Chemoprevention of melanoma

The United States is experiencing a surge in the incidence of cutaneous malignant melanoma. Because melanoma is typically refractory to available anticancer therapy, exploration of preventive strategies has become a priority. In this review, the rationale for chemoprevention, a new and potentially powerful approach to controlling melanoma, is discussed. Chemoprevention success is based on the principles that ultraviolet-induced melanoma is a multistep process, and that molecular events and pathways associated with these steps can be targeted. Early studies using genetically engineered mice have begun to identify a number of relevant molecular pathways in melanoma. For example, Ras signaling pathways comprise all melanoma-related alterations in N-Ras, B-RAF, MAPK/ERK, and Rho proteins, and thus provide a host of potential molecular targets for melanoma chemoprevention. Among the available prospects, the statins, which inhibit Ras and Rho, have shown much promise as chemoprevention agents. However, thorough evaluation of chemoprevention candidates will require the identification of surrogate biomarkers for risk and molecular targets for intervention, as well as high-risk groups in which to focus clinical studies. We anticipate that melanoma chemoprevention research will progress in step with advances in genomics, proteomics, and preclinical mouse modeling, and ultimately provide us with powerful weapons in our struggle to control this escalating, often fatal disease.     

Chemoprevention of melanoma: theoretical and practical considerations.

BACKGROUND: Chemoprevention refers to the use of agents to reverse, suppress, or prevent carcinogenic progression of cancer. The use of chemoprevention is an unexplored strategy in melanoma prevention. METHODS: A retrospective review of the literature was undertaken regarding the important elements in evaluating chemoprevention as a strategy in melanoma. RESULTS: Several considerations need to be addressed before a chemoprevention agent can be moved to a large randomized trial. Statins have both experimental and epidemiologic evidence to support their further development as candidate chemopreventive agents, but the evidence is insufficient to justify large-scale phase III studies. A strong scientific rationale, a systematic approach to chemoprevention agent development with rigorous chemoprevention designs, and careful selection of surrogate endpoint biomarkers are critical issues in developing a chemoprevention strategy. CONCLUSIONS: Addressing these relevant considerations will allow for the development of chemoprevention in melanoma.     

Chemoprevention: an essential approach to controlling cancer

Mortality that results from the common forms of cancer is still unacceptably high. Despite immense advances in the understanding of the mechanisms of carcinogenesis, in bringing potent new drugs to the clinic and in treating several relatively rare forms of cancer, overall mortality statistics are unlikely to change in a fundamental way until there has been a re-orientation of emphasis in cancer research that will direct greater resources towards prevention of new disease, rather than treatment of end-stage disease.     

Chemoprevention of head and neck cancer: an update

Squamous cell carcinoma of the head and neck is an important public health problem worldwide that is clearly associated with the widely accepted risk factors of tobacco smoking and alcohol use and is the end result of a multiyear, multipath disease process of progressive genetic and associated tissue damage. Chemoprevention, the use of drugs or other agents to inhibit, delay, or reverse this process, is recognized as a very promising and important area in head and neck cancer research. Chemoprevention research is based on the increasing body of knowledge of the biology underlying head and neck tumorigenesis and is expected to ultimately result in a decrease in the incidence of head and neck cancer.     

Prospective evaluation of a follow-up schedule in cutaneous melanoma patients: recommendations for an effective follow-up strategy.

PURPOSE: To prospectively examine and evaluate the results of follow-up procedures in a large cohort of cutaneous melanoma patients. PATIENTS AND METHODS: This was a prospective study in 2,008 consecutive patients with stage I to IV cutaneous melanoma from 1996 to 1998 on the yield of stage-appropriate follow-up examinations according to the German guidelines. Documentation of patient and follow-up data comprised patient demography, primary tumor specifics, and any clinical and technical examinations performed. The detection of metastasis was classified as early or late, and the means of their detection and the resulting overall survival probabilities were examined. RESULTS: A total of 3,800 clinical examinations and 12,398 imaging techniques were documented. Sixty-two second primary melanomas in 46 patients and 233 disease recurrences in 112 patients were detected during this time. In stage I to III disease, physical examination was responsible for the discovery of 50% of all recurrences. In the primary tumor stages, 21% of all recurrences were discovered by lymph node sonography, with the majority being classified as early detection. Forty-eight percent of the recurrences were classified as early detection, and these patients had a significant benefit of overall survival probability. CONCLUSION: The results of our study suggest that an elaborated follow-up schedule in cutaneous melanoma is suitable for the early detection of second primary melanomas and early recurrences. The intensity of clinical and technical examinations can be reduced during follow-up of patients in the primary tumor stages and may be intensified in locoregional disease. Recommendations for an effective follow-up strategy are outlined.     

Chemoprevention of second cancers.

BACKGROUND: "Second cancers" can be thought of in two general categories: (a) those occurring as a consequence of cancer treatment and (b) primary cancers that are thought to develop largely as a consequence of prior lifestyle habits (e.g., chronic smoking, drinking, sun exposures), genetic susceptibility, or interactions of the two. Because there has been limited work on chemoprevention of treatment-related secondary cancers, this minireview will focus on chemoprevention of second cancers with lifestyle/genetic origins. METHODS/RESULTS: Trials aimed at preventing second cancers in patients with tobacco-related cancers (head and neck, lung), skin cancers, breast cancer, and colorectal adenomatous polyps have been completed with some success. However, one finding that has emerged is that, across several cancer sites, subgroups are found with differential response to the chemopreventive agent. For example, smoking status, alcohol consumption, nutritional status, and host tumor characteristics seem to modify chemopreventive efficacy. Stratum-specific (subgroup) findings may occur by chance, requiring a need for supportive evidence from observational epidemiologic studies of the agent (where available), mechanistic studies, or results of other related trials. CONCLUSIONS: Although chemoprevention of second cancers has been realized, it has become increasingly apparent that not all benefit equally. The finding of subgroup effects in completed trials results in the need to consider such subgroup effects in the design of future trials, by either restricting enrollment to particular subgroups (e.g., never or former smokers), or by increasing sample size requirements to allow for variation in response in subgroups in a statistically powerful way.     

Chemoprevention of epithelial cancers.

Over the past 2 years, new insights into mutator and stromal epithelial cell interactions have enhanced the understanding of the carcinogenesis process and have identified potential new approaches to chemoprevention in diverse epithelial sites. Data testing the efficacy of chemopreventive agents in genetically mutated animal carcinogenesis models as screening tools for chemopreventive agents remain immature and point to a continued need for chemical carcinogenesis models to screen for the potential efficacy of chemopreventive agents. The Breast Cancer Prevention Trial is a published, risk-reduction trial that demonstrated a tamoxifen-induced reduction of the risk for breast cancer and focused attention on the clinical use of chemopreventive agents in healthy women. This trial highlighted the potential chemopreventive activity of selective estrogen-receptor antagonists as chemopreventives for breast cancer. New data from animal and human models continue to support the development of nonsteroidal anti-inflammatory agents as chemopreventives for colorectal cancer. Micronutrient- and diet-intervention trials for colorectal chemoprevention present a mixed picture. Although calcium and vitamin supplements, including folate, reduce the recurrence of adenomatous polyps in humans, the effect is small. Fiber supplementation does not reduce the incidence of polyps or colorectal cancer. New approaches for the chemoprevention of esophageal adenocarcinomas, hepatomas, and squamous cell skin cancers represent promising new approaches to the chemoprevention of epithelial cancers.     

Chemoprevention of colorectal cancer.

Chemopreventive strategies hold substantial promise for reducing the incidence of colorectal cancer, the second leading cause of cancer-related mortality in the United States. This review focuses on recent advances in the identification of molecular targets and novel strategies for chemopreventive intervention. Many clinical trials are now in progress to assess the ability of synthetic agents or nutritional supplements to alter either the number of colorectal adenomas or biomarkers associated with colorectal tumorigenesis. Populations under study include genetically defined high-risk people and those with increased risk based on a personal history of colorectal neoplasia. A recent study showing that celecoxib, a cyclooxygenase-2 inhibitor, can alter the natural history of polyp formation in patients with familial adenomatous polyposis has provided a benchmark for the clinical development of other chemopreventive agents and heightened awareness that colorectal cancer is a preventable disease.     

Chemoprevention of breast cancer.

Trials with tamoxifen have clearly shown that the risk of developing oestrogen receptor positive breast cancer can be reduced at a late stage in the natural history with prophylactic agents. About half of the oestrogen receptor positive cases were prevented, but there was no beneficial effect on ER-negative cancers. The current challenge is to find new agents which achieve this or better efficacy but with fewer side effects. Recent results indicate that the SERM raloxifene has similar efficacy to tamoxifen, but leads to fewer endometrial cancers, gynaecologic symptoms, and thromboembolic events. Results for contralateral tumours in adjuvant trials suggest that aromatase inhibitors may be able to prevent up to 70-80% of ER-positive breast cancers, and this is currently being investigated in two large prevention trials, one using anastrozole (IBIS-II) and the other exemestane (MAP.3). New agents are needed, for receptor negative breast cancer and several possibilities are currently under investigation.     

D.N.C.B. for malignant melanoma: significance in the treatment strategy

2-4 Dinitrochlorobenzene (D.N.C.B.) is a synthetic primary allergenic molecule which has proved to have at least two useful clinical applications as regards neoplastic conditions. As a diagnostic measure, it serves in the detection of global alterations of cellular immunity. As a therapeutical measure, its epicutaneous use has proved to stimulate immune defence reactions loco-regionally if not systemically. This second property finds an important field of application in the treatment of malignant melanoma (M.M.), the reason for this being that natural immune defence reactions seem to play an important role in the natural history of this type of tumor. This review collects literature data on the therapeutical use of D.N.C.B: which, together with personal cases, show that this type of treatment may be proposed as a palliative measure for the treatment of skin metastases or as an adjuvant measure for surgery in the treatment of M.M. with surgically accessible metastases. D.N.C.B. appears to be part of a new therapeutical group, the Biological Response Modifiers (B.R.M.), and would seem to have a place in future treatment protocols associating B.R.M. with other treatment methods (e.g. chemotherapy).     

Treatment strategy for cutaneous malignant melanoma

The incidence of cutaneous malignant melanoma has been rising in Japan. With education, recent advances in accurate diagnosis and establishment of the concept, more lesions are being diagnosed as early melanomas, for which there is a high cure rate. However, many patients will still present with thicker lesions or nodal involvement, which carries a significantly worse prognosis. Recently there have been advances in the management and treatment of cutaneous melanoma. This article reviews the clinical evidence behind the current treatment recommendations for primary and recurrent cutaneous melanoma in Japan.     

Immunotherapy of melanoma: an update

The incidence of melanoma has been increasing worldwide. A relationship between melanoma and the immune system was established years ago. Modulating the immune system in the management of different stages of melanoma has been the focus of numerous large randomized trials worldwide. This article reviews the current status of immunotherapy for melanoma, with a focus on the recent promising results from using vaccines, cytotoxic T-lymphocyte antigen-4 (CTLA-4) antibodies, and adoptive cell therapy.     

Chemoprevention of breast cancer with retinoids.

Fenretinide [N-(4-hydroxyphenyl)retinamide, 4-HPR] is an effective agent for the inhibition of N-nitroso-N-methylurea-induced breast cancer in rats. This compound has been studied extensively and proved to be safer and less teratogenic than many other retinoids. A major characteristic of 4-HPR is its ability to concentrate in the granular and fat tissue of the breast instead of in the liver. Between January and June 1986, we carried out a phase I study on 101 patients divided into four randomized groups receiving placebo and 100, 200, and 300 mg/day of 4-HPR. Patients received the drug for 6 months without any major toxic effect. This finding was confirmed by another 6-month study in which patients received a common dose of 200 mg/day. In March 1987, a phase III study was started to evaluate the effectiveness of 4-HPR in preventing contralateral primary tumors in women who had already been treated for breast cancer. If 4-HPR succeeds in preventing second primaries in breast cancer patients, it may be useful for a wider group of subjects at high risk for breast cancer. This randomized study was designed with two arms: an intervention group versus a group receiving no treatment. Patients in the intervention group will be treated with 200 mg/day 4-HPR for 5 years. Patients in the control group will not be treated. A further 2 years of follow-up is planned for both groups. Currently, 2450 patients have been recruited. We expect a total accrual of 3500 patients by the end of 1992.     

黏膜黑色素瘤的探索与治疗策略

黏膜黑色素瘤是黑色素瘤的一种罕见亚型,具有独特的生物学和临床特征.研究其特有的低突变负荷、高结构变异负荷和独特的驱动基因将有助于了解其自然病程及其对各种治疗的反应.目前仍缺乏黏膜黑色素瘤最佳治疗策略的共识.新的靶向治疗和免疫治疗的联合治疗是目前临床试验研究的方向.血管内皮生长因子(vascular endothelia...     

Risks of BCG intralesional therapy: an experience with melanoma.

A nearly fatal allergic reaction to intratumor BCG injections was associated with a complete remission of recurrent malignant melanoma. Clinical course and histologic sections suggested both anaphylactic and Arthus reactions. The occurrence of reactions at BCG injection sites as well as at uninjected sites of tumor suggests common BCG and melanoma antigens. The management of events involved in this often fatal postimmunotherapy complication involves the early administration of parenteral fluids, antituberculous therapy, antihistamines, and possible steroids. The prophylactic use of antihistamines and an in-hospital administration of intralesional BCG immunotherapy are strongly suggested. In the future, prophylactic INH may prove to be both therapeutically efficacious and protective against infectious complications.