ONCOLOGY Vol 17 No 9

People Living With Cancer(www.plwc.org, Figure 1), thepatient-oriented website postedby the American Society for ClinicalOncology (ASCO), has emergedas one of the preeminent cancer patienteducation sites, and for goodreason: It offers excellent site organization,easy navigability, and usefulinformation.

In the current issue of ONCOLOGY,Drs. Emens and Jaffee haveprovided an excellent overview ofthe basic mechanisms involved in thetumor-specific immune response, aswell as a comprehensive update ofresearch on immune-based therapiesfor breast cancer.

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).

Congress should strengthen the powers of the director of theNational Institutes of Health (NIH) and reconsider the specialstatus and authority of the National Cancer Institute (NCI),according to a National Academy of Sciences (NAS) committee thatassessed the organization and management of NIH. The congressionallymandated study also recommended several mergers within NIH but didnot endorse a major restructuring of the agency, as some critics had urged.

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.

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.

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.

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.

The outcomes for patients with metastatic or recurrent esophagealcancer are dismal, with 1-year survival rates of approximately 20%. Inthis phase II study, we studied the combination of docetaxel (Taxotere)and irinotecan (CPT-11, Camptosar) in patients with metastatic orrecurrent esophageal cancer. Eligible patients included those withhistologic or cytologic diagnosis of adenocarcinoma or squamouscancer of the esophagus or gastroesophageal junction who had receivedno previous chemotherapy for metastatic esophageal cancer. Previouschemotherapy in the neoadjuvant or adjuvant setting was allowed.Patients received irinotecan at 160 mg/m2 over 90 minutes followed bydocetaxel at 60 mg/m2 intravenously over 1 hour, with chemotherapycycles repeated every 21 days. Patients were reevaluated every twocycles. Of a planned 40 patients, 15 were enrolled, with 14 patientsevaluable for toxicity and 10 evaluable for response and survival. Thecombination of docetaxel and irinotecan resulted in a response rate of30%. An additional 40% achieved stable disease. The median survivalwas 130 days, with three patients still alive at the time of this analysis.The toxicities included 71% incidence of grade 4 hematologic toxicities,with 43% febrile neutropenia. One patient died of cecal perforationafter one cycle. There was no evidence of pharmacokinetic interaction,as systemic clearance of both drugs was similar to that seen after singleagentadministration. In conclusion, the regimen of docetaxel andirinotecan is active in metastatic or recurrent esophageal cancer.However, this combination chemotherapy regimen has an unacceptablerate of febrile neutropenia. This regimen needs to be modified toreduce the incidence of febrile neutropenia.

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.

Irinotecan (CPT-11, Camptosar) is one of the new generation ofchemotherapeutic agents that has activity in advanced colorectal cancer.It has antitumor efficacy as a single agent, and also has beencombined with fluorouracil (5-FU) and leucovorin (IFL) to treat thesepatients. Randomized studies have confirmed the superiority of IFL to5-FU and leucovorin alone with regard to patient survival, time toprogression, and tumor response rate. The optimal schedule for combiningthese agents remains uncertain, but in the United States, theschedule of IFL weekly for 4 consecutive weeks repeated every 6 weeks,according to the schedule reported by Saltz et al, has been widely used,although with some toxicity (especially myelosuppression and diarrhea).In an attempt to improve the tolerability of IFL, some haveadvocated modifying the schedule of IFL to weekly for 2 weeks, withrepeated cycles every 21 days. Twenty-three patients with advancedcolorectal cancer have been treated on this schedule at a single institution.Therapy was well tolerated, with 35% of patients experiencinggrade 3/4 neutropenia, two of whom had episodes of febrile neutropenia,and 9% with grade 3/4 diarrhea. The median relative dose intensityof irinotecan administered in the first 18 patients treated with thisregimen was 94%. These data support the hypothesis that modifying theschedule of administration of IFL improves the tolerability and abilityto deliver the regimen, but must be confirmed by randomized prospectivestudies, which may also attempt to evaluate the role of bolus 5-FUin the treatment of advanced colorectal cancer.

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.

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]

Carter et al provide a nice summaryof current knowledge ofsexual dysfunction in and rehabilitationof women with invasivecervical cancer. The prevailing perspectiveof their review, however,seems to be that most women treatedfor cervical cancer are white, middleclasspatients at major cancer centers.In order to make a difference in thequality of life of the majority of cervicalcancer survivors, we have to understandwho they are and recognizethe impact of social and gender inequalityon their lives and relationships.

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.

As outlined in the review byDrs. Emens and Jaffee entitled“Toward a Breast CancerVaccine: Work in Progress,” the developmentof anticancer vaccines hasclosely paralleled advances in the fieldof immunology. Basic immunologyhas provided and will continue toprovide important insights intohuman immunity that directly relateto the design and study of immunotherapeutics.To date, the mostimportant scientific observations applicableto immunotherapy include thefollowing:

Congress is considering a Medicare prescription drug bill thatwill cut $16 billion of Medicare funding for cancer care-areduction of about 30% per year-over the next 10 years, accordingto estimates released by the Congressional Budget Office.

The importance of quality of lifeduring and after treatment forcervical cancer has been ignoredfor too long. The pervasive attitudethat focuses on cure, withmorbidity an afterthought, is stillparamount in many patients’ and oncologists’minds. However, at the insistenceof patients and families, manyclinicians have recognized and startedto address these issues over thepast 2 decades.

Advances in biotechnology and basic immunology have convergedto create an unprecedented opportunity to use vaccines to harness thepower of the immune system in the fight against breast cancer. Cancervaccines have several therapeutic advantages over more traditionalbreast cancer treatment modalities. First, targeting the antitumorimmune response to critical tumor-specific antigens defines a therapywith exquisite specificity and minimal toxicity. Second, immune-mediatedtumor destruction occurs by mechanisms distinct from those underlyingthe efficacy of chemotherapy and hormone therapy. Thus, immunotherapyoffers an approach to circumventing the intrinsic drugresistance that currently underlies therapeutic failure. Third, thephenomenon of immunologic memory endows immunotherapy withthe potential for creating a durable therapeutic effect that is reactivatedat the onset of disease relapse. Moreover, immunologic memory alsounderlies the potential future use of vaccines for the prevention ofbreast cancer. Early clinical trials have highlighted the promise ofbreast cancer vaccines, and have further defined the challenges facingtranslational scientists and clinical investigators. The judicious applicationof laboratory advances to clinical trial design should facilitatethe development of immunotherapy as an additional major therapeuticmodality for breast cancer, with the potential for breast cancer preventionas well as treatment.

Local-regional carcinoma of the esophagus is often diagnosed inadvanced stages because the diagnosis is established when symptomsare severe. The prognosis of patients with local-regional carcinoma ofthe esophagus continues to be grim. While preoperative chemoradiotherapyincreases the fraction of patients who achieve pathologiccomplete response, that percentage is approximately 25%. In an attemptto increase the number of patients with either no cancer in the surgicalspecimen or only microscopic cancer, we adopted a three-step strategy.The current study utilized up to two 6-week cycles of induction chemotherapywith irinotecan (CPT-11, Camptosar) and cisplatin as step 1.This was followed by concurrent radiotherapy and chemotherapy withcontinuous infusion fluorouracil (5-FU) and paclitaxel as step 2. Oncethe patients recovered from chemoradiotherapy, a preoperative evaluationwas performed and surgery was attempted. All patients signed aninformed consent prior to their participation on the study. A total of 43patients were enrolled. The baseline endoscopic ultrasonography revealedthat 36 patients had a T3 tumor, five patients had a T2 tumor, andtwo had a T1 tumor. Twenty-seven patients had node-positive cancer(N1). Thirty-nine (91%) of the 43 patients underwent surgery; all hadan R0 (curative) resection. A pathologic complete response was noted in12 of the 39 patients. In addition, 17 patients had only microscopic(< 10%) viable cancer in the specimen. Therefore, a significant pathologicresponse was seen in 29 (74%) of 39 taken to surgery or 29 (67%)of all 43 patients enrolled on the study. With a median follow up beyond25 months, 20 patients remain alive and 12 patients remain free ofcancer. Our preliminary data suggest that the proportion of patientswith significant pathologic response can be increased by using thethree-step strategy.

The limited effectiveness of chemotherapy in esophageal cancerused to palliate metastatic disease or to combine with radiotherapy inlocally advanced disease has prompted the evaluation of new systemicagents. Irinotecan (CPT-11, Camptosar) has shown promising activityin a number of gastrointestinal cancers, including esophageal cancer.The phase II evaluation of the combination of weekly irinotecan andcisplatin has shown encouraging response rates exceeding 30% to 50%in esophageal and gastric cancer. Novel regimens include the combinationof irinotecan with mitomycin (Mutamycin), the taxanes docetaxel(Taxotere) and paclitaxel, and continuous infusion fluorouracil(5-FU). Irinotecan is an active radiosensitizer, and trials have evaluatedthe combination of irinotecan with concurrent radiotherapy. We completeda phase I trial combining weekly irinotecan, cisplatin, andconcurrent radiotherapy in locally advanced esophageal cancer. Minimaltoxicity has been observed, with no grade 3/4 esophagitis ordiarrhea, and hematologic toxicity was also surprisingly minimal. Fulldoses of weekly irinotecan (65 mg/m2) and cisplatin (30 mg/m2) could becombined safely with concurrent radiotherapy, with a significant rate ofpathologic complete response. Phase II evaluation of this chemoradiotherapyregimen as preoperative therapy is planned at single institutionsand at the cooperative group level in the United States. Furtherphase I and II investigation of combined irinotecan, cisplatin, andconcurrent radiation is ongoing with the addition of targeted agents,including celecoxib (Celebrex), cetuximab (Erbitux), and bevacizumab(Avastin). Alternative combinations of irinotecan with radiotherapy,including the addition of docetaxel and continuous infusion 5-FU, arealso undergoing phase I and II evaluation.