Approximately 6% of colorectal cancers can be attributed to recognizable heritable germline mutations. Familial adenomatous polyposis is an autosomal dominant syndrome classically presenting with hundreds to thousands of adenomatous colorectal polyps that are caused by mutations in the APC gene.
The epidermal growth factor receptor (EGFR) promotes the growth of different cell types and has been implicated in tumorigenesis. The EGFR comprises a family of four structurally similar tyrosine kinases with a complex link to downstream signaling molecules that ultimately regulate key cell processes. Anti-EGFR agents have been developed as promising therapeutic anticancer targets, and some have been recently approved for the treatment of non-small-cell lung cancer and colon cancer. The two anti-EGFR therapies with the greatest clinical application are monoclonal antibodies that block the binding of ligands to EGFR and small-molecule tyrosine kinase inhibitors that inhibit the binding of adenosine triphosphate to the internal tyrosine kinase receptor of EGFR. We attempt to give an overview of the EGFR function and biology, focusing on the most important clinical findings and applications of EGFR inhibitors in lung and head and neck cancer.
In both chemonaive and heavily pretreated patients with non-small-cell lung cancer (NSCLC), investigations of canfosfamide (TLK286, Telcyta) are yielding "exciting" findings, Howard A. Burris III, MD, reported at the Chemotherapy Foundation Symposium XXIII (abstract 7).
Even an allergic reaction to a chemotherapeutic agent does not always preclude future administration of that drug. In some cases, few other options exist. Michelle J. Ciszewski, RN, BSN, OCN, discussed a desensitization protocol successfully used at her facility during the Oncology Nursing Society 30th Annual Congress (abstract 59).
In a clinical announcement, the National Cancer Institute (NCI), supported by six professional societies and advocacy groups, has urged physicians to use a combination of intravenous (IV) and intraperitoneal (IP) chemotherapy to treat women with advanced ovarian cancer.
The herbal supplement gingko biloba appeared to lower the risk of ovarian cancer in an epidemiologic study, while laboratory studies showed that two of the herb's components caused ovarian cancer cells to stop growing. The studies were presented at the annual fall prevention meeting of the American Association for Cancer Research (abstract 3654).
With the aging of the Western population, cancer in the older person is becoming increasingly common. After considering the relatively brief history of geriatric oncology, this article explores the causes and clinical implications of the association between cancer and aging. Age is a risk factor for cancer due to the duration of carcinogenesis, the vulnerability of aging tissues to environmental carcinogens, and other bodily changes that favor the development and the growth of cancer. Age may also influence cancer biology: Some tumors become more aggressive (ovarian cancer) and others, more indolent (breast cancer) with aging. Aging implies a reduced life expectancy and limited tolerance to stress. A comprehensive geriatric assessment (CGA) indicates which patients are more likely to benefit from cytotoxic treatment. Some physiologic changes (including reduced glomerular filtration rate, increased susceptibility to myelotoxicity, mucositis, and cardiac and neurotoxicity) are common in persons aged 65 years and older. The administration of chemotherapy to older cancer patients involves adjustment of the dose to renal function, prophylactic use of myelopoietic growth factors, maintenance of hemoglobin levels around 12 g/dL, and proper drug selection. Age is not a contraindication to cancer treatment: With appropriate caution, older individuals may benefit from cytotoxic chemotherapy to the same extent as the youngest patients.
With the aging of the Western population, cancer in the older person is becoming increasingly common. After considering the relatively brief history of geriatric oncology, this article explores the causes and clinical implications of the association between cancer and aging. Age is a risk factor for cancer due to the duration of carcinogenesis, the vulnerability of aging tissues to environmental carcinogens, and other bodily changes that favor the development and the growth of cancer. Age may also influence cancer biology: Some tumors become more aggressive (ovarian cancer) and others, more indolent (breast cancer) with aging. Aging implies a reduced life expectancy and limited tolerance to stress. A comprehensive geriatric assessment (CGA) indicates which patients are more likely to benefit from cytotoxic treatment. Some physiologic changes (including reduced glomerular filtration rate, increased susceptibility to myelotoxicity, mucositis, and cardiac and neurotoxicity) are common in persons aged 65 years and older. The administration of chemotherapy to older cancer patients involves adjustment of the dose to renal function, prophylactic use of myelopoietic growth factors, maintenance of hemoglobin levels around 12 g/dL, and proper drug selection. Age is not a contraindication to cancer treatment: With appropriate caution, older individuals may benefit from cytotoxic chemotherapy to the same extent as the youngest patients.
With the aging of the Western population, cancer in the older person is becoming increasingly common. After considering the relatively brief history of geriatric oncology, this article explores the causes and clinical implications of the association between cancer and aging. Age is a risk factor for cancer due to the duration of carcinogenesis, the vulnerability of aging tissues to environmental carcinogens, and other bodily changes that favor the development and the growth of cancer. Age may also influence cancer biology: Some tumors become more aggressive (ovarian cancer) and others, more indolent (breast cancer) with aging. Aging implies a reduced life expectancy and limited tolerance to stress. A comprehensive geriatric assessment (CGA) indicates which patients are more likely to benefit from cytotoxic treatment. Some physiologic changes (including reduced glomerular filtration rate, increased susceptibility to myelotoxicity, mucositis, and cardiac and neurotoxicity) are common in persons aged 65 years and older. The administration of chemotherapy to older cancer patients involves adjustment of the dose to renal function, prophylactic use of myelopoietic growth factors, maintenance of hemoglobin levels around 12 g/dL, and proper drug selection. Age is not a contraindication to cancer treatment: With appropriate caution, older individuals may benefit from cytotoxic chemotherapy to the same extent as the youngest patients.
Traditionally, most hereditarynonpolyposis colorectal cancer(HNPCC) syndrome patientshave been identified and cared for bygastroenterologists, colorectal surgeons,and gastrointestinal medicaloncologists. Hence, the realization thatgynecologic tumors actually play amajor role in HNPCC has come relativelylate. Consequently, much of theclinical and basic science focus ofresearch in HNPCC has concentratedon colorectal cancer.
Hereditary nonpolyposis colorectal cancer (HNPCC) is an autosomaldominant cancer susceptibility syndrome associated with inheriteddefects in the DNA mismatch repair system. HNPCC family membersare at high risk for developing colorectal, endometrial, and ovariancancers. Studies of HNPCC families have helped define the importantrole that mismatch repair genes play in the molecular pathogenesis ofendometrial and ovarian cancers. This review will describe some of theimportant clinical and molecular features of HNPCC-related endometrialand ovarian cancer and describe how genetic susceptibility can beidentified in patients with sporadic endometrial and ovarian cancers. Itis important to identify patients with HNPCC, as families of mutationcarriers may benefit from genetic counseling, testing, and intensifiedcancer surveillance.
In their article, Taylor and Mutchbring attention to the gynecologiccancer risks associated with hereditarynonpolyposis colorectal cancer(HNPCC).[1] The identificationof individuals and families at risk forHNPCC has often focused on the coloncancer phenotype, but the diagnosisof endometrial or ovarian cancershould also be considered.
The review by Vergote et al[1]presents a well-organized andcomprehensive summary of thedata addressing neoadjuvant chemotherapyfor ovarian cancer. The timingof debulking surgery for thisdisease is a common and clinicallyimportant question, but one that lacksdefinitive trial data. The assembleddata suggest a rationale for decisionmaking.The European Organizationfor Research and Treatment of Cancer(EORTC) and Gynecologic OncologyGroup (GOG) 152 trialspresent compelling evidence supportinga “maximal surgical effort” by anexperienced gynecologic surgeon,preferably at a specialty hospital, atsome point during primary therapy.
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.
