Ovarian Cancer

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]

This special supplement toOncology News International presents11 reports on novel agents targetingHER1/EGFR, VEGF, and HER2/neu receptorsin the treatment of non–small-cell lung cancer,colorectal cancer, mesothelioma, andglioblastoma. The reports summarizeselected presentations from theAmerican Society of Clinical Oncology (ASCO)39th Annual Meeting and a satellitesymposium held in conjunction with ASCO.

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.

The incidence of ovarian carcinoma increases with advancing age,peaking during the 7th decade of life and remaining elevated until age80 years. Despite the high prevalence of ovarian cancer in the elderly,the management of these patients is often less aggressive than that oftheir younger counterparts. As a result, many elderly cancer patientsreceive inadequate treatment. However, data do not support the conceptthat age, per se, is a negative prognostic factor. In fact, the majority ofelderly patients are able to tolerate the standard of care for ovariancancer including initial surgical cytoreduction followed by platinumand taxane chemotherapy. Because functional status has not demonstrateda reliable correlation with either tumor stage or comorbidity,each patient’s comorbidities should be assessed independently. Forelderly patients with significant medical comorbidity, the extent ofsurgery and aggressiveness of chemotherapy should be tailored to theextent of disease, symptoms, overall health, and life goals. In addition,enhanced cooperation between geriatricians and oncologists may assistthe pretreatment assessment of elderly patients and improve treatmentguidelines in this population.

As the population ages over thenext 50 years, the number ofcancer patients is expected todouble from the current 1.3 million to2.6 million, and the majority of thosepatients will be at least 75 years old.[1]Projected increases in life expectancyaccount for this change. For womenliving in industrialized countries, it isestimated that the average life span infuture decades will reach 90 years.[2]Most cancers increase in incidenceand mortality as a population ages,although the causal link between oncogenesisand senescence remainscomplex and elusive. Within the contextof an upsurge in cancer incidence,an analysis of the inequitable treatmentof older patients afflicted withcancer takes on an urgent need.

With the population aging,cancer in older persons isbecoming an increasinglycommon problem.[1] The benefit ofantineoplastic treatment may be diminishedand the risk enhanced byaging, due to a progressive reductionin life expectancy and in the functionalreserve of multiple organ systems.[2] To establish the most suitablecourse of action in individual cases,the practitioner needs to be able toaddress the following questions: Is thecancer going to compromise the survivalor the quality of life of the patient?Is the patient able to tolerate thepotential risk of cancer treatment?

Drs. Levine and Gemignanihave provided a comprehensivereview of the literatureregarding the management of patientswith hereditary breast/ovarian cancersyndrome. As noted, over 200,000new cases of breast cancer and 25,000new cases of ovarian cancer are estimatedfor 2003.[1] Only a small portionof these cases will be hereditary;however, these are the cases that maybenefit from preventive measures. Thepotential for risk-reducing strategiesin these patients has become a criticalissue over the past several years. Thisreview highlights the salient featuresof identifying “at-risk” patients, aswell as the benefits and limitations ofsurgical prophylaxis.

The ability to identify a womanwith a germ-line mutation inBRCA1 or BRCA2, throughclinical genetic testing, allows thatwoman’s physician to implement preventivestrategies that may spare herfrom developing breast or ovariancancer. Unfortunately, the most effectivestrategies currently are also themost drastic; namely, prophylacticmastectomy and/or prophylacticoophorectomy.

Drs. Levine and Gemignani havecomposed an excellent comprehensivereview of the issuessurrounding prophylactic surgeryin patients at high risk for breast andovarian cancer. Their article focuseson the role of BRCA1/2 mutations inthe risk of developing hereditary breastand ovarian cancer and the data supportingrisk reduction in mutation carriersundergoing prophylactic surgery.

The hereditary breast/ovarian cancer syndrome is responsible forapproximately 5% of all breast cancers and 10% of all ovarian cancers.Although this accounts for a small portion of these diseases, muchattention has been focused on this syndrome because of the abundanceof research in this area. The majority of the hereditary breast/ovariansyndrome can be attributed to germ-line mutations in the BRCA1 andBRCA2 genes. Reliable screening techniques for these mutations havebeen developed and are readily available in clinical practice. Forpatients who are thought to have the hereditary breast/ovarian cancersyndrome based on family history or genetic testing, options exist foreither intensive screening or prophylactic surgery. This review willdiscuss the mechanisms by which mutations in the BRCA genes lead tothe development of cancer, the limitations of currently available screeningtechniques, and the efficacy of prophylactic surgery. In general,prophylactic oophorectomy can be performed laparoscopically as anoutpatient procedure, carrying as its main drawback the associatedconsequence of surgical menopause. Prophylactic mastectomy is quiteeffective in reducing the risk of breast cancer but is a more extensivesurgical procedure and results in disfigurement. For any given patient,the best estimates of individual risk of breast or ovarian cancer shouldbe weighed against the benefits of prophylactic surgery and the patient’spersonal wishes.

BETHESDA, Maryland-New findings by proteomics researchers at the National Cancer Institute (NCI) and the Food and Drug Administration (FDA) have advanced efforts to enable physicians to monitor the response of cancer patients treated with molecularly targeted drugs and to diagnose ovarian cancer in the early stages of the disease.

NEW ORLEANS-With few exceptions, lymphadenectomy should be performed in ovarian cancer patients even if they have stage IA disease. This was the conclusion of French investigators who analyzed 276 women with epithelial ovarian cancer and reported their results at the 34th Annual Meeting of the Society of Gynecologic Oncologists (abstract 94).

NEW ORLEANS-The survival rate for patients with primary invasive epithelial ovarian cancer has steadily increased over the past 3 decades, despite rising diagnoses among African-American women and women over age 60, according to an analysis presented at the Society of Gynecologic Oncologists’ 34th annual meeting (abstract 3).

NEW YORK-Previously treated patients with ovarian cancer who received a novel glutathione (TLK286, Telik, Inc., San Francisco) have thus far survived a median of more than 56 weeks, according to preliminary results from an ongoing multicenter phase II trial. John J. Kavanagh, MD, presented the results at the Mount Sinai School of Medicine Chemotherapy Foundation Symposium XX.