Skin Cancer & Melanoma

Talabostat (PT-100, Point Therapeutics), an oral, small-molecule inhibitor of dipeptidyl peptidase (DPP) fast-tracked by the FDA for stage IIIB/IV non-small-cell lung cancer, also looks promising in salvage regimens for patients with advanced melanoma or chronic lymphocytic leukemia (CLL

The patient is an otherwise healthy male transferred from an outside hospital with a newly diagnosed melanoma from an unknown primary presenting as a large, left axillary mass.

During the past 18 months, researchers have developed substantial evidence supporting the notion that stem cells play a critical role in the development of at least some cancers, their progression, and the prognosis of patients, including breast, brain, lung, and prostate cancer, multiple myeloma, and melanoma.

On May 6, members of the American Academy of Dermatology (ADA) hope to set a Guinness World Record for the most people screened for skin cancer in a single day.

According to a 2005 survey conducted by the American Academy of Dermatology, 92% of the respondents understood that getting a tan from the sun is dangerous. Yet, 65% said that they think they look better when they have a tan.

ORLANDO-Adding the investigational antisense agent oblimersen sodium (Genasense, G3139) to dacarbazine (DTIC) significantly improved response and survival in patients with advanced malignant melanoma in a phase III trial. John M. Kirkwood, MD, of the University of Pittsburgh Cancer Institute, reported 2-year results at the 41st Annual Meeting of the American Society of Clinical Oncology (abstract 7506) (see Table).

Mohs surgery has been well-established as the gold standard for the treatment of BCCs and SCCs. And, as described in this article, preliminary reports suggest that it may play an equally important role in the management of several other cutaneous malignancies.

Drs. Pennington and Leffellhave provided an excellentoverview of the current uses ofMohs micrographic surgery. The procedurehas certainly come a long waysince the days of Frederic Mohs andthe application of zinc chloride paste(chemosurgery). Despite the fact that ithas indeed become the “gold standard”for the removal of basal cell carcinoma(BCC) and squamous cell carcinoma(SCC), there remain areas of controversyfor its use in melanoma and otherless common cutaneous neoplasms. Asmore dermatologists (and even a fewnondermatologists) have becometrained and gain experience in this specializedprocedure, and as more communitiesand university teaching centershave established growing Mohs practices,the procedure has become recognizedand embraced by health-careprofessionals and patients alike.

Statins inhibit the activity of the rate-limiting enzyme in the cholesterolbiosynthetic pathway, HMG-CoA reductase, and are widely prescribedfor lowering plasma lipid levels. Several statins have antitumor effects inexperimental models, and observational studies suggest that this anticanceractivity in the laboratory may translate into effective treatments and/orpreventive strategies for certain human cancers. This paper reviews thelaboratory and clinical evidence that statins have anticancer activity, discussesthe possible mechanisms by which tumor growth may be inhibitedby this class of drugs, and outlines strategies for the evaluation of theseagents in the prevention and treatment of human cancers.

Patients having locoregional or metastatic melanoma have a poorprognosis, with 50% to 100% of patients dying from the disease within5 years. Current chemotherapy regimens offer limited benefits to thesepatients, and more effective and less toxic treatments are needed. Wetherefore piloted a study of docetaxel (Taxotere), vinorelbine(Navelbine), granulocyte-macrophage colony-stimulating factor(GM-CSF, sargramostim [Leukine]), or the DVS regimen, in patientswith stage IV melanoma. Eight patients were treated after previousbiochemotherapy and two patients were given the regimen as an initialtreatment. The DVS regimen consisted of docetaxel at 40 mg/m2 IVover 1 hour, vinorelbine at 30 mg/m2 IV over 6 to 10 minutes every 14days, and GM-CSF at 250 mg/m2 SC on days 2 to 12. No grade 3 or 4toxicities were encountered. Of the 10 patients evaluable for response, 5were partial responders (50% response rate). Time to progression for the10 cases ranged from 2 to 26+ months (median: 8 months). The DVSregimen was active against advanced melanoma in both previously treatedand untreated patients. A larger study to confirm the activity of the DVSregimen for stage IV melanoma is currently under way.

Cytokines have been used in the treatment of patients with cutaneousmelanoma. Granulocyte-macrophage colony-stimulating factor(GM-CSF, sargramostim [Leukine]) leads to dendritic cell/macrophagepriming and activation, and also increases interleukin-2 (IL-2)receptor expression on T lymphocytes. IL-2 creates lymphokineactivatedkiller cells and tumor-infiltrating lymphocyte cells. In thisopen-label, single-arm study of 16 high-risk patients, we combined thesetwo agents to take advantage of their different but complementary functions.All patients underwent potentially curative surgery. Postoperatively,each patient received GM-CSF at 125 μg/m2/d subcutaneously(SC) for 14 days; this was followed by IL-2 at 9 million IU/m2/d SC for4 days, and then 10 to 12 days of no treatment. In addition, patientswho had large tumors that could yield over 100 million live tumor cellsreceived autologous melanoma vaccines. The duration of follow-upranged from 21 to 42 months (median: 27 months). During follow-up,five patients developed metastases. This program was carried out on anoutpatient basis, and no hospitalization was required. It was well toleratedwith minimal side effects. The combination treatment regimen ofGM-CSF and IL-2 with or without autologous vaccine used adjuvantlyappears to benefit high-risk melanoma patients; further clinical testingof this regimen is warranted.

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.

Cutaneous malignant melanoma is a relatively common neoplasm. In the United States in 1995, an estimated 34,000 cases of melanoma will be diagnosed, and 7,200 persons will die of melanoma [1]. Early primary melanoma is highly curable, but once the disease becomes disseminated, it is nearly always fatal. The overall survival rate has more than doubled from 40% in the 1960s to more than 80% today, but this increase is attributable to earlier diagnosis rather than to treatment advances [2].

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.

Vaccines are a promising but still experimental treatment for melanoma.They are intended to stimulate immune responses against melanomaand by so doing, increase resistance against and slow the progressionof this cancer. Key requirements for vaccines to be effectiveare that they contain antigens that can stimulate tumor-protective immuneresponses and that some of these antigens are present on thetumor to be treated. Unfortunately, these antigens are still not known.To circumvent this problem, polyvalent vaccines can be constructedcontaining a broad array of melanoma-associated antigens. Severalstrategies are available to construct such polyvalent vaccines; each hasadvantages and disadvantages. Clinical trials have shown that vaccinesare safe to use and have much less toxicity than current therapy formelanoma. Vaccines can stimulate both antibody and T-cell responsesagainst melanoma, with the type of response induced, its frequency,and its magnitude depending on the vaccine and the adjuvant agentused. A growing body of evidence suggests that vaccines can be clinicallyeffective. This evidence includes correlations between vaccineinducedantibody or T-cell responses and improved clinical outcome,clearance of melanoma markers from the circulation, improved survivalcompared to historical controls, and most convincingly, two randomizedtrials in which the recurrence-free survival of vaccine-treatedpatients was significantly longer than that of control groups.

There have been an astoundingnumber of published reviewson human cancer vaccines, andI take responsibility for my share. Apparentlythe interest of the medicalcommunity in cancer vaccines remainsintense, despite the modest progressthat has been made in our field and thepaucity of convincing, positive clinicalresults. Somehow the idea of treatinga cancer by inducing an antitumorimmune response or strengthening theexisting one is strongly appealing bothto physicians and to patients. Whetherthis enthusiasm is justified by the scienceis a question that should troublethe sleep of all of us who call ourselvestumor immunologists.

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.

The results of treatment for metastatic melanoma remain disappointing.Single-agent chemotherapy produces response rates ranging from8% to 15%, and combination chemotherapy, from 10% to 30%. However,these responses are usually not durable. Immunotherapy, particularlyhigh-dose interleukin (IL)-2 (Proleukin), has also shown a lowresponse rate of approximately 15%, although it is often long-lasting.In fact, a small but finite cure rate of about 5% has been reported withhigh-dose IL-2. Phase II studies of the combination of cisplatin-basedchemotherapy with IL-2 and interferon-alfa, referred to as biochemotherapy,have shown overall response rates ranging from 40% to60%, with durable complete remissions in approximately 8% to 10% ofpatients. Although the results of the phase II single-institution studieswere encouraging, phase III multicenter studies have reported conflictingresults, which overall have been predominantly negative. Variousfactors probably explain these discrepancies including differentbiochemotherapy regimens, patient selection, and, most importantly,“physician selection.” Novel strategies are clearly needed, and the mostencouraging ones for the near future include high-dose IL-2 in combinationwith adoptive transfer of selected tumor-reactive T cells afternonmyeloablative regimens, BRAF inhibitors in combination with chemotherapy,and the combination of chemotherapeutic agents andbiochemotherapy with oblimersen sodium (Genasense).

Dr. Buzaid’s article, “Managementof Metastatic CutaneousMelanoma,” is a review ofavailable treatment options with a historicalperspective. The conclusion includesa recommendation for the useof aggressive combination therapy inpatients who are young and otherwisehealthy enough to tolerate the toxicitiesof these aggressive forms of therapy,and consideration of single-agenttherapy for those who cannot tolerateaggressive combination regimens.While this review article includes thepublished reports as of the time of itssubmission, there are additional agentsand regimens that warrant mentiondue to their likelihood of improvingthe treatment landscape for future patientswith this devastating disease.Furthermore, some of the promisingregimens mentioned in this reviewshould be more closely scrutinized.The following commentary will coverthe topics included in Dr. Buzaid’sreport as well as updates on the currentstatus and future of selected investigationalagents.

Although chemotherapy regimenscan produce objectiveresponses in patients withmetastatic melanoma, curative responsesare extremely rare. It is thereforeof significant interest that themajority of complete responses to immunotherapywith high-dose interleukin(IL)-2 (Proleukin) alone aredurable and probably curative.[1]

The relationship between age andmelanoma prognosis is growingmore apparent and presentsinteresting scientific and social questions.My colleagues and I publishedtwo papers analyzing melanoma patientsfrom our institution. Our firstpaper examined a population of 620patients during a 26-year period, andour most recent paper analyzed 1,018melanoma patients over 30 years.[1,2]In both of these studies, age remainedan important prognostic predictor ofdisease-free and disease-specific survivalbased on multivariate analysis(Cox proportional hazard). We alsoapplied a novel classification and regressiontree (CART) evaluation ofthe data that showed age maintaininga significant influence on disease-freesurvival. Age maintained importancein disease-specific survival when genderwas used as the first parameter tosegregate the entire patient populationbefore applying tree-structuredstatistics.

Melanoma incidence and mortality continue to rise unabated in older individuals. Early clinical detection should take into account the different subtypes.

NEW YORK-Adding an antisense agent (oblimersen sodium, Genasense) to standard dacarbazine (DTIC) may significantly improve overall survival with only a slight increase in adverse effects, compared with DTIC alone, according to initial results from the largest-ever phase III trial in advanced metastatic melanoma. "We may have actually made a difference in overall survival in patients with metastatic melanoma," said researcher Anna C. Pavlick, DO, assistant professor of oncology, New York University School of Medicine.

The use of radiation as adjuvant therapy for patients with cutaneousmalignant melanoma has been hindered by the unsubstantiatedbelief that melanoma cells are radioresistant. An abundance of literaturehas now demonstrated that locoregional relapse of melanoma iscommon after surgery alone when certain clinicopathologic featuresare present. Features associated with a high risk of primary tumor recurrenceinclude desmoplastic subtype, positive microscopic margins,recurrent disease, and thick primary lesions with ulceration or satellitosis.Features associated with a high risk of nodal relapse include extracapsularextension, involvement of four or more lymph nodes, lymphnodes measuring at least 3 cm, cervical lymph node location, and recurrentdisease. Numerous studies support the efficacy of adjuvant irradiationin these clinical situations. Although data in the literatureremain sparse, evidence also indicates that elective irradiation is effectivein eradicating subclinical nodal metastases after removal of theprimary melanoma. Consequently, there may be an opportunity to integrateradiotherapy into the multimodality treatment of patients at highrisk of subclinical nodal disease, particularly those with an involvedsentinel lymph node. Such patients are known to have a low rate ofadditional lymph node involvement, and thus in this group, a shortcourse of radiotherapy may be an adequate substitute for regional lymphnode dissection. This will be the topic of future research.

Radiation therapy is not part ofthe traditional treatment approachto cutaneous melanoma.Aggressive surgical resection ofboth the primary site and regional nodalmetastases has long been consideredthe only option for achievinglong-term disease-free and overall survival.Many patients who present withmelanoma have thin lesions (< 1 mmBreslow thickness) and are essentiallycured with a wide local excision ofthe primary site. Patients with thickermelanomas and clinically negativeregional nodal basins often undergowide excision and sentinel node biopsyto identify occult nodal metastases.Those who have a sentinel lymphnode positive for metastatic diseaseor clinically positive nodes undergo atherapeutic lymph node dissection toprovide local control and possibly preventdistant metastatic disease. Recentarticles such as the one by Balloand Ang, however, highlight the in-creasedrole of external-beam radiationtherapy in the treatment of malignantmelanoma.

The rigorous assessment of thebenefits of radiotherapy formelanoma has been confoundedby superstition on one hand, andreligious fervor on the other. In thisissue, Ballo and Ang have reviewedthe use of radiotherapy for melanoma,focusing primarily on the controversialtopic of adjuvant postoperativeradiotherapy to the primary tumor bedand regional lymphatics.

In their article on radiotherapy forcutaneous malignant melanoma,Drs. Ballo and Ang discuss fourkey points, which we will addressbelow.

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.

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]