains one of the more controversial groups because it is still unclear whether chemotherapy should be given to these patients and, if so, whether it should be given before and/or after the surgical intervention. The second major group is more straightforward in its therapeutic pathways and decisions. This group is composed of patients who have regional metastasis but whose metastases are too large for immediate surgical resection. Clearly, these patients are exposed to chemotherapy combinations first, and then depending on their clinical benefit, decisions are made about surgical resections. There are data showing that patients who have immediately resectable disease experience a better outcome than patients who require downstaging, but the group that requires downstaging can still benefit from surgical resection, as has been shown by Adam and colleagues (Table 1).7
Dr Marshall has received research support from Amgen, Inc.; Bristol-Myers Squibb Company; Genentech, Inc.; Pﬁzer Inc.; Roche Pharmaceuticals; and sanoﬁ-aventis U.S.; and has served as a paid consultant or been on the Advisory Board of Amgen, Inc.; Bristol-Myers Squibb Company; Genentech; Inc.; Pﬁzer Inc.; Roche Pharmaceuticals; and sanoﬁ-aventis U.S.
Clinical Colorectal Cancer December 2008 •
Integrating Targeted Agents into Therapeutic Regimens for Resectable CRC Table 1 Survival in Patients with Colorectal Cancer and Resectable or Initially Nonresectable Liver Metastases7
Table 2 Results of Hepatic Resection for Metastatic Colorectal Cancer12
Resectable (n = 335)
Initially Nonresectable (n = 138)
Gayowski et al
Scheele et al (1995)14
Study (Year) Hughes et al (1986)12
Fong et al
Jenkins et al (1997)16
The fundamental principle of curing metastatic disease involves ensuring that there are no residual cancer cells left within a patient. Certainly, if we were better able to measure metastatic disease, then we could select patients more accurately for surgical resection. As it stands today, we base these decisions primarily on numbers of metastases, size of metastases, disease-free interval between the presentation of the primary tumor or diagnosis of the primary tumor and diagnosis of the metastatic lesions, and other nonobjective measures in decision-making. As a matter of fact, we operate on the majority of these patients without any sense of certainty as to whether the lesions being resected are the only lesions or merely the first to show themselves. Therefore, because of this relatively low probability of success, we bring to the clinical setting a bias that chemotherapy would be of further benefit. Clearly, in the traditional adjuvant setting of stage II and stage III colon cancer, there has been a demonstration of benefit of chemotherapy.8,9
The Role of Chemotherapy In the adjuvant and neoadjuvant settings, the chemotherapy is given to kill microscopic metastatic disease so that it never recurs. The same principle should hold true in patients with resected metastatic colon cancer from which the visible disease is removed, and any alleged microscopic metastatic disease can be treated using systemic chemotherapy.
Positive but Only 8 Percent Unfortunately, the major study that was performed to address the issue of the role of chemotherapy by itself in patients with surgically resectable metastases was underwhelming in the magnitude of its benefit. Nordlinger et al and Benoist et al published their randomized clinical trial comparing surgery alone in patients with liver metastasis versus chemotherapy for 6 cycles using FOLFOX4 followed by surgery, followed by 6 more cycles of FOLFOX4 (5-fluorouracil [5-FU]/leucovorin [LV]/oxaliplatin) chemotherapy.10,11 This trial design was, in essence, a pure adjuvant-type trial wherein half the group was treated with surgery only, and the other half was treated with chemotherapy plus surgery. The data showed that patients had an average 30% regression in the visibly detectable tumors. There was an expected complete and partial response rate of 45%, with a majority of patients having stable disease. Clinically, the chemotherapy worked. However, when one looked at the progression-free survival (PFS) at 3 years, there was only an 8% difference between the patients who received chemotherapy and surgery and patients who had surgery alone. These data, although positive in that chemotherapy did have a benefit, was underwhelming because the magnitude of the benefit was truly quite small. Therefore, our challenge as we move forward in this world of resectable metastatic colon cancer is
• Clinical Colorectal Cancer December 2008
Jamison et al
Fong et al (1999)18 Scheele et al
Choti et al (2002)20 Fernandez et al
Pawlik et al (2005)22
Operative Median Survival (%) Mortality Survival 1 5 (Months) Year Year (%)
not only to improve our patient selection through newer techniques, but also—and possibly more importantly—improve our therapies for use in patients in this setting.
Improvements in Surgery and Chemotherapy Yield Improved Results Surgical techniques have improved over the past decade or more in the setting of liver metastasis. Early trials have demonstrated roughly a 20%-30% 5-year survival rate with liver resections.1 Interestingly, although the patient population has become less ideal, (higher numbers of metastases present), the 5-year survival rate for patients undergoing hepatic resections has improved to > 50% in more recent clinical trials (Table 2).12-23 This suggests several things. First, it suggests that surgical techniques have improved and that, in centers performing these operations on a regular basis, the morbidity is falling, the operative mortality is falling, and their overall survival (OS) rates are improving. Second, we must assume that the improvement in 5-year survival rate is at least partially explained by the improvements in chemotherapy, namely, the biologic agents that have been incorporated during this same window of medical history.24 Although chemotherapy by itself (FOLFOX) has produced a relatively small benefit, these data suggest that, as we incorporate more drugs into this patient base, we are realizing a much higher 5-year OS rate. Therefore, we should turn our attention to newer agents that are playing a role in the management of patients with resectable CRC to explore their effect on this outcome.
Combination Chemotherapy Before focusing exclusively on the biologic agents, it is important to review a regimen known as FOLFOXIRI (5-FU/LV/oxaliplatin/irinotecan). Several clinical trials have been performed using this combination regimen containing only chemotherapy. Interestingly, with very high response rates ranging from nearly 60% to 70%, trials using this regimen have demonstrated high surgical resection rates and long 5-year median survivals.25,26 This combination regimen is a good example of how
John L. Marshall incorporating better, more active chemotherapy could translate into better long-term survival in patients who have undergone surgical resection of their metastatic disease.
Biologic Agents Enter the Field Vascular Endothelial Growth Factor Vascular endothelial growth factor (VEGF) has emerged as a valid target for anticancer therapies, and the monoclonal antibody bevacizumab was the first anti-VEGF drug to demonstrate benefit. Bevacizumab was the first biologic agent to play a significant role in patients with stage 4 disease who have not been treated with chemotherapy. As such, it was also the first agent to be studied with regard to its role and safety when patients are undergoing hepatic resections. In fact, the National Comprehensive Cancer Network (NCCN) guidelines suggest that, in patients with resectable liver metastasis, chemotherapy including bevacizumab should be considered as a standard approach. In several clinical trials, bevacizumab has demonstrated an improvement in response rate when combined with traditional chemotherapy.27 There has also been a dramatic improvement in PFS in these trials. However, balancing our enthusiasm for the agent has been the concern for the safety of this drug, namely bleeding and wound-healing complications. Several large clinical trials have examined this issue, and data have been published demonstrating that patients who underwent surgery for liver metastasis who had been treated with bevacizumab did not have a significant increase in wound-healing complications or bleeding complications, particularly if ≥ 60 days pass from the time of the last dose of bevacizumab to the time of the surgery.28 Although these are relatively small data sets, they have been very useful in guiding clinicians in making management decisions when bevacizumab is being used in patients as a chemotherapeutic option in the neoadjuvant or adjuvant setting for hepatic metastasis. Postoperatively, the data would suggest that bevacizumab can be incorporated safely 4-6 weeks after hepatic surgery. The documented safety and improved clinical benefit of incorporating bevacizumab into combination regimens for patients undergoing hepatic surgery justifies the NCCN guidelines, which support bevacizumab use in this setting. Patient selection for this agent is becoming increasingly interesting because we are beginning to understand more about the biologic agents in general.
Epidermal Growth Factor Receptor Epidermal growth factor receptor (EGFR) blockers, in contrast, have not been traditionally used as first-line treatment in patients with metastatic colon cancer. These drugs were developed in a somewhat different way and so have entered the clinical pipeline primarily as a last-line agent. More recent trials have addressed their role as first-line agents, and newer information on K-ras and patient selection is likely to have a large influence on their use. The EGFR monoclonal antibodies (MoAbs) cetuximab and panitumumab are being increasingly tested in patients with first-line metastatic CRC (mCRC). Several clinical trials have demonstrated that combining these agents with traditional combination chemotherapy results in an improvement in response rate. This improvement in response rate has also translated into an increased percentage of patients who have undergone liver resection for metastatic disease. Specifically, the CRYSTAL (Cetuximab Combined With Irinotecan in First-Line Therapy for Metastatic Colorectal Cancer) clinical trial compared FOLFIRI (5-FU/
LV/irinotecan) with FOLFIRI plus cetuximab in patients in first-line mCRC.29 A subset analysis of patients who underwent surgery with curative intent was performed and demonstrated that the addition of cetuximab resulted in a nearly 5% higher rate of liver metastasis resection. This consistent increase in response rate that was observed with the incorporation of EGFR antibodies did translate into improvements in hepatic resection rate. However, we all recognize at this point that the world of EGFR MoAb therapy has changed dramatically. Both the OPUS and the CRYSTAL trials were testing EGFR MoAbs in the setting of an un-enriched patient population. Our understanding of which patients will benefit from EGFR MoAbs has changed with our improved understanding of the role of mutations in the K-ras gene. When these clinical trials were reanalyzed more recently for the K-ras status and approximately 40% of the patients were excluded from the analysis because of their failure to benefit from cetuximab because of K-ras mutations, it was noted that the response rates in the remaining 60% increased dramatically.30,31 Said another way, if one enriches the patient population for just those patients who are more likely to respond to the EGFR therapy, then the magnitude of the benefit increases significantly. Because of this, there is a suggestion that we will see a shift in patients in first-line metastatic disease to different therapeutic choices based on their molecular phenotype. If one can demonstrate consistently that in patients with K-ras wild-type tumors a large improvement in response rate will be added, we might see an increasing use of the EGFR antibody in patients with potentially resectable or definitely resectable hepatic metastasis. Clearly, the negative side effects of the EGFR antibodies, most prominently being skin toxicity, might be better balanced by improved efficacy through patient population enrichment around the K-ras gene. Another positive aspect of EGFR MoAbs in this setting is the decreased concern over the wound-healing issues observed with the VEGF–targeted therapies. It is important to note that, at present, K-ras has been established only as a predictive marker of resistance to EGFR antibodies. It has not yet been shown to be a prognostic marker of outcomes for colon cancer in general. Also of note, skin rash appears to be independent of the K-ras wild type as a marker for clinical benefit. The established guidelines for management of patients with resectable or borderline resectable hepatic metastasis currently favor the incorporation of chemotherapy and bevacizumab. The role chemotherapy plays in this setting is established by the Nordlinger et al study but with a clear mandate to improve outcomes through improving response rates and increasing the number of patients who are able to undergo the curative surgical options. Biologic therapies are playing a major role in this process. The emergence of K-ras as a dividing line for patients with metastatic colon cancer has immediately affected the current thinking and treatment choices for patients with mCRC. EGFR antibodies will only be used in patients with K-ras wild-type tumors, and as more data emerge in the front-line setting, the incorporation of EGFR antibodies into chemotherapy regimens is likely to increase in this patient subset. Because patients with mutated K-ras genes will never be exposed to the EGFR MoAbs, the importance of bevacizumab in those patients will increase as the lone MoAb to help in that patient subpopulation. Unfortunately, although we were expecting dual-antibody therapy to further improve our clinical outcomes, this has not proven to be the case. Two large, randomized trials testing combinations of VEGF and EGFR antibodies with chemotherapy both had a negative outcome, sug-
Clinical Colorectal Cancer December 2008 •
Integrating Targeted Agents into Therapeutic Regimens for Resectable CRC gesting, in fact, a negative interaction particularly in the K-ras–mutated tumors.32,33 These trials tell us that we have much to learn about targeted agents and how best to use them in which patients.
The Future Our challenge for the future is to improve our outcomes in several different directions. First, we need to identify patients who are good candidates for hepatic resection. Currently, we are doing this based solely on anatomic imaging. It is hoped that in the near future we will gain an improved understanding of which patients do have isolated metastatic disease through some other techniques, including molecular characterization. This will further improve our ability to identify and subsequently cure the patients with isolated metastatic disease and not put other patients through surgery that will not help in the long run. Secondly, we have improved our understanding of which patients should receive which therapeutic agents. The K-ras gene expression has an immediate effect on therapeutic decision-making. If wild-type K-ras is found to be a prognostic marker, patients in this population could have a better prognosis and more therapeutic options, whereas the patients with mutated K-ras would have a poor prognosis and fewer therapeutic options. Both patient subtypes will be the subject of a great deal of research, but no longer will those patients be bundled into 1 clinical trial. They will now be separated into 2 parallel tracks. It is our hope that this will further improve outcomes for both patient populations. Thirdly, targeted agents in CRC remain important for our patients. Not only do our data further validate the role of VEGF and EGFR play, but new emerging targets are also recognized, with the hope that they will generate even better outcomes for our patients with mCRC and other cancers. Finally, we must note that the treatment of patients with resectable hepatic metastasis involves multimodality, multidisciplinary care. Communication between the disciplines is important, and coordination between chemotherapy and surgery and other modalities is typically the job of the medical oncology team. Therefore, medical oncologists must maintain a very high awareness of the issues for these patients. We do not want to miss the opportunity of curative therapy, but on the other hand, we do not want to put patients through surgical approaches that, in the long run, might not help. Therefore, this world of multimodality therapy, including targeted agents for patients with mCRC, is a very important issue with which all oncologists need to be familiar.
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