Ovarian Cancer

Because of the high rate of distant disease recurrence, the 5-yearsurvival of patients who have undergone complete surgical resectionof localized non–small-cell lung cancer (NSCLC) is approximately 50%.Initial results from early studies of adjuvant postoperative chemotherapyreported an adverse effect of alkylating agent and older chemotherapyregimens on survival. Cisplatin-based combinations were the first toshow a survival advantage. A 1995 meta-analysis of these studies suggesteda 13% reduction in the hazard ratio for death (HR = 0.87), leadingto a 5% survival benefit at 5 years. Still, these trials involved limitednumbers of patients (N = 1,394), and the results failed to reach statisticalsignificance (P = .08). Of the five largest subsequent randomizedtrials of platinum-based adjuvant therapy, three showed a significantsurvival advantage. Although it is impossible to determine the reasonsfor the differing outcomes of these studies, several key features distinguishthem, and the data suggest that medically fit patients with resectedstage IB or II NSCLC should be offered chemotherapy with a platinum/new drug combination.

Neoadjuvant, or induction, chemotherapyhas been usedextensively in selected carcinomas,particularly head andneck cancer (recently reviewed inONCOLOGY)[1] and locally advancedbreast cancer. Despite beneficialeffects on morbidity, long-termsurvival has not been significantly improvedby neoadjuvant chemotherapy.

Primary debulking surgery by a gynecologic oncologist remains thestandard of care in advanced ovarian cancer. Optimal debulking surgeryshould be defined as no residual tumor load. In retrospective analyses,neoadjuvant chemotherapy followed by interval debulking surgerydoes not seem to worsen prognosis compared to primary debulking surgeryfollowed by chemotherapy. However, we will have to wait for theresults of future randomized trials to know whether neoadjuvant chemotherapyfollowed by interval debulking surgery is as good as primarydebulking surgery in stage IIIC and IV patients. Interval debulking isdefined as an operation performed after a short course of induction chemotherapy.Based on the randomized European Organization for Researchand Treatment of Cancer–Gynecological Cancer Group (EORTC-GCG)trial, interval debulking by an experienced surgeon improves survival insome patients who did not undergo optimal primary debulking surgery.Based on Gynecologic Oncology Group (GOG) 152 data, intervaldebulking surgery does not seem to be indicated in patients who underwentprimarily a maximal surgical effort by a gynecologic oncologist.Open laparoscopy is probably the most valuable tool for evaluating theoperability primarily or at the time of interval debulking surgery.

Few would question the statementthat the role of surgery in themanagement of epithelial ovariancancer is unique in solid tumoroncology.

The review by Beth Peshkin andClaudine Isaacs in this issue ofONCOLOGY is an excellentoverview of the recognition, evaluation,and clinical management ofwomen with BRCA1 and BRCA2mutations. It is comprehensive andpractical, and emphasizes the approachthat a risk assessment and clinicalgenetics program might take tothe evaluation of an individual concernedabout the possibility thathereditary breast/ovarian cancer predispositionmight be present in herkindred. The authors clearly and conciselypresent the risks of breast, ovarian,and other cancers associated withBRCA1 and BRCA2 mutation carrierstatus, as well as some of the issues thathave arisen in the estimation of thoserisks. They provide a review of factorsthat may modify gene penetrance(cancer risks), and devote the finalsegment of their article to a clear andrational discussion of the surveillanceand preventive options available forthe management of the associatedbreast and ovarian cancer risks.

Following the discovery of theBRCA1 and BRCA2 genes justa decade ago, many felt it prematureto introduce these predictivemolecular markers into clinical practice.At the time, there were concernsregarding perceived limitations ofcancer genetic tests, including the limitedaccuracy of risk estimates associatedwith mutations of BRCA (andother susceptibility genes), the complextechnology needed for sequenceanalysis of large genes, the unprovenoptions for cancer prevention and earlydetection for mutation carriers, thelimited number of cancer genetic specialists,and the potential for adversesequelae following cancer genetic testing.The review by Peshkin and Isaacsprovides an excellent summary of theprogress over the past decade in addressingthese concerns. Nonetheless,as will be summarized here, importantchallenges remain in each of theseareas.

More than a decade has passedsince the cancer predispositiongenes BRCA1 andBRCA2 were cloned. Collectively,these genes are responsible for virtuallyall hereditary breast/ovarian cancerfamilies as well as a smaller subsetof hereditary site-specific breast cancerfamilies.[1] Their discovery helped usherin a new age of predictive and preventivemedicine for those at risk ofbreast and ovarian cancer, two of themost common forms of cancer in womenin the United States.[2] Peshkin andIsaacs provide an excellent summaryof cancer susceptibility due to inheritedmutations in BRCA1 and BRCA2,including approaches to assessing personaland family history for the likelihoodof finding these mutations, theirassociated cancer risks, and options forclinical management.

Genetic counseling and testing for susceptibility to breast and ovariancancer is often an integral component of management for womenwith a personal and/or family history of these malignancies. In thisarticle, we will briefly review the function and genetic epidemiology ofthe two major susceptibility genes, BRCA1 and BRCA2. We will thenaddress approaches to risk assessment for women at high risk with respectto the probability that they harbor a deleterious mutation in oneof these genes, and the likelihood that they will develop cancer if sucha mutation is identified. The process of genetic counseling and testingis discussed, including a summary of the potential benefits, limitations,and risks of testing as well as a summary of test result interpretation.We conclude with a review and appraisal of the various options forbreast and ovarian cancer risk reduction and screening options forwomen with a BRCA1 or BRCA2 mutation.

The management of ovarian cancer entails a complex blend of medicaland surgical interventions. Managing patients with recurrent ovariancancer increases the complexity of therapies and adds palliative interventions.The presence of recurrent ovarian cancer is both emotionally andphysically taxing for patients as well as their caregivers. With an increasinglyinformed patient population, a balance must be achieved betweeneasily accessible information enabling patients to know that they nowhave an incurable disease and support for their hopes and desires to stillovercome their cancer. The decision tree in the management of recurrentovarian cancer blends many different factors. This discussion will separatethose factors as if they are pure elements. We will address managementbased on response to primary therapy and time to recurrence, thelocation of recurrence, symptoms of recurrence, the patient’s histopathology,and the patient’s primary stage as it relates to the extent of diseasepresent at the start of chemotherapy.

In their article, Drs. Michener andBelinson make the case for treatingrecurrent ovarian cancer as achronic disease, with limiting morbidityand providing palliation of symptomstheir major goals. A review ofrecent literature would support their contention and management strategy.The cure rate for patients with recurrentovarian cancer is < 5%, and theaverage patient in the United Statesreceives more than five separate regimensof chemotherapy for recurrentdisease. Previous attempts at aggressivetreatment for recurrent disease haveshown, at best, very modest benefitwith significant expense and morbidity.What we are left with is a strategy oftrying to determine which patients maybenefit from aggressive salvage therapyand which are better managed witha chronic palliative attempt.

The Michener/Belinson articledeals not so much with what isnew in the treatment of ovariancancer, but with the changing managementparadigm. The authorscorrectly point out that one cannotexpect to offer curative options inovarian cancer patients who recur.Consequently, in planning therapy,the focus should be on the ability toprovide a lifelong strategy to controlthe disease through maintenance therapy.After first-line chemotherapy,complete responders have reasonablylong remissions in the absence of anyintervening therapies, but this is notlikely to be the case with recurrentdisease. In fact, Markman et al[1] havestressed that remissions followingtreatment for recurrence are neverlonger than the preceding ones.

In this installment of Second Opinion, we are presenting two cases of tumors of the female genital tract, specifically, the ovary and uterus, which contain both epithelial and mesenchymal components and therefore have unique diagnostic and therapeutic implications. The first has an unusually poor prognosis and the second is notoriously difficult to diagnose.

Significant improvements in the management of patients with endstagerenal disease (ESRD) who are on chronic renal replacementtherapy (CRRT), has led to an increased prevalence of this populationamong older Americans. Since cancer is also common in the elderly,oncologists are likely to be faced with patients who suffer from bothcancer and ESRD. There is a paucity of information regarding issuessurrounding the optimal management of such patients, especially thoseneeding chemotherapy. This review surveys the relevant problemsoncologists may encounter in such patients and summarizes the availableliterature on chemotherapeutic management of common cancers.The reader is strongly urged to consult the original references for detailsof chemotherapy administration prior to use in an individualpatient.

Thromboembolism affects many patients with solid tumors and clonalhematologic malignancies. Pathogenetic mechanisms include inflammatory-and tissue factor-mediated coagulation, natural anticoagulantdeficiencies, fibrinolytic alterations, hyperviscosity, and activationof platelets, endothelial cells, and leukocytes. High rates of venousthromboembolism (VTE) occur with advanced pancreatic, breast, ovarian,germ cell, lung, prostate, and central nervous system cancers.Hodgkin disease, non-Hodgkin's lymphoma, myeloma, paroxysmalnocturnal hemoglobinuria, and certain leukemias also predispose tovenous thromboembolism. Arterial and venous events occur with polycythemiavera and essential thrombocythemia. Central venous cathetersand prothrombotic antitumor regimens augment the risk in somepatients. Part 1 of this two-part article addresses pathophysiology, clinicalpresentations, and risk of malignancy-associated thrombosis. Part 2,which will appear in next month's issue, covers prophylaxis and treatmentof these thromboembolic complications.

The improved survival associated with adding the anti-vascular endothelialgrowth factor (VEGF) monoclonal antibody bevacizumab(Avastin) to chemotherapy for the treatment of patients with metastaticcolorectal cancer demonstrates the importance of targeting collateralcells involved in tumor growth, progression, and metastatic spread.Based on the Gompertzian model of tumor growth, adding anti-VEGFagents to standard chemotherapy may be especially effective in earlystages of cancer. By improving chemotherapy delivery to the tumor andinhibiting regrowth between treatment cycles, anti-VEGF agents mayalter the growth pattern of a tumor such that it is more susceptible toeradication. These concepts also suggest that anti-VEGF agents couldenhance the effectiveness of chemotherapy given conventionally or ina dose-dense fashion. As such, it is possible that the effectiveness ofchemotherapy could be maintained or improved, even at lower cumulativedoses, which may improve its tolerability. Additionally, the effectsof anti-VEGF agents on metronomic chemotherapy, which is reportedto have antiangiogenic properties on its own, warrant further evaluation.Preclinical data demonstrate that cytostatic angiogenesis inhibitorsare potent complementary agents to metronomic chemotherapy,producing sustained complete regressions in some models of humancancer. Dose-dense and metronomic chemotherapy have in common ashortened dosing interval and resultant increased and/or prolongedexposure of tumor cells to chemotherapy in vivo. Optimizing the use ofanti-VEGF agents in the clinic demands further investigation of themost appropriate way to combine them with chemotherapy, particularlyregimens designed to exploit known tumor growth patterns andthose designed to target the endothelial cells involved inneovascularization with multiple agents.

High-dose chemotherapy (HDCT) with autologous stem-cell is effective against a wide range of malignant diseases. This approach is increasingly used for treating hematologic malignancies and selected solid tumors. Since 1990, the number of autologous transplantations has exceeded the number of allogeneic transplantations.

Unknown primary carcinomas are a significant health problem, constituting 3% to 10% of all tumors diagnosed in the United States each year [1,2]. While the majority of patients with metastatic carcinoma of unknown primary origin have short survival times and disease resistant to treatment, recent findings suggest that certain subsets of patients have tumors that are responsive to chemotherapy. Others can be successfully treated with regional therapy.

Biologic therapies are an increasingly important part of cancer treatment. In this chapter, we review the current status of studies of colony-stimulating factors (CSFs), erythropoietin (Epogen, Procrit), thrombopoietin, the retinoids, and monoclonal antibodies (MoAbs). The interferons, interleukin-2 (IL-2, aldesleukin [Proleukin]), and adoptive cellular immunotherapy are discussed in a separate chapter.

Colony-stimulating factors are glycoproteins that act on hematopoietic cellsby binding to specific cell surface receptors and stimulating proliferation,differentiation commitment, and a degree of end-cell functional activation.Granulocyte colony-stimulating factor (G-CSF), produced by monocytes,fibroblasts, and endothelial cells, regulates the production of neutrophils within thebone marrow and affects neutrophil progenitor proliferation.[1,2]

Granulocyte-macrophage colony-stimulating factor (GM-CSF,sargramostim [Leukine]) is a powerful cytokine that is able to stimulatethe generation of dendritic cells. Adjuvant treatment with continuous lowdoseGM-CSF has been shown to prolong survival of stage III/IV melanomapatients. Data on continuous low-dose GM-CSF therapy in tumorsother than prostate cancer are still lacking.

Gestational trophoblastic tumors (GTTs) encompass a spectrum of neoplastic disorders that arise from placental trophoblastic tissue after abnormal fertilization. GTTs are classified histologically into four distinct groups: hydatidiform mole (complete and partial), chorioadenoma destruens (invasive mole), choriocarcinoma, and placental site tumor [1,2].

The Lynch syndrome (hereditary nonpolyposis colorectal cancer[HNPCC]), is the most common form of hereditary colorectal cancer(CRC), accounting for 2% to 7% of all CRC cases. The next most commonhereditary CRC syndrome is familial adenomatous polyposis (FAP),which accounts for less than 1% of all CRC. Lynch syndrome is ofcrucial clinical importance due to the fact that it predicts the lifetimerisk for CRC and a litany of extra-CRC cancers (of the endometrium,ovary, stomach, small bowel, hepatobiliary tract, upper uroepithelialtract, and brain) through assessment of a well-orchestrated family history.A Lynch syndrome diagnosis is almost certain when a mutation ina mismatch repair gene-most commonly MSH2, MLH1, or, to a lesserdegree, MSH6-is identified. Once diagnosed, the potential for significantreduction in cancer-related morbidity and mortality through highlytargeted surveillance may be profound. Particularly important iscolonoscopy initiated at an early age (ie, 25 years) and repeated annuallydue to accelerated carcinogenesis. In women, endometrial aspirationbiopsy and transvaginal ultrasound are important given the extraordinarilyhigh risk for endometrial and ovarian carcinoma. Thesecancer control strategies have a major impact on at-risk family membersonce they have been counseled and educated thoroughly aboutLynch syndrome’s natural history and their own hereditary cancer risk.

Combined-modality positronemissiontomography (PET)–computed tomography (CT) isbecoming the imaging method ofchoice for an increasing number ofoncology indications. The goal of thispaper is to review the evidence-basedliterature justifying PET-CT fusion.The best evidence comes from prospectivestudies of integrated PETCTscans compared to other methodsof acquiring images, with histopathologicconfirmation of disease presenceor absence. Unfortunately, veryfew studies provide this kind of data.Retrospective studies with similarcomparisons can be used to provideevidence favoring the use of integratedPET-CT scans in specific clinicalsituations. Also, inferential conclusionscan be drawn from studies whereclinical rather than pathologic dataare used to establish disease presenceor absence.

Recent technical advances leadingto the development of integratedpositron-emissiontomography (PET)–computed tomography(CT) have been a boon for oncologicimaging. Combining these twoimaging modalities into the same imagingunit has greatly simplified visualfusion of function (PET) andanatomic (CT) data. The popularityof this modality has resulted in over60% of all PET sales currently beingPET-CT units.

In this well-balanced overview, Dr.Blank and colleagues explore thecurrent status of clinical investigationinto a possible role for inhibitingthe activity of epidermal growthfactors as a management approach inpatients with ovarian cancer.

In many respects, Lynch syndromeserves as the paradigm of cancergenetic syndromes. It is relativelycommon and accounts for approximately3% to 5% of colorectal cancer cases.The genetic basis is clearly understood,and genetic testing is clinically availableand routinely incorporated intoclinical practice. Furthermore, the diagnosishas a profound impact on themanagement of individuals at risk, andinterventions have been shown tosubstantially reduce morbidity andmortality. These advances in our understandingare attributable, in largepart, to the seminal work of Dr. HenryLynch and his colleagues.[1-3]

The majority of patients with ovarian cancer, especially those whopresent with stages IIIC and IV, will relapse soon after completion ofplatinum-based induction treatment. It is imperative to find ways to improveand/or enhance the efficacy of induction and to prolong the durationof the first remission. The epidermal growth factor receptor (EGFR)family has been exploited, and currently, three agents that directly targetthis group of receptors are in use in the treatment of colorectal,non–small-cell lung and breast cancers. EGFR and HER2/neu areoverexpressed in a significant percentage of epithelial ovarian cancers.Thus, it would be reasonable to explore directly targeted therapyin ovarian cancer. Numerous investigational trials involving a varietyof EGFR inhibitors in ovarian cancer are ongoing. Our institution hasan active phase II clinical study that seeks to define the role of erlotinib(Tarceva) in potentiating first-line chemotherapy, and to determinewhether the drug offers a significant contribution as maintenancetherapy. It is hoped that data from these and other studies will helpinvestigators to understand more clearly the biology of ovarian cancerand to delineate the role of EGFR inhibitors in the management ofovarian cancer.

Dr. Henry Lynch was one ofthe first to recognize the existenceof hereditary nonpolyposiscolorectal cancer (HNPCC).While a relatively small percentage offamilies have this cancer predispositionsyndrome, identification of individualsat risk is now standard of careand includes the potential for the preventionof colorectal cancer. Dr. Lynchand Jane Lynch have written a guidehighlighting key points for physiciansregarding the diagnosis, surveillance,and management of this disorder. Severalaspects of clinical care mentionedin the article are expanded upon here.

Ovarian cancer is the deadliestof the gynecologic malignancies.Approximately threequartersof patients present with advanced-stage disease. With aggressivecytoreductive surgery followed byplatinum-based chemotherapy, mostpatients will achieve remission. Despitethis initially good response totreatment, most patients experiencerecurrence and ultimately die of theirdisease. Novel treatment strategies areneeded. Molecularly targeted therapiesoffer the promise of improvedefficacy with decreased toxicity. Inthis article, Drs. Stephanie Blank, RichardChang, and Franco Muggiapresent an excellent summary of thecurrent status of epidermal growth factorreceptor (EGFR) inhibitors in thetreatment of ovarian cancer. They describethe promise of these drugs aswell as some of the questions regardingthe best way to integrate theminto therapy for ovarian cancer.

ROCKVILLE, Maryland-The Food and Drug Administration (FDA) has given full approval to Doxil (doxorubicin HCl liposome injection, Tibotec Therapeutics, Division of Ortho Biotech Products, L.P.) for the treatment of ovarian cancer in women whose disease has progressed or recurred after platinum-based chemotherapy