ONCOLOGY Vol 17 No 7

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.

Dr. Kelly has written an excellentarticle demonstrating theclinical significance of achievingstable disease in advanced non–small-cell lung cancer (NSCLC)patients. This hypothesis is supportedby clinical data from two phase IItrials (Iressa Dose Evaluation in AdvancedLung Cancer [IDEAL-1 andIDEAL-2]) of the epidermal growthfactorreceptor (EGFR) inhibitor gefitinib(ZD1839, Iressa) in previouslytreated patients. She appropriatelypoints out that although tumor shrinkageis a conventionally used end pointfor cytotoxic drugs, it may not be appropriatefor the “novel” cytostaticagents. For these agents, stabilizationof disease without obvious tumorshrinkage may result in a clinicalbenefit.

The article by Bisseck and colleagueshighlights an importantissue encountered increasinglyby physicians-melanoma in childrenand adolescents. The incidence andmortality of melanoma continues torise.[1] It is now the fifth most commoncancer in men and the seventhmost common cancer in women. Inour practice at the Johns HopkinsMelanoma Center, we have treated agrowing number of children and adolescentswith melanoma, includingmany with stage III disease identifiedby sentinel node technology, similarto that described by Bisseck andcolleagues.

Paragangliomas most commonly occur in the carotid body, jugulotympanicarea, and vagus nerve but have also been reported in otherareas of the head and neck. These tumors are highly vascular andcharacteristically have early blood vessel and neural involvement,making their treatment particularly challenging. Surgery has traditionallybeen the preferred method of treatment, especially in light of recentadvances in technique. However, compared to radiation therapy, it canresult in a higher incidence of cranial nerve dysfunction. Radiationtherapy has the advantage of avoiding the increased morbidity ofsurgery while offering an equal possibility of cure. Part 1 of this two-partarticle focuses on techniques for diagnosing paraganglioma and theindications for and use of surgery as primary treatment. The complicationscommonly associated with surgery are reviewed, and strategies forrehabilitation of affected patients are presented.

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.

Dr. Karen Kelly has written atimely discussion on the clinicalbenefit of achieving stabledisease in advanced non–smallcelllung cancer (NSCLC). The goalsof current therapy are to palliate symptoms,optimize quality of life (QOL),and prolong survival. It is argued thattumor shrinkage may not be mandatoryto achieve these goals, particularlyin the evaluation of moleculartargeted therapies that may be cytostaticrather than cytotoxic in theirmechanism of action. However, stabledisease is not regarded as evidenceof therapeutic efficacy byregulatory authorities. Furthermore, ifbased on radiologic measurements Continued on page 968.alone, this designation encompasses aheterogeneous population that includespatients who demonstrate unequivocaltumor shrinkage as well asmany with tumor growth. Therefore,the case is presented to define stabledisease in terms of clinical benefit byincorporating alternative trial endpoints such as symptom control, QOL,or biologic end points.

The surgical management of cutaneousmelanoma remainscontroversial in part becausethere is no consensus regarding themargins of excision for the primarytumor or the therapeutic benefit ofremoving clinically normal appearingregional lymph nodes (electivelymph node dissection).[1] Intraoperativelymphatic mapping with sentinellymph node dissection hasrevolutionized the management of regionallymph nodes by allowing thesurgeon to perform a minimally invasiveprocedure instead of electivelymph node dissection, and by allowingthe pathologist to focus on one ortwo lymph nodes rather than all thenodes in a complete lymph node dissectionspecimen.[2]

The presence or absence oflymph node metastases is themost significant prognostic factorfor survival and recurrence in malignantmelanoma. Lymph node diseasedecreases the 5-year survival by 40%to 50%. The number of metastatic nodesand whether nodal metastases are clinicallyoccult or apparent are independentpredictors of survival.[1]

The cytostatic, molecular-targeted therapies becoming available forlung cancer and other human solid tumors are more likely to result instable disease than to produce tumor regression. In the setting ofadvanced lung cancer, stable disease provides significant benefit to thepatient. However, in the context of clinical trials, stable disease isvaguely defined, difficult to measure, and may represent a heterogeneouspatient population. The inclusion of alternative trial end pointssuch as symptom improvement and biologic activity may help to identifypatients who have achieved clinically relevant stable disease. Theepidermal growth factor receptor–tyrosine kinase inhibitor gefitinib(Iressa) has been shown to produce partial responses and stable diseasein patients with advanced lung cancer who have previously receivedtreatment with standard chemotherapies. In the monotherapy trials ofgefitinib, stable disease was correlated with improvements in diseaserelatedsymptoms and quality of life-the most meaningful end pointsfor the patient with advanced lung cancer. Thus, with the introductionof new molecular-targeted agents, stable disease with clinical benefitshould become an important goal of anticancer therapy.

Head and neck melanoma is a rare and aggressive childhoodmalignancy. Surgery remains the primary treatment, with lymphaticinvolvement determined by neck dissection. In the adult population,sentinel lymph node biopsy has emerged as a less morbid yet accuratemethod of staging regional lymph nodes. This innovative technique canalso be used in the pediatric population.

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.