Colorectal Cancer

The Lynch syndrome (hereditary nonpolyposis colorectal cancer[HNPCC]), is the most common form of hereditary colorectal cancer(CRC), accounting for 2% to 7% of all CRC cases. The next most commonhereditary CRC syndrome is familial adenomatous polyposis (FAP),which accounts for less than 1% of all CRC. Lynch syndrome is ofcrucial clinical importance due to the fact that it predicts the lifetimerisk for CRC and a litany of extra-CRC cancers (of the endometrium,ovary, stomach, small bowel, hepatobiliary tract, upper uroepithelialtract, and brain) through assessment of a well-orchestrated family history.A Lynch syndrome diagnosis is almost certain when a mutation ina mismatch repair gene-most commonly MSH2, MLH1, or, to a lesserdegree, MSH6-is identified. Once diagnosed, the potential for significantreduction in cancer-related morbidity and mortality through highlytargeted surveillance may be profound. Particularly important iscolonoscopy initiated at an early age (ie, 25 years) and repeated annuallydue to accelerated carcinogenesis. In women, endometrial aspirationbiopsy and transvaginal ultrasound are important given the extraordinarilyhigh risk for endometrial and ovarian carcinoma. Thesecancer control strategies have a major impact on at-risk family membersonce they have been counseled and educated thoroughly aboutLynch syndrome’s natural history and their own hereditary cancer risk.

Combined-modality positronemissiontomography (PET)–computed tomography (CT) isbecoming the imaging method ofchoice for an increasing number ofoncology indications. The goal of thispaper is to review the evidence-basedliterature justifying PET-CT fusion.The best evidence comes from prospectivestudies of integrated PETCTscans compared to other methodsof acquiring images, with histopathologicconfirmation of disease presenceor absence. Unfortunately, veryfew studies provide this kind of data.Retrospective studies with similarcomparisons can be used to provideevidence favoring the use of integratedPET-CT scans in specific clinicalsituations. Also, inferential conclusionscan be drawn from studies whereclinical rather than pathologic dataare used to establish disease presenceor absence.

In many respects, Lynch syndromeserves as the paradigm of cancergenetic syndromes. It is relativelycommon and accounts for approximately3% to 5% of colorectal cancer cases.The genetic basis is clearly understood,and genetic testing is clinically availableand routinely incorporated intoclinical practice. Furthermore, the diagnosishas a profound impact on themanagement of individuals at risk, andinterventions have been shown tosubstantially reduce morbidity andmortality. These advances in our understandingare attributable, in largepart, to the seminal work of Dr. HenryLynch and his colleagues.[1-3]

Dr. Henry Lynch was one ofthe first to recognize the existenceof hereditary nonpolyposiscolorectal cancer (HNPCC).While a relatively small percentage offamilies have this cancer predispositionsyndrome, identification of individualsat risk is now standard of careand includes the potential for the preventionof colorectal cancer. Dr. Lynchand Jane Lynch have written a guidehighlighting key points for physiciansregarding the diagnosis, surveillance,and management of this disorder. Severalaspects of clinical care mentionedin the article are expanded upon here.

This special “annual highlights” supplement to Oncology News International (ONI)is a compilation of selected news on important advances in the management ofgastrointestinal cancers over the past year, as reported in ONI. Guest Editor, Dr.James L. Abbruzzese, comments on the reports included herein and discussesdevelopments in the clinical management of GI cancers, with a look at the impactof targeted agents with cytotoxic chemotherapy, first-line and adjuvant therapies foradvanced disease, and the role of statins and COX-2 inhibitors in prevention.

Vascular endothelial growth factor (VEGF) plays a crucial role inthe growth and metastatic spread of cancer. Bevacizumab (Avastin) isthe first commercially available VEGF inhibitor, earning US Food andDrug Administration (FDA) approval in February 2004. In combinationwith fluorouracil (5-FU)-based chemotherapy, this agent significantlyprolongs overall and progression-free survival of patients withmetastatic colorectal cancer. This review details the emerging role ofthe drug, its unique side effects, and other practical considerations relatedto bevacizumab therapy. Ongoing trials attempting to define additionalindications for bevacizumab as well as the development ofother promising angiogenesis inhibitors are also reviewed.

In this issue of ONCOLOGY, Olszewski,Grossbard, and Kozuchprovide an excellent overview ofthe role of antiangiogenic therapy inthe treatment of patients with metastaticcolorectal cancer. The authorshave brought several important issuesto the forefront that warrant furtherdiscussion, and these issues will beaddressed in this commentary.

Olszewski and colleagues reviewpreclinical and clinicaldata regarding vascular endothelialgrowth factor (VEGF) inhibitors,with particular attention to thedevelopment of bevacizumab (Avastin)in patients with colorectal cancer.The translation from biologic conceptto clinical proof of concept has beenstriking in its rapidity. However, manyimportant questions remain, and thisstory is only beginning to unfold. Inthis commentary, we will highlightsome of those questions that bear onthe optimal use of VEGF inhibitors inpatients with colorectal cancer.

BETHESDA, Maryland-Data from the randomized, phase III E3200 trial show that patients with advanced colorectal cancer who were treated with bevacizumab (Avastin) in combination with the oxaliplatin (Eloxatin)-based regimen known as FOLFOX4 had a significant survival advantage, compared with patients treated with FOLFOX4 alone. The National Cancer Institute (NCI) released the results from an interim analysis at the recommendation of the trial’s data monitoring committee (DMC), after the trial monitors determined that the study had met its primary endpoint of improved overall survival.

ATLANTA-Two neoadjuvant chemoradiation regimens-one using hyperfractionated radiation therapy and one using intensified chemotherapy-achieved pathologic complete responses (pCRs) in more than one-fourth of patients with advanced distal rectal cancer, according to a randomized phase II study. Mohammed Mohiuddin, MD, presented the findings at the 46th Annual Meeting of the American Society for Therapeutic Radiology and Oncology (abstract 16).

There are two conventional treatments for clinically resectable rectalcancer. The first is surgery followed by postoperative combinedmodalitytherapy if the tumor is T3 and/or N1/2. The second, if thetumor is ultrasound T3 or clinical T4, is preoperative combined-modalitytherapy followed by surgery and postoperative chemotherapy. Thereare a number of new chemotherapeutic agents that have been developedfor the treatment of colorectal cancer. Phase I/II trials are examiningthe use of new chemotherapeutic agents in combination with pelvicradiation therapy, most commonly in the preoperative setting. Thereis considerable interest in integrating irinotecan (Camptosar) into preoperativecombined-modality therapy regimens for rectal cancer. Basedon these trials, the recommended regimen for patients who receiveirinotecan-based combined-modality therapy is continuous infusionfluorouracil (5-FU), irinotecan, and pelvic radiation. New trials examiningpreoperative combined-modality therapy regimens substitutingcapecitabine (Xeloda) for continuous infusion 5-FU are in progress.

Variations of fluorouracil (5-FU) therapy have formed the backboneof chemotherapy for advanced colorectal cancer for many years.With the advent of newer agents that often work best with or even requirechemotherapy to optimize their activity, the issue of the optimalschedule and regimen of administration of 5-FU has taken on a renewedimportance. The combination of irinotecan with 5-FU/leucovorinhas consistently improved survival and response rates in comparisonto 5-FU/leucovorin alone. However, the combination also increasesthe toxicity of the treatment, thus resulting in continuing attemptsto improve on the toxicity profile of the combination, while retainingor improving upon the therapeutic outcomes. This article reviewsthe various combinations of irinotecan with 5-FU/leucovorin.

The epidermal growth factor receptor (EGFR) plays an importantrole in cell growth, differentiation, and survival. Targeting EGFR inpatients with colorectal cancer has become an important therapeutictool. Recently, a monoclonal antibody against the extracellular domainof the receptor (cetuximab [Erbitux]) has been approved for the treatmentof patients with EGFR-positive metastatic disease refractory toirinotecan (Camptosar)-based therapy. The role of other targeted agentsagainst EGFR, including other monoclonal antibodies as well as inhibitorsof the intracellular tyrosine kinase domain, will also be discussed.

The 6th University of Texas M. D. Anderson Cancer Center Investigators’Workshop was held on July 16–20, 2003, in Amelia Island, Florida.The purpose of these annual workshops has been to review the latest data onnew agents, with a particular emphasis on the broadly used agent irinotecan(Camptosar), and also novel regimens or agents.

ROCKVILLE, Maryland-The FDA has approved a new indication for Eloxatin (oxaliplatin for injection, Sanofi-Synthelabo)-as a treatment combined with conventional chemotherapy for the postsurgical treatment of patients with stage III colon cancer after complete tumor resection. The drug, as with its previous two US approvals, is to be used in combination with infusional fluorouracil/leucovorin (5-FU/LV). The company noted that the supplemental approval provides the first new adjuvant treatment for colon cancer in more than a decade.

ATLANTA-In a phase III trial of patients who had undergone surgery for rectal cancer, three regimens of fluorouracil (5-FU)-based chemotherapy and radiation therapy achieved similar rates of relapse-free and overall survival, although the three regimens had somewhat differing toxicity profiles.

The definition of overtreatment of rectal cancer is controversial,and thus it is difficult to accurately quantitate its prevalence. All componentsof rectal cancer treatment are associated with significant potentialfor morbidity and dysfunction that may have a negative impacton the patient’s quality of life. No one would disagree with the tenetthat overtreatment should be avoided whenever possible. Despite thatconsensus, little attention is given in the literature to the issues ofovertreatment of rectal cancer. This review article presents a varietyof clinical scenarios and summarizes available data demonstratingthat overtreatment of some patients with rectal cancer is occurring ona regular basis. It is hoped that this will stimulate clinicians to criticallyreview their own practices to eliminate such overtreatment. Developmentof new clinical trials to determine whether current practiceguidelines are promoting overtreatment of selected rectal cancer patientsis proposed.

Pemetrexed (Alimta) shows single-agent activity in advancedcolorectal cancer. In two phase II studies in which patients receivedpemetrexed at 600 mg/m2 or 500 mg/m2 as first-line treatment for metastaticdisease, objective response rates were 15.4% and 17.2%.

Pemetrexed (Alimta) is an antifolate that is effective in the inhibitionof multiple enzyme targets including thymidylate synthase,dihydrofolate reductase, and glycinamide ribonucleotide formyl transferase.The compound has been evaluated in several phase I trials, bothas single agent and in combination with other cytotoxic agents. Theinitial schedule selected for further investigation in phase II trials waspemetrexed 600 mg/m2 as a 10-minute infusion on day 1 every 21 days.During the subsequent phase II development, the dose of pemetrexedwas adjusted to 500 mg/m2 due to bone marrow and gastrointestinaltoxicities. The adjusted dose of pemetrexed was well tolerated throughoutthe late-phase drug development program. Preclinical evidencesuggests that pemetrexed has additive or synergistic activity when combinedwith many other clinically important anticancer agents, includinggemcitabine (Gemzar), fluorouracil, carboplatin (Paraplatin),oxaliplatin (Eloxatin), paclitaxel, and vinorelbine (Navelbine). Doselimitingtoxicities in these studies were primarily hematologic, and therewas no evidence of cumulative hematologic toxicity. During the drugdevelopment program it was discovered that supplementation with folicacid and vitamin B12 profoundly increased the tolerability ofpemetrexed. The studies discussed in this review demonstrate thatpemetrexed is well tolerated as a single agent and will be an importantcontribution to combination chemotherapy regimens.

The 30 reports in this special supplement to Oncology News International represent highlights of ongoing major clinical trials and new research presented at ASCO 2004 regarding state-of-the-art chemotherapeutic management of gastrointestinal and other cancers. Important developments in capecitabine as adjuvant therapy, novel targeted agents, and new combinations are discussed.

NEW ORLEANS-In a retrospective, observational study of nearly 4,000 patients in northern Israel, statin use for at least 5 years reduced the risk of colorectal cancer by 46%, after adjustment for known protective factors, including use of aspirin and nonsteroidal anti-inflammatory drugs (NSAIDs). The effects seen do not appear to be the result of a reduction in cholesterol levels. While the investigators, from the Molecular Epidemiology of Colorectal Cancer (MECC ) Study Group, cautioned that it is premature to change either the standard of care for colorectal cancer or the indications for statins, they said statins merit further investigation in this area.

Hand-foot syndrome is a localized cutaneous side effect associatedwith the administration of several chemotherapeutic agents, includingthe oral fluoropyrimidine capecitabine (Xeloda). It is never life-threateningbut can develop into a painful and debilitating condition thatinterferes with patients' normal daily activities and quality of life. Severalsymptomatic/prophylactic treatments have been used to alleviatehand-foot syndrome, but as yet there is insufficient prospective clinicalevidence to support their use. The only proven method of managinghand-foot syndrome is treatment modification (interruption and/or dosereduction), and this strategy is recommended for patients receivingcapecitabine. Retrospective analysis of safety data from two largephase III trials investigating capecitabine as first-line therapy in patientswith colorectal cancer confirms that this strategy is effective inthe management of hand-foot syndrome and does not impair the efficacyof capecitabine. This finding is supported by studies evaluatingcapecitabine in metastatic breast cancer. Notably, the incidence andmanagement of hand-foot syndrome are similar when capecitabine isadministered in the metastatic and adjuvant settings, as monotherapy,or in combination with docetaxel (Taxotere). It is important that patientslearn to recognize the symptoms of hand-foot syndrome, so thatprompt symptomatic treatment and treatment modification strategiescan be implemented.

BETHESDA, Maryland-Convincing evidence indicates that physical activity can significantly reduce the risk of colon and breast cancer, according to a newly released National Cancer Institute (NCI) fact sheet. Moreover, studies also suggest a link between exercise and a reduced risk of cancers of the prostate, lung, and endometrium. However, despite the documented cancer and other health benefits of exercise, "recent studies have shown that more than 60% of Americans do not engage in enough regular physical activity," NCI said. The new publication summarizes the evidence supporting the role of exercise in cancer risk reduction and the possible underlying biological mechanisms

The use of hepatic arterial infusion (HAI) chemotherapy in patientswith liver-only colorectal metastases is based on the pharmacologicprinciple that the regional administration of some drugs can lead tohigher drug concentrations at the site of the metastases and avoid systemictoxicity. Early randomized trials resulted in high response ratesbut did not lead to a survival advantage with HAI. More recent trialshave utilized improved surgical techniques and strict guidelines regardingdose reduction or cessation of HAI chemotherapy, resulting in asignificant reduction in toxicity. In patients with unresectable liver metastases,two recent European trials using HAI fluorouracil (5-FU)again failed to demonstrate an improvement in survival, but both wereplagued by a high complication rate with an associated high proportionof patients failing to receive the assigned treatment. In contrast,the preliminary results of a recent Cancer and Leukemia Group B trialdid demonstrate a survival advantage with HAI floxuridine when comparedto systemically administered 5-FU. Trials investigating the useof HAI chemotherapy in the adjuvant setting have yielded mixed results.Moreover, in light of improved response rates and overall survivalwith newer more active chemotherapeutic and novel agents, theabsolute role of HAI chemotherapy remains undefined.

Adjuvant therapy with chemotherapy and/or radiation therapy inaddition to surgery improves outcome for patients with high-risk carcinomasof the colon or rectum. For colon cancer, fluorouracil (5-FU)combined with leucovorin is a current standard of care that improveslong-term survival. A recent European trial (MOSAIC) has documentedsignificant improvement in 3-year disease-free survival when oxaliplatin(Eloxatin) was added to infusional 5-FU and leucovorin in the FOLFOXregimen. Two US cooperative group trials will evaluate the addition ofantiangiogenesis therapy with bevacizumab (Avastin) to chemotherapy.A third trial will evaluate FOLFOX, irinotecan (Camptosar) combinedwith infusional 5-FU and leucovorin (FOLFIRI), and the sequentialuse of FOLFOX followed by FOLFIRI. In rectal cancer, postoperative5-FU–based chemotherapy combined with irradiation can improve bothlocal tumor control and survival. The German Rectal Cancer Grouphas recently reported that preoperative combined-modality therapy isless toxic and more effective in preventing local tumor relapse comparedto similar treatment given postoperatively. A coordinated pair ofcooperative group clinical trials will evaluate oral capecitabine (Xeloda)as a radiation enhancer in the preoperative setting, and the FOLFOXand FOLFIRI regimens compared to 5-FU and leucovorin followingsurgery. Predictive and prognostic molecular markers will be studiedin these new adjuvant therapy clinical trials for both colon and rectalcancer with the goal of developing future regimens tailored to individualpatients. There has been a recent and dramatic increase in thepace of drug development for colorectal cancer which holds promise tofurther improve curative therapy as part of a multidisciplinary approachin the surgical adjuvant setting.

The treatment of colorectal cancer has undergone enormous changesin the past decade. From a disease with a single treatment option (ie,fluorouracil, a modestly effective drug), the treatment options haveevolved to include at least five new classes of antineoplastic agents.Among the considerable number of recently approved drugs, two aremonoclonal antibodies and are the testing ground for our rapidly emergingknowledge about cancer cell biology. Cetuximab (Erbitux) targetsthe epidermal growth factor receptor, an important molecule involvedwith cell cycling, survival, invasion, and metastasis. Bevacizumab(Avastin) neutralizes the vascular endothelial growth factor, blockingits ability to activate its receptor on the endothelial cells. The developmentof both antibodies resulted from decades of research in molecularand cell biology, as well as preclinical and clinical studies, and signalsa new paradigm where the tumor cells’ own unique features areexploited in a rational way.

Colorectal cancer is the second most common cause of cancerrelateddeath in the United States. Approximately 30% to 40% of patientswith colorectal cancer have locoregionally advanced or metastaticdisease on presentation and cannot be cured with surgical therapy.After many years without significant change, systemic therapy forcolorectal cancer is rapidly evolving. The past decade has seen the introductionof new chemotherapeutic agents such as irinotecan(Camptosar), oxaliplatin (Eloxatin) and the oral 5-FU prodrugcapecitabine (Xeloda). Combination studies of these new agents withthe standard 5-FU/leucovorin have extended median survival in patientswith advanced colorectal cancer for up to 21 months. In addition,targeted agents with activity in colorectal cancer have emergedand are promising. This article reviews the current treatment recommendationsfor patients who present with advanced colorectal cancer.Survival in patients with advanced colorectal cancer is on a positivetrajectory. The hope that some patients with advanced disease will belong-term survivors (even without surgery) appears to be within therange of possibility.

The past decade has given rise toan explosion of rationally designed,molecularly targetedtherapeutic agents. The epidermalgrowth factor receptor (EGFR) hasserved as the principal platform forthe development of such novel targetedtherapies, resulting in a paradigmshift in the treatment of a vast array ofsolid malignancies. Damjanov andMeropol have provided a comprehensiveand insightful overview of the roleof EGFR-directed therapeutics in colorectalcancer. They have chosen tofocus their discussion on the compoundsthat are furthest along in clinicaldevelopment and, hence, havereviewed the monoclonal antibodiescetuximab (Erbitux), ABX-EGF, andEMD 72000, as well as the small-moleculetyrosine kinase inhibitors gefitinib(Iressa) and erlotinib (Tarceva).

Damjanov and Meropol havedone an excellent job of reviewingboth the complex biologyof epidermal growth factor signalingand the current status ofepidermal growth factor receptor(EGFR, ErbB-1) inhibition for thetreatment of colorectal cancer. As theypoint out, several factors have madeEGFR a potentially high-value targetin cancer therapy. In addition, theyreview several phase II studies thathave demonstrated clinical activity foranti-EGFR antibodies in patients withadvanced colorectal cancer.

The epidermal growth factor receptor (EGFR) is commonly expressedin colorectal cancers but not in most normal tissues, raising the possibilitythat this receptor could serve as a target for highly selective therapy.Based on preclinical studies demonstrating that antagonists of EGFRresulted in the inhibition of tumor growth, the development of clinicalreagents has been aggressively pursued. Early clinical studies demonstratedantitumor activity of EGFR inhibitors in patients with advancedcolorectal cancer, with acceptable toxicity. This early success fueledrapid clinical development. In this article, we will review the currentstatus of EGFR inhibitors in the treatment of patients with colorectalcancer, in an effort to describe both how far we have come as well aswhere we need to go in optimizing this promising therapeutic approach.