Skin Cancer & Melanoma

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]

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.

NEW YORK-An antisense oligonucleotide directed against Bcl-2 is yielding "remarkable" responses in specific melanoma patients enrolled in a phase III trial, according to Anna C. Pavlick, DO, assistant professor of medicine, New York University School of Medicine.

NEW YORK-Antigenics Inc. announced positive final results from a phase II study of the company’s personalized heat shock protein cancer vaccine Oncophage (HSPPC-96) in patients with metastatic melanoma. The study included 39 evaluable patients with stage IV melanoma who underwent surgery to remove tumor tissue, which was used to produce their personalized Oncophage vaccine.

KING OF PRUSSIA, Pennsylvania-Protarga, Inc. has received comments from the FDA that allow it to proceed with two separate phase III clinical studies of its new cancer drug Taxoprexin Injection (DHA-pacli-taxel) for the treatment of metastatic melanoma and pancreatic cancer. Taxoprexin is made by linking the fatty acid docosahexaenoic acid (DHA) to paclitaxel, the company said in a news release.

Despite significant advances in the treatment of a variety of malignancies, highly effective therapies for most patients with metastatic renal cell carcinoma or metastatic melanoma are rare. Traditional oncologic treatment methods, such as

Interleukin-2 (IL-2, Proleukin) is one of the most effective agents in the treatment of metastatic renal cell carcinoma and metastatic melanoma. High-dose IL-2 therapy produces overall response rates of 15% to 20%;

Although high-dose interleukin-2 (IL-2, Proleukin), a highly toxic agent used in the treatment of renal cell carcinoma and melanoma, was initially associated with treatment-related mortality, it can, in the appropriate

NEW ORLEANS-Because of their malignant potential and their cosmetic appearance, congenital nevi elicit much concern from parents. Ashfaq A. Marghoob, MD, assistant professor of dermatology and director of the Pigmented Lesion Group, Memorial Sloan-Kettering Cancer Center, presented new insights into this disorder at a symposium on melanoma held during the American Academy of Dermatology annual meeting.

Flavopiridol [2-(2-chlorophenyl 5 ,7-dihydroxy-8-[cis-(3-hydroxy-1-methyl-4-piperidinyl)-4H-1-benzopyran-4-one, hydrochloride] is a semisynthetic flavone with a novel structure compared with that of polyhydroxylated flavones, such as quercetin and genistein.[1] It is derived from rohitukine, an alkaloid isolated from the stem bark of Dysoxylum binectariferum, a plant indigenous to India.[2] Originally synthesized and supplied by Hoechst India Limited, flavopiridol is provided to the Division of Cancer Treatment and Diagnosis of the National Cancer Institute (NCI) by Aventis Pharmaceuticals, Inc.

Two of the most important predictors of relapse (and, therefore, survival) in patients with melanoma are the Breslow thickness of the primary melanoma and regional lymph node involvement. Patients with melanomas greater than 4 mm in thickness have approximately a 50% risk of recurrence, and those with lymph node involvement have a 50% to 85% risk of recurrence depending on the number of lymph nodes involved. Thus, a group of patients can be identified who are at high risk of death from melanoma and are, therefore, appropriate candidates for postsurgical adjuvant therapy.

Despite more than 2 decades of active clinical study, the use of interferon as adjuvant therapy for high-risk melanoma remains controversial. The controversy has centered on dose, schedule, and toxicity of treatment. Agarwala and Kirkwood superbly summarize the clinical studies to date and highlight many of the salient issues relevant to clinicians.

Melanoma is almost 100% curable when diagnosed early, but when metastatic to distant organs, it is associated with a poor survival. The interferons have shown the most promise in the treatment of melanoma and interferon

The authors are to be complimented on a thoughtful and complete review of the application of the sentinel node paradigm to colorectal cancer. This paradigm is inherently quite different for colorectal cancer because, except for the occasional demonstration of variant anatomy, the technique will not alter the extent of surgery as it has done in melanoma and breast cancer.

The role of sentinel lymph node identification has been investigated over the past decade in a variety of malignancies. It has become part of standard care for melanoma. Its role in breast cancer is evolving, but with the completion of two large randomized clinical trials, it will probably be added to the surgical armamentarium for the management of most breast cancers. Studies have been proposed or are under way to evaluate sentinel node mapping in head and neck cancer, penile and vulvar cancer, and gastrointestinal cancers.