Gastrointestinal Cancer

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).

The 5th University of Texas M. D. Anderson Cancer Center Investigators’Workshop was held on July 24-28, 2002, in San Diego, California.The purpose of these annual workshops has been to review the latest data onnew agents, with a particular focus on the broadly used agent irinotecan (CPT-11,Camptosar).

Both irinotecan (CPT-11, Camptosar) and paclitaxel have beenshown to have single-agent activity in adenocarcinomas of the esophagusand gastric cardia. A phase I trial of the combination at UCLAestablished the dose as irinotecan at 225 mg/m2 and paclitaxel at100 mg/m2 every 3 weeks. Preliminary data from a phase II trial of thisregimen in adenocarcinomas of the gastroesophageal junction showgood tolerability and promising activity (response rate of 27%), even inA previously treated patients.

CHICAGO-According to two parallel phase III clinical trials in the United States, Europe, and Asia, imatinib mesylate (Gleevec) is highly active in the treatment of gastrointestinal stromal tumors (GISTs). The optimal dose of the drug nevertheless is still unclear. While the safety profile was more favorable with a 400 mg/d dose than an 800 mg/d dose in both studies, the efficacy of the two doses diverged. In the US trial, progression-free survival was similar among patients who received 400 mg or 800 mg of imatinib. In the European trial, the 800-mg dose produced significantly improved progression-free survival.

Despite a dramatic decline in the incidence of gastric carcinoma inthe United States during the past century, treatment remains a challengingproblem for oncologists. Surgery continues to be the primarymodality for managing early-stage gastric cancer, but up to 80% ofpatients who undergo a "curative" resection develop locoregional ordistant recurrence. Given these sobering statistics, there has been greatinterest in developing strategies to prevent recurrences after surgeryand improve overall mortality. In this article, we review data onadjuvant treatment modalities for this disease, including radiotherapy,chemotherapy, combination chemotherapy and radiation, intraperitonealtreatment, and immunotherapy. We focus attention on the recentwidespread acceptance of adjuvant chemoradiotherapy, based on theresults of Intergroup trial 0116. Future strategies incorporating differentmodalities of treatment will be outlined.

In the current issue of ONCOLOGYDrs. Bendell and Ryan have provideda valuable review of analcancer. They describe the dramaticeffect of multimodality therapy onthe quality of life and survival ofanal cancer patients. Currently, themajority of patients enjoy long-termsurvival without requiring major surgeryor a stoma. At Memorial Sloan-Kettering Cancer Center, we basetreatment recommendations on stageat presentation and the presence ofcomorbid disease.

Anal cancer accounts for 1.5% of digestive system malignancies inthe United States. In the past 30 years, substantial progress has beenmade in understanding the pathophysiology and treatment of thedisease. Anal cancer was once believed to be caused by chronic localinflammation of the perianal area, and treatment was abdominoperinealresection. From epidemiologic and clinical studies, we nowknow that the development of anal cancer is associated with humanpapillomavirus infection and that the disease has a pathophysiologysimilar to that of cervical cancer. Less invasive treatments have alsobeen developed, and the majority of patients with anal cancer can nowbe cured with preservation of the anal sphincter using concurrentexternal-beam radiation therapy and fluorouracil (5-FU)/mitomycin(Mutamycin) chemotherapy. Current areas under investigation includethe incorporation of platinum agents into the chemotherapyregimen and the use of cytologic screening studies for high-riskpopulations.

The article by Drs. Bendell andRyan reviews the associationbetween anal cancer and humanpapillomavirus (HPV) infectionand discusses current managementstrategies for patients with squamouscell carcinoma of the anal canal. Theauthors should be complimented ona thorough review of the literature,which supports that association andthe use of chemoradiation as the goldstandard for treatment of this groupof patients.

DUBLIN, California-Super-Gen Inc. has begun submission of a New Drug Application (NDA) for Orathecin, an oral camptothecin, for the treatment of pancreatic cancer patients who are refractory/resistant to available therapies. The submission will occur on a rolling basis and is ex-pected to be completed by the end of the first quarter of 2003. The submission will contain data on more than 2,700 patients treated under Orathecin study protocols, the company said in a news release.

NEW YORK-Total mesorectal excision (TME) has reduced the risk of local recurrence in rectal cancer, but adjuvant therapy is still needed in node-positive cases, according to Bruce Minsky, MD, vice chairman of radiation oncology at Memorial Sloan-Kettering Cancer Center in New York.

NANTES, France-European researchers are moving beyond colorectal cancer regimens based on infusional fluorouracil (5-FU) to comparing combinations and to examining the effects of scheduling on response and time to progression, according to Jean-Yves Douillard, MD, PhD. Professor Douillard, who developed a widely-used regimen for colorectal cancer, is professor of medical oncology and head of the department of medical oncology, Centre Rene Gauducheau, at the University of Nantes in France.

BALTIMORE-Between 11,000 and 12,000 colorectal cancer patients present with liver metastases each year. Surgical resection is ideal but does not remove microscopic metastases and disease left behind after surgery. "Today, treatment should start with neoadjuvant therapy in all colorectal cancer patients that have liver metastases," Yehuda Z. Patt, MD, said.

GLASGOW, Scotland-"Development of capecitabine (Xeloda) was inspired by the fact that what is wanted is an oral tablet that will mimic infusional fluorouracil (5-FU) and will have tumor-selective activation. Clearly, about 90% of patients prefer oral therapy, but they do not want to sacrifice efficacy for convenience," Christopher Twelves, MD, stated. A number of recent clinical trials suggest that capecitabine might be a simpler substitute for 5-FU in colorectal cancer regimens and Dr. Twelves, a consultant in medical oncology at Cancer Research UK, Glasgow, Scotland, discussed this possibility at the First International Colorectal Cancer Congress in Palm Beach, Florida.