Pancreatic Cancer

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.

Although in centers where pancreatectomy is performed frequently,associated morbidity and mortality rates have improved, long-term outcomesin pancreatic adenocarcinoma patients remain poor when surgeryis the sole therapeutic modality. The impact of adjuvant chemotherapyon survival in patients with localized pancreatic cancer remainsincompletely defined. The European Study Group for Pancreatic Cancer(ESPAC)-1 trial has suggested that overall survival rates are superiorwhen chemotherapy is added to surgery, even when regimens believedto be relatively ineffective in the treatment of advanced diseaseare used. The role of radiotherapy given with chemotherapy is alsounresolved, but chemoradiation continues to receive consideration inthe multimodality approach to localized pancreatic cancer. Enhancedcollaboration and increased involvement by pancreatic surgeons havehelped in the recruitment of pancreatic cancer patients for large-scalerandomized clinical trials in Europe and the United States. Many newerchemotherapeutic agents with efficacy in gastrointestinal cancers haveyet to be investigated in the adjuvant and neoadjuvant settings.

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.

Pancreatic cancer is the fifth leading cause of cancer death in the United States.In the year 2005, an estimated 32,180 new cases will be diagnosed, and 31,800deaths will be ascribed to this cancer.

Unresectable pancreatic cancer has few therapeutic options and adismal prognosis. Cyclooxygenase-2 (COX-2) expression is increasedat the RNA and protein levels in most human pancreatic cancers. Thepurpose of this trial was to determine whether the addition of a COX-2inhibitor to chemotherapy was beneficial. To date, 11 patients with inoperablepancreatic cancer have been treated with the combination ofgemcitabine (Gemzar), irinotecan (Camptosar), and celecoxib(Celebrex) at 400 mg orally twice daily. Encouraging pain relief, improvementin performance status, and decreases in CA 19-9 andcarcinoembryonic antigen levels have been observed.

From the results of recent studies, it is likely that multimodality therapy with chemotherapy and radiation treatment may improve the overall outcome of locally advanced upper gastrointestinal (GI) malignancies, including esophageal, gastric, pancreatic, and biliary tract carcinomas. However, more effective, more optimal, and less toxic chemotherapy regimen(s) with concomitant radiotherapy are needed beyond the concurrent continuous-infusion fluorouracil (5-FU) with radiation that is commonly applied in general practice. Epirubicin (Ellence), cisplatin, and irinotecan (Camptosar) are all active cytotoxic chemotherapy agents in upper GI cancers. Two phase I studies were designed to test the tolerability of the combination of radiotherapy with infusional 5-FU, epirubicin, and cisplatin (ECF) or 5-FU, irinotecan, and epirubicin (EIF) in the treatment of locally advanced upper GI malignancies.

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

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. Abbruzzesecomments on the reports included herein and discusses advances in the clinical management 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.

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. Abbruzzesecomments on the reports included herein and discusses advances in the clinical management 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.

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.

Chemotherapeutic agents that are highly responsive to ionizing radiationand enhance the effectiveness of radiation treatment are termedradiation sensitizers. Radiation sensitizers act in a number of ways tomake cancer cells more susceptible to death by radiation than surroundingnormal cells, and several such compounds are now available forthe treatment of solid tumors. This review discusses the biology thatunderlies chemotherapy and radiation interactions for oneradiosensitizerSMQ-8212-SMQgemcitabine (Gemzar). It also provides a brief assessmentof how to modify treatment regimens for various cancers to maximizethe radiosensitization potential of gemcitabine in order to furtherincrease efficacy. Newer molecularly targeted agents and their antitumorpotential as monotherapy or in combination with radiation arealso reviewed.

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.

PHOENIX, Arizona-Chronic regular aspirin use may dramatically increase women’s risk of pancreatic cancer, according to results from a prospective study of 88,378 participants in the Nurses’ Health Study, one of the largest US studies of major risk factors for chronic disease.

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.

It is a continuing challenge for oncologists to effectively treatadvanced/metastatic pancreatic and biliary cancer. Both irinotecan(CPT-11, Camptosar) and gemcitabine (Gemzar) have shown activityagainst these diseases with different mechanisms. Preclinical andclinical data also suggest additive or synergistic effects of the combinationof these two agents with few or no overlapping toxicities. Phosphorylationof gemcitabine, a process of intracellular activation of theagent, is dose-rate dependent. It has been suggested that the fixed-doserateinfusion of gemcitabine increases the concentration of intracellulartriphosphate gemcitabine, which in turn may result in more objectiveresponses and longer median survival compared to the standard infusion.This phase I study tests the toxicity of the combination of irinotecanwith fixed-dose-rate infusion of gemcitabine, and determines thedose of the combination for phase II investigation.

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.

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.

SEATTLE-Telomerase may be an early biomarker of pancreatobiliary malignancies, and telomerase enzyme immunostaining represents a potential breakthrough in screening for and diagnosing cancer in patients with biliary strictures, Tarun Mullick, MD, said at the president’s plenary session of the 67th Annual Meeting of the American College of Gastroenterology (ACG abstract 3).

Approximately 30,300 people will be diagnosedwith pancreatic cancer in the UnitedStates this year. The 99% mortality rate is thehighest of any cancer, and most patients die within 1year of diagnosis.[1] There are only two drugs approvedas a first-line indication for pancreatic cancerpatients, and treatment options are very limited.These patients have poor prognoses and few options,and must make decisions in short time frames.

Drs. Konner and O’Reilly have provided a thorough review of current perspectives on pancreatic cancer. The disease is lethal, difficult to diagnose in its early stages, and resistant to standard chemotherapy regimens. Surgery can be curative if performed when the tumor is small (< 2 cm), but only a minority of patients have small tumors.

The review by Drs. Konner and O’Reilly addresses a number of important issues in pancreatic cancer. Adenocarcinoma of the pancreas is a devastating disease,[1] not only because it will occur in approximately 30,000 Americans this year, and perhaps 200,000 people worldwide, but also because of its high associated mortality. Pancreatic adenocarcinoma is one of the least treatable and, therefore, most lethal of all cancers. Fully 95% of all patients with an established diagnosis of adenocarcinoma of the pancreas will die of their disease.

Pancreatic cancer is a leading cause of cancer-related mortality. Treatment has limited efficacy, and 5-year survival rates remain less than 5%. Insights from epidemiology and discoveries in molecular genetics have laid

ORLANDO-In a randomized multicenter phase II study of advanced pancreatic carcinoma by the European Organization for Research and Treatment of Cancer (EORTC) Gastrointestinal Cancer Group, the combination of docetaxel (Taxotere) and gemcitabine (Gemzar) was "promising" relative to docetaxel/cisplatin (Platinol), Manfred P. Lutz, MD, of University Hospital, Ulm, Germany, said at the 38th Annual Meeting of the American Society of Clinical Oncology (abstract 498).

KING OF PRUSSIA, Pennsylvania-Protarga, Inc. has received comments from the FDA that allow it to proceed with two separate phase III clinical studies of its new cancer drug Taxoprexin Injection (DHA-pacli-taxel) for the treatment of metastatic melanoma and pancreatic cancer. Taxoprexin is made by linking the fatty acid docosahexaenoic acid (DHA) to paclitaxel, the company said in a news release.

ORLANDO-The combination of pemetrexed (Alimta) and gemcitabine (Gemzar) is active in pancreatic cancer with acceptable toxicity and a promising 32% 1-year survival rate, according to an oral presentation at the 38th Annual Meeting of the American Society of Clinical Oncology (abstract 499).