Maintaining professional activity during breast cancer treatment.

The question of returning to work and pursuing professional activity during cancer treatment is an increasingly important consideration. The present work focuses on factors affecting the feasibility of maintaining professional activity during treatment for breast cancer, for women who wished to do so. Written questionnaires were collected from 216 patients between March and November 2012. Since the onset of their treatment, 31.4% of the women (68/216) had not been on sick-leave. The main factors associated with the pursuit of professional activity were: considering the availability of their physician to answer questions as unimportant [OR = 18.83 (3.60-98.53); P ≤ 0.05]; considering the diagnosis of cancer as likely to have a weak impact on career perspectives [OR = 4.07 (2.49-6.64); P ≤ 0.05]; not having any children in the household [OR = 3.87 (2.38-6.28); P ≤ 0.05]; being in a managerial position [OR = 3.13 (1.88-5.21); P ≤ 0.05]. Negative predictive factors were: physician mentioning adverse effects of the treatment [OR = 0.31 (0.16-0.58); P ≤ 0.05], and patient rating workload as high [OR = 0.26 (0.15-0.46); P ≤ 0.05]. As a result of advances in therapeutic strategies, more patients will expect healthcare professionals, as well as employers and occupational health societies, to prioritise issues pertaining to the maintenance of professional activities during cancer treatment.

Concurrent trastuzumab with adjuvant radiotherapy in HER2-positive breast cancer patients: acute toxicity analyses from the French multicentric study.

BACKGROUND: Trastuzumab (T) combined with chemotherapy has been recently shown to improve outcome in HER2-positive breast cancer (BC). The aim of this study was to evaluate the toxic effects of concurrent radiation therapy (RT) and T administration in the adjuvant setting. PATIENTS AND METHODS: Data of 146 patients with stages II-III HER2-positive BC were recorded. Median age was 46 years. In all, 32 (23%) and 114 (77%) patients received a weekly and a 3-week T schedule, respectively. A median dose of 50 Gy was delivered after surgery. Internal mammary chain (IMC) was irradiated in 103 (71%) patients. RESULTS: Grade >2 dermatitis and esophagitis were noted in 51% and 12%, respectively. According to the Common Toxicity Criteria v3.0 scale and HERA (HERceptin Adjuvant) trial criteria, respectively, 10% and 6% of the patients had a grade >/=2 of left ventricular ejection fraction (LVEF) decrease after RT. Multivariate analyses revealed two independent prognostic factors: weekly T administration (for LVEF decrease) and menopausal status (for dermatitis). Higher level of T cumulative dose (>1600 mg) was only borderline of statistical significance for acute esophagitis toxicity. CONCLUSION: We showed that weekly concurrent T and RT are feasible in daily clinical practice with, however, a decrease of LVEF. Cardiac volume sparing and patient selections for IMC irradiation are highly recommended. Longer follow-up is warranted to evaluate late toxic effects.

Phase II study of sequential administration of docetaxel followed by doxorubicin and cyclophosphamide as first-line chemotherapy in metastatic breast cancer.

PURPOSE: To evaluate the feasibility and efficacy of a sequential administration of four cycles of docetaxel (100 mg/m(2) every 3 weeks) followed by four cycles of doxorubicin and cyclophosphamide (AC; 60/600 mg/m(2) every 3 weeks), with subsequent consolidation with docetaxel or AC, as first-line chemotherapy in patients with metastatic breast cancer (MBC). PATIENTS AND METHODS: Forty-eight patients received 443 cycles of chemotherapy (median, 11 cycles/patient; range, 1 to 13 cycles). A total of 267 cycles of docetaxel (60.3%) and 176 of AC (39.7%) were given. Consolidation therapy was given to 33 patients (29 with docetaxel). RESULTS: Grade 4 neutropenia was the most frequent toxicity (83% of patients). This was not cumulative and was rarely complicated by febrile neutropenia or severe infection. The nonhematologic safety profile was favorable: there were no grade 4 adverse events, and grade 3 episodes were infrequent. Docetaxel-specific toxicities were generally not severe. With a median cumulative doxorubicin dose of 397 mg/m(2) (range, 150 to 543 mg/m(2)), two incidences of unrelated congestive heart failure after further treatment with anthracyclines and two of asymptomatic left ventricular ejection fraction decrease were observed. Among the 42 assessable patients, five (12%) had complete and 25 (60%) had partial responses, for an overall response rate of 71% (95% confidence interval, 55% to 84%). Median duration of response was 53 weeks (range, 12 to 72 weeks), and median time to progression was 46 weeks (range, 3 of 72 weeks). With a median follow-up of 40.4 months, median survival was 32 months (range, 2 to 55 months). CONCLUSION: This docetaxel-based sequential schedule is safe and effective in first-line therapy for MBC, without incurring cumulative toxicity, and provides a feasible chemotherapeutic option in this clinical setting.

Endogenous interleukin 6 levels in patients with metastatic malignant melanoma: correlation with tumor burden.

The involvement of interleukin (IL-) 6 in malignant disease has been investigated in a variety of different malignancies. To evaluate whether serum IL-6 is a useful disease marker in metastatic malignant melanoma (MMM), we studied the time course of endogenous IL-6 secretion in 41 patients treated with cisplatinum, IL-2, and IFN-alpha. Furthermore, the relationship of endogenous IL-6 concentrations to the tumor burden and/or the clinical response was also evaluated. The baseline serum IL-6 levels were significantly higher in patients with MMM than in the control group (P = 0.002). When tumor burden was taken into consideration, we found that IL-6 levels were higher in patients with high tumor burden than in patients with low tumor burden. During treatment in the whole patient population, a higher serum IL-6 level was observed in nonresponding as compared to responding patients at days 7 (P = 0.0005), 21 (P = 0.002), and 35 (P = 0.009). The follow-up of serum IL-6 in patients with MMM according to the tumor burden and clinical response demonstrated that: (a) IL-6 levels were significantly higher at days 7 and 21 in patients with high tumor burden as compared to those with low tumor burden; and (b) IL-6 levels remain significantly higher in nonresponding patients as compared to responding patients regardless of the tumor burden. From these results, we can conclude that endogenous IL-6 may play a role in the failure of IL-2 therapy in such patients, since the very early IL-6 increase is correlated with the tumor mass and nonresponse to biochemotherapy. Therefore, it seems that the early detection of endogenous IL-6 may represent valuable information for monitoring the response to biochemotherapy in patients with MMM.

Preliminary results of a phase I/II study of paclitaxel, cisplatin, and cyclophosphamide in advanced ovarian carcinoma.

The clinical activity and toxicity of the triple combination of paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ), cyclophosphamide, and cisplatin was assessed in both previously treated and untreated women with advanced ovarian carcinoma. Paclitaxel 175 mg/m2 was administered over 3 hours following standard premedication (prednisolone, dexchlorpheniramine, and cimetidine). Cisplatin 80 mg/m2 and cyclophosphamide 600 mg/m2 were given 6 to 12 hours after paclitaxel. Treatment was given at 3-week intervals for six cycles. Twenty-seven patients entered the study; 23 were evaluable for toxicity and 17 for response. Paclitaxel appeared to add additional efficacy to the standard cisplatin/cyclophosphamide regimen. Both the overall and complete remission rates were very high (88% and 70%, respectively), and histologically confirmed complete remissions exceeded 60%. Longer follow-up is needed to determine the duration of these responses. The primary toxicities included leukoneutropenia, peripheral neuropathy, asthenia, and alopecia. Only two of 23 patients withdrew because of toxicity, however, and only two treatment cycles were complicated by neutropenic fever requiring intravenous antibiotics. No life-threatening toxicities were encountered, although the peripheral neuropathy was poorly and slowly reversible and may have a significant impact on the patients' quality of life.

Phase I/II study of paclitaxel, cisplatin, and cyclophosphamide in advanced ovarian carcinoma: preliminary results.

In this phase I/II study, we assessed the impact of paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) in the treatment of advanced ovarian carcinoma combined with the standard regimen cisplatin/cyclophosphamide given as follows: paclitaxel 175 mg/m2 (over 3 hours perfusion with standard premedication), cisplatin 80 mg/m2 (6 to 12 hours after paclitaxel), and cyclophosphamide 400 mg/m2. From February 1994 to January 1996, 27 patients (median age, 55 years; age range, 35 to 74 years) were entered into the study. Eight patients had distant metastases and 19 had early locoregional disease (stage III, 18 patients; stage IC, one patient). Twenty-two patients had undergone prior surgery (simple biopsy, six patients; optimally debulked, nine patients; suboptimally debulked, seven patients). Twenty-one patients had received no prior chemotherapy and six were previously treated with at least one platinum-based regimen. A maximum of six courses of paclitaxel/cisplatin/cyclophosphamide were given every 21 days. Twenty-three patients were evaluable for toxicity: neutropenia (World Health Organization grade 3/4), 91% of patients; thrombopenia (World Health Organization grade 3/4), 13% of patients; two episodes of neutropenia with fever; and neurotoxicity grade 3, 17% of patients. Alopecia grade 3 was reported in all patients. No hypersensitivity reactions and no cardiac toxicity was observed. Among 17 patients evaluable for response (patients with stage IV disease or stage III suboptimally debulked), 12 (70%) clinical complete responses (CRs) and three (18%) partial responses were observed. Among the 12 patients with CRs, 10 underwent second-look laparotomy and seven of them (70%) achieved a pathologic CR. In the group of 11 chemotherapy-naive patients evaluable for response, eight (72%) achieved a CR and three (28%) achieved a partial response. This combination seems to be safe, with very acceptable toxicity, and also seems to be highly active in the treatment of patients with advanced ovarian carcinoma.

European School of Oncology European consensus on the use of granulocyte colony-stimulating factor: the example of breast cancer.

An apparent chemotherapeutic dose-response relationship for patients with breast cancer has provided clinicians with the impetus to investigate further the usefulness of dose-intensification strategies in this setting. These approaches have provided promising results: noticeable improvements in response rates in terms of disease-free survival have been recorded, particularly when dose intensification has been used as first-line consolidation therapy for chemosensitive advanced disease and as consolidation in adjuvant therapy for high-risk patients. It may also be of use in the treatment of inflammatory and locally advanced disease. Although the results of prospective studies will help to define the potential advantages of dose-intensification strategies further, comparisons of myeloablative and subablative intensification regimens are needed to define the role of dose and dose intensity in this setting.

Serum caspase-1 levels in metastatic melanoma patients: relationship with tumour burden and non-response to biochemotherapy.

Interleukin-1beta converting enzymes (ICEs/caspases) are involved in programmed cell death (apoptosis). This study sought to quantify the caspase-1 level in metastatic malignant melanoma patients and to try to establish a correlation between the level of caspase-1 and different parameters related to this pathology. In addition, we evaluated the possible relationship between the clinical response to biochemotherapy and the caspase-1 level. The serum caspase-1 level was determined in 81 metastatic malignant melanoma patients and 50 normal volunteers using enzyme-linked immunosorbent assay (ELISA). Patients received cisplatin, recombinant interleukin-2 (Proleukin) and alpha-interferon (Roferon A) in two induction cycles, and assessment of clinical response was performed according to World Health Organization (WHO) criteria. The median caspase-1 level in melanoma patients was significantly higher (P = 0.0035) than in control samples. Interestingly, a positive correlation between caspase-1 level and the tumour burden was shown (rs = 0.629, P = 0.009). When the clinical response was taken into consideration, the level of caspase-1 was significantly higher in biochemorefractory patients compared with responding ones (P = 0.04). After treatment, the caspase-1 level remained very high in biochemorefractory patients, while in responding ones no change was observed. Furthermore, a positive correlation between the clinical response and the caspase-1 level was established (rs = 0.404, P = 0.024). In conclusion, we observed an elevated caspase-1 level in metastatic malignant melanoma patients. In addition, the correlations obtained between the caspase-1 level and both the tumour burden and the clinical response to the treatment support the concept that disrupted apoptosis pathways might be involved in the progressive disease of advanced melanoma and/or may confer resistance to treatment.

Is there any relationship between interleukin-6/interleukin-6 receptor modulation and endogenous interleukin-6 release in metastatic malignant melanoma patients treated by biochemotherapy?

During recent years it has become clear that the production of most cytokines could play an important role in malignancies. We previously demonstrated that a high endogenous interleukin-6 (IL-6) level is significantly correlated with a high tumour burden and resistance to biochemotherapy in metastatic malignant melanoma patients. However, little is known about the origin of IL-6 and the pattern of IL-6 receptor (IL-6R) expression. In this report, we studied the expression of IL-6R and intracellular IL-6 using flow cytometry in tumour cells provided by fine-needle aspiration of lymph nodes and palpable metastatic lesions from 14 patients refractory to biochemotherapy and six responder patients. Moreover, we established the relationship between these parameters and the serum IL-6 level. Our results demonstrated that, following treatment, the percentage of HMB45-positive (HMB45+) cells expressing functional IL-6R, intracellular IL-6 or both IL-6R and IL-6 significantly decreased in patients refractory to biochemotherapy. In contrast, in responder patients the percentage of HMB45+ cells expressing IL-6R increased and those expressing IL-6 remained stable. Regarding the serum IL-6 level, an 11-fold increase was observed in the patients refractory to biochemotherapy, but only a 1.8-fold increase in the responder patients. In conclusion, in metastatic malignant melanoma patients with a poor prognosis, the endogenous production of IL-6 is concomitant with a decrease in functional IL-6R and intracellular IL-6 expression, suggesting the involvement of an IL-6/IL-6R complex.

The role of irinotecan and oxaliplatin in the treatment of advanced colorectal cancer.

Colorectal carcinoma is one of the most common malignancies in the western world, and although fluorouracil (5-FU) has been used in its treatment for almost 40 years, new agents with significant activity have been introduced recently. Irinotecan (CPT-11, Camptosar), a topoisomerase I inhibitor, administered at 300 to 350 mg/m2 every 3 weeks is significantly more active than continuous-infusion 5-FU in patients who have experienced disease progression after conventional therapy with 5-FU. In comparison to best supportive care, irinotecan improves survival and preserves quality of life despite treatment-related toxicity. Moreover, the combination of irinotecan and 5-FU has been explored in a number of different schedules. In previously untreated patients, overall response rates are high. Irinotecan can also be combined with mitomycin (mitomycin-C [Mutamycin]), oxaliplatin, or raltitrexed (Tomudex). Oxaliplatin is a new-generation platinum compound that has demonstrated activity against colorectal carcinoma in preclinical trials. It has been evaluated as a single agent against advanced colorectal carcinoma in the salvage setting and also in combination with 5-FU as initial therapy for metastatic disease (where it shows significant activity). The toxicity profile of oxaliplatin (chiefly characterized by neurotoxicity) differs from that of irinotecan (primarily producing diarrhea) and the potential, therefore, exists for combining these agents or for exploiting their possible synergy with 5-FU. The introduction of these two new active agents of different pharmacologic classes promises to enable significant improvements in the treatment of patients with colorectal carcinoma.

European experience with irinotecan plus fluorouracil/folinic acid or mitomycin.

Tremendous progress has been made in the medical treatment of advanced colorectal cancer during the past 2 to 3 years, due to the availability of several new drugs. Of these new agents, irinotecan (CPT-11 [Camptosar]) seems to be one of the most active against advanced colorectal cancer. It is, therefore, a good candidate for combination with the more classic cytotoxic agents for this disease. This article summarizes several European phase I and II studies in which irinotecan has been combined with (1) fluorouracil (5-FU) alone, given as a repeated bolus injection or a protracted infusion; (2) 5-FU modulated by folinic acid (leucovorin) according to different schedules; or (3) mitomycin (Mutamycin). All of these studies have demonstrated clinical responses in patients with advanced colorectal carcinoma, including complete responses. The toxicity profiles of the various combinations seem to be acceptable; neutropenia and delayed diarrhea are the most frequent side effects. Large phase III studies are still warranted to demonstrate the benefit of these irinotecan-based regimens.

Phase I-II study of irinotecan in combination with mitomycin C in patients with advanced gastrointestinal cancer.

This phase I-II study was conducted to determine the maximum tolerated dose and optimal schedule of a combination of irinotecan (CPT 11) and mitomycin C (MMC) in a population of previously treated patients with gastrointestinal malignancies. Four cohorts of patients were recruited with MMC given at 8 mg/m2 for the first 3 levels together with irinotecan at 300 mg/m2, 325 mg/m2, and 350 mg/m2; the fourth dose level was given with MMC at 10 mg/m2 and irinotecan at 325 mg/m2. All treatment was repeated at 21-day intervals. The dose-limiting toxicity was hematologic (thrombocytopenia at level 4), and the recommended doses for subsequent phase II studies are MMC 8 mg/m2 with irinotecan 325 mg/m2. Evidence of efficacy was seen at all dose levels examined and justifies further exploration of this combination in a less heavily pretreated patient population.

A phase II study of tamoxifen combined with cisplatin-interleukin 2 and alpha-interferon in metastatic melanoma.

Tamoxifen (TAM) has been reported to enhance cisplatin (CDDP) cytotoxicity in experimental and clinical melanoma studies. Based on our previous experience with sequential cisplatin-interleukin-2 (IL2)-interferon (IFN), we performed a phase II study of TAM combined with our original CDDP-IL2-IFN regimen in 22 pretreated metastatic melanoma patients. With a 41% response rate (95% CI, 21-61) we confirmed the interesting antitumor activity of CDDP-IL2-IFN combination; however, TAM enhanced neither the response rate nor the duration of response, but appeared to induce significantly more myelotoxicity, as compared to our previous results with CDDP-IL2-IFN alone. Whereas mechanisms by which TAM may modulate CDDP cytotoxicity in melanoma tumors remain unknown, the exact place of TAM, if any, and its safety in chemotherapeutic or chemoimmunotherapeutic combinations require further investigations.

ONCODOC: a successful experiment of computer-supported guideline development and implementation in the treatment of breast cancer.

Originally published as textual documents, clinical practice guidelines have poorly penetrated medical practice because their editorial properties do not allow the reader to easily solve, at the point of care, a given medical problem. However, despite the proliferation of implemented clinical practice guidelines as decision support systems providing an easy access to patient-centered information, there is still little evidence of high physician compliance to guidelines recommendations. Apart from physicians' psychological reluctance, the incompleteness of guideline knowledge and the impreciseness of the terms used, another reason may be that, although suited to average patients, clinical practice guideline recommendations are not a substitute for the physician-controlled clinical judgement that should be applied to each actual individual patient. Therefore, computer-based approaches based on the automation of context-free operationalization of guideline knowledge, although providing uniform optimal strategies to problem-focused care delivery, may generate inappropriate inferences for a specific patient that the physician does not follow in practice. Rather than providing automated decision support, ONCODOC allows the clinician to control the operationalization of guideline knowledge through his hypertextual reading of a knowledge base encoded as a decision tree. In this way, he has the opportunity to interpret the information provided in the context of his patient, therefore, controlling his categorization to the closest matching formal patient. Experimented in life-size ONCODOC demonstrated good appropriation of the system by physicians with significantly high scores of compliance. We successfully tested the implemented strategy and the knowledge base in a second medical institution, giving then a noticeable example of reuse and sharing of encoded guideline knowledge across institutions.

[The role of new drugs in the treatment of locally advanced urothelial tumors of the bladder]. / Place des nouvelles drogues dans le traitement des tumeurs urothéliales de vessie localement évoluées.

Although the optimal management of muscle-invasive bladder cancer remains a continued subset of controversy, results achieved with either radical cystectomy, or radiation therapy or combinations of the two lead to cure rates of only 50% with up to 50% of patients who will develop metastases, usually within two years. For the past ten years, chemotherapy of advanced urothelial tumors has focused on cisplatin-based combinations such as methotrexate-vinblastine-adriamycin-cisplatin (M-VAC), cisplatin-methotrexate-vinblastine (CMV) or cisplatin-adriamycin-cyclophosphamide (CISCA). Such regimens have provided interesting results with responses rate up to 70% and some long term survival (in 10 to 20% of patients), but this has focused achieved with moderate to severe toxicity. Thus, if the chemosensitivity of advanced urothelial tumors is obvious, it is clear that a therapeutic plateau has been reached and only the search for new active agents can provide any hope to improve the results of these established regimens. Recently some single agents under investigation including taxanes (paclitaxel and docétaxel) and gemcitabine have been identified and have entered clinical development. Preliminary data of several phase II studies are now available and they appear promising, providing the basis of new combinations regimens that will attempt to improve results that have been achieved with standard regimens during the past decade. The activity of these new single agents and new combination are reviewed.

[Patient-centered consultation of "good practice guidelines": OncoDoc, a decision support system for the management of breast cancer patients]. / Consultation centrée-patient d'un 'guide de bonnes pratiques': OncoDoc, un système d'aide à la décision thérapeutique appliqué au cancer du sein.

Beyond considerations of cost-effectiveness, clinical practice guidelines (CPG) can reduce practice variations and thus improve the quality of care. However, despite the proliferation of implemented CPG and their wide diffusion thanks to Internet-based technologies, physicians' compliance with formal standards is weak. Developed according to a document-based paradigm, OncoDoc proposes an original framework for implementing CPG. Domain knowledge has been encoded as a decision tree whose branches are both exclusive and exhaustive. This generic knowledge is operationalized at the point of care by the interactive building, through hypertextual navigation, of a patient-based clinical context leading to specific therapeutic recommendations. OncoDoc has first been applied to the management of breast cancer patients and demonstrated within a full-scale experimentation in a clinical setting a compliance of 80 per cent.

[Clinical imaging of osteo-condensed metastases]. / Imagerie clinique des métastases ostéocondensantes.

INTRODUCTION: Due to the occurrence of osteoblastic metastases in the course of various cancers, particularly in the course of prostate cancer, we are faced with diagnosis and follow-up issues different from those associated with lytic metastasis. We therefore analyzed the respective advantages of imaging techniques. CURRENT KNOWLEDGE AND KEY POINTS: Most of the time, osteoblastic metastases are evidenced by standard radiography. Due to its ability to demonstrate metastases localization, extent and signs, CT scan is not only of value when osteoblastic metastases are suspected but also for patient's follow-up. MRI provides further information in regard to both the lesion content and osteoblastic degree. Though MRI must be performed after all other imaging procedures, it is of value for multiplanar study of the whole spine. FUTURE PROSPECTS AND PROJECTS: Studies focusing on either the lesion content and volume or helical CT are in progress and aim at better monitoring follow-up, while the objective of dynamic MRI studies is to better analyze lesion content.

A before-after study using OncoDoc, a guideline-based decision support-system on breast cancer management: impact upon physician prescribing behaviour.

Guideline-based decision support systems have been developed to influence the prescribing behaviour of clinicians, but they have not yet shown to increase physician compliance with best practices in routine. OncoDoc is a non-automated system that allows flexibility in guideline interpretation to obtain best patient-specific recommendations at the point of care. OncoDoc is applied to breast cancer management. We have experimented the system at the Institut Gustave Roussy with a before-after study in which treatment decisions for breast cancer patients were measured before and after using the system in order to evaluate its impact upon physicians' prescribing behaviour. After 4 months, 127 decisions were recorded. Physicians compliance with OncoDoc was significantly improved (p < 10(-4) ) to reach 85.03% after using the system. Comparison of initial and final decisions showed that physicians modified their prescription in 31% of the cases. Clinical trial accrual rate increased of 50%, though not statistically significant because estimated on small figures.

Effect of endogenous interleukin-6 on Fas (APO-1/CD95) receptor expression in advanced melanoma patients.

Interleukin-6 (IL-6) has been shown to support either autocrine or paracrine growth in melanoma, and may prevent programmed cell death in different cell types. We have previously demonstrated that the endogenous IL-6 level is significantly correlated with tumor burden and nonresponse to biochemotherapy in metastatic malignant melanoma patients. In the present study, we investigated the relationship between endogenous IL-6 and apoptosis signal through Fas (APO-1/CD95) receptor expression in 9 responder and 15 refractory patients with metastatic disease treated by biochemotherapy. Before any treatment, double immunostaining demonstrated that 61.5% of the tumor cells were HMB45+CD95+. At day 49 in refractory patients, a significant decrease (p = 0.04) of total Fas expression was observed. Furthermore, a significant reduction (p = 0.032) in the percentage of HMB45+CD95* cells occurred. An 11-fold increase in serum IL-6 level was detected (p < 0.002). This increase was negatively correlated (r = -0.2, p = 0.008) with the decrease in total Fas expression. However, in responding patients, no detectable decrease in Fas expression was observed, while a very low increase in serum IL-6 (2-fold) was detected. These results suggest that the increased endogenous IL-6 level in refractory patients may inhibit apoptosis via modulation of Fas expression. These preliminary results must be interpreted with caution, and further study with a greater number of patients is needed to understand the mechanism by which IL-6 inhibits apoptosis in melanoma.