Gastrointestinal Cancer

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

In the United States, cancer of the large bowel is the second most common cause of cancer deaths after cancer of the lung [1]. 1995 estimates place large bowel cancer as the third most common malignancy, behind lung and prostate carcinomas in men and behind lung and breast cancers in women.

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.

Pancreatic, hepatic, and biliary carcinomas in adults represent three of the most challenging malignancies facing the oncologist. Although groups at high risk for these malignancies are recognized, screening and early-detection strategies have not been successful.

Neuroendocrine tumors manifest in the gastrointestinal tract mainly as carcinoid and pancreatic islet-cell tumors. They comprise an interesting group of rare neoplasms that are derived from neuroendocrine cells interspersed within the gastrointestinal system amd throughout the body. Neuroendocrine tumors are well known for producing various hormonal syndromes and for their indolent clinical course in most patients, although some of these tumors do not produce hormones of clinical significance. Patients may have symptoms for many years before the diagnosis is suspected and confirmed.

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.

Pisters and colleagues from theM. D. Anderson Cancer Centeroffer a state-of-the-art discussionof the staging and treatment ofpancreatic cancer. Their treatise addressesmost of the current issues ofcontroversy surrounding this diseasefrom a largely nonparochial standpoint,and should serve as a primerfor the multidisciplinary approach tothe treatment of pancreatic ductal cancer.Their call for and justification ofregionalization of treatment in patientswith potentially resectable diseaserings true with virtually all nationaland international studies that have examinedthis topic from the aspect ofmorbidity, mortality (and thus survival),duration of hospitalization, andof course in our current economic climate,cost.[1-7] This topic should nolonger be considered controversial.

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.

Drs. Pisters, Wolff, Crane, andEvans have provided an excellentoverview of contemporaryapproaches to staging, surgicalmanagement, and treatment ofpatients with potentially resectablepancreatic cancer. Given the impressiveadvances in our understandingof the biology and genetics of pancreaticcancer, we would agree thatcurrent opportunities for progressagainst this malignancy are encouraging.The reality, however, is thatmortality rates still exceed 95%.While the article addresses the clinicalmanagement of patients with operablepancreatic cancer, this subsetof patients constitutes only 10% to15% of all patients with the disease.This group as well as patients withlocally advanced and metastatic diseaseare in need of new and innovativetreatment strategies. In thisreview, we will highlight several ofthe points made by the authors.

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.