Colorectal Cancer

Advances in the treatment ofmetastatic colorectal cancer inthe past several years havebeen expeditious and exciting-evenchaotic-but with the median survivaldoubled since the use of single-agentfluoropyrimidines alone. However, newquestions continue to arise, directly affectingour daily practice in the care ofpatients with colorectal cancer. One ofthese issues, the optimal therapy formetastatic colorectal cancer, is wonderfullyexplored by Dr. Saltz in thisissue of ONCOLOGY. To understandthis issue better, we may have to approachthe question a little differently:That is, is it possible to standardizetreatment options for metastatic colorectalcancer?

Overweight and obesity increase the risk of developing several cancers.Once cancer develops, individuals may be at increased risk of recurrenceand poorer survival if they are overweight or obese. A statisticallysignificant association between overweight or obesity and breast cancerrecurrence or survival has been observed in the majority of populationbasedcase series; however, adiposity has been shown to have less of aneffect on prognosis in the clinical trial setting. Weight gain after breastcancer diagnosis may also be associated with decreased prognosis. Newevidence suggests that overweight/obesity vs normal weight may increasethe risk of poor prognosis among resected colon cancer patients and therisk of chemical recurrence in prostate cancer patients. Furthermore, obesecancer patients are at increased risk for developing problems followingsurgery, including wound complication, lymphedema, second cancers,and the chronic diseases affecting obese individuals without cancer suchas cardiovascular disease and diabetes. Mechanisms proposed to explainthe association between obesity and reduced prognosis include adiposetissue-induced increased concentrations of estrogens and testosterone,insulin, bioavailable insulin-like growth factors, leptin, and cytokines.Additional proposed mechanisms include reduced immune functioning,chemotherapy dosing, and differences in diet and physical activityin obese and nonobese patients. There have been no randomized clinicaltrials testing the effect of weight loss on recurrence or survival inoverweight or obese cancer patients, however. In the absence of clinicaltrial data, normal weight, overweight, and obese patients should beadvised to avoid weight gain through the cancer treatment process. Inaddition, weight loss is probably safe, and perhaps helpful, for overweightand obese cancer survivors who are otherwise healthy.

HOLLYWOOD, Florida-British researchers report that a three-step strategy of neoadjuvant chemotherapy, synchronous chemoradiation, then total mesorectal excision (TME) for patients with MRI-defined poor-risk rectal cancer produced

Many elderly individuals have substantial life expectancy, even inthe setting of significant illness. There is evidence to indicate that elderlyindividuals derive as much survival benefit as younger patientsfrom standard chemotherapy approaches in advanced colorectal cancer.Effective treatments should not be withheld from older patients onthe basis of age alone. Treatment decisions should be based on functionalstatus, presence of comorbidities, and consideration of drug-specifictoxicities that can be exacerbated in older individuals due to decreasedfunctional reserve. Infusional and weekly fluorouracil (5-FU)regimens are better tolerated than bolus and monthly regimens. Oralcapecitabine (Xeloda) reduces the frequency of a number of toxicitiescompared with bolus 5-FU, including stomatitis, a particularly debilitatingtoxicity in many elderly patients. The effectiveness and tolerabilityof oxaliplatin and irinotecan (Camptosar) appear to be similar inolder and younger patients. Older patients can also receive bevacizumab(Avastin), although caution is warranted in those with cardiovasculardisease. Overall survival in metastatic colorectal cancer improves withthe availability of multiple effective chemotherapeutic agents. The fullrange of effective therapies in advanced colorectal cancer should beextended to elderly patients.

Significant advances have been made in the treatment of advancedcolorectal cancer over the past 5 years, namely due to the introductionof three novel cytotoxic agents-capecitabine (Xeloda), irinotecan(Camptosar), and oxaliplatin (Eloxatin)-and the recent approval oftwo biologic agents-bevacizumab (Avastin) and cetuximab (Erbitux).During this time period, the median survival of patients with advanced,metastatic disease has gone from 10 to 12 months to nearly 24 months.Intense efforts have focused on identifying novel targeted therapies thattarget specific growth factor receptors, critical signal transduction pathways,and/or key pathways that mediate the process of angiogenesis.Recent clinical trial results suggest that the anti-VEGF antibodybevacizumab can be safely and effectively used in combination witheach of the active anticancer agents used in colorectal cancer. Despitethe development of active combination regimens, significant improvementsin the actual cure rate have not yet been achieved. Combinationregimens with activity in advanced disease are being evaluated in theadjuvant and neoadjuvant settings. The goal is to integrate these targetedstrategies into standard chemotherapy regimens so as to advancethe therapeutic options for the treatment of advanced colorectal cancer.Finally, intense efforts are attempting to identify the critical molecularbiomarkers that can be used to predict for either clinicalresponse to chemotherapy and/or targeted therapies and/or the drugspecificside effects. The goal of such studies is to facilitate the evolutionof empiric chemotherapy to individually tailored treatments forpatients with colorectal cancer.

Although the idea of utilizing antiangiogenic agents to hinder tumor growthis not new,[1] and the discovery of angiogenesis in tumors is evenolder,[2] this field of research is still in its infancy. Much has been learnedabout angiogenesis in tumor growth and development, yet the process is exceedinglycomplex and tightly regulated by a sophisticated interplay between pro- andantiangiogenic factors. Decades will pass before these regulatory mechanisms arewell elucidated and understood.

There is substantial preclinical and clinical evidence that angiogenesisplays a role in the development of tumors and the progression ofmalignancies. Inhibiting angiogenesis has been shown to suppress tumorgrowth and metastasis in many preclinical models. These benefitshave translated to the clinic with both marketed and investigationalantiangiogenesis agents. The most prominent target of these compoundsis vascular endothelial growth factor (VEGF) and its receptors. However,several other factors are of interest as well. These include integrins,matrix metalloproteinases, and endogenous antiangiogenic factors. Datafrom late-stage clinical trials support the role of antiangiogenic agents incancer therapy and the significant role that VEGF plays in angiogenesis.Future research will focus on determining the tumor types and stages thatwill benefit most from antiangiogenic therapy and combining therapiesthat target different factors in the angiogenesis pathway.

The improved survival associated with adding the anti-vascular endothelialgrowth factor (VEGF) monoclonal antibody bevacizumab(Avastin) to chemotherapy for the treatment of patients with metastaticcolorectal cancer demonstrates the importance of targeting collateralcells involved in tumor growth, progression, and metastatic spread.Based on the Gompertzian model of tumor growth, adding anti-VEGFagents to standard chemotherapy may be especially effective in earlystages of cancer. By improving chemotherapy delivery to the tumor andinhibiting regrowth between treatment cycles, anti-VEGF agents mayalter the growth pattern of a tumor such that it is more susceptible toeradication. These concepts also suggest that anti-VEGF agents couldenhance the effectiveness of chemotherapy given conventionally or ina dose-dense fashion. As such, it is possible that the effectiveness ofchemotherapy could be maintained or improved, even at lower cumulativedoses, which may improve its tolerability. Additionally, the effectsof anti-VEGF agents on metronomic chemotherapy, which is reportedto have antiangiogenic properties on its own, warrant further evaluation.Preclinical data demonstrate that cytostatic angiogenesis inhibitorsare potent complementary agents to metronomic chemotherapy,producing sustained complete regressions in some models of humancancer. Dose-dense and metronomic chemotherapy have in common ashortened dosing interval and resultant increased and/or prolongedexposure of tumor cells to chemotherapy in vivo. Optimizing the use ofanti-VEGF agents in the clinic demands further investigation of themost appropriate way to combine them with chemotherapy, particularlyregimens designed to exploit known tumor growth patterns andthose designed to target the endothelial cells involved inneovascularization with multiple agents.

Angiogenesis is an essential step in the growth and spread of solidtumors-the cause of more than 85% of cancer mortality. Inhibitingangiogenesis would therefore seem to be a reasonable approach to preventor treat cancer. However, tumor angiogenesis differs from normalangiogenesis in that the resulting vessels are tortuous, irregularlyshaped, and hyperpermeable. These abnormalities result in irregularblood flow and high interstitial fluid pressure within the tumor, whichcan impair the delivery of oxygen (a known radiation sensitizer) anddrugs to the tumor. Emerging evidence suggests that antiangiogenictherapy can prune some tumor vessels and normalize the structure andfunction of the rest, thereby improving drug delivery and normalizingthe tumor microenvironment. This normalization effect may underliethe therapeutic benefit of combined antiangiogenic and cytotoxic therapies.This paper reviews current and emerging concepts of the mechanismof action of antiangiogenic therapies and discusses the implicationsof these mechanisms for their optimal clinical use.

HOLLYWOOD, Florida-Preliminary data from the TREE-2 randomized study of first-line regimens for metastatic colorectal cancer show that bevacizumab (Avastin) can be safely added to oxaliplatin (Eloxatin)/fluoro-pyrimidine regimens

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.