Ovarian Cancer

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

Positron-emission tomography(PET) and computed tomography(CT) fusion imaging is arapidly evolving technique that is usefulin the staging of non–small-celllung cancer (NSCLC), Hodgkin’s disease,ovarian cancer, gastrointestinalstromal tumors, gynecologic malignancies,colorectal malignancies,and breast cancer. In their article,Rusthoven et al[1] describe the roleof PET-CT in head and neck malignanciesand include a review of allcurrently available literature. Accordingto the authors, PET-CT is usefulfor staging head and neck carcinomasand for target volume delineation duringradiation treatment planning.

Drs. Bystryn and Reynoldspresent an overview of melanomavaccines, including atheoretical rationale to support the approach,criteria for an effective vaccine,and a discussion of the challengesto optimal vaccine design. Results ofclinical trials where vaccine-inducedimmune responses correlated withimproved clinical outcome are discussed,as well as limitations of monitoringvaccine-induced immuneresponses. A series of randomized, concurrentlycontrolled trials with complex,polyvalent whole-cell vaccines,extracts, lysates, or shed antigens arereviewed. The authors conclude thatmelanoma vaccines' "potentially mostsignificant application" may be the preventionof melanoma in individuals athigh risk of developing the disease.Their review discusses the generallyaccepted rationale for selecting vaccineantigens and does a thoughtfuljob of reviewing the current state ofcomplex melanoma vaccines.

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.