Survival of Women Previously Diagnosed of Melanoma with Subsequent Pregnancy: A Systematic Review and Meta-Analysis and a Single-Center Experience.

Melanoma incidence has increased over the last few decades. How the prognosis of a previously diagnosed melanoma may be affected by a woman's subsequent pregnancy has been debated in the literature since the 1950s, and the outcomes are essential to women who are melanoma survivors in their childbearing years. The main objective of this systematic review is to improve the understanding of whether the course of melanoma in a woman may be altered by a subsequent pregnancy and to help clinicians' diagnosis. Eligible studies for the systematic review were clinical trials, observational cohort studies and case-control studies that compared prognosis outcomes for non-pregnant patients with melanoma, or pregnant before melanoma diagnosis, versus pregnant patients after a diagnosis of melanoma. The search strategy yielded 1101 articles, of which 4 met the inclusion criteria for the systematic review. All the studies were retrospective non-randomised cohorts with patients with melanomas diagnosed before pregnancy. According to our findings, a subsequent pregnancy was not a significant influence on the outcome of a previous melanoma. However, given the small number of identified studies and the heterogeneous data included, it is recommended to approach these patients with caution, and counselling should be given by known prognostic factors. We also reviewed the medical records of 84 patients of childbearing age (35.8 ± 6.3 years, range 21-45 years) who were diagnosed with cutaneous invasive melanoma in our hospital between 2008 and 2018 (N = 724). Of these, 11 (13.1%) had a pregnancy after melanoma diagnosis (age at pregnancy: 35.6 ± 6.3 years). No statistical differences in outcome were detected.

Interferon alpha for the adjuvant treatment of cutaneous melanoma.

BACKGROUND: Interferon alpha is the only agent approved for the postoperative adjuvant treatment of high-risk cutaneous melanoma. However, the survival advantage associated with this treatment is unclear, especially in terms of overall survival. Thus, adjuvant interferon is not universally considered a gold standard treatment by all oncologists. OBJECTIVES: To assess the disease-free survival and overall survival effects of interferon alpha as adjuvant treatment for people with high-risk cutaneous melanoma. SEARCH METHODS: We searched the following databases up to August 2012: the Cochrane Skin Group Specialised Register, CENTRAL in The Cochrane Library (2012, issue 8), MEDLINE (from 2005), EMBASE (from 2010), AMED (from 1985), and LILACS (from 1982). We also searched trials databases in 2011, and proceedings of the ASCO annual meeting from 2000 to 2011. We checked the reference lists of selected articles for further references to relevant trials. SELECTION CRITERIA: We included only randomised controlled trials (RCTs) comparing interferon alpha to observation (or any other treatment) for the postoperative (adjuvant) treatment of patients with high-risk skin melanoma, that is, people with regional lymph node metastasis (American Joint Committee on Cancer (AJCC) TNM (tumour, lymph node, metastasis) stage III) undergoing radical lymph node dissection, or people without nodal disease but with primary tumour thickness greater than 1 mm (AJCC TNM stage II). DATA COLLECTION AND ANALYSIS: Two authors extracted data, and a third author independently verified the extracted data. The main outcome measure was the hazard ratio (HR), which is the ratio of the risk of the event occurring in the treatment arm (adjuvant interferon) compared to the control arm (no adjuvant interferon). The survival data were either entered directly into Review Manager (RevMan) or extrapolated from Kaplan-Meier plots and then entered into RevMan. Based on the presence of between-study heterogeneity, we applied a fixed-effect or random-effects model for calculating the pooled estimates of treatment efficacy. MAIN RESULTS: Eighteen RCTs enrolling a total of 10,499 participants were eligible for the review. The results from 17 of 18 of these RCTs, published between 1995 and 2011, were suitable for meta-analysis and allowed us to quantify the therapeutic efficacy of interferon in terms of disease-free survival (17 trials) and overall survival (15 trials). Adjuvant interferon was associated with significantly improved disease-free survival (HR (hazard ratio) = 0.83; 95% CI (confidence interval) 0.78 to 0.87, P value < 0.00001) and overall survival (HR = 0.91; 95% CI 0.85 to 0.97; P value = 0.003). We detected no significant between-study heterogeneity (disease-free survival: I² statistic = 16%, Q-test P value = 0.27; overall survival: I² statistic = 6%; Q-test P value = 0.38).Considering that the 5-year overall survival rate for TNM stage II-III cutaneous melanoma is 60%, the number needed to treat (NNT) is 35 participants (95% CI = 21 to 108 participants) in order to prevent 1 death. The results of subgroup analysis failed to answer the question of whether some treatment features (i.e. dosage, duration) might have an impact on interferon efficacy or whether some participant subgroups (i.e. with or without lymph node positivity) might benefit differently from interferon adjuvant treatment.Grade 3 and 4 toxicity was observed in a minority of participants: In some trials, no-one had fever or fatigue of Grade 3 severity, but in other trials, up to 8% had fever and up to 23% had fatigue of Grade 3 severity. Less than 1% of participants had fever and fatigue of Grade 4 severity. Although it impaired quality of life, toxicity disappeared after treatment discontinuation. AUTHORS' CONCLUSIONS: The results of this meta-analysis support the therapeutic efficacy of adjuvant interferon alpha for the treatment of people with high-risk (AJCC TNM stage II-III) cutaneous melanoma in terms of both disease-free survival and, though to a lower extent, overall survival. Interferon is also valid as a reference treatment in RCTs investigating new therapeutic agents for the adjuvant treatment of this participant population. Further investigation is required to select people who are most likely to benefit from this treatment.

Surgical excision margins for primary cutaneous melanoma.

BACKGROUND: Cutaneous melanoma accounts for 75% of skin cancer deaths. Standard treatment is surgical excision with a safety margin some distance from the borders of the primary tumour. The purpose of the safety margin is to remove both the complete primary tumour and any melanoma cells that might have spread into the surrounding skin.Excision margins are important because there could be trade-off between a better cosmetic result but poorer long-term survival if margins become too narrow. The optimal width of excision margins remains unclear. This uncertainty warrants systematic review. OBJECTIVES: To assess the effects of different excision margins for primary cutaneous melanoma. SEARCH STRATEGY: In August 2009 we searched for relevant randomised trials in the Cochrane Skin Group Specialised Register; the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library (Issue 3, 2009), MEDLINE, EMBASE, LILACS, and other databases including Ongoing Trials Registers. SELECTION CRITERIA: We considered all randomised controlled trials (RCTs) of surgical excision of melanoma comparing different width excision margins. DATA COLLECTION AND ANALYSIS: We assessed trial quality, and extracted and analysed data on survival and recurrence. We collected adverse effects information from included trials. MAIN RESULTS: We identified five trials. There were 1633 participants in the narrow excision margin group and 1664 in the wide excision margin group. Narrow margin definition ranged from 1 to 2 cm; wide margins ranged from 3 to 5 cm. Median follow-up ranged from 5 to 16 years. AUTHORS' CONCLUSIONS: This systematic review summarises the evidence regarding width of excision margins for primary cutaneous melanoma. None of the five published trials, nor our meta-analysis, showed a statistically significant difference in overall survival between narrow or wide excision.The summary estimate for overall survival favoured wide excision by a small degree [Hazard Ratio 1.04; 95% confidence interval 0.95 to 1.15; P = 0.40], but the result was not significantly different. This result is compatible with both a 5% relative reduction in overall mortality favouring narrower excision and a 15% relative reduction in overall mortality favouring wider excision. Therefore, a small (but potentially important) difference in overall survival between wide and narrow excision margins cannot be confidently ruled out.The summary estimate for recurrence free survival favoured wide excision [Hazard Ratio 1.13; P = 0.06; 95% confidence interval 0.99 to 1.28] but again the result did not reach statistical significance (P < 0.05 level).Current randomised trial evidence is insufficient to address optimal excision margins for primary cutaneous melanoma.

Anterior tab flap versus standard underlay myringoplasty in children.

OBJECTIVES: Tympanic membrane (TM) perforation closure can present a problem in children, especially in anterior and total perforations, because of the anterior's lack of support for the graft. It was suggested that the anterior tab flap (ATF) myringoplasty, an underlay graft with an anterior tab under the TM annulus, could provide better stability of the graft. We undertook a prospective, randomized, controlled study to compare the ATF myringoplasty with the standard underlay (SU) myringoplasty in children. METHODS: We randomly assigned 59 children to undergo ATF myringoplasty and 52 to undergo SU myringoplasty at a tertiary care pediatric institution. Surgery was performed under general anesthesia in all patients. The primary outcome was the healing of the TM; the secondary outcomes were anterior blunting of the graft and presence of retraction of the TM. Two years of follow-up were obtained in all enrolled children. RESULTS: At 2 years of follow-up, there were 55 stable TM closures in the ATF arm and 44 in the SU arm. Although the TM closure was higher in the ATF arm than in the SU arm (93.2 and 84.6%, respectively), the results were not statistically significant (odds ratio = 0.4, 95% confidence interval = 0.12-1.41). Anterior blunting and TM retraction were not encountered. CONCLUSION: The ATF myringoplasty is a safe and effective method for TM closure in children. However, compared with the SU myringoplasty, the ATF myringoplasty is not associated with an overall decrease in the incidence of the residual perforations. Further assessment in a larger study is proposed.

Contact-diode laser repair of bony choanal atresia: a preliminary report.

OBJECTIVES: To demonstrate the use of the contact-diode laser (CDL) at 810 nm wavelength for the transnasal endoscopic repair of bilateral bony choanal (BBCA) in low-weight newborns. METHODS: Prospective study at a tertiary-care pediatric institution of four neonates with BBCA aged 3-5 days, weighing on average 2.34 kg. BBCA was opened by transnasal delivery of CDL through a 600 microm diameter glass fiber. Children were stented post-operatively, and revision surgery performed when needed. RESULTS: All children were successfully treated for BBCA with CDL. Two children needed only one surgery, one child needed two surgeries, and one patient required three procedures, in order to establish patient choanae at last follow-up ranging from 16 to 30 months. CONCLUSION: We found the fiber-delivered contact-diode laser to permit correction of BBCA in four low-birth weight neonates. To the best of our knowledge, this report is the first to demonstrate the successful use of CDL for the management of BBCA.

Excision margins for primary cutaneous melanoma: updated pooled analysis of randomized controlled trials.

OBJECTIVE: To determine the effectiveness of wide vs narrow excision margins in the treatment of primary cutaneous melanoma. DATA SOURCES: We conducted a search of MEDLINE and the Cochrane Controlled Trials Register as well as a manual search of the reference lists of all relevant papers. No language or date restrictions were applied. STUDY SELECTION: Only prospective randomized trials were included. DATA EXTRACTION: Two reviewers independently extracted the data from each study. Outcomes evaluated were local and locoregional recurrences and overall mortality. Data were analyzed using Cochrane Collaboration Review Manager software. DATA SYNTHESIS: Five randomized trials comprising 3313 participants were retrieved and analyzed. Pooled data showed no statistically significant difference in overall mortality when comparing wide vs narrow excision margins (odds ratio, 0.98; 95% confidence interval, 0.72-1.22; and test for overall effect of P = .88). There was no statistically significant difference in the occurrence of locoregional recurrence between 2 groups of patients (odds ratio, 1.18; 95% confidence interval, 0.98-1.41; and test for overall effect not significant at P = .08). Although statistically significant heterogeneity was not detected among included trials, there was considerable clinical heterogeneity. CONCLUSIONS: Although this meta-analysis did not show any statistically significant difference between patients treated with wide or narrow excision margins insofar as overall mortality and locoregional and local recurrences, current evidence is insufficient to address the optimal excision margins for all types of melanomas. Further research is required to establish the appropriate local treatment for different types of primary melanoma and subgroups of patients.

Effect of pregnancy on survival in women with cutaneous malignant melanoma.

PURPOSE: An adverse influence of pregnancy on the risk of death in women with cutaneous melanoma was suggested historically by anecdotal reports. Previous studies included small numbers of women observed for short periods. METHODS: Using data from the Swedish National and Regional Registries, we performed a retrospective cohort study of all Swedish women who were diagnosed with cutaneous melanoma during their reproductive period, from January 1, 1958, to December 31, 1999. The relationship between pregnancy status at the diagnosis of melanoma and overall survival was examined in multivariable proportional-hazards models. RESULTS: The cohort comprised 185 women (3.3%) diagnosed with melanoma during pregnancy and 5,348 (96.7%) women of the same childbearing age diagnosed with melanoma while not pregnant. There was no statistically significant difference in overall survival between pregnant and nonpregnant groups (log-rank chi(2)1[r] = 0.84, P = .361). Pregnancy status at the time of diagnosis of melanoma was not related to survival in a multivariable Cox model in the 2,101 women (hazard ratio for death in the pregnant group was 1.08; 95% CI, 0.60 to 1.93). In the multivariable analysis, pregnancy status after diagnosis of melanoma was not a significant predictor of survival (hazard ratio for death in women who had pregnancy subsequent to the diagnosis of melanoma was 0.58; 95% CI, 0.32 to 1.05). CONCLUSION: The survival of pregnant women with melanoma is not worse than the survival of nonpregnant women with melanoma. Pregnancy subsequent to the diagnosis of primary melanoma was not associated with an increased risk of death.

Systemic chemotherapy in the treatment of malignant melanoma.

Different postsurgical therapies are used for the treatment of metastatic melanoma. This article reviews the use of chemotherapeutic agents in the treatment of patients with metastatic malignant melanoma. A variety of single chemotherapy agents have been evaluated, although the most widely used chemotherapeutic in the treatment of metastatic melanoma is dacarbazine. In order to improve the rate and duration of responses, combination chemotherapy was developed. The most common combined chemotherapy regimens used as standard for the treatment of metastatic melanoma are Dartmouth regimen, CVD (cisplatin + vinblastine + dacarbazine) and BOLD (bleomycin + vincristine + lomustine + dacarbazine). However, Phase III trials have failed to demonstrate a significant benefit in survival in patients treated with polychemotherapy compared to those treated with dacarbazine alone. The use of classical systemic chemotherapy still has a role in the treatment of patients with metastatic melanoma. Immunotherapy and biochemotherapy have no additional advantage over chemotherapy.

The role of biological response modifiers in malignant melanoma.

This article reviews the existing data in an attempt to address the role of biological response modifiers (IFN-alpha and IL-2) in the management of melanoma. Eight prospective controlled Phase III trials evaluating IFN-alpha therapy are discussed. As the results from these trials have been heterogeneous and inconsistent, the role of IFN-alpha in the adjuvant treatment of stage II and III melanoma patients remains to be defined. IL-2 possesses modest antitumour activity in melanoma yielding objective response in approximately 15% of patients. Many toxic effects are induced by high-dose IL-2 therapy. Combinations of chemotherapy and biological response modifiers and their impact on tumour response and survival are discussed.

Use of tamoxifen in the treatment of malignant melanoma.

BACKGROUND: Tamoxifen has been used in the treatment of patients with metastatic malignant melanoma either as a single agent or, more commonly, in combination with other chemotherapeutic agents. The aim of the current study was to summarize the available clinical evidence on the role of the tamoxifen in different combination chemotherapy regimens because clinical studies including tamoxifen have produced inconclusive results. METHODS: The authors designed a systematic review and metaanalysis of published randomized controlled trials to assess the benefit of tamoxifen added to various single-agent or multiagent chemotherapy or biochemotherapy regimens. RESULTS: Six randomized trials met the inclusion criteria and were analyzed. These 6 trials involved a combined total of 912 patients. Of this number, 455 patients were randomized to receive tamoxifen added to chemotherapy or biochemotherapy regimens and 457 were randomized to receive chemotherapy or biochemotherapy without tamoxifen. The overall response rate was not improved significantly by the addition of tamoxifen to the chemotherapy regimen (odds ratio [OR], 1.16; 95% confidence interval [CI], 0.75-1.82; test for overall effect: P = 0.14). The results were not statistically significant for complete response (OR, 0.64; 95% CI, 0.33-1.25; test for overall effect: P = 0.19). CONCLUSIONS: The current metaanalysis demonstrated that tamoxifen does not improve the overall response rate, complete response rate, or survival rate when administered along with combined chemotherapy regimens. Currently, the strength of evidence does not support the use of tamoxifen in combination with other systemic chemotherapy for the treatment of metastatic melanoma.

Isolated limb perfusion with melphalan in the treatment of malignant melanoma of the extremities: a systematic review of randomised controlled trials.

Isolated limb perfusion is a surgical procedure for delivering a high dose of chemotherapeutic or immunochemotherapeutic agent to a localised area, thus avoiding the severity of side-effects caused by systemic administration. This technique is generally used for treatment of patients with tumours of the limbs and extremities. We have done a systematic review of randomised controlled trials assessing the effectiveness of this treatment in patients with melanoma of the extremities. Four trials of 1038 patients met our inclusion criteria and were analysed. Although our analysis confirmed the reported increase in survival in two of the trials, neither had sufficient power to detect significant benefit for perfusion. Results from the trials showed that prophylactic perfusion has an equivocal effect on survival in patients with limb melanoma. Therefore, current evidence suggests that prophylactic isolated limb perfusion cannot be recommended as a routine adjunct to standard surgery in patients with high-risk primary limb melanoma, but only as a treatment for local disease control if other forms of locoregional therapy are not available.

Excision margins in the treatment of primary cutaneous melanoma: a systematic review of randomized controlled trials comparing narrow vs wide excision.

BACKGROUND: The optimal excision margin for primary cutaneous melanoma remains controversial, although several clinical studies have suggested that wide local excision is unnecessary. HYPOTHESIS: Wide excision margins do not improve survival in patients with melanoma. OBJECTIVES: To describe the published evidence and determine the effectiveness of wide surgical margins compared with narrow surgical margins. DESIGN: Systematic review of randomized controlled trials that compared narrow margins with wide excision margins for cutaneous melanoma. SETTING: Randomized controlled trials available by March 2001. SUBJECTS: The included trials comprised 2406 participants. INTERVENTION: Surgical excision of melanoma using narrow excision margins compared with excision using wide excision margins. MAIN OUTCOME MEASURE: Effect of width of excision margin on melanoma recurrences, disease-free survival, and overall survival. RESULTS: We identified and analyzed 4 randomized controlled trials. All 4 trials failed to demonstrate statistically significant differences in overall survival and disease-free survival when comparing wide vs narrow excision. Peto pooled odds ratio for overall survival was 0.79 (95% confidence interval, 0.61-1.04) and for disease-free survival was 0.89 (95% confidence interval, 0.69-1.13), indicating a statistically nonsignificant improvement with wide excision. CONCLUSIONS: Not one of the included studies showed any statistically significant difference between the 2 groups treated with narrow or wide excision margins with regard to recurrences and survival. However, current evidence is not sufficient to address the optimal surgical margins for all melanomas, and further research is required.

Elective lymph node dissection in patients with melanoma: systematic review and meta-analysis of randomized controlled trials.

HYPOTHESIS: Elective lymph node dissection does not improve survival in patients with melanoma without clinically detectable lymph node metastases. OBJECTIVE: To determine whether elective lymph node dissection in patients with melanoma without clinically detectable regional metastases decreases overall mortality. DESIGN: Systematic review and meta-analysis of randomized controlled trials comparing elective lymph node dissection with delayed lymphadenectomy at the time of clinical recurrence. SETTING: Randomized controlled trials available by February 2001. SUBJECTS: The included trials comprised 1533 participants. INTERVENTION: Elective lymph node dissection compared with delayed lymphadenectomy or no lymphadenectomy in patients with melanoma without clinically detectable regional metastases. MAIN OUTCOME MEASURE: Overall mortality in treatment groups as compared with control groups at the end of a 5-year follow-up period. RESULTS: Three randomized controlled trials met the inclusion criteria. The pooled odds ratio for overall mortality for the 3 trials was 0.86 (95% confidence interval, 0.68-1.09). Results are statistically nonsignificant, but they have potential clinical significance. CONCLUSIONS: This systematic review of randomized controlled trials comparing elective lymph node dissection with surgery delayed until the time of clinical recurrence shows no significant overall survival benefit for patients undergoing elective lymph node dissection. Trials included in this review, however, contain significant bias. The question is not answered for all patients, and the results do not exclude the possibility that some subgroups may benefit from elective lymph node dissection. Further research is required.

Interferon alfa therapy for malignant melanoma: a systematic review of randomized controlled trials.

PURPOSE: No standard systemic adjuvant therapy has been proven to increase overall survival in melanoma patients. The effect of interferon alfa (IFNalpha) as a single agent or in combination has been widely explored in clinical trials. The purpose of this study was to assess the benefit of IFNalpha therapy in malignant melanoma. METHODS: We performed a systematic review of randomized controlled trials comparing regimens with or without IFNalpha adjuvant therapy in melanoma patients. We assessed the effect of IFNalpha therapy on overall survival (OS), disease-free survival (DFS), melanoma recurrences, and toxicity. The quality of each trial was systematically evaluated. RESULTS: Nine randomized controlled trials (RCTs) of IFNalpha therapy in melanoma patients were identified. Eight were published and one was unpublished. Eight trials comprising 3,178 patients fulfilled our inclusion criteria and were analyzed. Quality assessment scores ranged from 22 to 71, with a mean score of 55.4 (95% confidence interval, 53.8 to 57.0). For OS, only one trial reported a statistically significant benefit for IFNalpha, but our analysis did not confirm it. Two trials reported statistically significant benefit in DFS for the patients treated with IFNalpha, but our analysis confirmed it in only one trial. There was a wide clinical heterogeneity between included trials, making meta-analysis inappropriate. CONCLUSION: In our review, results from included RCTs demonstrated no clear benefit of IFNalpha therapy on OS in melanoma patients. A large RCT is required to answer whether a full regimen of IFNalpha therapy is effective and to identify the subgroups of patients who might benefit from IFNalpha treatment.