Gastrointestinal Cancer

Traditionally, most hereditarynonpolyposis colorectal cancer(HNPCC) syndrome patientshave been identified and cared for bygastroenterologists, colorectal surgeons,and gastrointestinal medicaloncologists. Hence, the realization thatgynecologic tumors actually play amajor role in HNPCC has come relativelylate. Consequently, much of theclinical and basic science focus ofresearch in HNPCC has concentratedon colorectal cancer.

Hereditary nonpolyposis colorectal cancer (HNPCC) is an autosomaldominant cancer susceptibility syndrome associated with inheriteddefects in the DNA mismatch repair system. HNPCC family membersare at high risk for developing colorectal, endometrial, and ovariancancers. Studies of HNPCC families have helped define the importantrole that mismatch repair genes play in the molecular pathogenesis ofendometrial and ovarian cancers. This review will describe some of theimportant clinical and molecular features of HNPCC-related endometrialand ovarian cancer and describe how genetic susceptibility can beidentified in patients with sporadic endometrial and ovarian cancers. Itis important to identify patients with HNPCC, as families of mutationcarriers may benefit from genetic counseling, testing, and intensifiedcancer surveillance.

In their article, Taylor and Mutchbring attention to the gynecologiccancer risks associated with hereditarynonpolyposis colorectal cancer(HNPCC).[1] The identificationof individuals and families at risk forHNPCC has often focused on the coloncancer phenotype, but the diagnosisof endometrial or ovarian cancershould also be considered.

In the past several years, the impact of the new biologic therapies oncolorectal cancer has been dramatic. The focus of this article is to summarizesome of the key advances of incorporating biologically targetedtherapies into the routine management of patients with colorectal cancer.We will review important data presented at the 2005 American Society ofClinical Oncology annual meeting and discuss the incorporation of thesedata into the most optimal management of our patients, including howbest to manage side effects and keep quality of life as high as possible.

Several developments in the past few years have incrementally progressedthe field and provided additional insights into the managementof advanced colorectal cancer. This review discusses the componentsof current cytotoxic chemotherapy regimens for advanced colorectalcancer: fluorouracil (5-FU), capecitabine (Xeloda), irinotecan(Camptosar), and oxaliplatin (Eloxatin). The equivalence of severalfront-line regimens has provided opportunities for increased tailoringof therapies for individual patients. Preliminary data onpharmacogenomics provides hope that we will be able to better matchpatients with regimens and doses on the basis of individualized predictionsof toxicity and response. The importance of second-line therapyin overall survival has again been highlighted; the best outcomes haveoccurred in patients treated with 5-FU, oxaliplatin, and irinotecan incombination with targeted therapies during the course of their disease.Elderly patients are no exception to this finding. Combination regimensand second-line therapy should be offered to elderly patients whohave adequate performance status and no contraindicated comorbidconditions, without regard for their chronological age.

Colorectal cancer is a worldwide public health problem, with nearly 800,000new cases diagnosed each year resulting in approximately 500,000deaths. In the United States, it is the second leading cause of cancer mortality,and nearly 60,000 deaths will be attributed to this disease in 2005. Whendiagnosed as advanced, metastatic disease, colorectal cancer is traditionally associatedwith a poor prognosis, with 5-year survival rates in the range of 5% to 8%. Thissurvival rate has remained unchanged over the past 35 to 40 years. However, duringthe past 5 years, significant advances have been made in treatment options so thatimprovements in 2-year survival are now being reported, with median survival ratesin the 21- to 24-month range in patients with metastatic disease.

Continuing advances in immunology and molecular biology duringthe past several decades have provided optimism that immunomodulatorystrategies may be clinically useful in patients with cancer.Key advances have included: (1) recognition of the critical role of theantigen-presenting cell and greatly improved understanding of antigenprocessing and presentation, including the molecular interactionsbetween HLA molecules and antigenic epitopes on the antigen-processingcell and the receptors on T cells, and (2) the roles ofcostimulatory molecules such as B7.1, ICAM-1, and LFA-3 in the inductionand maintenance of an immune response. In addition, newtechniques have allowed us to identify immunogenic antigenic determinants,alter their binding affinities, and evaluate the overall successof the intervention through both in vivo and in vitro assays.Carcinoembryonic antigen (CEA) is overexpressed in a large numberof gastrointestinal, lung, and breast cancers. Clinical trials have establishedtreatment protocols using viral vectors to immunize patients toCEA without producing deleterious autoimmune phenomena. By combiningvarious vectors to include MUC-1 and/or CEA plus costimulatorymolecules in a prime-and-boost regimen, we are beginning to see signsthat this intervention can not only produce changes in immune functionbut also potentially improve clinical outcomes. Phase III studies totest these hypotheses are under way.

Kauh and colleagues nicely outlinethe major problems facingclinicians who treat humanimmunodeficiency virus (HIV)-positivepatients with squamous cell carcinomaof the anus. This is a highly curabledisease with combined-modality therapy,though the HIV-positive populationpresents unique challenges. Weagree with the approaches outlined bythe authors and would also like to emphasizeseveral principles in the managementof anal cancer.

Squamous cell anal cancer remains an uncommon entity; however,the incidence appears to be increasing in at-risk populations, especiallythose infected with human papillomavirus (HPV) and human immunodeficiencyvirus (HIV). Given the ability to cure this cancer using synchronouschemoradiotherapy, management practices of this disease arecritical. This article considers treatment strategies for HIV-positive patientswith anal cancer, including the impact on chemoradiation-inducedtoxicities and the role of highly active antiretroviral therapy in the treatmentof this patient population. The standard treatment has beenfluorouracil (5-FU) and mitomycin (or cisplatin) as chemotherapy agentsplus radiation. Consideration to modifying the standard treatment regimeis based on the fact that patients with HIV tend to experience greatertoxicity, especially when CD4 counts are below 200; these patients alsorequire longer treatment breaks. Additional changes to the chemotherapydosing, such as giving 5-FU continuously and decreasing mitomycin dose,are evaluated and considered in relation to radiation field sizes in an effortto reduce toxicity, maintain local tumor control, and limit need forcolostomy. The opportunity for decreasing the radiation field size andusing intensity-modulated radiation therapy (IMRT) is also considered,particularly in light of the fact that IMRT provides dose-sparing whilemaximizing target volume dose to involved areas. The impact of the immunesystem in patients with HIV and squamous cell carcinoma of theanus and the associated response to therapy remains unknown. Continuedstudies and phase III trials will be needed to test new treatment strategiesin HIV-infected patients with squamous cell cancer of the anus todetermine which treatment protocols provide the greatest benefits.

Dr. Marshall has done an excellentjob in his review of thecurrent status of the design,development, and delivery of cancervaccines with emphasis on vaccinesfor the treatment of gastrointestinalcancers. He has clearly delineated boththe promise and potential limitationsof this actively emerging field ofinvestigation.

Dr. Marshall has written a clearand concise review of the rationalefor and preliminarydata from studies using therapeuticvaccines in patients with establishedgastrointestinal (GI) malignancies.He has summarized the recent advancesleading to a better understandingof basic immunology. These have hadan important influence on the possibilitythat an effective therapeutic vaccineor vaccines can be developed.

The identification of key signaltransduction pathways and, inparticular, specific proteins thatare involved in the regulation of cancercell growth has provided unprecedentedopportunities for researchersinterested in targeted cancer treatment.The identification of molecular target-specific therapy offers the potentialof maximal therapeutic benefitwhile minimizing toxicity to normalcells. The accomplishment that led tothe sequencing and analysis of theentire human genome in 2001 has providedresearchers with the basic criticaltools to begin to identify anddifferentiate cancer from normal tissueat the genetic level.[1,2] Whilethe implications of this landmarkachievement are still being realized,it has become evident that the identificationof critical genes and proteinsinvolved in cell division and growthare just the beginning. The complexrelationships between multiple signaltransduction pathways, the surroundingtumor microenvironment, andpathways involved in immune-systemregulation have gained new appreciation.The ability to manipulate thesemultiple interactive systems with targetedtherapies represents a new treatmentparadigm in oncology.

The article by Kauh and colleaguesprovides a timely reviewof the therapeutic approachto invasive carcinoma of theanus in human immunodeficiency virus(HIV)-infected patients, which isan emerging clinical problem. Importantlimitations of the published experience,however, need to be pointedout; given the present pursuit of moretargeted anticancer therapy, new avenuesare being explored, even in themanagement of HIV-associated analcancer.

Despite enormous advances in the treatment of colorectal cancer,there is no single standard treatment approach for all patients. However,there are general principles of management that can be used toguide therapy. The clinician who fails to individualize therapy forcolorectal cancer is likely not taking full advantage of all therapeuticoptions available. Reviewing key clinical evidence that can help informdecision-making, this article addresses important questions in colorectalcancer management, including: Should bevacizumab (Avastin) be acomponent of most patients’ first-line treatment? Is there a role forcontinuing bevacizumab in subsequent regimens? Is there a role forcetuximab (Erbitux) in standard first-line chemotherapy? Are therepractices in colorectal cancer that have become widely accepted withoutdirect supportive data?

ROCHESTER, MINNESOTA-A phase II study from the NorthCentral Cancer Treatment Group(NCCTG) showed that oxaliplatin(Eloxatin) combined with lower-dosecapecitabine (Xeloda) is active as first

ORLANDO-Chemotherapy given before and after surgery is better than surgery alone for operable gastric and lower esophageal cancers, David Cunningham, MD, reported (abstract 4001).

NAPLES, ITALY-As firstlinetherapy in elderly patients withmetastatic colorectal cancer, XELOX(capecitabine [Xeloda] and oxaliplatin(Eloxatin]) achieved an objectivetumor response rate of 41% (abstract

HOUSTON-Concomitantboost radiotherapy plus capecitabine(Xeloda) produces pathologic responserates comparable to those of

BEIJING, CHINA-“Capecitabine (Xeloda) plus cisplatin is highly active and well tolerated as first-line treatment of Chinese patients with advanced gastric cancer, with an overall

ORLANDO-Neoadjuvantcapecitabine (Xeloda), oxaliplatin(Eloxatin), and preoperative pelvicradiotherapy (XELOX-RT) is a welltoleratedregimen in patients with locallyadvanced rectal cancer and pro

ORLANDO-In first-line metastaticcolorectal cancer, capecitabine(Xeloda) is better tolerated than fluorouracil/leucovorin (5-FU/LV), and

Because of recent advances ineach discipline we commonlyrecommend and deliver threemodalities-chemotherapy, radiation,and surgery-in the management oflocalized gastrointestinal cancers inpatients who are judged to be suitablecandidates for aggressive therapy.After years of experimentation andsome therapeutic misadventures, combinationchemotherapy can now bedelivered with greater safety and effectiveness.This is based in part onbetter antiemetics, better supportivetherapies such as judicious use of granulocytecolony-stimulating factors,and more accurate models for adjustingdosages based on pharmacokineticand pharmacodynamic profiling.

In this issue, Dr. Saltz articulateshis opinion on a variety of questionsconcerning therapy for patientswith metastatic colorectal cancer.My commentary will reflect myopinions concerning these questions.

Gastric cancer is a global health issue. Most cases are diagnosed atan advanced stage with poor prognosis. Current therapies have a modestimpact on survival. Surgery remains the only potentially curativetreatment, but is associated with a high rate of locoregional recurrenceand distant metastases. Total gastrectomy for proximal cancers is complicatedby postoperative morbidity and quality-of-life impairment.Combined-modality therapy may improve outcomes in this disease.Adjuvant therapy for gastric cancer has now become the standard inthe Western world. However, adjuvant therapy improves survival by onlya few months and is associated with high morbidity. Neoadjuvant therapyis commonly used for esophageal and gastroesophageal junction cancers,but is still regarded as investigational in gastric cancer. Severalsmall phase II studies indicate the feasibility of neoadjuvant strategies.The incorporation of novel, targeted agents into neoadjuvant programsand an assessment of biologic changes within the tumor may refinetherapy. This article provides a concise review of the literature onneoadjuvant therapy for gastric cancer and suggests avenues for furtherinvestigation.

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?

ANAHEIM, California-Heavy consumption of red meat and processed meats may increase the risk of pancreatic cancer, according to a multiethnic study. The results suggest that carcinogenic substances related to meat preparation, rather than the

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.

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