The management of colorectal cancer is a complex endeavor that requires treatment individualization founded on molecular characterization of the tumor, an in-depth understanding of the patient, and an appreciation of the interaction between the two. Patients are initially managed based on curability vs noncurability, and an accurate, dispassionate assessment of this fundamental differential is critical to providing optimal care. Failure to recognize a realistic opportunity for cure is unacceptable. That said, failure to recognize and/or failure to accept that a patient is not, in fact, realistically curable, can lead to use of inappropriate therapies and procedures that can have substantial and unnecessary toxicities and risks.
Resectability and Curability
For all practical purposes, the only patients with metastatic colorectal cancer who have a realistic potential for cure are those with a limited number of metastases in an appropriate location such that all disease can be resected. However, not all patients who can have all metastatic cancer surgically resected are realistically resectable for cure. The term “resectable” has thus become a source of confusion in recent years. In one context, it can mean that it is technically feasible to remove the cancer under discussion; that is, we can expect that an operation would remove all tissue containing macroscopic disease, with clear margins of resection, in a manner that would still be compatible with life. As such, a tumor that encases the celiac trunk would be unresectable, since its removal would require removal of a critical vascular structure. In contrast, a patient with two lung metastases, three liver metastases, two periportal lymph node metastases, and an ovarian metastasis would be, within this context of the word, technically resectable.
However, such a patient would not be realistically resectable for cure, and there lies the source of confusion. Historically, as the once-heretical concept of performing curative-intent surgery on patients with liver metastases of colorectal cancer was being established, the term “resectable” was used colloquially to mean “resectable with a realistic chance of cure.” Over time, the two meanings of “resectable” have become blurred. It is important to be clear in discussions, with each other and with our patients, which meaning is being assigned to the word “resectable” at the time of its use. Too often, the term “resectable” may mean different things to two individuals participating in the same conversation. Resection with realistic curative intent is part of standard practice; however, resection when the chance of actual cure is virtually nil has become increasingly common. Whether this is truly in our patients’ best interest or not is a matter of disagreement and debate among experts in the field. I believe that when we refer to a patient with metastatic cancer as being “resectable,” it should mean “resectable for cure.” If the risks and expense of resection are to be incurred in a setting in which cure (not some other soft-endpoint metric such as extended progression-free survival, but cure) is not a realistic goal, then both the doctors and the patient should have a clear understanding of this truth. It is noteworthy in this context that a published long-term experience from Memorial Sloan Kettering shows that patients with three or fewer liver metastases and no extrahepatic disease had reasonable cure rates; however, patients with greater numbers of hepatic lesions, while found to have an overall favorable long-term survival, had a virtually nonexistent cure rate, defined in terms of absence of cancer recurrence over the next 5 to 10 years.[1]
When patients have disease that is liver-dominant with isolated lung metastasis, the potential for cure still exists[2-4]; however, when the cancer has spread to intra-abdominal or periportal lymph nodes, for all practical purposes, these patients are incurable and should not be considered candidates for curative-intent resection.
Conversion therapy
The concept of “conversion to resectability” has been largely misunderstood. Patients are potentially convertible from incurable to curable if only a small number of oligometastatic lesions in a single organ are in close proximity to a critical vascular structure such as a hepatic vein.[5] In such patients, chemotherapy may decrease the size of the lesion and create a potential plane for resection. Patients with multiple sites of extrahepatic disease that appear to disappear on CT scans or go cold on a PET scan should not be regarded as having been converted to resectable status, as the chance of pathologic complete resection of all cancer is virtually nil.
For patients deemed potentially resectable for cure, a multidisciplinary management approach is required. Coordination between the liver surgeon, the colorectal surgeon, and the medical oncologist for determination of timing and sequencing of therapy is necessary to provide an optimal result.
Management of Unresectable Disease
First-line treatment
Patients with metastatic colorectal cancer that is deemed to be incurable require careful evaluation in terms of extent of disease, molecular evaluation of disease, and detailed discussion of their tolerance for individual potential toxicity. Tumor tissue should be obtained and all patients with metastatic disease should have determination of tumor RAS mutation status, inclusive of exon 2 and non–exon 2 KRAS mutations, as well as NRAS mutations.[6] In addition, the mutational status of BRAF should be determined, as response to anti–epidermal growth factor receptor (EGFR) therapy in the non–first-line setting for BRAF-mutated colorectal cancer is virtually nonexistent.[7]
One serious consideration that is too often overlooked is the possibility of a period of observation prior to initiation of chemotherapy. Patients with bulky and/or symptomatic disease require initiation of chemotherapy, which is given in an attempt to decrease tumor bulk. However, patients with small-volume, asymptomatic disease, especially those with multifocal lung-only disease, should be considered for a period of watchful waiting with assessment of the natural pace of the disease. Typically I will do the first interval scan at approximately 8–10 weeks. If progression has been rapid, or if disease-related symptoms have developed, then chemotherapy is initiated; however if, as is often enough the case, progression is minimal and the patient remains symptom-free, then watchful waiting can be continued with interval scans approximately every 12 weeks. Indications for initiation of therapy in this setting would be either rapid progression or pain/symptoms due to tumor bulk. Some patients will require initiation of treatment rapidly, while others may live many months or even several years with slowly progressing, asymptomatic disease; such patients are spared the toxicity of chemotherapy until the benefits of treatment justify the risks and toxicities.
Patients with metastatic disease, once deemed appropriate candidates for treatment, will for all practical purposes be treated with a chemotherapy backbone of either FOLFOX (folinic acid [leucovorin, LV], 5-fluorouracil [5-FU], oxali-platin) or FOLFIRI (LV, 5-FU, irinotecan). Single-agent 5-FU, alone or with bevacizumab (see below) is a consideration in patients who are not well enough to receive combination chemotherapy.[8,9] While some data do support use of single-agent fluoropyrimidine in first-line therapy for medically fit patients, in practice I rarely do this and rarely see it done. Regarding FOLFOX vs FOLFIRI, multiple studies have shown these two regimens to have equivalent efficacy.[10,11] Further, although for a period of time there had been a substantial cost difference between these two agents, this is no longer the case since generic versions of both oxaliplatin and irinotecan are now available. While the overall incidence of toxicity is quite similar, the toxicity profiles of the regimens are quite different; the major adverse events with oxaliplatin are cold-sensitivity neuropathy during treatment, as well as a more insidious and long-term progressive neuropathy characterized by numbness, tingling, and loss of proprioception and fine motor skills that is not, to a large extent, cold-sensitive. These are certainly problematic to anyone whose livelihood or interests require fine motor dexterity. The obvious exclusions for selection of an oxaliplatin-based first-line treatment would be surgeons or musicians; however, one would also need to consider excluding from oxaliplatin treatment people doing manual labor in cold environments, such as construction workers or fishermen.
The major toxicity of consideration that differentiates FOLFIRI from FOLFOX is actually alopecia, which is far more common with irinotecan-based therapy than with oxaliplatin. Although there is a perception that diarrhea is substantially increased with FOLFIRI, the existing data do not support this to any large degree, and the increased risk of diarrhea over that with the FOLFOX regimen is modest. One issue that I do consider in choosing between irinotecan vs oxaliplatin is the extent of liver disease. Irinotecan is a prodrug converted into the active metabolite, SN-38, and SN-38 is virtually 100% cleared via glucuronidation and biliary excretion. Oxaliplatin is not hepatically metabolized. For this reason, if a patient has an elevated bilirubin level, I favor oxaliplatin as a first-line agent. If, however, a patient has extensive liver disease but a normal bilirubin value, I may lean towards use of irinotecan first, with the thought that if first-line therapy failure leads to biliary obstruction, I would still be able to use second-line oxaliplatin, whereas the opportunity to use irinotecan might be lost.
Capecitabine, an oral prodrug, is converted into 5-FU in the systemic circulation. It is an acceptable substitute for parenteral 5-FU and LV, either in the FOLFOX regimen (ie, CapeOx)[12] or when using fluoropyrimidine therapy without either irinotecan or oxaliplatin. It should be noted that not all patients are good candidates for capecitabine. Oral chemotherapy puts considerable responsibility for adherence and compliance on the patient, and some patients are better equipped to handle this than others. Patients must have both the motivation to take their oral medication according to the prescribed, complicated schedule, and the ability to succeed in that intention. Of note, data on efficacy and toxicity of the combination of irinotecan plus capecitabine have been less compelling. At least in patients being treated in the United States, I do not favor the use of this combination.
Once a first-line chemotherapy regimen is selected for use in the setting of metastatic colorectal cancer, it is typically given with a 5 mg/kg dose of bevacizumab on an every-other-week schedule, or a comparable 7.5 mg/kg dose every 3 weeks when a capecitabine-based schedule is used. In my opinion there is no role for the 10 mg/kg or higher dose in colorectal cancer; such an elevated dose adds expense and potential toxicity without compelling evidence of superior activity. All 5 mg/kg doses of bevacizumab can be administered over 10 minutes, and the 7.5 mg/kg dose can be administered over 15 minutes.[13] Regardless of a patient’s RAS mutation status, I am not in favor of use of anti-EGFR agents in the front-line setting. Recent data from the Cancer and Leukemia Group B/ Southwest Oncology Group (CALGB/SWOG) 80405 trial, which compared front-line use of cetuximab vs bevacizumab in conjunction with either FOLFOX or FOLFIRI, did not show a meaningful difference in outcome[14]; in my opinion, however, the skin toxicity associated with the anti-EGFR agents makes them inappropriate for use in virtually all patients receiving first-line therapy. The rash caused by these agents, when at the grade 2 or 3 level, is socially debilitating, regardless of data suggesting that “quality of life” is maintained with these regimens. It is clear that only patients with substantial (grade 2 or 3) rashes benefit from anti-EGRF agents, and the concept that such a socially debilitating rash does not cause a meaningful negative impact on a person’s quality of life is simply unreasonable. It suggests that the instruments being used for “quality of life” measurements in clinical trials are inadequate to reflect the reality of the situation.
The risks of bevacizumab do need to be regarded, especially in patients with cardiovascular risk factors, as patients with a substantial cardiovascular history would be at increased risk of arterial thrombotic events. On this basis, one may choose not to use bevacizumab. Since, in my opinion, the additional benefit garnered by addition of bevacizumab to oxaliplatin-based regimens is modest at best (with a 1.4-month nonsignificant trend in survival improvement in the one large-scale randomized trial reported to date),[15] I typically do not use another antibody in its place but rather use FOLFOX alone for first-line treatment.
Second-line treatment
In my opinion, second-line treatment in patients who have undergone therapy with a FOLFOX-based regimen would be irinotecan alone, as opposed to FOLFIRI, since we have no data suggesting synergy between fluoropyrimidines and irinotecan, and a patient who has progressed through treatment with FOLFOX would be considered fluoropyrimidine-resistant. Continued use of bevacizumab in second-line therapy is supported by TML study data,[16] and for this reason, I would continue it in the absence of contraindications. Aflibercept, a fusion protein targeting all isoforms of vascular endothelial growth factor (VEGF) as well as platelet-derived growth factor (PDGF), is an alternative to bevacizumab with second-line FOLFIRI; however, based on nonrandomized comparisons it does not appear to be superior,[17] and based on nonrandomized cross-study comparisons, it does appear to have potentially higher toxicity. It also carries a higher price tag in many markets. I have not used it and have no immediate plans to do so. Patients who receive a FOLFIRI-based front-line regimen would be appropriate for FOLFOX therapy in the second line. Oxaliplatin is virtually inactive without the presence of a concurrent fluoropyrimidine, so either 5-FU or capecitabine must be given with it.[18]
Third-line therapy
Once a patient has developed disease progression through an oxaliplatin-based and an irinotecan-based regimen, therapeutic options become more limited. In patients whose tumors do not harbor mutations in RAS or BRAF, I favor use of one of the anti-EGFR agents, cetuximab or panitumumab, in conjunction with continuation of irinotecan at the scheduled doses previously tolerated. My preference is for use of panitumumab, given its lower incidence of hypersensitivity reactions and its more convenient administration schedule, as well as the fact that it is currently priced slightly lower than cetuximab; however, use of either agent would be considered appropriate. I do not favor use of cetuximab or panitumumab in second-line therapy for the same reasons that I do not use either agent in first-line therapy; the skin toxicity is a very undesirable adverse event that I would rather delay until I do not have other options. Use of cetuximab with irinotecan in second-line treatment did not show a survival benefit over irinotecan alone in that setting, presumably, as the authors of that trial speculated, because third-line use of cetuximab produced a similar survival outcome.[19] For tumor progression in patients with RAS-mutated or BRAF-mutated tumors, use of EGFR agents would be inappropriate and therapeutic options remain extremely limited.
Key Points in the Management of Metastatic Colorectal Cancer (mCRC)
- No single strategy is adequate for treating mCRC; care must be individualized based on molecular characteristics of the tumor as well as toxicity preferences and tolerances of the patient.
- A limited number of patients with oligometastatic disease are potentially curable. A realistic determination of curability vs incurability is necessary for proper treatment planning.
- FOLFOX and FOLFIRI are equally acceptable chemotherapy backbones for first-line therapy.
- Bevacizumab is typically added to first- and second-line regimens. I do not believe that data support use of single-agent bevacizumab. I do not use or recommend aflibercept.
- Although data suggest anti–epidermal growth factor receptor (EGFR) agents (cetuximab and panitumumab) are active with first-line regimens, I do not use or recommend these in first-line treatment, due to the impact of skin toxicity.
- Efficacy of anti-EGFR agents is limited to patients who develop grade 2 or 3 rash. Anti-EGFR agents should not be used in any line of therapy in patients with KRAS or NRAS mutations.
Regorafenib
Regorafenib, an oral multitargeted tyrosine kinase inhibitor, is currently approved by the US Food and Drug Administration for use in patients with metastatic colorectal cancer when other available treatments have failed. In a randomized, placebo-controlled study, patients treated with regorafenib had a median survival benefit of 42 days[20]; however, there was a dichotomy in the progression-free survival outcomes, with approximately 40% of patients showing a larger improvement relative to placebo and about 60% experiencing minimal or no benefit. Regorafenib has nontrivial toxicity in terms of fatigue and hand-foot syndrome and has therefore been of limited utility in patient management. I have not approached it with great enthusiasm and have utilized it only in settings in which other alternatives were not available and the patient wanted to proceed with therapy.
Supportive care
Ultimately in the course of managing incurable metastatic colorectal cancer, we reach a point at which there are no good therapeutic alternatives. In such a situation, administering best supportive care is the most appropriate course of action. This requires a frank and detailed discussion with the patient in terms of goals of care, a clear acknowledgment of the patient’s incurability, and a discussion of end-of-life preferences. Patients with incurable colorectal cancer are virtually never appropriate, in my opinion, for subjection to cardiac resuscitation or advanced life-support maneuvers; for this reason, a “do not resuscitate” (DNR) order must be discussed with the patient and family, and, with the patient’s agreement, implemented. A palliative medicine consultation may be useful under these conditions, if one has not already been requested. An emphasis on nutrition, comfort, and quality of life becomes paramount in these circumstances.
Investigational Therapies
Clearly at any point of patient management, consideration of experimental therapy is appropriate. Currently there is a great deal of interest in immune checkpoint inhibition as well as combinations of targeted therapies to overcome feedback inhibition in patients with identified driver mutations. Participation in appropriate investigational studies is to be encouraged, with appropriate respect for patient preferences and the informed consent process.
Summary
Metastatic colorectal cancer is a multifaceted disease that requires extensive individualization of management based on a given patient’s clinical and molecular characteristics. No “one size fits all” approach is adequate. A respect for limitations of therapeutic efficacy as well as toxicities of treatment is necessary in order to provide the most appropriate management for patients with this disease. Ongoing research efforts are focused on improving outcome and modulating toxicities in patients with metastatic colorectal cancer.
Financial Disclosure:Dr. Saltz receives research funding from Amgen, Bayer, Genentech, ImClone, Lilly, and Roche.
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