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Oncologists have increasinglyrecognized that bone loss andits resultant complicationshave a major impact on the lives ofcancer patients. Bone loss in this populationmay be a consequence of directcancer involvement in the boneor of treatments that affect gonadalfunction or otherwise have a negativeimpact on bone.

Irinotecan and Fixed-Dose-Rate Gemcitabine in Advanced Pancreatic and Biliary Cancer: Phase I Study

Weijing Sun, MD, FACP;Daniel G. Haller, MD

September 1st 2003

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.

Gemcitabine and Irinotecan in Locally Advanced or Metastatic Biliary Cancer: Preliminary Report

Pankaj Bhargava, MD;Chirag R. Jani, MD;Diane M. F. Savarese, MD;Judith L. O’donnell, RN;Keith E. Stuart, MD;Caio Max S. Rocha Lima, MD

September 1st 2003

Chemotherapy has had limited success in biliary tract cancer. Of thenewer agents, gemcitabine (Gemzar) and irinotecan (CPT-11, Camptosar)both have single-agent activity in patients with advanced disease.We conducted a phase II trial to study the efficacy and toxicity of thecombination of gemcitabine plus irinotecan in patients with locallyadvanced or metastatic biliary tract cancer. The study has enrolled 14patients with histologically or cytologically documented cancer of thebiliary tract or gallbladder with bidimensionally measurable disease,Eastern Cooperative Oncology Group performance status 0 or 1,decompressed biliary tree, and no prior exposure to chemotherapy.Gemcitabine at 1,000 mg/m2 and irinotecan at 100 mg/m2 were bothadministered on days 1 and 8, every 21 days. In patients who had lessthan grade 3 hematologic and less than grade 2 nonhematologic toxicityfollowing cycle 1, the dose of irinotecan was increased to 115 mg/m2 forsubsequent cycles. A total of 65 cycles of chemotherapy have beenadministered, with an average of 4.5 cycles per patient (range: 1 to 11cycles). The median treatment duration was 3 months (range: 0.75 to 8months). An objective partial response was determined radiographicallyin two patients (14%) while stable disease for periods ranging from 4to 11.5 months was noted in six patients (43%). Toxicity consisted ofgrade 3/4 neutropenia in seven patients (50%) with no episodes offebrile neutropenia, grade 3/4 thrombocytopenia in four (28%), grade3 diarrhea in two (14%), and grade 3 nausea in one patient. Thecombination of gemcitabine plus irinotecan appears to possess modestclinical activity, and it is well tolerated in patients with advanced biliarycancer. Patient accrual is ongoing to this study.

Cervical Cancer: Issues of Sexuality and Fertility

Jeanne Carter, PhD;Sarah Auchincloss, MD;Yukio Sonoda, MD;Michael Krychman, MD

September 1st 2003

Cervical cancer rates have fallen in the United States; regardless, thedisease remains a significant concern for women, especially those whoare premenopausal. The management of cervical cancer is dependenton stage of disease at diagnosis, and specific needs emerge for patientsboth during and following treatment. Over the past decade, the focus hasbeen to maintain adequate tumor control while reducing long-termnegative consequences. However, problems with sexuality and fertilitypersist for women treated for cervical cancer despite these advances.Sexual dysfunction following treatment for gynecologic cancer hasbeen well documented in the literature, and recent studies demonstratethe success of brief psychosexual interventions. Treatment of sexualdifficulties in cancer patients can be achieved through the provision ofinformation, support, and symptom management, ideally as part of asexual health program. Resources are not always available to developsuch a program. However, medical professionals can identify individualsand organizations with expertise in treating sexual and fertilityconcerns, which can be provided to their patients, making help withthese problems more accessible as needs arise.

Commentary (Fanale/Hortobagyi): Bisphosphonates in the Prevention and Treatment of Bone Metastases

Michelle Fanale, MD;Gabriel N. Hortobagyi, MD, FACP

September 1st 2003

Drs. Ramaswamy and Shapiropresent a timely and comprehensivereview of the potentialuses of bisphosphonates and theirindications in the prevention and treatmentof bone metastasis. The reviewprovides a concise summary of thepathophysiology of skeletal metastasesand describes emerging biologicprinciples that open the door for novel,highly targeted therapeutic interventions.It is generally accepted thatrelative osteoclast hyperactivity resultsin excess bone resorption, which isthe basic process behind bone metastasis,osteoporosis, and hypercalcemiaof malignancy. Osteoprotegerin,the receptor activator of nuclear factor–kappa B (RANK), and the kappa Bligand (RANK-L) have critical rolesin osteoclastogenesis. In addition,parathyroid hormone–related proteinalso plays a major role in osteoblastactivation and production of RANKLas well as terminal osteoclast differentiationand activation.

Commentary (Hillner): Bisphosphonates in the Prevention and Treatment of Bone Metastases

Bruce E. Hillner, MD

September 1st 2003

In this issue, Ramaswamy and Shapiroprovide another excellent reviewof the recent literature on therole of bisphosphonates in the managementof bone metastases frombreast cancer and selected other cancers.Bisphosphonates and bone metastaseshave been the subject ofnumerous similar publications. In aquick Medline search of papers publishedsince January 2002, I found 12different review articles including asimilar manuscript in this journal.[1]

Bisphosphonates in the Prevention and Treatment of Bone Metastases

Bhuvaneswari Ramaswamy, MD;Charles L. Shapiro, MD

September 1st 2003

Bisphosphonates have an established role in treating tumor-inducedhypercalcemia and decreasing the incidence of skeletal-related events.Recent data suggest that these agents may also prevent skeletal metastases.This review explains how cancer metastasizes to bone and howbisphosphonates may block this process, with a summary of clinicaltrials supporting the use of bisphosphonates to treat and prevent bonemetastases. For skeletal metastases in patients with breast cancer,multiple myeloma, or other solid tumors, bisphosphonates are importantadjuncts to systemic therapy. Despite promising results in metastaticprostate cancer, additional trials are needed before bisphosphonatesbecome part of standard treatment in this setting. Ongoing trials areevaluating the preventive role of the third-generation bisphosphonatesin breast cancer patients. Until the results of these trials are presented,bisphosphonates should only become a component of adjuvant treatmentin the context of a clinical trial. Bone loss, a common consequenceof cancer treatment, should be treated with the usual measures indicatedfor the management of osteoporosis, including bisphosphonates.

Capecitabine Shows Substantial Activity and Comparable Efficacy When Combined With Either Irinotecan or Oxaliplatin