Ovarian Cancer

Proteasome inhibition is a novel, targeted approach in cancertherapy. Both natural and synthetic proteasome inhibitors selectivelypenetrate cancer cells, disrupting the orderly destruction of key regulatoryproteins involved in tumorigenesis and metastasis. Disrupting theorderly destruction of regulatory proteins causes an imbalance of theseproteins within the cell, which interferes with the systematic activationof signaling pathways required to maintain tumor cell growth and survival;therefore, cellular replication is inhibited and apoptosis ensues.

This year alone, more than 215,000 women in the United States will bediagnosed with, and over 40,000 will die from, invasive breast cancer.Recently, mortality from female breast cancer has declined despite anincrease in its incidence. This decline corresponds with improved screeningfor prompt tumor detection, and advances in the treatment of earlydisease. Of these, endocrine therapy has played a prominent role. Forwomen with estrogen receptor (ER)-positive and/or progesterone receptor(PR)-positive breast cancers, endocrine therapy has proven to be amajor component of adjuvant therapy, but it is not effective in womenwhose breast cancers lack ERs and PRs. The selective estrogen-receptormodulator (SERM) tamoxifen has been well established as safe and effectivein the adjuvant care of both pre- and postmenopausal women withhormone-receptor–positive early breast cancer. For premenopausalwomen, ovarian suppression is an important option to be considered.Additionally, the aromatase inhibitors have recently demonstrated utilityin postmenopausal women. The ideal sequencing of treatment withtamoxifen and/or an aromatase inhibitor is the subject of several ongoingstudies. Factors involved in selecting an appropriate endocrine regimenhave grown considerably over the past decade. It is becoming more importantfor those caring for women with breast cancer to fully understandthe available endocrine treatment options and the prognostic and predictivefactors available to help select the most appropriate treatment. Thegoal of this article is to assist clinicians in making decisions regardingadjuvant hormonal therapy and to provide information regarding availableclinical trials. To achieve this, the therapeutic options for hormonaltherapy will be reviewed, as will prognostic and predictive factors used inmaking decisions. Finally, four cases illustrating these difficult decisionswill be discussed, with recommendations for treatment.

Defects in the regulation of apoptosis (programmed cell death) makeimportant contributions to the pathogenesis and progression of mostcancers and leukemias. Apoptosis defects also figure prominently inresistance to chemotherapy, radiotherapy, hormonal therapy, andimmune-based treatments. Apoptosis is caused by activation ofintracellular proteases, known as caspases, that are responsible directlyor indirectly for the morphologic and biochemical events thatcharacterize the apoptotic cell. Numerous proteins that regulate thesecell death proteases have been discovered, including proteins belongingto the Bcl-2, inhibitor of apoptosis, caspase-associated recruitmentdomain, death domain, and death effector domain families. Thesecaspase-regulating proteins provide mechanisms for linkingenvironmental stimuli to cell death responses or to maintenance of cellsurvival. Alterations in the expression and function of several apoptosisregulatinggenes have been demonstrated in cancer, suggesting targetsfor drug discovery. Knowledge of the molecular details of apoptosisregulation and the three-dimensional structures of apoptosis proteinshas revealed new strategies for identifying small-molecule drugs thatmay yield more effective treatments for malignancies. Apoptosisregulatinggenes are also beginning to find utility as targets for antisenseoligonucleotides.

Pemetrexed (Alimta) is an antifolate that is effective in the inhibitionof multiple enzyme targets including thymidylate synthase,dihydrofolate reductase, and glycinamide ribonucleotide formyl transferase.The compound has been evaluated in several phase I trials, bothas single agent and in combination with other cytotoxic agents. Theinitial schedule selected for further investigation in phase II trials waspemetrexed 600 mg/m2 as a 10-minute infusion on day 1 every 21 days.During the subsequent phase II development, the dose of pemetrexedwas adjusted to 500 mg/m2 due to bone marrow and gastrointestinaltoxicities. The adjusted dose of pemetrexed was well tolerated throughoutthe late-phase drug development program. Preclinical evidencesuggests that pemetrexed has additive or synergistic activity when combinedwith many other clinically important anticancer agents, includinggemcitabine (Gemzar), fluorouracil, carboplatin (Paraplatin),oxaliplatin (Eloxatin), paclitaxel, and vinorelbine (Navelbine). Doselimitingtoxicities in these studies were primarily hematologic, and therewas no evidence of cumulative hematologic toxicity. During the drugdevelopment program it was discovered that supplementation with folicacid and vitamin B12 profoundly increased the tolerability ofpemetrexed. The studies discussed in this review demonstrate thatpemetrexed is well tolerated as a single agent and will be an importantcontribution to combination chemotherapy regimens.

Pemetrexed (Alimta) is active in a variety of solid tumors, includingbreast and gynecologic cancers. Phase II trials of pemetrexed at a doseof 600 mg/m2 without vitamin B12 and folic acid supplementation inlargely pretreated metastatic breast cancer patients demonstrated objectiveresponse rates of 21% and 28%, with generally manageableneutropenia constituting the primary toxicity. In phase II trials using500 mg/m2 with or without vitamin supplementation in anthracyclineandtaxane-pretreated patients, response rates were lower (approximately9%) and treatment was generally well tolerated irrespective ofvitamin supplementation status. A phase II trial is currently comparingpemetrexed doses of 600 and 900 mg/m2 with vitamin B12 supplementationin patients with previously untreated advanced breast cancer. In aphase II trial in patients with advanced cervical cancer, pemetrexed at600 mg/m2 without vitamin supplementation and 500 mg/m2 with supplementationproduced similar response rates, with the frequency of neutropeniabeing somewhat lower among patients receiving the lower doseand vitamin supplementation. Preliminary results in an ongoing phaseII trial indicate activity of the regimen of gemcitabine (Gemzar) at1,000 mg/m2 plus pemetrexed at 500 mg/m2 with vitamin supplementationin patients with ovarian cancer. Ongoing and future studies willestablish optimal dosing regimens of pemetrexed and potential benefitsof vitamin supplementation in the settings of metastatic breastcancer and gynecologic malignancies.

I would like to compliment the authorson their comprehensive reviewof cytoreductive surgery forovarian cancer. However, some oftheir interpretation of the literaturewarrants amplification, and some conclusionsmerit presentation of an alternativeperspective.

Tumor resection without expectationof complete excision violatesthe traditional tenets ofsurgical oncology. The concept of operabilitycarries the implication ofcomplete tumor excision with a marginof normal tissue. This classic viewwas challenged by Griffith’s landmark1975 paper showing an improved survivalwith surgical cytoreduction-atechnique that cut across tumor andrarely attained negative margins.[1] Heshowed in 70 patients that survival timewas inversely proportional to the sizeof the residual tumor after surgery.

The majority of ovarian cancer patients present with advanced-stagedisease, for which the goal of surgery is not only to document the extentof disease but also to perform surgical cytoreduction or tumordebulking. Cytoreductive surgery for ovarian cancer is generally performedat the time of diagnosis, when it is referred to as primarycytoreduction. It is also performed during primary chemotherapy (intervalcytoreduction) and after disease recurrence (secondarycytoreduction). Over the past 3 decades, numerous retrospective analyseshave established the role of primary cytoreduction in the managementof advanced-stage ovarian cancer. However, recent studies havereported that certain patients benefit from a neoadjuvant chemotherapeuticapproach, in which chemotherapy is given to those with presumedadvanced ovarian cancer prior to cytoreductive surgery. Althoughseveral theoretical advantages of this approach over primarycytoreduction have been reported, significant concerns remain. Therole of neoadjuvant chemotherapy is being investigated in a randomizedstudy currently being conducted by the European Organizationfor the Research and Treatment of Cancer (EORTC) and the NationalCancer Institute of Canada. The benefit of interval cytoreduction wasinvestigated in two randomized prospective trials conducted by theEORTC and the Gynecologic Oncology Group (GOG). Final resultswere somewhat conflicting, but both studies supported an extensiveattempt at surgical cytoreduction during primary therapy. In the managementof recurrent disease, the majority of retrospective studies demonstratea benefit to secondary cytoreduction. The GOG is currentlyattempting to better define the role of secondary cytoreduction in aprospective, randomized trial.

AN ANTONIO-Breast cancer patients with BRCA 1 or 2 mutations undergoing breast-conserving surgery plus radiotherapy do not have more in-breast recurrences or radiotherapy complications than their counterparts without the germ-line mutation, and they derive particular benefits from prophylactic bilateral oophorectomy, according to 10-year results from a large collaborative database reported at the 26th San Antonio Breast Cancer Symposium (abstract 5).

Biomedical research is in themidst of unprecedented transformationstemming from theoverall impact of molecular biologyon medical research, including theemerging high-throughput genomicsbasedtechnologies. These new paradigmsare leading to better definitionof the disease state as well as moreprecise and less toxic therapeutic strategies.But even as we begin to understandthe implications of gene-basedinformation on the genesis, pathophysiology,and progression of disease andon the development of novel therapeuticapproaches, the dawn of theera of proteomics is heralding evenmore radical changes.

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.

For the clinician who is facedwith treating individual patients,the article by Ornstein and Petricoinmight raise the famous questionfrom the Wendy’s commercial:Where’s the beef? When we hear ofthese Star Wars technologies and complexexplanations, we are often frustrated.On the one hand, we havenothing to offer our patients right now,and on the other, our patients readabout these technologies and expectthem to be applied right now.

Proteomics is a rapidly emerging scientific discipline that holds greatpromise in identifying novel diagnostic and prognostic biomarkers forhuman cancer. Technologic improvements have made it possible to profileand compare the protein composition within defined populationsof cells. Laser capture microdissection is a tool for procuring pure populationsof cells from human tissue sections to be used for downstreamproteomic analysis. Two-dimensional polyacrylamide gel electrophoresis(2D-PAGE) has been used traditionally to separate complex mixturesof proteins. Improvements in this technology have greatly enhancedresolution and sensitivity providing a more reproducible and comprehensivesurvey. Image analysis software and robotic instrumentationhave been developed to facilitate comparisons of complex protein expressionpatterns and isolation of differentially expressed proteins spots.Differential in-gel electrophoresis (DIGE) facilitates protein expressionby labeling different populations of proteins with fluorescent dyes.Isotope-coded affinity tagging (ICAT) uses mass spectroscopy for proteinseparation and different isotope tags for distinguishing populationsof proteins. Although in the past proteomics has been primarilyused for discovery, significant efforts are being made to developproteomic technologies into clinical tools. Reverse-phase protein arraysoffer a robust new method of quantitatively assessing expressionlevels and the activation status of a panel of proteins. Surface-enhancedlaser-desorption/ionization time-of-flight (SELDI-TOF) mass spectroscopyrapidly assesses complex protein mixtures in tissue or serum. Combinedwith artificial intelligence–based pattern recognition algorithms,this emerging technology can generate highly accurate diagnostic information.It is likely that mass spectroscopy–based serum proteomicswill evolve into useful clinical tools for the detection and treatment ofhuman cancers.

In this issue of ONCOLOGY, Sonodaprovides a systematic reviewof the management of early ovariancancer. The author rightfully concludesthat comprehensive surgicalstaging should be performed in thesepatients and that, based on severalEuropean randomized studies, patientswith high-risk early ovarian cancershould be treated with adjuvant platinum-based chemotherapy. Importantquestions remain, however, including:How should high-risk early ovariancancer be defined? and Is there a needfor adjuvant chemotherapy in patientswho have undergone comprehensivesurgical staging?

Dr. Sonoda has provided a thoroughsummary of the managementof early-stage ovariancancer. He highlights the importanceof accurate and completesurgical staging of this disease entity.Laparoscopic staging is discussed asa potential alternative to the classicopen laparotomy staging procedure.In addition, the author includes anextensive review of trials discussingchemotherapy, radiation therapy, andintraperitoneal therapy as adjuvanttreatment for early-stage disease.

Epithelial ovarian cancer is the leading cause of death from gynecologicmalignancies in the United States due, in large part, to the advancedstage at which it is commonly diagnosed. However, approximatelyone-third of cases are discovered at an early stage, when tumoris limited to the pelvis. Certain prognostic factors have been identified,which place patients with early disease at risk for recurrence and warrantthe use of adjuvant therapy. Systemic chemotherapy remains themost commonly used adjuvant therapy in this setting, and several randomizedEuropean trials have recently suggested a benefit to its use.These studies, however, suffered from the lack of comprehensive staging,which must be considered when interpreting the literature on earlystagedisease. Ideally, these patients should have access to a gynecologiconcologist prior to their initial surgical procedure.

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.

CHICAGO-An advanced three-dimensional (3D) fly-through-reality form of virtual colonoscopy is an effective frontline screening tool for an average-risk, asymptomatic population, according to a prospective, multicenter trial. "It is accurate for finding clinically important polyps, and it is comparable in sensitivity to the accepted gold standard of conventional colonoscopy," Perry Pickhardt, MD, associate professor of radiology, University of Wisconsin, Madison, said at a press conference at the 89th Annual Meeting of the Radiological Society of North America (RSNA).

Dr. Wood has provided a comprehensivebut succinct reviewof the clinical managementoptions available to women withan increased risk of breast cancer. Heclearly defines his approach to riskstratificationamong women likely tosee a breast surgeon with concernsabout their breast cancer risk basedon family history-ie, BRCA1/2 mutationcarriers, those who have not yetbeen tested for BRCA1/2 mutations, and those who have tested negativefor BRCA1/2 mutations but have sufficientfamily and personal history tohave ongoing concern despite the negativetest. In the past, breast surgeonsmight have seen a wider range ofwomen at risk, but many are now toobusy to see anyone who is not contemplatingbilateral mastectomies. It is evenmore important, therefore, that they befamiliar with the basic workings of genetictesting.

Women with any family history of breast cancer assume a high probabilityof risk. Counseling women involves ascertainment of an accuratefamily history and use of the best predictive models to assess boththe risk of a known mutation and the risk of breast cancer. This riskmust then be considered in the contexts of both the woman’s lifetimeand the next decade, in each instance carefully separating the risk ofdeveloping cancer from the risk of mortality. These two risks are oftenemotionally melded in women who have watched a loved one die ofcancer. The options for a woman at significantly increased risk of breastcancer include optimal surveillance, chemoprevention, and prophylacticsurgery. This entire field is in continuing evolution as better methodsof diagnosis, screening, and chemoprevention continue to enter clinicalpractice.

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.

This special supplement to Oncology News International presents 17 reports fromthe first annual Geriatric Oncology Consortium (GOC) multidisciplinary conference,‘‘Advancing Cancer Care in the Elderly.’’ Reports focus on issues in geriatric oncology,in particular team-based patient assessment and care delivery,adherence to medication, accrual to clinical trials, appropriate dosingthrough supportive therapy, radiation therapy, cognition problems, pain management,reassessment of outcomes, and caregiving issues.

Rash is a class effect of HER1/epidermal growth factor receptor(EGFR)-targeted agents, and has occurred with high frequency and ina dose-dependent manner in clinical trials of these agents in cancerpatients. Analysis of phase II trials of erlotinib (Tarceva) in non–smallcelllung cancer, head and neck cancer, and ovarian cancer shows asignificant association between rash severity and objective tumor response.Rash severity was highly significantly associated with survivalin patients with non–small-cell lung cancer receiving erlotinib; mediansurvival in patients with no rash was 46.5 days, compared with257 days in those with grade 1 rash (P < .0001) and 597 days in thosewith grade 2/3 rash (P < .0001). Similarly, for the combined non–smallcelllung cancer, head and neck cancer, and ovarian cancer studies,median survival in patients with no rash was 103 days, compared with191 days in those with grade 1 rash (P = .0001) and 266 days in thosewith grade 2/3/4 rash (P = .0001). Similar findings have been madewith cetuximab (Erbitux) and in some settings with gefitinib (Iressa).The strong association of rash severity with response/survival suggeststhat rash may serve as a marker of response to erlotinib treatment andmay be used to guide treatment to obtain optimal response. Dosingerlotinib at the maximum tolerated dose, which is associated with morefrequent and more severe rash, may improve response rates and survivaldurations. Further study of the potentially important associationbetween rash and outcome of treatment with EGFR-targeted agents isneeded.

The article by Trimble andTrimble nicely summarizes thestate of knowledge on ovariantumors of low malignant potential(LMP) and underscores the fact thatgaps in that knowledge have led toconfusion and controversy regardingseveral issues related to these interestingneoplasms. Many of these controversiescan be characterized as debatesbetween the "lumpers" and the "splitters.'The Johns Hopkins group haslong been at the forefront of researchon ovarian LMP tumors. In this review,I will attempt to place some of theauthors' comments into perspectiveand, at times, present a different pointof view.

Myelosuppression and neutropenia represent the major dose-limitingtoxicity of cancer chemotherapy. Chemotherapy-induced neutropeniamay be accompanied by fever, presumably due to life-threateninginfection, which generally requires hospitalization for evaluationand treatment with empiric broad-spectrum antibiotics. The resultingfebrile neutropenia is a major cause of the morbidity, mortality, andcosts associated with the treatment of patients with cancer. Furthermore,the threat of febrile neutropenia often results in chemotherapydose reductions and delays, which can compromise long-term clinicaloutcomes. Prophylactic colony-stimulating factor (CSF) has been shownto reduce the incidence, severity, and duration of neutropenia and itscomplications. Guidelines from the American Society of Clinical Oncologyrecommend the use of CSF on the basis of the myelosuppressivepotential of the chemotherapy regimen. The challenge in ensuring theappropriate and cost-effective use of prophylactic CSF is to determinewhich patients would be most likely to benefit from it. A number ofpatient-, disease-, and treatment-related factors are associated with anincreased risk of neutropenia and its complications. A number of clinicalpredictive models have been developed from retrospective datasetsto identify patients at greater risk for neutropenia and its complications.Early studies have demonstrated the potential of such models toguide the targeted use of CSF to those patients who are most likely tobenefit from the early use of these supportive agents. Additional prospectiveresearch is needed to develop more accurate and valid riskmodels and to evaluate the efficacy and cost-effectiveness of modeltargeteduse of CSF in high-risk patients.

Cancer is a disease of the elderly, and its incidence and mortalityincrease with age. The number of persons with cancer is expected todouble between 2000 and 2050, from 1.3 million to 2.6 million, withthe elderly accounting for most of this increase. Studies have shownthat otherwise-healthy older patients treated with chemotherapy of similarintensity obtain benefits comparable to those obtained by youngerpatients. However, chemotherapy-induced neutropenia and its complicationsare more likely in older patients; they are also more often hospitalizedbecause of life-threatening infectious complications. Furthermore,most neutropenic episodes in elderly patients occur in the earlycycles of chemotherapy. To minimize the occurrence of chemotherapyinducedneutropenia, older patients are often treated with less-aggressivechemotherapy and with dose reductions and delays, which maycompromise treatment outcome. The proactive management ofmyelosuppression is therefore essential in elderly patients. Research todetermine the predictors for neutropenia has found that age itself is asignificant risk factor. The benefit of treating elderly patients withcolony-stimulating factors is well established, with their use beginningin the first cycle of chemotherapy being crucial for minimizing neutropeniaand its complications and facilitating the delivery of full-dosechemotherapy. Such prophylaxis should be routinely considered in elderlypatients with cancer treated with myelosuppressive chemotherapy.

This special “annual highlights” supplement to Oncology News International is acompilation of major advances in the management of lung cancer during 2003, asreported in ONI. Guest editor Dr. Roy Herbst comments on the reports includedherein and discusses advances in the clinical management of lung cancer, with afocus on developments in targeted therapy, new combinations, adjuvant therapy,induction therapy, and what to watch for in 2004.

The Trimbles have provided auseful overview of the majorclinical and pathobiologic issuesinvolving ovarian borderlinetumors (also termed atypical proliferativetumors or tumors of low malignantpotential). The borderline category ofovarian tumors comprises a heterogeneousgroup of neoplasms that, whensubdivided according to histologicappearance and the presence of peritoneallesions, form distinctive subgroups,each with characteristicpathologic features and a distinctiveclinical course. Thus, retrospectivereviews of thousands of reported caseshave shown that borderline tumors ofall types that are confined to the ovaries(ie, lack peritoneal “implants”)are associated with virtually 100%survival and an extremely low recurrencerate.[1]

Clinical and laboratory reports suggest that ovarian tumors of lowmalignant potential (LMP) represent a “grab bag” of tumors, withdifferent etiologies, molecular biologies, and prognoses. As a result,data on incidence and prognosis may be quite unreliable. Diagnosis isbest made on permanent section. Half of women under age 40 undergoconservative, fertility-sparing surgery when diagnosed with anovarian tumor of LMP, but no adjuvant therapy has been shown toprolong survival in this population. In addition to the various controversiessurrounding LMP tumors, this review will address prognosticmarkers, risk of malignant transformation, treatment of progressivedisease, surveillance after conservative surgery, and future directionsfor research.

CHAPEL HILL, North Carolina-Mass spectroscopy-based screening of serum samples from men with elevated PSA levels can distinguish benign from malignant disease and significantly reduce the need for biopsies, according to David Ornstein, MD, and his colleagues at the Food and Drug Administration (FDA) and National Cancer Institute (NCI). Dr. Ornstein is assistant professor of surgery, Division of Urology, University of North Carolina School of Medicine. [See Figure]