RÉSUMÉ
Information about extramammary Paget's (EMPD) treatment is limited because of the rarity of the disease. The prognosis differs between in situ EMPD and invasive EMPD; therefore, therapy should be planned according to the disease stage. We collected data on 643 EMPD cases treated between 2015 and 2019 in Japan and assessed recent trends in EMPD treatment and prognosis based on the EMPD-oriented TNM staging. Among the 643 patients, 317 had stage 0 (49.3%), 185 had stage I (28.8%), 51 had stage II (7.9%), 18 had stage IIIA (2.8%), 48 had stage IIIB (7.5%) and 24 had stage IV (3.7%) disease. Each stage showed a distinct survival curve, with the exception of stages II and IIIA. Curative surgery was most common in patients with stage 0-III disease. Chemotherapy was the first-line therapy, mainly in patients with stage IIIB and IV disease, most commonly with docetaxel (DTX), followed by DTX + tegafur gimeracil oteracil potassium (TS-1) and TS-1. Patients with local disease exhibited a 4.4% recurrence rate. Univariate analysis revealed no prognostic differences according to age, sex or primary tumour site. SLNB was not related to disease-specific survival. In multivariate analysis, female sex significantly predicted local relapse in stage 0-I (HR 3.09; 95% CI, 1.13-8.43), and initial treatment with curative surgery was significantly protective in terms of disease-specific survival in stage II-IIIA (HR, 0.17; 95% CI, 0.04-0.71) and stage IIIB-IV (HR 0.16; 95% CI, 0.05-0.51). Further clinical studies are needed to improve the prognosis of patients with stage II-IV EMPD.
Sujet(s)
Maladie de Paget extramammaire , Silicates , Titane , Humains , Femelle , Maladie de Paget extramammaire/traitement médicamenteux , Maladie de Paget extramammaire/anatomopathologie , Récidive tumorale locale/anatomopathologie , Pronostic , Stadification tumoraleRÉSUMÉ
ABSTRACT: Sweat gland carcinoma with neuroendocrine differentiation (SCAND) is a newly proposed tumor entity of primary cutaneous apocrine/eccrine adnexal tumor with neuroendocrine differentiation. The histopathologic variations are not yet well known. In this article, we present a case of SCAND mimicking male breast cancer and syringocystadenocarcinoma papilliferum. A 68-year-old man presented with a reddish 12-mm nodule on his left areola. No lymph node or distant metastases were observed. The patient was disease free 1 year and 9 months after the tumor was surgically resected but died of cerebral hemorrhage. Histopathological examination revealed a predominantly intradermal tumor with marked syringotropism, mimicking a component of mammary ductal carcinoma in situ. In addition, another tissue section displayed a cup-shaped papillated tumor with syringocystadenocarcinoma papilliferum-like features, which were also seen because of marked syringotropism. Diffuse immunoexpression of cytokeratin 7, cytokeratin 19, chromogranin A, synaptophysin, INSM1, estrogen receptor, carcinoembryonic antigen, epithelial membrane antigen, and GATA3 was observed in the tumor, but no BRAF immunoexpression was seen. The present case would help us to understand the histopathological variation and differential diagnosis of SCAND. The histopathological diagnosis of male breast cancer or syringocystadenocarcinoma papilliferum should be made by ruling out SCAND.
Sujet(s)
Tumeur du sein de l'homme , Carcinome des annexes cutanées , Tumeurs cutanées , Tumeurs des glandes sudoripares , Sujet âgé , Tumeur du sein de l'homme/diagnostic , Tumeur du sein de l'homme/chirurgie , Chromogranine A , Humains , Kératine-19 , Kératine-7 , Mâle , Mucine-1 , Mamelons/anatomopathologie , Récepteurs des oestrogènes , Protéines de répression , Tumeurs cutanées/anatomopathologie , Tumeurs des glandes sudoripares/diagnostic , Tumeurs des glandes sudoripares/anatomopathologie , Tumeurs des glandes sudoripares/chirurgie , Glandes sudoripares/anatomopathologie , SynaptophysineRÉSUMÉ
We report a case of secondary adrenal insufficiency due to nivolumab. An 83-year-old man with acral lentiginous types of melanoma on the right sole visited our department in March 2017. He received primary surgery at referred hospital in June 2017, and pathological stage was IIIC (pT3bN3M0) according to AJCC (American Joint Committee on Cancer) 7th edition criteria. During the follow-up period, a lot of in-transit metastases appeared on the right leg. While we were resecting in-transit metastases, we concurrently started nivolumab in September 2018. After 17 cycles of nivolumab treatment, he developed severe nausea and anorexia. At baseline, his cortisol and adrenocorticotropic hormone levels were both at normal range, but corticotropin-releasing hormone loading test revealed secondary adrenal insufficiency. We diagnosed isolated adrenal insufficiency due to nivolumab. Treatment by hydrocortisone immediately relieved nausea and anorexia, and we could have continued treatment of nivolumab.
RÉSUMÉ
BACKGROUND: Paclitaxel is a standard of care for patients with primary cutaneous angiosarcoma of the scalp and face. However, no standard second-line treatment for paclitaxel-resistant patients has ever been established. Since primary cutaneous angiosarcoma expresses a high level of vascular endothelial growth factor receptor, the multitargeted tyrosine kinase inhibitor pazopanib seemed to be the most promising agent, and several retrospective studies have demonstrated its activity against this disease. However, the efficacy and safety of pazopanib in paclitaxel-resistant patients with primary cutaneous angiosarcoma have never been evaluated in a clinical trial. METHODS: In February 2018 the Dermatologic Oncology Group of Japan Clinical Oncology Group started a single-arm confirmatory trial to evaluate the efficacy and safety of pazopanib as a second-line treatment for patients with primary cutaneous angiosarcoma whose disease was resistant to paclitaxel or who were unable to tolerate paclitaxel (JCOG1605, JCOG-PCAS). Patients with primary cutaneous angiosarcoma not associated with lymphedema or radiation, progressing despite first-line paclitaxel monotherapy are included in the study. No prior systemic chemotherapy other than paclitaxel is permitted. Pazopanib is administered orally at an initial dosage of 800 mg once daily. Dose modifications for adverse events are made according to the dose reduction criteria described in the protocol. Treatment is continued until recurrence, disease progression, unacceptable toxic effects, patient refusal, or death. The primary endpoint is progression-free survival, secondary endpoints include overall survival, response rate, disease control rate, adverse events, and serious adverse events. We plan to recruit 30 participants in 5.5 years from 23 Japanese institutions. The follow-up period is set as 1 year after completion of accrual. The study protocol was approved by the Japan Clinical Oncology Group Protocol Review Committee in December 2017. Ethical approval for this study was granted by Ethics Committee of each institute. DISCUSSION: If the primary endpoint is met, pazopanib will be regarded as a standard of care for paclitaxel-resistant patients for whom no standard second-line treatment is established. TRIALS REGISTRATION: Registry number: UMIN000031438 [ http://www.umin.ac.jp/ctr/index.htm ]. Date of Registration: 23/Feb/2018. Date of First Participant Enrollment: 8/Mar/2018.
Sujet(s)
Antinéoplasiques d'origine végétale/usage thérapeutique , Résistance aux médicaments antinéoplasiques/effets des médicaments et des substances chimiques , Hémangiosarcome/traitement médicamenteux , Paclitaxel/pharmacologie , Pyrimidines/usage thérapeutique , Thérapie de rattrapage , Tumeurs cutanées/traitement médicamenteux , Sulfonamides/usage thérapeutique , Adulte , Sujet âgé , Sujet âgé de 80 ans ou plus , Femelle , Études de suivi , Hémangiosarcome/anatomopathologie , Humains , Indazoles , Mâle , Adulte d'âge moyen , Pronostic , Plan de recherche , Tumeurs cutanées/anatomopathologie , Jeune adulteRÉSUMÉ
Treatment for patients with unresectable melanoma has been dramatically changed by the use of immunocheckpoint inhibitors (ICI). In this study, we reviewed patients with unresectable stage III/IV melanoma, who were treated with nivolumab between July 2014 and March 2017 at the Department of Dermatologic Oncology, National Cancer Center Hospital, Tokyo, and retrospectively recorded cutaneous adverse events (cAE), development of vitiligo, clinical characteristics and clinical responses. We identified 128 patients, 61 (47.7%) of whom showed cAE, including 30 (23.4%) with development or exacerbation of vitiligo. The prognosis of patients with melanoma treated with ICI correlated with cAE, including development of vitiligo. Patients with cAE showed better objective responses (41.0% vs 6.0%, P < 0.001), progression-free survival (PFS) (377 vs 61 days, P < 0.001) and overall survival (OS) (763 vs 209 days, P < 0.001) than did patients without cAE. Patients who developed vitiligo showed better objective responses (53.3% vs 29.0% vs 6.0%, P < 0.001), PFS (median, not reached vs 317 vs 65 days, P < 0.001) and OS (not reached vs 689 vs 209 days, P < 0.001) than did patients with other cAE and patients without cAE. Landmark analysis showed development of vitiligo starting 20 weeks after starting nivolumab correlated with better OS. In multivariate analysis, OS correlated with performance status, number of metastasized organs, cAE other than vitiligo and development of vitiligo. Despite the fact that the correlation between other cAE and OS was less than that of vitiligo, cAE may be a simple marker of favorable prognosis.
Sujet(s)
Antinéoplasiques immunologiques/effets indésirables , Mélanome/traitement médicamenteux , Nivolumab/effets indésirables , Tumeurs cutanées/traitement médicamenteux , Vitiligo/épidémiologie , Adolescent , Adulte , Sujet âgé , Sujet âgé de 80 ans ou plus , Antinéoplasiques immunologiques/administration et posologie , Relation dose-effet des médicaments , Calendrier d'administration des médicaments , Femelle , Humains , Mâle , Mélanome/diagnostic , Mélanome/immunologie , Mélanome/mortalité , Adulte d'âge moyen , Stadification tumorale , Nivolumab/administration et posologie , Pronostic , Survie sans progression , Études rétrospectives , Peau/immunologie , Peau/anatomopathologie , Tumeurs cutanées/diagnostic , Tumeurs cutanées/immunologie , Tumeurs cutanées/mortalité , Vitiligo/induit chimiquement , Vitiligo/immunologie , Jeune adulteRÉSUMÉ
We evaluated the efficacy of nivolumab in patients with metastatic uveal melanoma previously untreated with ipilimumab. We performed a retrospective study at the National Cancer Center Hospital in Tokyo, Japan, where nivolumab was approved 1 year earlier than ipilimumab. Clinical efficacy outcomes were determined by assessing best overall response according to the Response Evaluation Criteria in Solid Tumors (version 1.1), progression-free survival and overall survival. Fourteen patients were analyzed; none had received any prior systemic therapies although eight had undergone transarterial chemoembolization. The median follow-up period was 15 months. The objective response and disease control rates were 7.1% and 42.9%, respectively (one partial response and five stable diseases). The median progression-free survival and overall survival were 10 (range, 4-105) and 60 (range, 5-105) weeks, respectively. Liver metastases in three patients were all programmed cell death-1 ligand negative. Lower lactate dehydrogenase, development of vitiligo, and a neutrophil-to-lymphocyte ratio less than 5 at week 6 were associated with favorable progression-free survival and overall survival; of these, only a neutrophil-to-lymphocyte ratio less than 5 at week 6 was statistically significant. Even with the use of nivolumab before ipilimumab, metastatic uveal melanoma appears to remain refractory to nivolumab monotherapy. However, because one patient in our cohort achieved an objective response, and the median overall survival exceeded 1 year, treatment strategies that incorporate anti-PD1 antibody should be further investigated. Whether a neutrophil-to-lymphocyte ratio less than 5 at week 6 is a favorable early on-treatment marker should be validated in larger cohorts.
Sujet(s)
Antinéoplasiques immunologiques/usage thérapeutique , Mélanome/traitement médicamenteux , Nivolumab/usage thérapeutique , Tumeurs de l'uvée/traitement médicamenteux , Adulte , Sujet âgé , Antinéoplasiques immunologiques/pharmacologie , Femelle , Humains , Mâle , Mélanome/mortalité , Adulte d'âge moyen , Métastase tumorale , Nivolumab/pharmacologie , Survie sans progression , Études rétrospectives , Tumeurs de l'uvée/mortalitéRÉSUMÉ
BACKGROUND: Amputation is the standard of care even for early-stage subungual melanomas (SUMs), known as nail apparatus melanoma, because the nail bed and nail matrix are close to the distal phalanx. However, a recent study demonstrated that not all patients with SUMs had histologic invasion of the underlying distal phalanx. As most SUMs occur in the thumb or big toe, amputation of either the thumb or big toe substantially interferes with activities of daily living, including poor cosmesis, loss of function, and phantom pain. Non-amputative digit preservation surgery can thus be applied in such cases without compromising patient prognosis. METHODS: We are conducting a multi-institutional single-arm trial to confirm the safety and efficacy of non-amputative digit preservation surgery. We will compare our results with those reported in the Japanese Melanoma Study, in which patients underwent amputation for SUMs as a traditional standard of care. Patients aged between 20 and 80 years with stage I, II, or III without evidence of tumor invasion to the underlying distal phalanx on preoperative radiograph are included in the study. The primary endpoint is major relapse-free survival (major RFS), which does not include local recurrence as an event; secondary endpoints include overall survival, digit-preservation survival, relapse-free survival, local relapse-free survival, partial relapse-free survival, and incidence of adverse events. A total of 85 patients from 21 Japanese institutions will be recruited within 5.5 years, and the follow-up period will last at least 5 years. The Japan Clinical Oncology Group Protocol Review Committee approved this study protocol in August 2017, and patient enrollment began in November 2017. Ethical approval was obtained from each institution's Institutional Review Board prior to patient enrollment. DISCUSSION: This is the first prospective trial to confirm the safety and efficacy of non-amputative digit preservation surgery for SUM without distant metastasis or bony invasion. The results of this trial could provide evidence to support this less-invasive surgery as a new standard of care to preserve adequately functioning digits. TRIAL REGISTRATION: Registry number: UMIN000029997 . Date of Registration: 16/Nov/2017. Date of First Participant Enrollment: 12/Dec/2017.
Sujet(s)
Mélanome/épidémiologie , Mélanome/chirurgie , Interventions chirurgicales mini-invasives/effets indésirables , Interventions chirurgicales mini-invasives/méthodes , Onychopathies/épidémiologie , Onychopathies/chirurgie , Activités de la vie quotidienne , Adulte , Sujet âgé , Sujet âgé de 80 ans ou plus , Amputation chirurgicale/effets indésirables , Amputation chirurgicale/méthodes , Survie sans rechute , Femelle , Études de suivi , Humains , Incidence , Japon/épidémiologie , Mâle , Oncologie médicale/méthodes , Adulte d'âge moyen , Récidive tumorale locale , Pronostic , Études prospectives , Pouce/anatomopathologie , Pouce/chirurgie , Orteils/anatomopathologie , Orteils/chirurgie , Jeune adulteRÉSUMÉ
To describe the treatment patterns of nivolumab and ipilimumab in Japan, a retrospective observational study was conducted in melanoma patients who received nivolumab and ipilimumab sequentially. Patients who received nivolumab and ipilimumab in combination were excluded from this study. Efficacy was evaluated by the Response Evaluation Criteria in Solid Tumors (RECIST) in terms of the overall response rate (ORR), progression-free survival (PFS), and disease control rate (DCR). Overall survival (OS) was also evaluated. Safety was assessed by the Common Terminology Criteria for Adverse Events (CTCAE). The treatment for all 68 patients enrolled involved switching from nivolumab to ipilimumab in 61 patients and switching from ipilimumab to nivolumab in seven patients. Switching occurred because of progressive disease in 55 patients and adverse events in eight patients. The median number of ipilimumab doses was three. Ipilimumab treatment achieved an ORR and DCR of 4.9% and 21.3%, respectively, and the median OS from start of ipilimumab was 7.0 months. During the study period, no new safety signals were noted. Independent factors which were indicative of poor prognosis for PFS were high neutrophil-to-lymphocyte ratio (NLR) and high C-reactive protein (CRP) levels before ipilimumab treatment. An evaluation over a washout period indicated that no significant relationship existed with efficacy or safety. For the sequential administration of nivolumab and ipilimumab in Japanese melanoma patients, switch from nivolumab to ipilimumab was common, and the major reason for switching was progressive disease. The major prognostic factors for ipilimumab PFS after nivolumab were NLR and CRP before ipilimumab treatment.
Sujet(s)
Antinéoplasiques immunologiques/administration et posologie , Protocoles de polychimiothérapie antinéoplasique/usage thérapeutique , Ipilimumab/administration et posologie , Mélanome/traitement médicamenteux , Nivolumab/administration et posologie , Tumeurs cutanées/traitement médicamenteux , Adulte , Sujet âgé , Sujet âgé de 80 ans ou plus , Anticorps monoclonaux/administration et posologie , Calendrier d'administration des médicaments , Femelle , Humains , Japon , Mâle , Adulte d'âge moyen , Études rétrospectivesRÉSUMÉ
Melanoma is one of the most serious form of skin cancer. Nowadays, ipilimumab is used for advanced melanoma refractory to first-line anti-programmed death 1 (PD-1) antibodies. Thirty patients (male : female ratio, 18:12; median age, 60.5 years) sequentially treated with ipilimumab after anti-PD-1 antibody (nivolumab or pembrolizumab), while 58 (male : female ratio, 27:31; median age, 66.5 years) with anti-PD-1 antibody only. The kind of therapy and schedules were as follows: nivolumab, 2 mg/kg at 3-week intervals or at 3 mg/kg every 2 week; pembrolizumab, 2 mg/kg every 3 weeks; ipilimumab, 3 mg/kg at 3-week intervals for four doses. The sequential therapy was selected for the patients with disease progression and/or recovered from severe (immune-related [ir]) adverse events (AE) after PD-1 blockade monotherapy. We evaluated multiple parameters and analyzed their relevance to overall survival (OS). The best objective response rate was 6.7% in sequential ipilimumab treatment. Median OS was 163 days (range, 16-489). Baseline absolute lymphocyte count (ALC) and performance status (PS) before sequential ipilimumab were associated with OS in univariate analyses. Baseline PS and irAE within 6 weeks after ipilimumab administration showed significant differences on multivariate analysis. Prior to first-line PD-1 blockade, these parameters were not associated with OS. The other factors (i.e. age, sex, number of doses, absolute neutrophil counts, neutrophil : lymphocyte ratio, lactate dehydrogenase and C-reactive protein) were not associated with OS. [Correction added on 17 April 2019, after first online publication: 'not related to OS' has been amended to 'not associated with OS'.] Ipilimumab as sequential therapy did not appear to improve OS and was associated with more severe irAE than PD-1 blockade monotherapy. We need to carefully consider treating patients with poor PS and low ALC.
Sujet(s)
Antinéoplasiques immunologiques/administration et posologie , Protocoles de polychimiothérapie antinéoplasique/administration et posologie , Ipilimumab/administration et posologie , Mélanome/traitement médicamenteux , Tumeurs cutanées/traitement médicamenteux , Sujet âgé , Anticorps monoclonaux humanisés/administration et posologie , Anticorps monoclonaux humanisés/effets indésirables , Antinéoplasiques immunologiques/effets indésirables , Protocoles de polychimiothérapie antinéoplasique/effets indésirables , Antigène CTLA-4/antagonistes et inhibiteurs , Antigène CTLA-4/immunologie , Évolution de la maladie , Calendrier d'administration des médicaments , Résistance aux médicaments antinéoplasiques/immunologie , Femelle , Humains , Ipilimumab/effets indésirables , Mâle , Mélanome/diagnostic , Mélanome/mortalité , Mélanome/anatomopathologie , Adulte d'âge moyen , Stadification tumorale , Nivolumab/administration et posologie , Nivolumab/effets indésirables , Récepteur-1 de mort cellulaire programmée/antagonistes et inhibiteurs , Récepteur-1 de mort cellulaire programmée/immunologie , Survie sans progression , Études rétrospectives , Indice de gravité de la maladie , Peau/immunologie , Peau/anatomopathologie , Tumeurs cutanées/diagnostic , Tumeurs cutanées/mortalité , Tumeurs cutanées/anatomopathologie , Analyse de survieSujet(s)
Anticorps monoclonaux/effets indésirables , Protocoles de polychimiothérapie antinéoplasique/effets indésirables , Granulome pyogénique/induit chimiquement , Paclitaxel/effets indésirables , Tumeurs de l'estomac/traitement médicamenteux , Sujet âgé , Anticorps monoclonaux/administration et posologie , Anticorps monoclonaux humanisés , Protocoles de polychimiothérapie antinéoplasique/administration et posologie , Biopsie , Face , Femelle , Granulome pyogénique/anatomopathologie , Humains , Mâle , Paclitaxel/administration et posologie , Peau/effets des médicaments et des substances chimiques , Peau/anatomopathologie ,RÉSUMÉ
BACKGROUND: In patients with cutaneous angiosarcoma of the scalp and face, the validity of surgery remains controversial, because of the potentially diffuse nature of involvement and difficulty in obtaining negative margins. OBJECTIVE: To evaluate the survival benefit of surgery as a primary treatment. PATIENTS AND METHODS: Fifty-one patients with primary cutaneous angiosarcoma of the scalp and face presenting with locoregional involvement were referred to National Cancer Center Hospital, Tokyo, Japan, between May 1982 and March 2013. Data of those patients in whom the diagnosis had been confirmed histologically and the primary treatments had been initiated at our center were analysed retrospectively. Only untreated cases were selected with aim to evaluate actual survival benefit of surgery as a primary treatment. RESULTS: Of the 51 patients, 38 were found to be eligible for inclusion in this analysis; of these 38 patients, 29 (29/38 = 76.3%) patients had tumour diameter > 5 cm, and 29 underwent surgery with curative intent (curative-intent surgery) as the initial treatment. Histologically positive margins were found in 10 patients. Multivariate analysis identified curative-intent surgery as being significantly associated with improved overall survival (OS; HR = 0.26; 95% CI, 0.10-0.63). In the Surgery group, neither negative margins nor combined-modality treatment had any significant influence on the OS. CONCLUSION: Removal of primary tumour with curative-intent surgery may be a valid treatment option even for patients with primary cutaneous angiosarcoma of the scalp and face larger than 5 cm in size, regardless of the histological surgical margin status.
Sujet(s)
Tumeurs de la tête et du cou/thérapie , Hémangiosarcome/thérapie , Cuir chevelu , Tumeurs cutanées/thérapie , Sujet âgé , Sujet âgé de 80 ans ou plus , Association thérapeutique , Survie sans rechute , Tumeurs de la face/diagnostic , Tumeurs de la face/mortalité , Tumeurs de la face/thérapie , Femelle , Tumeurs de la tête et du cou/diagnostic , Tumeurs de la tête et du cou/mortalité , Hémangiosarcome/diagnostic , Hémangiosarcome/mortalité , Humains , Japon/épidémiologie , Mâle , Adulte d'âge moyen , Études rétrospectives , Tumeurs cutanées/diagnostic , Tumeurs cutanées/mortalité , Taux de survie/tendances , Résultat thérapeutiqueRÉSUMÉ
The combination of dabrafenib and trametinib demonstrated encouraging antitumor activity and tolerability, at initial analysis, in Japanese patients with BRAF V600 mutant advanced melanoma warranting further investigation. This study evaluated the safety and tolerability, pharmacokinetics (PK) and preliminary efficacy of dabrafenib 150 mg b.i.d. plus trametinib 2 mg q.d. in Japanese patients with BRAF V600E/K mutant solid tumors (phase 1) and melanoma (phase 2). Phase 1 was primarily intended to assess safety and tolerability as assessed by adverse events (AE), and the primary end-point in phase 2 was to assess confirmed overall response rate (ORR). The secondary end-points in phase 1 included PK, confirmed/unconfirmed ORR and duration of response (DOR). The secondary end-points in phase 2 were PK, unconfirmed ORR, DOR, safety and tolerability. A total of 12 cutaneous melanoma patients were enrolled in the study (six in phase 1 and six in phase 2) and received the combination therapy of dabrafenib and trametinib. Common AE (≥50.0%) included pyrexia (75%), increased aspartate aminotransferase (67%), peripheral edema (50%) and nasopharyngitis (50%). The investigator-assessed ORR was reported in five patients (83%) in phase 1 and was also reported in five patients (83%; 95% confidence interval, 35.9-99.6; P < 0.0001) in phase 2. Plasma concentrations of both dabrafenib and trametinib seemed to a reach steady state by week 3. Overall, efficacy and PK properties for the dabrafenib plus trametinib combination in Japanese patients were comparable with those seen in global studies.
Sujet(s)
Protocoles de polychimiothérapie antinéoplasique/usage thérapeutique , Imidazoles/usage thérapeutique , Mélanome/traitement médicamenteux , Oximes/usage thérapeutique , Pyridones/usage thérapeutique , Pyrimidinones/usage thérapeutique , Tumeurs cutanées/traitement médicamenteux , Adulte , Sujet âgé , Protocoles de polychimiothérapie antinéoplasique/pharmacocinétique , Survie sans rechute , Femelle , Humains , Imidazoles/pharmacocinétique , Japon , Estimation de Kaplan-Meier , Mâle , Mélanome/génétique , Mélanome/mortalité , Adulte d'âge moyen , Mutation , Oximes/pharmacocinétique , Protéines proto-oncogènes B-raf/génétique , Pyridones/pharmacocinétique , Pyrimidinones/pharmacocinétique , Tumeurs cutanées/génétique , Tumeurs cutanées/mortalité , Résultat thérapeutique , Jeune adulteRÉSUMÉ
The mitogen-activated protein kinase pathway regulates cell growth and differentiation and is activated by BRAF mutations. BRAF mutations are present in about 40-50% of cutaneous melanomas. More than 90% of BRAF mutations are the V600E type. BRAF inhibitor (dabrafenib or vemurafenib) and MEK inhibitor (trametinib or cobimetinib) combination therapies are effective for BRAF-mutant advanced melanomas. A variety of side effects have been observed with combination therapy including pyrexia, fatigue, nausea, and vomiting. Rhabdomyolysis is one of the most severe adverse events, but it is very rare. Only two cases of rhabdomyolysis have been reported in clinical trials. A 41-year-old Japanese woman with cutaneous melanoma was started on a combination of dabrafenib and trametinib therapy after failure of immune checkpoint therapy. One month later, she complained of myalgia and fatigue and was shifted to our hospital. She was diagnosed with trametinib-induced rhabdomyolysis and showed improvement only with a high volume of fluid infusion. We stopped combination therapy, but there were no useful treatment options for her. After resuming dabrafenib, followed by trametinib, she did not have any problems. This is the first case of a patient with metastatic cutaneous melanoma who could recommence combination therapy after trametinib-associated rhabdomyolysis. We assume that not all patients experience recurrence of rhabdomyolysis in trametinib-induced rhabdomyolysis. As few cases have been reported, more information is needed. We have to evaluate safety carefully if rechallenging combination therapy.
Sujet(s)
Protocoles de polychimiothérapie antinéoplasique/effets indésirables , Protocoles de polychimiothérapie antinéoplasique/usage thérapeutique , Mélanome/traitement médicamenteux , Rhabdomyolyse/induit chimiquement , Tumeurs cutanées/traitement médicamenteux , Adulte , Femelle , Humains , Imidazoles/administration et posologie , Oximes/administration et posologie , Pyridones/administration et posologie , Pyridones/effets indésirables , Pyrimidinones/administration et posologie , Pyrimidinones/effets indésirablesRÉSUMÉ
Background Dabrafenib is a BRAF inhibitor that has demonstrated clinical activity with a good tolerability profile in patients with BRAF V600E mutated metastatic melanoma. This study evaluated the safety and tolerability, pharmacokinetics and preliminary efficacy of dabrafenib in Japanese patients. Methods This phase I, open-label, dose escalation study was conducted in 12 Japanese patients with BRAF V600 mutation positive solid tumours. Primary endpoint was safety, assessed by monitoring and recording of all adverse events (AEs), serious AEs, drug-related AEs; secondary endpoints were pharmacokinetic profiles and efficacy measured by tumour response. This study is registered with ClinicalTrials.gov, number NCT01582997. Results Of the 12 patients enrolled, 3 each received 75 mg and 100 mg dabrafenib while 6 received 150 mg dabrafenib twice daily orally. Melanoma and thyroid cancer were the primary tumours reported in 11 (92%) and 1 (8%) patients respectively. Most AEs were grade 1 or 2 and considered related to study treatment. Most common AEs reported in the 12 patients were alopecia in 7 (58%); pyrexia, arthralgia and leukopenia in 6 (50%) each, hyperkeratosis and nausea in 4 (33%) each. Partial response as best overall response was reported in 7 of 12 (58%) patients and in 6 (55%) with malignant melanoma. No dose-limiting toxicity (DLTs) were reported during the DLT evaluation periods. Conclusions Dabrafenib was well tolerated and rapidly absorbed administered as single- or multiple dose. Comparable safety and pharmacokinetic profiles were observed compared with non-Japanese patients. Dabrafenib has promising clinical activity in Japanese patients with BRAF mutated malignant melanoma.
Sujet(s)
Asiatiques , Imidazoles/effets indésirables , Imidazoles/pharmacocinétique , Mutation/génétique , Tumeurs/traitement médicamenteux , Tumeurs/génétique , Oximes/effets indésirables , Oximes/pharmacocinétique , Protéines proto-oncogènes B-raf/génétique , Adulte , Relation dose-effet des médicaments , Femelle , Humains , Imidazoles/administration et posologie , Imidazoles/usage thérapeutique , Mâle , Adulte d'âge moyen , Oximes/administration et posologie , Oximes/usage thérapeutique , Résultat thérapeutiqueRÉSUMÉ
The Dermatologic Oncology Group of Japan Clinical Oncology Group has started a randomized phase III trial to confirm the superiority of adjuvant therapy with locoregional interferon beta in overall survival over surgery alone for patients with pathological stage II/III cutaneous melanoma (JCOG1309). Patients in the interferon beta arm receive intra- or subcutaneous injections of interferon beta directly into the surgical site at a flat dose of 3 million units once per day. Treatment is repeated for 10 consecutive days every 8 weeks for a total of 3 courses during the induction phase, then 1-day injection every 4 weeks for 2.5 years. A total of 240 patients will be accrued from 17 Japanese institutions within 6.5 years. Primary endpoint is overall survival. Secondary endpoints are relapse-free survival, distant metastasis-free survival, pattern of recurrence, and adverse events. This trial has been registered at the UMIN Clinical Trials Registry as UMIN000017494 [http://www.umin.ac.jp/ctr/index.htm].
Sujet(s)
Interféron bêta/usage thérapeutique , Oncologie médicale , Mélanome/traitement médicamenteux , Mélanome/chirurgie , Tumeurs cutanées/traitement médicamenteux , Tumeurs cutanées/chirurgie , Traitement médicamenteux adjuvant , Association thérapeutique , Survie sans rechute , Humains , Japon , Sélection de patients , Résultat thérapeutique ,RÉSUMÉ
Nail apparatus melanoma (NAM) is a rare subtype of malignant melanoma with a prevalence that varies among populations. Conservative surgical approaches for thin to intermediate NAMs have recently been reported, however, their adoption is controversial, and resulting long-term prognoses are unknown. The purpose of this study was to determine the prognosis of NAM in a sample Asian population, and to investigate whether there is a difference in the local control and overall survival (OS) rates according to the extent of resection of the primary tumour. We performed a retrospective study of NAM patients treated at five medical institutions in Japan between 2000 and 2013. Outcomes according to surgery (amputation vs. resection) and tumour thickness were compared. We identified 151 cases of NAM in 83 men and 68 women; the thumb (n = 50; 33.1%) and hallux (n = 55; 36.4%) were the most common sites. No local recurrence was detected following any of the surgical procedures; Kaplan-Meier survival analysis revealed that the surgical procedure type was not significantly associated with disease-free survival (p = 0.786) or OS (p = 0.997). Five-year OS rates according to tumour thickness were 100% for in situ, 94.4% for ≤1-mm, 91.7% for 1.01-2.0-mm, 72.7% for 2.01-4.0-mm, and 47.6% for ≥4.01-mm tumours. Surgical procedure type does not influence survival as long as total primary tumour resection is accomplished. The prognosis of NAM is comparable to that of other types of melanoma.
Sujet(s)
Mélanome/chirurgie , Onychopathies/chirurgie , Tumeurs cutanées/chirurgie , Adulte , Sujet âgé , Sujet âgé de 80 ans ou plus , Femelle , Humains , Japon/épidémiologie , Mâle , Mélanome/mortalité , Adulte d'âge moyen , Onychopathies/mortalité , Pronostic , Études rétrospectives , Tumeurs cutanées/mortalitéSujet(s)
Antinéoplasiques/effets indésirables , Kératose/induit chimiquement , Protéines proto-oncogènes B-raf/antagonistes et inhibiteurs , Sujet âgé , Femelle , Humains , Kératose/anatomopathologie , Mélanome/génétique , Protéines proto-oncogènes B-raf/génétique , Peau/anatomopathologie , Tumeurs cutanées/génétiqueRÉSUMÉ
BACKGROUND: Although both immune-checkpoint inhibitors and targeted therapies such as MEK inhibitors have been evaluated in metastatic uveal melanoma, the efficacy of these therapies is modest to date. The purpose of this study was to evaluate the efficacy and toxicity of transarterial chemoembolization (TACE) therapy for liver metastasis from uveal melanoma in an Asian population. METHODS: We retrospectively assessed the clinical data of patients with liver metastases from uveal melanoma who received TACE therapy using cisplatin (70 mg/m2) and gelatin sponge between 1997 and 2008. RESULTS: We identified 29 eligible patients. The overall response rate was 21%. The median survival time was 23 months, and the 1-, 2-, and 5-year survival rates were 72.4, 39.4, and 0%, respectively. The favorable prognostic factors were partial response and stable disease, <25% of the tumor volume within the liver at baseline, and normal serum lactate dehydrogenase (LDH) and normal alkaline phosphatase at baseline. Among them, normal LDH at baseline was the only independent prognostic factor in multivariate analysis. The common adverse events (AEs) were liver enzyme elevation (100%), nausea (72.4%), abdominal pain (65.5%), vomiting (55.2%), post-embolization syndrome (34.5% of patients, 9.6% of TACE procedures), and pyrexia (24.1%). Grade ≥3 AEs consisted of aspartate aminotransferase elevation (34.5%), alanine aminotransferase elevation (51.7%), and serum creatinine elevation (3.4%). CONCLUSION: TACE therapy has a certain degree of clinical efficacy with a tolerable toxicity and, therefore, can still be one of the treatment options. However, considering the lack of long-term efficacy of this therapy, further treatment strategies need to be developed.
Sujet(s)
Chimioembolisation thérapeutique/méthodes , Tumeurs du foie/secondaire , Tumeurs du foie/thérapie , Mélanome/anatomopathologie , Tumeurs de l'uvée/anatomopathologie , Adulte , Sujet âgé , Antinéoplasiques/usage thérapeutique , Chimioembolisation thérapeutique/effets indésirables , Cisplatine/usage thérapeutique , Femelle , Gélatine , Humains , Tumeurs du foie/mortalité , Mâle , Mélanome/mortalité , Adulte d'âge moyen , Études rétrospectives , Taux de survie , Résultat thérapeutique , Charge tumorale , Tumeurs de l'uvée/mortalitéRÉSUMÉ
BACKGROUND: An anti-programmed cell death protein 1 monoclonal antibody, nivolumab, is one of the most effective drugs for advanced melanoma. Tumor cell-derived or immune cell-derived markers and clinical predictors such as serum lactate dehydrogenase (LDH) and cutaneous adverse events, have already been described as prognostic factors for advanced melanoma treated with nivolumab. We sought to identify further clinical predictors that can be determined in routine clinical practice. METHODS: We retrospectively analyzed clinical findings of 98 consecutive patients with unresectable stage III or IV melanoma treated with nivolumab, at the National Cancer Center Hospital or at Keio University Hospital, in Tokyo, Japan, between July 2014 and July 2016. These patients had been administered nivolumab at a dose of 2mg/kg every 3 weeks. RESULTS: As for pretreatment prognostic factors, ECOG performance status (PS) ≥1, maximum tumor diameters of ≥30mm, elevated LDH and elevated C-reactive protein were significantly associated with poor overall survival (OS) (hazard ratio [HR] 0.29 [P<0.001], HR 0.40 [p=0.003], HR 0.29 [P<0.001], HR 0.42 [P=0.004], respectively) on univariate analysis. Among these factors, PS and LDH were identified as independent variables by multivariate analysis. As for early markers examined during therapy, patients with absolute lymphocyte count (ALC) ≥ 1000/µl (Week3: HR 0.40 [P=0.004], Week6: HR 0.33 [P=0.001]) and absolute neutrophil count (ANC) <4000/µl (Week3: HR 0.46 [P=0.014], Week6: HR 0.51 [P=0.046]) had significantly better OS. CONCLUSION: ALC≥1000/µl and ANC<4000/µl during treatment appear to be early markers associated with OS. Nivolumab might have minimal efficacy in patients with a massive tumor burden.