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Gastrointestinal Cancer |
a Division of Hematology/Oncology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA; b Division of Hematology/Medical Oncology, Vanderbilt University, Nashville, Tennessee, USA; c Digestive Oncology Unit, University Hospital Gasthuisberg, Leuven, Belgium; d Division of Hematology/Oncology, Northwestern University, Chicago, Illinois, USA; e Oregon Health & Science University Cancer Institute, Portland, Oregon, USA; f Division of Hematology/Oncology, University of Alabama School of Medicine, Birmingham, Alabama, USA; g Division of Medical Oncology, Mayo Clinic College of Medicine, Rochester, Minnesota, USA; h Division of Medical Oncology, University of Southern California, Los Angeles, California, USA; i Divisions of Medical Science and Population Science, Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA; j Division of Hematology/Oncology, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania, USA; k Division of Hematology/Oncology, University of Texas Southwestern Medical Center, Dallas, Texas, USA; l Department of Adult Health Nursing, Rush University Medical Center, Chicago, Illinois, USA; m University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA; n Department of Nursing at University of California San Francisco Medical Center, San Francisco, California, USA
Key Words. Colorectal cancer • Chemotherapy • Biologic therapy
Correspondence: Mace L. Rothenberg, M.D., 777 Preston Building, Hematology/Oncology, Vanderbilt University Medical Center, Nashville, Tennessee 37232-6307, USA. Telephone: 615-936-1796; Fax: 615-343-7602; e-mail: mace.rothenberg{at}vanderbilt.edu
Received May 19, 2006; accepted for publication September 5, 2006.
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LEARNING OBJECTIVES
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Learning Objectives
Abstract
Introduction
From Single-Agent Therapy to...
Treatment Approaches
Future Questions
Conclusions
Disclosure of Potential...
References
After completing this course, the reader should be able to:
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ABSTRACT |
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INTRODUCTION |
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TopLearning ObjectivesAbstractIntroductionFrom Single-Agent Therapy to...Treatment ApproachesFuture QuestionsConclusionsDisclosure of Potential...References |
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Since the mid-1980s, both the incidence and mortality rates of colorectal cancer have decreased, due at least in part to increased rates of screening—particularly colonoscopy—and polyp removal [1]. The 5-year survival rate for colorectal cancer is 90% if detected early when still localized, but only 39% of colorectal cancers are found at this stage [1]. Nearly one fourth of patients have metastatic disease at diagnosis [2], with a 5-year survival of less than 10%. A significant number of individuals diagnosed with locoregional disease go on to develop distant metastases, and approximately 75,000 patients undergo treatment for metastatic colorectal cancer (mCRC) annually in the U.S. [2].
After decades during which there was only one active agent in the armamentarium for the treatment of mCRC, five such agents have been approved in the past 10 years (irinotecan, capecitabine, oxaliplatin, bevacizumab, and cetuximab), and the number of available regimens has grown substantially. Patients can also now benefit from three cytotoxic drugs and two biologic agents, also termed "targeted therapies." Clinical trials investigating the use of these agents have demonstrated an increase in median survival in patients with mCRC—from 6 to 8 months with supportive care alone to more than 20 months with the use of combination chemotherapy. Today, a diagnosis of metastatic colorectal cancer no longer automatically means a rapid downhill course, as many patients live for years with what might be classified as a chronic disease.
At the present time, patients with mCRC are typically administered a first-line chemotherapy regimen that is continued until documented disease progression. At progression, treatment is switched to a regimen with demonstrated activity in the refractory disease setting. This pattern of treatment until progression and then switching to noncross-resistant therapies continues until the patient has received all five active classes of agents. At that point, patients may be referred for phase I clinical trials or provided with symptom-directed care.
We propose a paradigm shift in the treatment of mCRC. Instead of viewing each chemotherapeutic regimen as a distinct line of therapy to be initiated when disease progresses, a treatment continuum approach should be considered. This continuum incorporates several concepts that distinguish it from present practice:
When multiple active agents are considered and integrated (as appropriate) into a comprehensive treatment plan, a strategic disease management continuum is possible. Most patients with advanced colorectal cancer can receive multiple treatment regimens, changing therapies to optimize response or as a consequence of toxicity, patient preference, or disease progression. Therapy should be individualized such that each regimen complements the next. Thus, treatment is sequenced through phases, rather than lines, of therapy and takes into account the long-term treatment plan for each patient. Ideally, this approach leads to decision-making in which an individual patient’s characteristics are considered in light of the differing efficacy and toxicity profiles of available agents and regimens. The central goal is to optimize survival, time without toxicity from chemotherapy, and quality of life.
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FROM SINGLE-AGENT THERAPY TO MULTIPLE OPTIONS: THE ROAD TO A TREATMENT CONTINUUM |
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TopLearning ObjectivesAbstractIntroductionFrom Single-Agent Therapy to...Treatment ApproachesFuture QuestionsConclusionsDisclosure of Potential...References |
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The first real advance in first-line chemotherapy for patients with mCRC came in the late 1990s with the addition of active cytotoxic agents to a 5-FU/LV base. The addition of irinotecan to bolus 5-FU/LV (IFL) increased median survival in patients with mCRC from 12 to 14.8 months [3]. This rate was increased further by combining irinotecan or oxaliplatin with infusion-based 5-FU/LV, and doublets such as irinotecan plus infusional 5-FU/LV (FOLFIRI) or oxaliplatin plus infusional 5-FU/LV (FOLFOX) prolonged median survival to more than 20 months (Table 1
) [3–8]. Because 5-FU/LV administration by continuous i.v. infusion is clearly less toxic and slightly more efficacious than bolus administration, infusional regimens evolved to become the preferred choice for patients receiving i.v. fluoro-pyrimidines [9], with FOLFIRI replacing IFL in the United States.
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) [11]. An interesting alternative approach was demonstrated recently in a randomized phase III trial in which the triplet combination of irinotecan, oxaliplatin, and 5-FU/LV was found to be superior to FOLFIRI as first-line treatment of mCRC, with median survival times of 22.6 months versus 16.7 months, respectively [12].
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TREATMENT APPROACHES |
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Current Treatment Platforms
A number of regimens are available for initial and subsequent treatment phases of mCRC; Figure 2 shows several of the options used in clinical practice [5, 14–17]. For the initial treatment of patients with unresectable metastatic disease, FOLFIRI and FOLFOX have been shown to produce similar response rates, times to tumor progression, and survival outcomes [7, 18].
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FOLFOX has also been studied in combination with bevacizumab as second-line therapy in 829 patients with mCRC who progressed despite previous treatment with 5-FU/LV and irinotecan. Median survival times in patients randomized to receive FOLFOX plus bevacizumab versus FOLFOX alone were 12.5 months and 10.7 months, respectively (p < .002) [19]. In first-line treatment, the randomized trial Three Regimens of Eloxatin Evaluation (TREE)-2 compared three oxaliplatin-based regimens, with or without the addition of bevacizumab. Recently reported results showed an overall response rate of 52% for patients treated with FOLFOX plus bevacizumab versus 41% for patients treated with FOLFOX alone. Median time to progression for patients treated with FOLFOX plus bevacizumab was 9.9 months. TREE-2 was also important in that it demonstrated that capecitabine could be combined successfully with oxaliplatin and bevacizumab in American patients, resulting in a 48% response rate and a 10.3-month median time-to-tumor progression [20, 21].
Mature phase III trials of FOLFIRI plus bevacizumab and FOLFOX plus bevacizumab as first-line treatment for mCRC are not available. Preliminary results have been reported in a small nonrandomized sample treated with combination first-line FOLFIRI plus bevacizumab. An overall response rate of 70% was observed 9–35 weeks after the initial treatment cycle in 21 patients [22]. Given the equivalent first-line efficacy of FOLFIRI and FOLFOX and preliminary data establishing the safety and activity of these regimens in combination with bevacizumab, it is reasonable to initiate sequential therapy with either FOLFIRI plus bevacizumab or FOLFOX plus bevacizumab for patients with unresectable mCRC. The choice of initial therapy should be tailored to the individual needs of the patient and will depend on the differing toxicity profiles of each regimen (see following discussion) as well as the potential impact of initial therapy on later phases of the treatment continuum.
A patient with mCRC who has a potential for cure (e.g., surgical resection of metastases limited in number, size, and/or sites of involvement) should be treated aggressively, generally with two cytotoxic agents and a biologic agent, usually bevacizumab. The patient with limited metastatic disease should be evaluated by a surgeon and, if deemed to be unresectable initially, reevaluated at intervals during therapy to determine whether that patient has had a sufficient response to therapy to now be considered for definitive surgical resection of all metastases. For such patients, the acceptable balance of efficacy and toxicity is different than in those with nonresectable disease, in that the possibility for curative resection may outweigh potential toxicities and obviate the need for long-term chemotherapy.
Although the mechanism remains poorly understood, systemic chemotherapy, particularly oxaliplatin, frequently causes morphological lesions to the hepatic microvasculature, leading to sinusoidal dilatation and erythrocyte extravasation [23]. Nonalcoholic steatohepatitis has also been observed and associated with preoperative administration of irinotecan or oxaliplatin, especially in patients who are obese, which may affect the ability to perform large liver resections [24]. The presence of steatohepatitis increases 90-day mortality after hepatic surgery [25]. Therefore, in patients with hepatic colorectal metastases, chemotherapeutic regimen and timing of surgery should be carefully considered, and many hepatic surgeons plan for a 4 – 6-week interval between the administration of chemotherapy/biologic drugs and liver surgery.
Toxicity Issues
The severity, type, and duration of treatment-related toxicity may affect the patient’s willingness to continue treatment and influence decisions regarding time on therapy and the need for breaks from chemotherapy [5, 7, 10]. Given that patients are now likely to receive multiple drugs in sequential phases of therapy, toxicities need to be managed effectively to avoid compromising activities of daily living, quality of life, and the ability to receive further systemic therapy. These considerations raise the question: How do characteristics of potential toxicity affect treatment selection and continuation?
Each of the available agents has clinically significant toxicities. In determining which agents to use in which combination and at which point in the treatment continuum, it is important that these toxicity profiles be considered in light of individual patient characteristics and preferences, as well as potential effects on the patient’s clinical status and ability to receive subsequent therapy [17].
For instance, diarrhea, neutropenia, and mucositis are the most common side effects of bolus administration of 5-FU/LV regimens. There are significant reductions in hematologic and gastrointestinal toxicity with infusional regimens, which have an increased incidence of hand-foot syndrome. Until 2001, bolus 5-FU regimens were favored in the U.S. because of their ease of administration, and associated toxicities were considered to be manageable. However, with the incorporation of irinotecan and oxaliplatin into 5-FU-based regimens, additional types and increasingly severe toxicities were encountered. These factors led to a shift to the less toxic infusional 5-FU regimen as the cornerstone for multiagent chemotherapy for patients with advanced colorectal cancer [16, 26].
The toxicity profiles associated with FOLFIRI and FOLFOX have been well documented in several large clinical trials. Approximately 10%–15% of patients treated with either regimen experience severe (grade 3 or 4) diarrhea (Table 2) [5, 7, 14, 18], although the severity and clinical impact of irinotecan-induced diarrhea may be greater than that caused by oxaliplatin. In contrast, when irinotecan is administered in combination with bolus 5-FU/LV, grade 3 or 4 diarrhea occurs in approximately 25% of patients [3, 5, 8]. The incidence of neutropenia and thrombocytopenia are usually reported to be somewhat higher with FOLFOX than with FOLFIRI, although Colucci et al. [18] observed a similar incidence of neutropenia. In the trial reported by Tournigand et al. [7], febrile neutropenia occurred in 7% of patients treated with FOLFIRI first-line versus 0% with FOLFOX. Either regimen is unlikely to cause grades 3 and 4 nausea and vomiting. However, Tournigand et al. reported grade 3 or 4 nausea and vomiting in a greater number of patients treated first-line with FOLFIRI than with FOLFOX. Alopecia (grade 1 or 2) is more frequent in patients receiving FOLFIRI than in those receiving FOLFOX (
60% vs. 28%, respectively). Rates of fatigue and asthenia in the two regimens are comparable.
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To tailor the choice of regimen to the needs and preferences of the patient, the oncologist should discuss the toxicity profiles of FOLFIRI and FOLFOX with the patient and clarify his/her understanding prior to starting therapy. If oxaliplatin-associated peripheral neuropathy is a potentially significant problem for a patient, such as one who requires finger or hand dexterity or who works outdoors in a cold climate, FOLFIRI plus bevacizumab may be a preferred choice for front-line treatment. Furthermore, patients who receive FOLFOX as adjuvant treatment might experience cumulative neurotoxicity earlier if FOLFOX is reinitiated at the time of disease recurrence, although definitive data addressing this issue are not available. If alopecia or diarrhea is a particularly important issue, patients may prefer FOLFOX plus bevacizumab. In patients with Gilbert’s disease or elevated bilirubin, FOLFOX plus bevacizumab is also a preferred choice, as dose reductions are not necessary to avoid the potential for severe toxicity. Ongoing studies will provide additional data on the effects of different regimens on quality of life and patient willingness to continue treatment and proceed to later phases of therapy.
Time on Treatment
Toxicities may affect time on treatment, which raises important clinical questions. Should patients be treated until disease progression, to a predefined maximum dose limit, or to maximal response?
Maughan et al. [33] studied 354 patients with advanced colorectal cancer who had responded to, or who had stable disease after, 12 weeks of initial treatment with 5-FU-based chemotherapy or raltitrexed. Patients were randomized either to continue chemotherapy until progression or unacceptable toxicity or to discontinue chemotherapy with a planned resumption of treatment at the time of disease progression. At randomization, 41% of patients had achieved an objective response, and 59% were stable. The primary endpoint was overall survival. The difference in survival between the two arms was not significant (10.8 months median survival for the intermittent group vs. 11.3 months for the continuous group; p = .23). Time to disease progression in patients treated with continuous chemotherapy was approximately 1 month longer, but the difference also was not significant. Only 37% of patients on the intermittent arm restarted chemotherapy at the time of progression as planned. Intermittent treatment was associated with modestly reduced toxicity [33].
The Intergroup Trial N9741 found that patients receiving IFL were more likely to be treated until disease progression than those receiving FOLFOX4 [5]. Treatment was discontinued in 67% of patients on IFL due to disease progression or death, whereas in 62% of FOLFOX-treated patients, treatment was discontinued for reasons other than progressive disease. The most common reasons were neurotoxicity (23%) or myelosuppression (23%). Median time to response in FOLFOX-treated patients was 2.2 months, whereas grade 2 sensory peripheral neurotoxicity developed at a median of 5 months and grade 3 neurotoxicity at 6 months.
The OPTIMOX1 trial was initiated in an attempt to address the problem of dose-limiting peripheral neurotoxicity from FOLFOX. Patients were randomly assigned to receive FOLFOX4 administered every 2 weeks until disease progression or high-dose oxaliplatin with 5-FU/LV (FOLFOX7) for six cycles followed by 5-FU/LV alone for 12 cycles and resumption of FOLFOX7. The FOLFOX7 reintroduction strategy resulted in a median duration of disease control (defined as the initial progression-free survival plus progression-free survival following reintroduction) of 10.6 months, which was similar to the 9.0-month median duration of disease control for those receiving the conventional regimen. Median survival times were also comparable. Overall, oxaliplatin was reintroduced in 40% of scheduled patients. Grade 3 neurotoxicity was documented in 13% of patients treated with FOLFOX7 plus reintroduction, versus 18% of those who received FOLFOX4. Overall rates of any grade of neurotoxicity were approximately equal (91% vs. 89%) [34]. These results suggest that a planned interruption of oxaliplatin does not compromise the overall efficacy of treatment in this group of patients.
In OPTIMOX2 [35], patients were randomized to receive six cycles of modified FOLFOX7 (mFOLFOX7) followed by 5-FU/LV until disease progression and reintroduction of mFOLFOX7 (OPTIMOX1 arm; the OPTIMOX1 strategy) or six cycles of mFOLFOX7 followed by complete cessation of chemotherapy and reintroduction of mFOLFOX7 before tumor progression had reached baseline measures (OPTIMOX2 arm). Response rates were similar between the two groups. Median duration of disease control, defined as progression-free survival from the first FOLFOX7 regimen plus progression-free survival from FOLFOX reintroduction (if no progression at first evaluation), was 41 weeks in the OPTIMOX1 arm and 36 weeks in the OPTIMOX2 arm; this difference was not statistically significant. Median duration of the chemotherapy-free interval in the OPTIMOX2 arm was 4.6 months. These results extend those of OPTIMOX1 and suggest that the introduction of a chemotherapy-free period or treatment break in patients with stable or responding mCRC does not adversely affect the duration of disease control.
In a study of intermittent FOLFIRI (2 months on, 2 months off) versus continuous FOLFIRI administered until disease progression in patients with advanced colorectal cancer, median overall survival was found to be similar between the two groups—16.9 months for the intermittent arm versus 17.6 months for the continuous therapy arm [36].
To further evaluate the approach of treatment interruption, the ongoing Combined Oxaliplatin Neurotoxicity Prevention Trial (CONcePT) is randomizing patients to a regimen of modified FOLFOX7 plus bevacizumab on an intermittent schedule with reintroduction versus continuous therapy until treatment failure. Each arm is further randomized to receive either calcium and magnesium versus placebo to explore a potential for neuroprotection [37]. Whether these "stop-and-go" approaches involve a risk of developing clinical resistance is unknown.
In contrast to OPTIMOX1, OPTIMOX2, and CONcePT, which discontinue FOLFOX and "fall back" on 5-FU/LV, other investigations are asking whether programmed sequencing with optimally active regimens—FOLFOX followed by FOLFIRI instead of 5-FU/LV—might be a better approach. In the ongoing Organization to Assess Strategies for Ischaemic Syndromes (OASIS) trial, patients receive a limited number of cycles of FOLFOX plus bevacizumab, which is followed by randomization to either FOLFIRI or 5-FU/LV alone.
The Role of Biologic Agents
The exact mechanism of action of bevacizumab, a vascular endothelial growth factor inhibitor, in mCRC remains unknown. However, bevacizumab seems to deliver concurrently administered cytotoxic chemotherapy to tumor tissue more effectively [17], possibly by lowering intratumor interstitial pressure [38].
In addition to the data cited earlier about the contribution of bevacizumab to improvement in survival with first-line chemotherapy, there are data to suggest that using biologic agents later in the treatment continuum can delay time to disease progression and may prolong survival (Table 3) [19, 39, 40]. For instance, in one study, the addition of bevacizumab to FOLFOX4 in second-line treatment significantly prolonged overall survival compared with FOLFOX4 alone in patients who had not received bevacizumab first-line [19]. It should be noted that there are currently no data supporting the efficacy of continuing bevacizumab second-line in patients who have progressed following treatment with a bevacizumab-containing regimen first-line. A phase III trial to address this question is in development. Future investigations will also focus on evaluating maintenance therapy with targeted agents alone.
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Trials have also shown that the addition of cetuximab to irinotecan in second and later lines of therapy in patients refractory to prior irinotecan treatment significantly prolongs progression-free survival compared with cetuximab alone [39, 40]. In the initial Study EMR 62202-007 ("BOND") study [39], irinotecan plus cetuximab resulted in a response rate of 22.9% versus 10.8% for cetuximab alone, as well as a longer time to disease progression—4.1 months versus 1.5 months (p < .001). Of further interest, all patients enrolled in the BOND trial had previously been treated with irinotecan and had manifested progressive disease while or shortly after receiving it. The BOND-2 trial evaluated the combination of cetuximab plus bevacizumab alone versus cetuximab plus bevacizumab combined with irinotecan. Patients had not received bevacizumab previously. Response rates were 20% and 37%, respectively, with a median progression-free survival of 7.9 months for patients treated with the two biologic agents plus chemotherapy [40].
Cetuximab has also been evaluated as a component of first-line therapy in patients with advanced colorectal cancer. A randomized phase III trial of cetuximab plus FOLFIRI versus FOLFIRI alone as initial treatment for mCRC (CRYSTAL) is ongoing. Preliminary results of a phase II study of cetuximab in combination with FOLFOX first-line (ACROBAT) showed a response rate of 70% in 20 evaluable patients [42]. Early results from a phase I/II study of cetuximab plus FOLFIRI first-line showed an objective response in 14 of 21 patients (67%) [43]. In addition, a current phase III Gastrointestinal Intergroup study, led by the Cancer and Leukemia Group B and Southwest Oncology Group C80405, is investigating the combination of cetuximab plus bevacizumab, versus each agent alone, as first-line treatment in combination with either FOLFOX or FOLFIRI chemotherapy.
The Role of Capecitabine
When used as a single agent for initial treatment of mCRC, capecitabine provides superior response rates and identical survival compared with those for 5-FU/LV administered according to the bolus Mayo Clinic regimen [44, 45]. In addition, capecitabine is associated with lower rates of diarrhea, stomatitis, nausea, and neutropenia but increased rates of hand-foot syndrome [44, 45]. However, the efficacy and safety of capecitabine as a replacement for 5-FU/LV in standard infusional combination regimens such as FOLFOX or FOLFIRI have not yet been demonstrated in randomized phase III studies. These trials are ongoing or nearing completion and results are pending.
Individualizing Therapy
Prognostic and predictive factors are being evaluated and are not yet routinely used in practice. In the future, increasing use of these factors, as well as genomic microarray data, are expected to allow greater individualization of therapy. Examples of several currently identified predictive and prognostic markers and their clinical application are listed in Table 4 [46]. For example, patients who have a 7/7 polymorphism in the TATA sequence of the promoter region of UGT1A1 (UGT1A1*28), which codes for UDP-glucurono-syltransferase, undergo slower hepatic metabolism of SN-38, the active metabolite of irinotecan, to SN-38G, an inactive metabolite. Patients with the UGT1A1*28 polymorphism who are treated with single-agent irinotecan have been reported to be at increased risk for developing severe neutropenia or neutropenic sepsis (but not severe diarrhea) compared with patients with the wild-type (6/6) UGT1A1 gene. The UGT1A1*28 genotype is found in approximately 10% of North Americans [47–49]. According to current recommendations, a reduced initial dose of irinotecan should be considered for patients identified as homozygous UGT1A1*28 (7/7) [50]. Studies to determine the effect of this particular genotype on response to treatment as well as on toxicity in patients treated with combination regimens, such as FOLFIRI, are ongoing.
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T polymorphism at codon 118 of the ERCC1 gene, which seems to play a role in response to oxaliplatin. The ERCC1 gene is involved in the repair of DNA-platinum adducts; preliminary reports suggest that higher levels of ERCC1 gene expression may be associated with resistance to oxaliplatin, whereas lower ERCC1 levels may be associated with higher likelihood of tumor response [51]. Although molecular profiling is expected to play an increasing role in helping to identify patients who will best respond to specific treatment regimens, predictive markers for response and toxicity will most likely turn out to be polygenic, and more data will be required before specific recommendations can be made. Trials designed to individualize drug dosages based on pharmacogenomic profiles have been initiated [28].
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FUTURE QUESTIONS |
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CONCLUSIONS |
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TopLearning ObjectivesAbstractIntroductionFrom Single-Agent Therapy to...Treatment ApproachesFuture QuestionsConclusionsDisclosure of Potential...References |
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Because there are no prospective data to determine with precision which patients might benefit from which regimens and sequences at present, therapy should be individualized based on known clinical factors. Prospective clinical trials as well as retrospective analyses of existing clinical databases will provide more definitive guidance.
There is also a need to investigate and identify molecular predictors of efficacy and toxicity. Ongoing studies of biomarkers, tumor genetics, and pharmacogenomics will aid in individualizing treatment. In the future, genotype-directed clinical trials may help determine the utility of various markers, and utilization of a combination of markers from multiple genes may be the best strategy for tailoring therapy [53]. Ideally, every patient will be managed along an individually planned treatment continuum that offers optimal benefit with a minimal probability of severe and dose-limiting adverse effects.
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DISCLOSURE OF POTENTIAL CONFLICTS OF INTEREST |
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The opinions expressed in this article are solely those of the authors.
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ACKNOWLEDGMENT |
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