Gastrointestinal Cancer

Single-agent gemcitabine (Gemzar) is the standard of chemotherapyfor advanced pancreatic cancer, with no phase III trials to date havingshown significantly improved survival with gemcitabine-based combinationsvs single-agent treatment. The multitargeted antifolate agentpemetrexed (Alimta) shows synergistic effects in vitro in combinationwith gemcitabine, and activity and good tolerability when used as singleagenttreatment in advanced pancreatic cancer. In a phase II trial inpatients with advanced pancreatic cancer, the combination ofgemcitabine at 1,250 mg/m2 on days 1 and 8 plus pemetrexed at 500mg/m2 on day 8 after gemcitabine every 21 days resulted in a mediansurvival of 6.5 months and a 1-year survival rate of 29%. Neutropeniawas the primary toxicity, with grade 4 toxicity in 51% of patients. Thepromising results of this trial prompted the initiation of a phase IIItrial comparing gemcitabine at 1,000 mg/m2 on days 1, 8, and 15 every28 days vs the 21-day gemcitabine/pemetrexed regimen given with vitaminsupplementation in patients with pancreatic cancer. The primaryoutcome measure was overall survival, with secondary measures includingresponse rate, progression-free survival, and quality of life.While an increase in response and time to progression was reported forthe gemcitabine/pemetrexed combination, there were no significantdifferences in survival between treatment arms.

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.

WASHINGTON-The 2004 US Surgeon General’s report on the health risks of smoking adds five cancers to the list of diseases caused by cigarettes-acute myeloid leukemia, and stomach, pancreatic, cervical, and kidney cancers. Other newly

Dr. O’Connell has done a remarkablejob of discussingmodalities available for patientswith intermediate- to high-riskfully resected large bowel malignancies.Indeed, the title “Current Statusof Adjuvant Therapy for ColorectalCancer” is an underestimate of thearticle’s contents, as he nicely detailsthe past development of standard-ofcareadjuvant (and neoadjuvant, whenappropriate) treatments as well. As isclearly pointed out in the article, adjuvanttherapy works. Adding fluorouracil(5-FU) with or without radiationto surgery already saves thousandsof lives each year, and the enticing possibilityof throwing newer chemotherapeuticagents (eg, oxaliplatin)and/or targeted therapies (bevacizumab[Avastin]) into the mix makespotential future successes even greater.

The manuscript written by Drs.Hoff, Ellis, and Abbruzzese isan outstanding overview of thedevelopment, mechanism of action,and key clinical data for bevacizumab(Avastin) and cetuximab (Erbitux).Over the past several years,the landscape for treating patients withcolorectal cancer has changed dramaticallywith the inclusion of irinotecan(Camptosar), oxaliplatin (Eloxatin),and capecitabine (Xeloda). Then, beforewe can even catch our breath,along come cetuximab and bevacizumab.The next several years will befocused on testing these agents in avariety of clinical trial settings to optimizetheir use for patients with colorectalcancers. Three issues come tomind after reviewing the Hoff et almanuscript: (1) semantics, (2) awkwardUS Food and Drug Administration(FDA) indications, and (3) money.

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.

In the “Current Status of AdjuvantTherapy for Colorectal Cancer,”Dr. O’Connell provides importanthighlights of historical and recent developmentsin adjuvant treatment forcolon and rectal cancer. In addition,he provides insight into the future directionsof research for adjuvant therapyof cancer of the colon and rectum.As the review is thorough, wewould like to expand upon a coupleof areas including lymph node evaluation,changes to the staging system,and the use of molecular prognosticand predictive markers in futurestudies.

Drs. Whisenant and Venookhave provided us with a summaryof the role of hepaticarterial infusion (HAI) chemotherapyfor patients with metastatic colorectalcancer. In their abstract they state thatthere is confusion about whether HAIfor unresectable liver metastases isuseful, because European studies havebeen negative; they go on to say thatthe work in adjuvant therapy hasmixed results. I would like to offersome different interpretations.

Drs. Hoff, Ellis, and Abbruzzesehave provided a thoroughand useful overview of thecurrent status of the two new monoclonalantibodies, cetuximab (Erbitux)and bevacizumab (Avastin), that haverecently become available for the treatmentof colorectal cancer.

In the past 5 years, the treatment ofmetastatic colorectal cancer hasseen unparalleled advances. Medianoverall survivals reported inphase III trials have almost doubledand are poised to break the 2-yearbarrier very soon, perhaps as early asthis year. This has been made possiblethrough the introduction of a varietyof active agents into the treatmentof this disease.

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.

This special “annual highlights” supplement to Oncology News International is a compilation of some of the major advances in the management of gastrointestinal cancers during 2003–2004, as reported in ONI. Guest editor Dr. James L. Abbruzzese comments on the reports included herein and discusses advances in the clinical management of GI cancers, with a focus on developments in targeted therapy, new combinations, adjuvant therapy, and what to watch for in 2004.

This special “annual highlights” supplement to Oncology News International is acompilation of some of the major advances in the management of gastrointestinalcancers during 2003–2004, as reported in ONI. Guest editor Dr. James L. Abbruzzesecomments on the reports included herein and discusses advances in the clinicalmanagement of GI cancers, with a focus on developments in targeted therapy, newcombinations, adjuvant therapy, and what to watch for in 2004.

This special “annual highlights” supplement to Oncology News International is acompilation of some of the major advances in the management of gastrointestinalcancers during 2003–2004, as reported in ONI. Guest editor Dr. James L. Abbruzzesecomments on the reports included herein and discusses advances in the clinicalmanagement of GI cancers, with a focus on developments in targeted therapy, newcombinations, adjuvant therapy, and what to watch for in 2004.

Dr. Paul Sugarbaker’s reviewon management of the peritonealsurface component ofgastrointestinal cancer represents alifetime of experience with an aggressivetherapeutic approach to patientshistorically considered poor surgicalcandidates. This strategy combinestumor-directed peritoneal stripping(peritonectomy) and major abdominalvisceral organ resection, with“heated intraoperative intraperitonealchemotherapy” followed by “earlypostoperative intraperitoneal chemotherapy,”to improve outcome in patientswith seemingly fatal disease.The manuscript is thorough, informative,and reasonable. It provides historicalbackground, a discussion of thepathophysiology of peritoneal carcinomatosis,a rationale for pursuing thisapproach, a description of surgical technique,drug administration, and patientselectioncriteria, and a discussion ofselected results in the literature. Morbidity,mortality, and ethical considerationsare also briefly mentioned.

Until recently, peritoneal carcinomatosis was a universally fatalmanifestation of gastrointestinal cancer. However, two innovations intreatment have improved outcome for these patients. The new surgicalinterventions are collectively referred to as peritonectomy procedures.During the peritonectomy, all visible cancer is removed in an attemptto leave the patient with only microscopic residual disease. Perioperativeintraperitoneal chemotherapy, the second innovation, is employed toeradicate small-volume residual disease. The intraperitoneal chemotherapyis administered intraoperatively with moderate hyperthermia.Part 1 of this two-part article, which appeared in the January issue,described the natural history of gastrointestinal cancer with carcinomatosis,the patterns of dissemination within the peritoneal cavity, andthe benefits and limitations of peritoneal chemotherapy. Peritonectomyprocedures were also defined and described. Part 2 discusses the mechanicsof delivering perioperative intraperitoneal chemotherapy andthe clinical assessments used to select patients who will benefit fromcombined treatment. The results of combined treatment as they vary inmucinous and nonmucinous tumors are also discussed.

No American surgeon has thesame breadth of experiencewith extensive peritoneal resectionas Dr. Paul Sugarbaker. Moreover,only a few clinicians worldwidehave the same level of experiencewith intraperitoneal chemotherapy fora variety of intraperitoneal cancers,particularly after peritoneal resection.[1] The value of these therapiesis unquestionable in patients with lowgradetumors confined to the peritonealcavity. A number of patientstreated in this fashion show no evidenceof recurrent disease a decadeor more posttreatment.

Dr. Paul H. Sugarbaker hasspent most of his surgical oncologycareer researching andtreating patients with peritoneal surfacemalignancies. His participationin the treatment of 385 patients withappendiceal malignancy over a 15-year period is probably the largestsuch experience ever reported.[1] Dr. Sugarbaker has demonstrated that inpatients with peritoneal carcinomatosisfrom gastrointestinal malignancies,the best treatment results are associatedwith mucinous epithelial malignancyof the appendix.

Until recently, peritoneal carcinomatosis was a universally fatalmanifestation of gastrointestinal cancer. However, two innovations intreatment have improved outcome for these patients. The new surgicalinterventions are collectively referred to as peritonectomy procedures.During these procedures, all visible cancer is removed in an attempt toleave the patient with only microscopic residual disease. Perioperativeintraperitoneal chemotherapy, the second innovation, is employed toeradicate small-volume residual disease. The intraperitoneal chemotherapyis administered in the operating room with moderate hyperthermiaand is referred to as heated intraoperative intraperitoneal chemotherapy.If tolerated, additional intraperitoneal chemotherapy canbe administered during the first 5 postoperative days. The use of thesecombined treatments, ie, cytoreductive surgery and intraperitoneal chemotherapy,improves survival, optimizes quality of life, and maximallypreserves function. Part 1 of this two-part article describes the naturalhistory of gastrointestinal cancer with carcinomatosis, the patterns ofdissemination within the peritoneal cavity, and the benefits and limitationsof peritoneal chemotherapy. Peritonectomy procedures are also definedand described. Part 2, to be published next month in this journal,discusses the mechanics of delivering perioperative intraperitoneal chemotherapyand the clinical assessments used to select patients who willbenefit from combined treatment. The results of combined treatment asthey vary in mucinous and nonmucinous tumors are also discussed.

SALT LAKE CITY-Compared with patients with locally advanced rectal cancer who receive chemoradiotherapy postoperatively, those who receive chemoradiotherapy preoperatively have a downstaging of their cancer at surgery, a lower rate of local recurrence, a higher rate of sphincter preservation when tumors are low lying, and a lower rate of adverse effects, according to early results of the German Rectal Cancer Study (CAO/ARO/AIO-94). Lead author Rolf Sauer, MD, director of the Strahlenklinik, Erlangen, Germany, presented the results at the 45th Annual Meeting of the American Society for Therapeutic Radiology and Oncology (ASTRO plenary session, abstract 2).

Both advanced nonSMQ-8211-SMQsmall-cell lung cancer and pancreatic cancer pose significanttherapeutic challenges to clinicians due to their high mortalityrates. The past 2 decades witnessed an evolution in the approach to thetreatment of these diseases. In metastatic nonSMQ-8211-SMQsmall-cell lung cancer, trials ofrecently developed chemotherapy regimens have shown increased response ratesand improved quality of life. Several large, randomized phase III trials in unresectablenonSMQ-8211-SMQsmall-cell lung cancer have demonstrated that treatment with chemotherapyand radiation in combination leads to superior outcomes compared with radiationalone. This supplement highlights current treatment options with chemoradiationfor patients with advanced nonSMQ-8211-SMQsmall-cell lung cancer and pancreatic cancer.

Cancer of the pancreas remains a formidable challenge in oncology.This malignancy ranks as the fourth leading cause of cancer deathin the United States in 2003, with an estimated 30,700 new cases to bediagnosed and 30,000 deaths. Although gains have been achieved inthe clinical management of these patients, this malignancy is rarelycurable. Long-term survival is limited to patients undergoing resection.For patients with localized but unresectable malignancy, radiationtherapy combined with fluorouracil, gemcitabine (Gemzar), orpaclitaxel has shown modest improvements in survival and symptompalliation. However, there has been significant progress in the diagnosticevaluation of pancreatic cancer patients, which has aided cliniciansin caring for these patients and in selecting therapies. The use ofcomputed tomography, endoscopic ultrasonography, and laparoscopytechniques will be discussed. Newer techniques of radiation therapy,such as intraoperative electron-beam radiation therapy and threedimensionalconformal radiation therapy, with the integration of newbiologically targeted agents may provide new avenues of research andprogress in this disease.

Although their overall incidence is uncommon, gastrointestinal stromaltumors (GIST) are the most frequently encountered mesenchymaltumors of the GI tract. Their pathology has been recently defined bythe presence of KIT (transmembrane receptor tyrosine kinase). Themajority of GISTs have c-kit gain-of-function mutations mainly in exon11 (highly conserved juxtamembrane region) that eventuates in constitutiveactivation of KIT, promoting proliferation and antiapoptotic signaling.Imatinib mesylate (Gleevec) is a specific inhibitor of KIT kinaseactivation, and in phase II clinical trials has proven to be remarkablyefficacious in heavily pretreated GIST patients with advanced disease.The molecular and genomic determinants of response/resistancepatterns are the subject of ongoing studies, and adjuvant studies arealso under way. The initial evaluations of imatinib provide proof ofconcept for the hypothesis-driven design of selective molecularly targetedtherapies for solid tumor malignancies.

Dr. Eisenberg has produced anexcellent, concise, yet comprehensivereview of the evolutionof the KIT inhibitor imatinibmesylate (Gleevec) and the preoperativeand postoperative treatmentdilemmas surrounding mesenchymalgastrointestinal stromal tumors(GISTs), particularly in the face ofadvanced disease and recurrences. Thefocus of the article is on the naturalhistory of GISTs, from a molecularand pathobiologic perspective, toclarify the rationale for the use ofimatinib.

Molecularly targeted therapy isa hot topic in oncology, andthe development of imatinibmesylate (Gleevec) for gastrointestinalstromal tumors (GISTs) is one ofour best examples of the successfultranslation of basic science researchinto effective treatment of malignancy.Dr. Eisenberg has thoroughly researchedthe impetus for the use ofimatinib in GISTs and has methodicallyreviewed the results of severalcompleted trials. He broadly discussesmechanisms of resistance to the drugand talks about future directions inGIST research. Dr. Eisenberg has successfullycaptured much of the earlyexcitement surrounding the success ofimatinib, and he appropriately mentionsthe possibility of applying targetedtherapy to other solid tumors.

CHICAGO-The XELOX regimen, which combines oral capecitabine (Xeloda) and oxaliplatin (Eloxatin), was safe and "highly active" in a phase II study of 35 elderly patients with advanced colorectal cancer. On behalf of the Southern Italy Cooperative Oncology Group, Pasquale Comella, MD, of the National Tumor Institute, Naples, presented the study in a poster at the 39th Annual Meeting of the American Society of Clinical Oncology (abstract 2939).