今日の臨床サポート

悪性黒色腫

著者: 藤澤康弘 筑波大学 医学医療系 皮膚科

著者: 田中亮多 筑波大学 医学医療系 皮膚科

監修: 戸倉新樹 掛川市・袋井市病院企業団立 中東遠総合医療センター 参与/浜松医科大学 名誉教授

著者校正/監修レビュー済:2020/02/19
参考ガイドライン:
  1. 日本皮膚科学会:日本皮膚科学会ガイドライン 皮膚悪性腫瘍ガイドライン第3版 メラノーマ診療ガイドライン2019
患者向け説明資料

概要・推奨   

  1. ダーモスコピーは、この診断法に習熟した医師が用いれば、悪性黒色腫の早期診断に役立つので、ダーモスコピー検査を施行することが勧められる(推奨度1)
  1. 高周波エコー(20-100MHz)はtumor thickness(原発巣の厚さ)を術前にある程度正確に予測することができるので、実施を考慮しても良い。他方でMRIは測定誤差が生じる事があるため、勧められない(推奨度2)
  1. 悪性黒色腫原発巣の部分生検により局所再発率やセンチネルリンパ節転移の陽性率が有意に上昇するという証拠はないので、全切除生検が不可能な場合には、部分生検を行ってもよい。しかし、頭頚部原発の悪性黒色腫患者では部分生検によって生存率が低下する危険性があるので、注意を要する(推奨度2)
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  1. 閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が
  1. 閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約
  1. 閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲 覧にはご 契約が必要となります。閲 覧にはご契約が必要となります。閲覧にはご契約が必要となりま
薬剤監修について:
オーダー内の薬剤用量は日本医科大学付属病院 薬剤部 部長 伊勢雄也 以下、林太祐、渡邉裕次、井ノ口岳洋、梅田将光による疑義照会のプロセスを実施、疑義照会の対象については著者の方による再確認を実施しております。
※薬剤中分類、用法、同効薬、診療報酬は、エルゼビアが独自に作成した薬剤情報であり、
著者により作成された情報ではありません。
尚、用法は添付文書より、同効薬は、薬剤師監修のもとで作成しております。
※薬剤情報の(適外/適内/⽤量内/⽤量外/㊜)等の表記は、エルゼビアジャパン編集部によって記載日時にレセプトチェックソフトなどで確認し作成しております。ただし、これらの記載は、実際の保険適用の査定において保険適用及び保険適用外と判断されることを保証するものではありません。また、検査薬、輸液、血液製剤、全身麻酔薬、抗癌剤等の薬剤は保険適用の記載の一部を割愛させていただいています。
(詳細はこちらを参照)
著者のCOI(Conflicts of Interest)開示:
藤澤康弘 : 講演料(ノバルティス,小野薬品),研究費・助成金など(エーザイ)[2021年]
田中亮多 : 特に申告事項無し[2021年]
監修:戸倉新樹 : 講演料(田辺三菱,サノフィ,マルホ,協和キリン),研究費・助成金など(ノバルティス,レオファーマ)[2021年]

改訂のポイント:
  1. すべての改訂を皮膚悪性腫瘍ガイドライン第3版 メラノーマ診療ガイドライン2019に基づいて行った。
  1. センチネルリンパ節生検陽性症例の診療方針について改訂を行った。
  1. 術後補助療法について改訂を行った。
  1. 上記改訂に伴い、治療アルゴリズムの改訂を行った。

病態・疫学・診察

疾患情報(疫学・病態)  
  1. 悪性黒色腫(メラノーマ)は、色素細胞(メラノサイト)由来のきわめて悪性度の高い悪性腫瘍である。
  1. わが国における発生頻度は、人口10万人あたり約1~1.5人と推測されている。
  1. わが国における発生患者数は年々徐々に増加傾向が示されているが、欧米のような急激な増加はみられていない。
  1. 皮膚悪性黒色腫の病型として、4つの病型が考えられ、それぞれ特徴的な臨床、病態を示す。
 
Acral lentiginous melanoma(末端黒子型メラノーマ)

悪性黒色腫の4つの病型のうち、日本人に最も頻度が多い病型である。足底、手掌、爪下部などに発生し、当初は色素斑から出現、徐々に拡大を示し、次いで結節ないし潰瘍が出現してくる。

出典

img1:  著者提供
 
 
 
Superficial spreading melanoma(表在拡大型メラノーマ)

悪性黒色腫の4つの病型のうち、欧米人(白色人種)に最も頻度が多い病型で、わが国では末端黒子型に次いで多く、最近増加傾向にある。躯幹・四肢中枢側など普段日光に露出しない部位に発生し、当初は色素斑から出現、徐々に拡大を示し、進行すると結節が出現してくる。

出典

img1:  著者提供
 
 
 
Nodular melanoma(結節型メラノーマ)

悪性黒色腫の4つの病型のうち、当初から結節として出現、徐々に増大を示し、周囲に色素斑をほとんど伴わない。早期から結節を形成することから腫瘍の厚さが厚い症例が多く、予後不良である。

出典

img1:  著者提供
 
 
 
Lentigo maligna melanoma(悪性黒子型メラノーマ)

高齢者の顔面など慢性日光曝露部位に濃淡不規則な不整形色素斑が出現し、進行してくると同色素斑に結節を生じてくる。

出典

img1:  著者提供
 
 
 
  1. 治療はTNM分類により規定された病期に基づき選択される。進行症例で治療抵抗性の場合には、予後は不良である。
問診・診察のポイント  
  1. いつ頃から色素斑が出現あるいは消退したことに気づいたか、以後の変化(大きさ、形、色調など)について詳しく聞く。

これより先の閲覧には個人契約のトライアルまたはお申込みが必要です。

最新のエビデンスに基づいた二次文献データベース「今日の臨床サポート」。
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文献 

著者: Naheed R Abbasi, Helen M Shaw, Darrell S Rigel, Robert J Friedman, William H McCarthy, Iman Osman, Alfred W Kopf, David Polsky
雑誌名: JAMA. 2004 Dec 8;292(22):2771-6. doi: 10.1001/jama.292.22.2771.
Abstract/Text CONTEXT: The incidence of cutaneous melanoma has increased over the past several decades, making its early diagnosis a continuing public health priority. The ABCD (Asymmetry, Border irregularity, Color variegation, Diameter >6 mm) acronym for the appraisal of cutaneous pigmented lesions was devised in 1985 and has been widely adopted but requires reexamination in light of recent data regarding the existence of small-diameter (< or =6 mm) melanomas.
EVIDENCE ACQUISITION: Cochrane Library and PubMed searches for the period 1980-2004 were conducted using search terms ABCD and melanoma and small-diameter melanoma. Bibliographies of retrieved articles were also used to identify additional relevant information.
EVIDENCE SYNTHESIS: Available data do not support the utility of lowering the diameter criterion of ABCD from the current greater than 6 mm guideline. However, the data support expansion to ABCDE to emphasize the significance of evolving pigmented lesions in the natural history of melanoma. Physicians and patients with nevi should be attentive to changes (evolving) of size, shape, symptoms (itching, tenderness), surface (especially bleeding), and shades of color.
CONCLUSIONS: The ABCD criteria for the gross inspection of pigmented skin lesions and early diagnosis of cutaneous melanoma should be expanded to ABCDE (to include "evolving"). No change to the existing diameter criterion is required at this time.

PMID 15585738  JAMA. 2004 Dec 8;292(22):2771-6. doi: 10.1001/jama.292.・・・
著者: M F Healsmith, J F Bourke, J E Osborne, R A Graham-Brown
雑誌名: Br J Dermatol. 1994 Jan;130(1):48-50.
Abstract/Text The seven-point checklist has been widely advocated as a sensitive screening test for malignant melanoma. A number of groups have questioned the sensitivity of this system, especially in the detection of early lesions. We have assessed the sensitivity and specificity of the revised seven-point checklist when applied to lesions seen in our department over a 26-month period and compared it with the American ABCDE evaluation system. All melanomas (n = 65) were detected using the revised seven-point checklist and all were found to have at least one of the three major criteria defined by that system. Five (7.7%) melanomas were not picked up by the ABCDE checklist. Of 100 randomly selected patients who attended the clinic during the same period, with clinically diagnosed benign pigmented lesions, 63 had at least one major feature of the revised seven-point checklist. Forty (62%) of the melanomas, compared with only (4%) of the benign lesions, had more than one major feature. This study confirms the sensitivity of the revised seven-point checklist in the diagnosis of cutaneous malignant melanoma.

PMID 8305316  Br J Dermatol. 1994 Jan;130(1):48-50.
著者: Jonathan C Ng, Sarah Swain, John P Dowling, Rory Wolfe, Pamela Simpson, John W Kelly
雑誌名: Arch Dermatol. 2010 Mar;146(3):234-9. doi: 10.1001/archdermatol.2010.14.
Abstract/Text OBJECTIVE: To compare partial and excisional biopsy techniques in the accuracy of histopathologic diagnosis and microstaging of cutaneous melanoma.
DESIGN: Prospective case series.
SETTING: Tertiary referral, ambulatory care, institutional practice. Patients Consecutive cases from 1995 to 2006. Interventions Partial and excisional biopsy. Other factors considered were anatomic site, physician type at initial management, hypomelanosis, melanoma subtype, biopsy sample size, multiple biopsies, and tumor thickness.
MAIN OUTCOME MEASURES: Histopathologic diagnosis (false-negative misdiagnosis-overall or with an adverse outcome-and false-positive misdiagnosis) and microstaging accuracy. Odds ratios (ORs) and 95% confidence intervals (CIs) obtained from multinomial logistic regression.
RESULTS: Increased odds of histopathologic misdiagnosis were associated with punch biopsy (OR, 16.6; 95% CI, 10-27) (P < .001) and shave biopsy (OR, 2.6; 95% CI, 1.2-5.7) (P = .02) compared with excisional biopsy. Punch biopsy was associated with increased odds of misdiagnosis with an adverse outcome (OR, 20; 95% CI, 10-41) (P < .001). Other factors associated with increased odds of misdiagnosis included acral lentiginous melanoma (OR, 5.1; 95% CI, 2-13) (P < .001), desmoplastic melanoma (OR, 3.8; 95% CI, 1.1-13.0) (P = .03), and nevoid melanoma (OR, 28.4; 95% CI, 7-115) (P < .001). Punch biopsy (OR, 5.1; 95% CI, 3.4-7.6) (P < .001) and shave biopsy (OR, 2.3; 95% CI, 1.5-3.6) (P < .001) had increased odds of microstaging inaccuracy over excisional biopsy. Tumor thickness was the most important determinant of microstaging inaccuracy when partial biopsy was used (odds of significant microstaging inaccuracy increased 1.8-fold for every 1 mm increase in tumor thickness; 95% CI, 1.4-2.4) (P < .001).
CONCLUSIONS: Among melanoma seen at a tertiary referral center, histopathologic misdiagnosis is more common for melanomas that have been assessed with punch and shave biopsy than with excisional biopsy. Regardless of biopsy method, adverse outcomes due to misdiagnosis may occur. However, such adverse events are more commonly associated with punch biopsy than with shave and excisional biopsy. The use of punch and shave biopsy also leads to increased microstaging inaccuracy.

PMID 20231492  Arch Dermatol. 2010 Mar;146(3):234-9. doi: 10.1001/arch・・・
著者: Tina J Hieken, Roberto Hernández-Irizarry, Julia M Boll, Jamie E Jones Coleman
雑誌名: Int J Surg Oncol. 2013;2013:196493. doi: 10.1155/2013/196493. Epub 2013 Sep 11.
Abstract/Text BACKGROUND AND OBJECTIVES: While excisional biopsy is recommended to diagnose cutaneous melanoma, various biopsy techniques are used in practice. We undertook this study to identify how frequently final tumor stage and treatment recommendations changed from diagnostic biopsy to final histopathology after wide local excision (WLE).
METHODS: We compared the histopathology of the dermatopathologist-reviewed diagnostic biopsy and final WLE in 332 cutaneous melanoma patients.
RESULTS: Tumor sites were extremity (51%), trunk (33%), and head/neck (16%). Initial biopsy types were excisional (56%), punch (21%), shave (18%), and incisional (5%). Most diagnostic biopsies were margin positive regardless of technique, and 36% of patients had residual melanoma on WLE. T-stage changed in 8% of patients, of whom 59% were diagnosed by punch biopsy, 15% by incisional biopsy, 15% by shave biopsy, and 11% by excisional biopsy (P < 0.0001). Treatment recommendations changed in 6%: 2% after excisional biopsy, 5% after shave biopsy, 18% after punch biopsy, and 18% after incisional biopsy (P < 0.0001).
CONCLUSIONS: Although most biopsy margins were positive, T-stage and treatment changed for only a minority of melanoma patients. Our data provide valuable information to inform patient discussion regarding the likelihood of a change in prognosis and the need for secondary procedures after WLE. These data support the superiority of dermatopathologist-reviewed excisional biopsy when feasible.

PMID 24102023  Int J Surg Oncol. 2013;2013:196493. doi: 10.1155/2013/1・・・
著者: Jacqueline Dinnes, Jonathan J Deeks, Naomi Chuchu, Lavinia Ferrante di Ruffano, Rubeta N Matin, David R Thomson, Kai Yuen Wong, Roger Benjamin Aldridge, Rachel Abbott, Monica Fawzy, Susan E Bayliss, Matthew J Grainge, Yemisi Takwoingi, Clare Davenport, Kathie Godfrey, Fiona M Walter, Hywel C Williams, Cochrane Skin Cancer Diagnostic Test Accuracy Group
雑誌名: Cochrane Database Syst Rev. 2018 Dec 4;12:CD011902. doi: 10.1002/14651858.CD011902.pub2. Epub 2018 Dec 4.
Abstract/Text BACKGROUND: Melanoma has one of the fastest rising incidence rates of any cancer. It accounts for a small percentage of skin cancer cases but is responsible for the majority of skin cancer deaths. Although history-taking and visual inspection of a suspicious lesion by a clinician are usually the first in a series of 'tests' to diagnose skin cancer, dermoscopy has become an important tool to assist diagnosis by specialist clinicians and is increasingly used in primary care settings. Dermoscopy is a magnification technique using visible light that allows more detailed examination of the skin compared to examination by the naked eye alone. Establishing the additive value of dermoscopy over and above visual inspection alone across a range of observers and settings is critical to understanding its contribution for the diagnosis of melanoma and to future understanding of the potential role of the growing number of other high-resolution image analysis techniques.
OBJECTIVES: To determine the diagnostic accuracy of dermoscopy alone, or when added to visual inspection of a skin lesion, for the detection of cutaneous invasive melanoma and atypical intraepidermal melanocytic variants in adults. We separated studies according to whether the diagnosis was recorded face-to-face (in-person), or based on remote (image-based), assessment.
SEARCH METHODS: We undertook a comprehensive search of the following databases from inception up to August 2016: CENTRAL; MEDLINE; Embase; CINAHL; CPCI; Zetoc; Science Citation Index; US National Institutes of Health Ongoing Trials Register; NIHR Clinical Research Network Portfolio Database; and the World Health Organization International Clinical Trials Registry Platform. We studied reference lists and published systematic review articles.
SELECTION CRITERIA: Studies of any design that evaluated dermoscopy in adults with lesions suspicious for melanoma, compared with a reference standard of either histological confirmation or clinical follow-up. Data on the accuracy of visual inspection, to allow comparisons of tests, was included only if reported in the included studies of dermoscopy.
DATA COLLECTION AND ANALYSIS: Two review authors independently extracted all data using a standardised data extraction and quality assessment form (based on QUADAS-2). We contacted authors of included studies where information related to the target condition or diagnostic threshold were missing. We estimated accuracy using hierarchical summary receiver operating characteristic (SROC),methods. Analysis of studies allowing direct comparison between tests was undertaken. To facilitate interpretation of results, we computed values of sensitivity at the point on the SROC curve with 80% fixed specificity and values of specificity with 80% fixed sensitivity. We investigated the impact of in-person test interpretation; use of a purposely developed algorithm to assist diagnosis; observer expertise; and dermoscopy training.
MAIN RESULTS: We included a total of 104 study publications reporting on 103 study cohorts with 42,788 lesions (including 5700 cases), providing 354 datasets for dermoscopy. The risk of bias was mainly low for the index test and reference standard domains and mainly high or unclear for participant selection and participant flow. Concerns regarding the applicability of study findings were largely scored as 'high' concern in three of four domains assessed. Selective participant recruitment, lack of reproducibility of diagnostic thresholds and lack of detail on observer expertise were particularly problematic.The accuracy of dermoscopy for the detection of invasive melanoma or atypical intraepidermal melanocytic variants was reported in 86 datasets; 26 for evaluations conducted in person (dermoscopy added to visual inspection), and 60 for image-based evaluations (diagnosis based on interpretation of dermoscopic images). Analyses of studies by prior testing revealed no obvious effect on accuracy; analyses were hampered by the lack of studies in primary care, lack of relevant information and the restricted inclusion of lesions selected for biopsy or excision. Accuracy was higher for in-person diagnosis compared to image-based evaluations (relative diagnostic odds ratio (RDOR) 4.6, 95% confidence interval (CI) 2.4 to 9.0; P < 0.001).We compared accuracy for (a), in-person evaluations of dermoscopy (26 evaluations; 23,169 lesions and 1664 melanomas),versus visual inspection alone (13 evaluations; 6740 lesions and 459 melanomas), and for (b), image-based evaluations of dermoscopy (60 evaluations; 13,475 lesions and 2851 melanomas),versus image-based visual inspection (11 evaluations; 1740 lesions and 305 melanomas). For both comparisons, meta-analysis found dermoscopy to be more accurate than visual inspection alone, with RDORs of (a), 4.7 (95% CI 3.0 to 7.5; P < 0.001), and (b), 5.6 (95% CI 3.7 to 8.5; P < 0.001). For a), the predicted difference in sensitivity at a fixed specificity of 80% was 16% (95% CI 8% to 23%; 92% for dermoscopy + visual inspection versus 76% for visual inspection), and predicted difference in specificity at a fixed sensitivity of 80% was 20% (95% CI 7% to 33%; 95% for dermoscopy + visual inspection versus 75% for visual inspection). For b) the predicted differences in sensitivity was 34% (95% CI 24% to 46%; 81% for dermoscopy versus 47% for visual inspection), at a fixed specificity of 80%, and predicted difference in specificity was 40% (95% CI 27% to 57%; 82% for dermoscopy versus 42% for visual inspection), at a fixed sensitivity of 80%.Using the median prevalence of disease in each set of studies ((a), 12% for in-person and (b), 24% for image-based), for a hypothetical population of 1000 lesions, an increase in sensitivity of (a), 16% (in-person), and (b), 34% (image-based), from using dermoscopy at a fixed specificity of 80% equates to a reduction in the number of melanomas missed of (a), 19 and (b), 81 with (a), 176 and (b), 152 false positive results. An increase in specificity of (a), 20% (in-person), and (b), 40% (image-based), at a fixed sensitivity of 80% equates to a reduction in the number of unnecessary excisions from using dermoscopy of (a), 176 and (b), 304 with (a), 24 and (b), 48 melanomas missed.The use of a named or published algorithm to assist dermoscopy interpretation (as opposed to no reported algorithm or reported use of pattern analysis), had no significant impact on accuracy either for in-person (RDOR 1.4, 95% CI 0.34 to 5.6; P = 0.17), or image-based (RDOR 1.4, 95% CI 0.60 to 3.3; P = 0.22), evaluations. This result was supported by subgroup analysis according to algorithm used. We observed higher accuracy for observers reported as having high experience and for those classed as 'expert consultants' in comparison to those considered to have less experience in dermoscopy, particularly for image-based evaluations. Evidence for the effect of dermoscopy training on test accuracy was very limited but suggested associated improvements in sensitivity.
AUTHORS' CONCLUSIONS: Despite the observed limitations in the evidence base, dermoscopy is a valuable tool to support the visual inspection of a suspicious skin lesion for the detection of melanoma and atypical intraepidermal melanocytic variants, particularly in referred populations and in the hands of experienced users. Data to support its use in primary care are limited, however, it may assist in triaging suspicious lesions for urgent referral when employed by suitably trained clinicians. Formal algorithms may be of most use for dermoscopy training purposes and for less expert observers, however reliable data comparing approaches using dermoscopy in person are lacking.

PMID 30521682  Cochrane Database Syst Rev. 2018 Dec 4;12:CD011902. doi・・・
著者: M L Bafounta, A Beauchet, P Aegerter, P Saiag
雑誌名: Arch Dermatol. 2001 Oct;137(10):1343-50.
Abstract/Text OBJECTIVE: To assess, by means of meta-analysis techniques for diagnostic tests, the accuracy of dermoscopic (also known as dermatoscopy and epiluminescence microscopy) diagnosis of melanoma performed by experienced observers vs. naked-eye clinical examination.
DATA SOURCES: MEDLINE, EMBASE, PASCAL-BIOMED, and BIUM databases were screened through May 31, 2000, without any language restrictions.
STUDY SELECTION: Original studies were selected when the following criteria were met: spectrum of lesions well described, histologic findings as standard criterion, and calculated or calculable sensitivity and specificity. Eight of 672 retrieved references were retained.
DATA EXTRACTION: Three investigators extracted data. In case of disagreement, consensus was obtained. Summary receiver operating characteristic curve analysis was used to describe the central tendency of the studies, and to compare dermoscopy and clinical examination.
DATA SYNTHESIS: Selected studies represented 328 melanomas, mostly less than 0.76 mm thick, and 1865 mostly melanocytic benign pigmented skin lesions. For dermoscopic diagnosis of melanoma, the sensitivity and specificity ranges were 0.75 to 0.96 and 0.79 to 0.98, respectively. Dermoscopy had significantly higher discriminating power than clinical examination, with respective estimated odds ratios of 76 (95% confidence interval, 25-223) and 16 (95% confidence interval, 9-31) (P =.008), and respective estimated positive likelihood ratios of 9 (95% confidence interval, 5.6-19.0) and 3.7 (95% confidence interval, 2.8-5.3). The roles of the number of lesions analyzed, the percentage of melanoma lesions, the instrument used, and dermoscopic criteria used in each study could not be proved.
CONCLUSION: For experienced users, dermoscopy is more accurate than clinical examination for the diagnosis of melanoma in a pigmented skin lesion.

PMID 11594860  Arch Dermatol. 2001 Oct;137(10):1343-50.
著者: H Kittler, H Pehamberger, K Wolff, M Binder
雑誌名: Lancet Oncol. 2002 Mar;3(3):159-65.
Abstract/Text The accuracy of the dinical diagnosis of cutaneous melanoma with the unaided eye is only about 60%. Dermoscopy, a non-invasive, in vivo technique for the microscopic examination of pigmented skin lesions, has the potential to improve the diagnostic accuracy. Our objectives were to review previous publications, to compare the accuracy of melanoma diagnosis with and without dermoscopy, and to assess the influence of study characteristics on the diagnostic accuracy. We searched for publications between 1987 and 2000 and identified 27 studies eligible for meta-analysis. The diagnostic accuracy for melanoma was significantly higher with dermoscopy than without this technique (log odds ratio 4.0 [95% CI 3.0 to 5.1] versus 2.7 [1.9 to 3.4]; an improvement of 49%, p = 0.001). The diagnostic accuracy of dermoscopy significantly depended on the degree of experience of the examiners. Dermoscopy by untrained or less experienced examiners was no better than clinical inspection without dermoscopy. The diagnostic performance of dermoscopy improved when the diagnosis was made by a group of examiners in consensus and diminished as the prevalence of melanoma increased. A comparison of various diagnostic algorithms for dermoscopy showed no significant differences in their diagnostic performance. A thorough appraisal of the study characteristics showed that most of the studies were potentially influenced by verification bias. In conclusion, dermoscopy improves the diagnostic accuracy for melanoma in comparison with inspection by the unaided eye, but only for experienced examiners.

PMID 11902502  Lancet Oncol. 2002 Mar;3(3):159-65.
著者: J S Lederman, A J Sober
雑誌名: J Am Acad Dermatol. 1985 Dec;13(6):983-7.
Abstract/Text A total of 472 patients with clinical Stage I cutaneous melanoma were analyzed to determine influence of type of diagnostic biopsy on survival. Of these patients, 119 had had an incisional biopsy (either punch or incision) and 353 had an excisional biopsy. Patients were grouped by thickness category and outcome compared between the biopsy types. Within each thickness category, there is no statistically significant difference in survival between the two groups. The observation that none of the seventy-six patients with primary tumors less than 1.70 mm have died following incisional biopsy strongly argues against any deleterious effect of incisional biopsy in this group. Alternatively, if the two highest-risk groups (greater than or equal to 1.70 mm) are analyzed as a single group, an adverse effect is seen in the incisional biopsy group (p less than 0.05). However, when the data from these groups are subjected to multivariate analysis, biopsy type is not a significant factor in the model. This study shows that either biopsy method may be used in first evaluating patients with suspected melanoma.

PMID 4078105  J Am Acad Dermatol. 1985 Dec;13(6):983-7.
著者: V C Lees, J C Briggs
雑誌名: Br J Surg. 1991 Sep;78(9):1108-10.
Abstract/Text After treatment for primary clinical Stage 1 invasive cutaneous malignant melanoma, 1086 patients were followed for a minimum of 5 years from initial operation. Patient data were retrieved from the unit's melanoma registry; 96 (8.8 per cent) were treated initially by incisional biopsy, 292 (26.9 per cent) by narrow margin excision biopsy and 698 (64.3 per cent) by wide margin excision. Logistic regression analysis was performed to assess the statistical significance of the association between the various factors. The method of initial biopsy was related to maximal tumour thickness, age, and sex. Incisional biopsy rendered 38 out of 96 (40 per cent) lesions not fully assessable on current histopathological criteria, significantly higher than for the other biopsy techniques (P less than 0.0001). Incisional biopsy did not adversely affect prognosis in terms of local recurrence and mortality. Prognosis was related to tumour thickness, age and sex of the patient, and not to biopsy technique. We recommend that all suspicious lesions should be submitted to excisional rather than incisional biopsy to avoid compromising the histological assessment, given the importance of maximal tumour thickness in determining treatment and prognosis.

PMID 1933198  Br J Surg. 1991 Sep;78(9):1108-10.
著者: Jan L Bong, Robert M Herd, John A A Hunter
雑誌名: J Am Acad Dermatol. 2002 May;46(5):690-4.
Abstract/Text BACKGROUND: There are many circumstances in clinical practice in which it is helpful to have a definitive diagnosis of melanoma before subjecting a patient to mutilating surgery. Previous studies on the effect of incisional biopsy on melanoma prognosis were conflicting and lacked a matched control group to account for the other prognostic indicators.
OBJECTIVE: We set up this study to investigate the effect of incisional biopsy on melanoma prognosis.
METHODS: The design was of a retrospective case control. Data were obtained from the database of the Scottish Melanoma Group; the database was set up in 1979 to collect detailed clinical, pathologic, and follow-up data on all patients diagnosed with melanoma in Scotland. Each incisional case was matched against 2 excision cases controlling for age, sex, sites, and Breslow thickness. The main outcome measures were time from initial biopsy to recurrence and to melanoma-related death.
RESULTS: Two hundred sixty-five patients who had incisional biopsy before definitive excision of melanoma were included in the study; these were matched with 496 cases of excisional biopsy specimens. Cox's proportional hazard model for survival analysis showed that biopsy type had no significant effect on recurrence (P =.30) or melanoma-related death (P =.34).
CONCLUSIONS: This study is the largest series on the effect of incisional biopsy on melanoma prognosis to date and the first to include matched controls. Melanoma prognosis is not influenced by incisional biopsy,. before definitive excision.

PMID 12004308  J Am Acad Dermatol. 2002 May;46(5):690-4.
著者: Robert C G Martin, Charles R Scoggins, Merrick I Ross, Douglas S Reintgen, R Dirk Noyes, Michael J Edwards, Kelly M McMasters
雑誌名: Am J Surg. 2005 Dec;190(6):913-7. doi: 10.1016/j.amjsurg.2005.08.020.
Abstract/Text BACKGROUND: In the era of sentinel lymph node (SLN) biopsy, there has been concern that manipulation, injection, and massage of intact primary melanomas (after incisional or shave biopsy) could lead to an artifactual increased rate of SLN micrometastases or an actual increased risk of recurrence. The aim of this study was to evaluate the difference in the incidence of SLN metastasis, locoregional recurrence (LRR), disease-free survival (DFS), distant disease-free survival (DDFS), or overall survival (OS) for patients who undergo excisional versus incisional versus shave biopsy.
METHODS: Analysis of database from a multicenter prospective randomized study from centers across the United States and Canada. Eligible patients were 18 to 71 years old, with cutaneous melanoma > or = 1.0 mm Breslow thickness. All patients underwent SLN biopsy using blue dye and radioactive colloid injection. SLNd were evaluated by serial histological sections with S100 immunohistochemistry. Statistical analysis was performed using univariate and multivariate analyses with a significance level of P < .05; survival analysis was performed by the Kaplan-Meier method with the log-rank test.
RESULTS: A total of 2,164 patients were evaluated; 382 patients were excluded for lack of biopsy information. Positive SLNs were found in 220 of 1,130 (19.5%), 58 of 281 (20.6%), and 67 of 354 (18.9%) of patients with excisional, incisional, or shave biopsy, respectively (no significant difference). There were significant differences among the 3 biopsy types in ulceration (P = .018, chi2) and regression (P = .022, chi2); there were no differences in age, gender, Breslow thickness, Clark level, lymphovascular invasion, tumor location, or histologic subtype. Biopsy type did not significantly affect LRR, DFS, DDFS, or OS.
CONCLUSIONS: The concern that incomplete excision of primary melanomas may result in an increased incidence of SLN micrometastases, artifactual or real, is unfounded. Similarly, there is no evidence that biopsy type adversely affects locoregional or distant recurrence. Although shave biopsy is generally discouraged because it may lead to inaccurate tumor thickness measurements, it does not appear to affect overall patient outcome.

PMID 16307945  Am J Surg. 2005 Dec;190(6):913-7. doi: 10.1016/j.amjsur・・・
著者: J R Austin, R M Byers, W D Brown, P Wolf
雑誌名: Head Neck. 1996 Mar-Apr;18(2):107-17. doi: 10.1002/(SICI)1097-0347(199603/04)18:2<107::AID-HED1>3.0.CO;2-5.
Abstract/Text BACKGROUND: This study was performed to determine the effect of biopsy type on survival rates and on local, regional, and distant metastasis in patients with head and neck cutaneous melanoma.
METHODS: A case series of 159 patients with melanoma of the head and neck referred to a tertiary-care center between 1983 and 1991, with a median follow-up of 38 months, was reviewed. Information analyzed included patient's age, sex, type of treatment, mode of biopsy, presence of residual melanoma in reexcision, location of lesion, presence of ulceration, Clark's level, Breslow thickness, and histologic type of the melanoma.
RESULTS: Excisional biopsy was performed in 79 patients, incisional biopsy in 48, and other procedures (shave, needle biopsy, cauterization, or cryotherapy) in 32. There were no significant pretreatment differences among the three groups in sex, thickness, histologic type, presence of nodal disease, or type of treatment. Pretreatment location of lesion was significantly different (p = .03) between the excisional and other biopsy types. Association between type of biopsy and survival rate was significant (p<.001):31.3% of patients in the incisional biopsy group died of disease, as did 25% of the other biopsy group, versus 8.9% of the excisional biopsy group; 31.3% of patients in the incisional biopsy group developed distant metastases, as did 28.1% of the other biopsy type, versus 10.1% of those in the excisional biopsy group (p = .01). There was no significant difference in local p = .37) or regional (p = 1.00) recurrence among the three biopsy groups. Multivariate analysis showed presence of tumor in the re-excision specimen, biopsy type, and nodal disease to be independent prognostic factors.
CONCLUSIONS: Our study suggests that the type of biopsy of cutaneous melanoma of the head and neck may influence the clinical outcome.

PMID 8647675  Head Neck. 1996 Mar-Apr;18(2):107-17. doi: 10.1002/(SIC・・・
著者: K Hoffmann, J Jung, S el Gammal, P Altmeyer
雑誌名: Dermatology. 1992;185(1):49-55.
Abstract/Text In order to assess the value of 20-MHz sonography in the pre-operative diagnosis of malignant melanomas, 54 melanomas were examined. The pre-operative ultrasound scans were compared with corresponding histological sections from the excised tumours. A computer-aided measurement of the tumour thickness (sonometry) and the internal echo density (densitometry) was performed in the ultrasound scans. The melanomas appeared as largely echolucent zones. There was a significant correlation between the tumour thickness measured in the ultrasound scan and those measured in the histological sections (r = 0.938, p less than 0.001). As a rule the tumour thickness determined by sonometry were greater than the histometrically determined values. Subtumoral inflammatory infiltrate and other hypo-echoic structures in the region of the tumour are possible causes of the discrepancies. Some of those hypo-echoic structures can be identified and disregarded in B scan measurement. Even if a definite differential diagnosis is not possible on the basis of the ultrasound scan alone, 20-MHz sonography provides additional information which can be of use in surgical planning.

PMID 1638071  Dermatology. 1992;185(1):49-55.
著者: Nathalie Lassau, Michele Lamuraglia, Serge Koscielny, Alain Spatz, Alain Roche, Jerome Leclere, Marie-Françoise Avril
雑誌名: Cancer Imaging. 2006 Apr 25;6:24-9. doi: 10.1102/1470-7330.2006.0009. Epub 2006 Apr 25.
Abstract/Text OBJECTIVE: To study the value of high-frequency sonography (HFS) and colour Doppler sonography (CDS) in evaluating the 5 year metastatic potential of primary cutaneous melanomas (CM).
MATERIALS AND METHODS: 111 CM were studied before surgical resection and 107 were depicted on HFS. The maximal HFS thickness was measured and compared with the Breslow thickness. A CDS study was performed in each tumour.
RESULTS: HFS thickness ranged from 0.26 to 8.0 mm and Breslow thickness from 0.15 to 8.0 mm. HFS and Breslow thickness correlated strongly (r > 0.93). Intratumour vessels were depicted in 43 of the 107 CM, of which 40 were thicker than 2 mm. The median follow-up was 61 months and 27 patients developed relapses. In the univariate analyses, neovascularization visualized with CDS, sonographic thickness and the Breslow thickness were significantly linked to relapses (p < 0.0001), as were lymph node status and ulceration (p = 0.007 and 0.004).
CONCLUSION: Vascularization was observed mainly in thick primary melanoma. A median follow-up of 5 years showed the prognostic value of angiogenesis evaluated by CDS.

PMID 16644502  Cancer Imaging. 2006 Apr 25;6:24-9. doi: 10.1102/1470-7・・・
著者: Dirk Schadendorf, Georgina V Long, Daniil Stroiakovski, Boguslawa Karaszewska, Axel Hauschild, Evgeny Levchenko, Vanna Chiarion-Sileni, Jacob Schachter, Claus Garbe, Caroline Dutriaux, Helen Gogas, Mario Mandalà, John B A G Haanen, Céleste Lebbé, Andrzej Mackiewicz, Piotr Rutkowski, Jean-Jacques Grob, Paul Nathan, Antoni Ribas, Michael A Davies, Ying Zhang, Mathilde Kaper, Bijoyesh Mookerjee, Jeffrey J Legos, Keith T Flaherty, Caroline Robert
雑誌名: Eur J Cancer. 2017 Sep;82:45-55. doi: 10.1016/j.ejca.2017.05.033. Epub 2017 Jun 22.
Abstract/Text AIM: Understanding predictors of long-term benefit with currently available melanoma therapies is the key for optimising individualised treatments. A prior pooled analysis of dabrafenib plus trametinib (D + T)-randomised trials (median follow-up, 20.0 months) identified baseline lactate dehydrogenase (LDH) and number of organ sites with metastasis as predictive factors for progression-free (PFS) and overall (OS) survival. However, longer-term follow-up analyses are needed to confirm which patients treated with D + T can achieve maximum benefit.
METHODS: Three-year landmark data were retrospectively pooled for D + T patients in phase 3 trials (COMBI-d [NCT01584648]; COMBI-v [NCT01597908]). Univariate and multivariate analyses assessed prognostic values of predefined baseline factors; regression tree analysis determined hierarchy and interactions between variables.
RESULTS: Long-term pooled outcomes were consistent with individual trial results (N = 563; 3-year PFS, 23%; 3-year OS, 44%). Baseline LDH level and number of organ sites remained strongly associated with and/or predictive of PFS and OS. In addition, baseline sum of lesion diameters (SLD) was identified as a predictor for progression. In the most favourable prognostic group (normal LDH, SLD <66 mm, <3 organ sites; n = 183/563 [33%]), 3-year PFS was 42%. Baseline number of organ sites was also predictive of outcomes in patients with PFS ≥ 6 months.
CONCLUSION: Using the largest phase 3 data set available for BRAF/MEK inhibitor combination therapy in melanoma, these results demonstrate that durable responses lasting ≥3 years are possible in subsets of patients with BRAF-mutant melanoma receiving D + T. Although the best predictive model evolved with longer follow-up, factors predicting clinical outcomes with the combination remained consistent with previous analyses.

Copyright © 2017 Elsevier Ltd. All rights reserved.
PMID 28648698  Eur J Cancer. 2017 Sep;82:45-55. doi: 10.1016/j.ejca.20・・・
著者: Anne Brecht Francken, Esther Bastiaannet, Harald J Hoekstra
雑誌名: Lancet Oncol. 2005 Aug;6(8):608-21. doi: 10.1016/S1470-2045(05)70283-7.
Abstract/Text Follow-up services for patients with localised cutaneous melanoma are widely discussed but there is no international consensus. Our aim was to discuss frequency and duration of follow-up, type of health professional involved, optimum intensity of routine investigation, and patients' satisfaction with follow-up. Searches of the published work were directed at publications between January, 1985, and February, 2004 on recurrences, subsequent primary melanoma, routine tests, and patients' satisfaction. In a selection of 72 articles, 2142 (6.6%) recurrences were reported, 62% of which were detected by the patients themselves. 2.6% of patients developed a subsequent primary melanoma. Most investigators do not support high-intensity routine follow-up investigations. Of the various follow-up investigations requested by physicians, only medical history and physical examination seem to be cost effective. Lymph-node sonography seems to be a promising method for detection, although survival benefit remains to be proven. Patients were found to be anxious about follow-up visits, although other research showed that provision of information to patients was much appreciated. Published work on the follow-up of patients with cutaneous melanoma has mainly been retrospective and descriptive. Recommendations can be given with only a low grade of evidence. For meaningful guidelines to be developed, prospective, high-quality methodological research is needed.

PMID 16054572  Lancet Oncol. 2005 Aug;6(8):608-21. doi: 10.1016/S1470-・・・
著者: C R Shumate, M M Urist, W A Maddox
雑誌名: Ann Surg. 1995 May;221(5):566-9; discussion 569-71.
Abstract/Text OBJECTIVE: The authors determined the roles of the physician and the patient in melanoma recurrence detection.
METHODS: The University of Alabama Melanoma Registry, consisting of 1475 patients surgically treated for cutaneous melanoma from 1958 to 1984, was searched to find 195 evaluable cases of melanoma recurrence. Patients were grouped by the type of return visit. Group I returned on a previously determined date, whereas group II returned before the scheduled visit.
RESULTS: Symptoms of recurrence were present in 90% of group I patients and 93% of group II and correlated with the site of recurrence in more than two thirds of cases. Recurrence sites were local, regional, and distant in 35%, 31%, and 29% of group I, respectively, and 42%, 25%, and 29% of group II. The median interval to recurrence was 24.2 months in group I and 37.7 months in group II (p = 0.059). Median overall survival was 57 months in group I and 62 months in Group II (p = 0.210).
CONCLUSIONS: Symptoms are present in 90% of the patients with recurrent melanoma and accurately predict the site of recurrence. Overall survival is not affected by the type of patient return visit.

PMID 7748038  Ann Surg. 1995 May;221(5):566-9; discussion 569-71.
著者: M M Mooney, M Kulas, B McKinley, A M Michalek, W G Kraybill
雑誌名: Ann Surg Oncol. 1998 Jan-Feb;5(1):54-63.
Abstract/Text BACKGROUND: The impact on survival by components of a surveillance program (physical examination, blood tests, and chest radiograph) used to detect recurrences in patients with cutaneous melanoma was assessed.
METHODS: Data were collected from medical records and tumor registry information on a historical cohort of 1004 patients who presented with AJCC Stage I or II cutaneous melanoma at Roswell Park Cancer Institute from 1971 through 1995.
RESULTS: Information on method of detection was available on 154 out of 174 identified first recurrences (89%). Physical examination detected 72% of recurrences, constitutional symptoms indicated 17% of recurrences, and chest radiograph revealed 11% of recurrences. Blood tests did not predict any recurrence. Only 9 of 17 patients with recurrences detected by chest radiograph alone underwent curative surgical resection. These patients had a statistically significant prolonged survival after diagnosis of recurrence compared to those surgical candidates who did not undergo resection. There was no statistically significant difference in overall survival between patients with asymptomatic pulmonary recurrences and those whose pulmonary recurrences were detected after symptoms of metastatic disease had developed.
CONCLUSIONS: Most recurrences are detected on physical examination. Blood tests have no role in surveillance programs. Chest radiographs can detect pulmonary recurrences in a small number of asymptomatic patients at a stage when surgery may prolong survival.

PMID 9524709  Ann Surg Oncol. 1998 Jan-Feb;5(1):54-63.
著者: P C Davis, P A Hudgins, S B Peterman, J C Hoffman
雑誌名: AJNR Am J Neuroradiol. 1991 Mar-Apr;12(2):293-300.
Abstract/Text For patients suspected of having cerebral metastases, double-dose delayed CT (DDD-CT) has proved significantly more sensitive than CT scans obtained immediately after administration of a lesser dose of iodinated contrast material. Previous reports confirm the advantages of postcontrast MR imaging over contrast-enhanced CT, but data comparing DDD-CT and contrast-enhanced MR have not been reported. This study describes comparative imaging results in 23 patients who had contrast-enhanced MR imaging to clarify equivocal findings on DDD-CT studies. Contrast-enhanced MR demonstrated more than 67 definite or typical parenchymal metastases. T2-weighted MR revealed more than 40, while DDD-CT revealed only 37 typical metastatic lesions. Three patients had five or fewer lesions on DDD-CT and lesions "too numerous to count" on MR. The frequency of equivocal or unconvincing lesions was similar on DDD-CT (11) and contrast-enhanced MR (10). On T2-weighted images, we noted a substantially higher number of equivocal lesions (19), fewer definite metastases, and a number of definite metastases that had no corresponding lesion on the enhanced studies, confirming the inability of T2-weighted imaging to specifically identify cerebral metastases. In one case, multiple tiny lesions on T2-weighted images were not apparent on DDD-CT scans and were recognized only in retrospect on contrast-enhanced MR images. In this series, MR with enhancement proved superior to DDD-CT for lesion detection, anatomic localization of lesions, and differentiation of solitary vs multiple lesions. Cost-benefit considerations precluded a comparison between the two techniques in all patients suspected of having cerebral metastases.(ABSTRACT TRUNCATED AT 250 WORDS)

PMID 1902031  AJNR Am J Neuroradiol. 1991 Mar-Apr;12(2):293-300.
著者: M Berwick, C B Begg, J A Fine, G C Roush, R L Barnhill
雑誌名: J Natl Cancer Inst. 1996 Jan 3;88(1):17-23.
Abstract/Text BACKGROUND: Although some evidence indicates that early detection protects against the development of lethal melanoma, no randomized clinical trials have been conducted to measure the efficacy of early detection (or screening) in preventing death from this disease. Since melanoma incidence in the United States is relatively rare, a randomized clinical trial to test the efficacy of screening would be extremely expensive.
PURPOSE: As an alternative to a randomized clinical trial, we conducted a population-based, case-control study to investigate whether early detection through skin self-examination (SSE) is associated with a decreased risk of lethal melanoma (includes the presence of advanced disease with distant metastases in addition to death from melanoma).
METHODS: SSE (conducting a careful, deliberate, and purposeful examination of the skin) was assessed in all subjects by use of a structured questionnaire and personal interviews. The major exposure variable, SSE, was defined following focus-group interviews with melanoma patients and healthy control subjects. The final study population consisted of 1199 Caucasian residents of the state of Connecticut enrolled from January 15, 1987, through May 15, 1989; 650 individuals were newly diagnosed with cutaneous melanoma, and the remaining 549 individuals were age- and sex-frequency matched control subjects from the general population. During the study interviews, nevi on the arms and backs of subjects were counted. In 5 years of follow-up (through March 1994), 110 lethal cases of melanoma were identified. The study design allowed separate estimation of the impact of SSE on reduced melanoma incidence (primary prevention) and survival among incident cases (secondary prevention). Odds ratios (ORs) were used to measure the associations between SSE and melanoma and between SSE and lethal melanoma.
RESULTS: SSE, practiced by only 15% of all subjects, was associated with a reduced risk of melanoma incidence (adjusted OR = 0.66; 95% confidence interval [CI] = 0.44-0.99; comparing case patients with control subjects). The data indicated further that SSE may reduce the risk of advanced disease among melanoma patients (unadjusted risk ratio = 0.58; 95% CI = 0.31-1.11); however, longer follow-up is required to confirm this latter estimate. If both estimates are correct, they suggest, in combination, that SSE may reduce mortality from melanoma by 63% (adjusted OR = 0.37; 95% CI = 0.16-0.84; comparing lethal cases with general population controls).
CONCLUSIONS AND IMPLICATIONS: SSE may provide a useful and inexpensive screening method to reduce the incidence of melanoma. SSE may also reduce the development of advanced disease. The results of this study need to be replicated before strategies to increase the practice of SSE are further developed and promoted.

PMID 8847720  J Natl Cancer Inst. 1996 Jan 3;88(1):17-23.
著者: Marko B Lens, Martin Dawes, Tim Goodacre, Julia A Newton Bishop
雑誌名: Arch Surg. 2002 Oct;137(10):1101-5.
Abstract/Text 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.

PMID 12361412  Arch Surg. 2002 Oct;137(10):1101-5.
著者: Philip I Haigh, L Andrew DiFronzo, David R McCready
雑誌名: Can J Surg. 2003 Dec;46(6):419-26.
Abstract/Text OBJECTIVE: To determine in patients with localized primary melanoma of the trunk or extremities the optimal excision margin that achieves the highest disease-free survival and overall survival and the lowest local recurrence rate.
DATA SOURCES: Trials comparing 2 different excision margins were identified by searching MEDLINE from 1966 to May 2002 using the term "melanoma," subheading "surgery," and limiting the search to human studies and randomized controlled trials (RCTs). Additional studies were found using the MeSH term "surgical procedures, operative," combining with "melanoma," and limiting to human studies. We searched EMBASE and the Cochrane Library in May 2002 using similar terminology. No language restriction was applied.
STUDY SELECTION: We selected studies for the overview using the following inclusion criteria: design--an RCT with wide excision versus narrower excision (margin width was not specified a priori); population--adult patients (> 18 yr) with cutaneous melanoma of the trunk or extremities without evidence of metastasis; intervention--surgical excision of the primary melanoma; and outcomes--at least 1 of overall survival, disease-free survival, local recurrence, wound complications and necessity for skin grafting.
DATA EXTRACTION: Information was abstracted for each outcome reported in the studies, and results were pooled by consensus. Statistical analysis was performed using RevMan 4.1 (The Cochrane Collaboration) software program. Relative risk and risk difference were reported with 95% confidence intervals. The number needed to harm was calculated for the need for skin grafting by taking the inverse of the risk difference.
DATA SYNTHESIS: Three trials and their follow-up studies met the inclusion criteria and included 2087 adults with localized cutaneous melanoma of the trunk or extremities. No statistically significant differences were found between wide surgical excision (margins ranging from 3-5 cm) and narrower surgical excision (margins ranging from 1-2 cm) with respect to mortality, disease-free survival or local recurrence rate.
CONCLUSIONS: Surgical excision margins no more than 2 cm around a melanoma of the trunk or extremities are adequate; overall survival, disease-free survival and recurrence rate are not adversely affected compared with a wider excision. There is more data to support a 2-cm margin than a 1-cm margin as the minimum margin of excision. Surgical margins should be no less than 1 cm around the primary melanoma.

PMID 14680348  Can J Surg. 2003 Dec;46(6):419-26.
著者: J Gregory McKinnon, Emma C Starritt, Richard A Scolyer, William H McCarthy, John F Thompson
雑誌名: Ann Surg. 2005 Feb;241(2):326-33.
Abstract/Text OBJECTIVE: Prospective trials have shown that 1-cm and 2-cm margins are safe for melanomas <1 mm thick and > or =1 mm thick, respectively. It is unknown whether narrower margins increase the risk of LR or mortality.
SUMMARY BACKGROUND DATA: To determine the relationship between histopathologic excision margin, local recurrence (LR) and survival for patients with melanomas < or =2 mm thick.
METHODS: Data were extracted from the Sydney Melanoma Unit database for all patients with cutaneous melanoma < or =2 mm thick, diagnosed up to 1996. Patients with positive excision margins or follow-up <12 months were excluded, leaving 2681 for analysis. Outcome measures were LR (recurrence <5 cm from the excision scar), in-transit recurrence, and disease-specific survival. Factors predicting LR and overall survival were tested with Cox proportional hazards analysis.
RESULTS: Median follow-up was 83.8 months. LR was identified in 55 patients (median time to recurrence, 37 months). At 120 months, the actuarial LR rate was 2.9%. Five-year survival after LR was 52.8%. In multivariate analysis, only margin of excision and tumor thickness were predictive of LR (both P = 0.003). When all patients with a margin <0.8 cm in fixed tissue (corresponding to a margin of <1 cm in vivo) were excluded from analysis, margin was no longer significant in predicting LR. Thickness, ulceration, and site were predictive of survival, but margin was not (P = 0.49).
CONCLUSIONS: Histopathologic margin affects the risk of LR. However, if the in vivo margin is > or =1 cm, it no longer predicts risk of LR. Patient survival is not affected by margin.

PMID 15650644  Ann Surg. 2005 Feb;241(2):326-33.
著者: C Bartoli, A Bono, C Clemente, I D Del Prato, S Zurrida, N Cascinelli
雑誌名: Cancer. 1996 Mar 1;77(5):888-92.
Abstract/Text BACKGROUND: The frequency of in situ melanoma is increasing, and it is often diagnosed fortuitously by histology.
METHODS: We retrospectively reviewed 121 melanomas in situ in 113 patients with the aim of identifying the clinical features of, and optimal surgical treatment for this cutaneous malignancy. Treatment was limited surgery with 3 mm margins of excision in 69 cases (57%) and wider margins of excision (more than 3 mm) in 52 cases (43%). The lesions had a median diameter of 1 cm (range, 2-35 mm) and were generally macular (92% of cases) asymmetric (87%), with an irregular border (88%) and nonuniform pigmentation (98%), usually in shades of brown (41%) and black (48%). These features had permitted a clinical diagnosis of melanoma or suspected melanoma in 62% of cases and of doubtful nevus in an additional 18% of cases.
RESULTS: At a median follow-up of 4 years, there were six local recurrences (three treated by limited surgery and three by wider excision), all in situ melanomas.
CONCLUSIONS: The typical clinical features of melanoma in situ, which are similar to those of early invasive melanoma, are usually sufficiently distinctive to suggest the clinical diagnosis of melanoma or suspected melanoma. Except for large size and superficially extended lesions (larger than 2 cm), adequate treatment is excision with 3 mm margins, although larger lesions (larger then 2 cm) may have an appreciable incidence of local recurrence.

PMID 8608479  Cancer. 1996 Mar 1;77(5):888-92.
著者: Joy H Kunishige, David G Brodland, John A Zitelli
雑誌名: J Am Acad Dermatol. 2012 Mar;66(3):438-44. doi: 10.1016/j.jaad.2011.06.019. Epub 2011 Dec 22.
Abstract/Text BACKGROUND: A controversy in the treatment of melanoma in situ is the required width of surgical margin. The currently accepted 5-mm margin is based on a 1992 consensus opinion, despite data since then showing this is inadequate.
OBJECTIVE: We sought to develop guidelines for predetermined surgical margins for excision of melanoma in situ.
METHODS: A prospectively collected series of 1072 patients with 1120 melanoma in situs was studied. All lesions were excised by Mohs micrographic surgery with frozen-section examination of the margin. The minimal surgical margin was 6 mm, and the total margin was calculated by adding an additional 3 mm for each subsequent stage required. The minimum surgical margin that would successfully remove 97% of all tumors was calculated. Local recurrence was also tabulated.
RESULTS: In all, 86% of melanoma in situs were successfully excised with a 6-mm margin; 9 mm removed 98.9% of melanoma in situs. The superiority of 9-mm to 6-mm margins was significant (P < .001). Gender, location, and diameter did not affect results. Recurrence rate for this set of patients treated with Mohs micrographic surgery was 0.3% (n = 3).
LIMITATIONS: Margins less than 6 mm were not studied. This is a referral center for melanoma in situ and 10% of tumors were previously treated before presentation to our clinic.
CONCLUSION: The frequently recommended 5-mm margin for melanoma is inadequate. Standard surgical excision of melanoma in situ should include 9 mm of normal-appearing skin, similar to that recommended for early invasive melanoma.

Copyright © 2011 American Academy of Dermatology, Inc. Published by Mosby, Inc. All rights reserved.
PMID 22196979  J Am Acad Dermatol. 2012 Mar;66(3):438-44. doi: 10.1016・・・
著者: Alexander M M Eggermont, Stefan Suciu, Alessandro Testori, Mario Santinami, Wim H J Kruit, Jeremy Marsden, Cornelis J A Punt, François Salès, Reinhard Dummer, Caroline Robert, Dirk Schadendorf, Poulam M Patel, Gaetan de Schaetzen, Alan Spatz, Ulrich Keilholz
雑誌名: J Clin Oncol. 2012 Nov 1;30(31):3810-8. doi: 10.1200/JCO.2011.41.3799. Epub 2012 Sep 24.
Abstract/Text PURPOSE: Adjuvant pegylated interferon alfa-2b (PEG-IFN-α-2b) was approved for treatment of resected stage III melanoma in 2011. Here, we present long-term follow-up results of this pivotal trial.
PATIENTS AND METHODS: In all, 1,256 patients with resected stage III melanoma were randomly assigned to observation (n = 629) or PEG-IFN-α-2b (n = 627) for an intended duration of 5 years. Stratification factors were microscopic (N1) versus macroscopic (N2) nodal involvement, number of positive nodes, ulceration and tumor thickness, sex, and center. Recurrence-free survival (RFS; primary end point), distant metastasis-free survival (DMFS), and overall survival (OS) were analyzed for the intent-to-treat population.
RESULTS: At 7.6 years median follow-up, 384 recurrences or deaths had occurred with PEG-IFN-α-2b versus 406 in the observation group (hazard ratio [HR], 0.87; 95% CI, 0.76 to 1.00; P = .055); 7-year RFS rate was 39.1% versus 34.6%. There was no difference in OS (P = .57). In stage III-N1 ulcerated melanoma, RFS (HR, 0.72; 99% CI, 0.46 to 1.13; P = .06), DMFS (HR, 0.65; 99% CI, 0.41 to 1.04; P = .02), and OS (HR, 0.59; 99% CI, 0.35 to 0.97; P = .006) were prolonged with PEG-IFN-α-2b. PEG-IFN-α-2b was discontinued for toxicity in 37% of patients.
CONCLUSION: Adjuvant PEG-IFN-α-2b for stage III melanoma had a positive impact on RFS, which was marginally significant and slightly diminished versus the benefit seen at prior follow-up (median, 3.8 years). No significant increase in DMFS or OS was noted in the overall population. Patients with ulcerated melanoma and lower disease burden had the greatest benefit.

PMID 23008300  J Clin Oncol. 2012 Nov 1;30(31):3810-8. doi: 10.1200/JC・・・
著者: Donald L Morton, John F Thompson, Alistair J Cochran, Nicola Mozzillo, Robert Elashoff, Richard Essner, Omgo E Nieweg, Daniel F Roses, Harald J Hoekstra, Constantine P Karakousis, Douglas S Reintgen, Brendon J Coventry, Edwin C Glass, He-Jing Wang, MSLT Group
雑誌名: N Engl J Med. 2006 Sep 28;355(13):1307-17. doi: 10.1056/NEJMoa060992.
Abstract/Text BACKGROUND: We evaluated the contribution of sentinel-node biopsy to outcomes in patients with newly diagnosed melanoma.
METHODS: Patients with a primary cutaneous melanoma were randomly assigned to wide excision and postoperative observation of regional lymph nodes with lymphadenectomy if nodal relapse occurred, or to wide excision and sentinel-node biopsy with immediate lymphadenectomy if nodal micrometastases were detected on biopsy.
RESULTS: Among 1269 patients with an intermediate-thickness primary melanoma, the mean (+/-SE) estimated 5-year disease-free survival rate for the population was 78.3+/-1.6% in the biopsy group and 73.1+/-2.1% in the observation group (hazard ratio for recurrence[corrected], 0.74; 95% confidence interval [CI], 0.59 to 0.93; P=0.009). Five-year melanoma-specific survival rates were similar in the two groups (87.1+/-1.3% and 86.6+/-1.6%, respectively). In the biopsy group, the presence of metastases in the sentinel node was the most important prognostic factor; the 5-year survival rate was 72.3+/-4.6% among patients with tumor-positive sentinel nodes and 90.2+/-1.3% among those with tumor-negative sentinel nodes (hazard ratio for death, 2.48; 95% CI, 1.54 to 3.98; P<0.001). The incidence of sentinel-node micrometastases was 16.0% (122 of 764 patients), and the rate of nodal relapse in the observation group was 15.6% (78 of 500 patients). The corresponding mean number of tumor-involved nodes was 1.4 in the biopsy group and 3.3 in the observation group (P<0.001), indicating disease progression during observation. Among patients with nodal metastases, the 5-year survival rate was higher among those who underwent immediate lymphadenectomy than among those in whom lymphadenectomy was delayed (72.3+/-4.6% vs. 52.4+/-5.9%; hazard ratio for death, 0.51; 95% CI, 0.32 to 0.81; P=0.004).
CONCLUSIONS: The staging of intermediate-thickness (1.2 to 3.5 mm) primary melanomas according to the results of sentinel-node biopsy provides important prognostic information and identifies patients with nodal metastases whose survival can be prolonged by immediate lymphadenectomy. (ClinicalTrials.gov number, NCT00275496 [ClinicalTrials.gov].).

Copyright 2006 Massachusetts Medical Society.
PMID 17005948  N Engl J Med. 2006 Sep 28;355(13):1307-17. doi: 10.1056・・・
著者: Mark B Faries, John F Thompson, Alistair J Cochran, Robert H Andtbacka, Nicola Mozzillo, Jonathan S Zager, Tiina Jahkola, Tawnya L Bowles, Alessandro Testori, Peter D Beitsch, Harald J Hoekstra, Marc Moncrieff, Christian Ingvar, Michel W J M Wouters, Michael S Sabel, Edward A Levine, Doreen Agnese, Michael Henderson, Reinhard Dummer, Carlo R Rossi, Rogerio I Neves, Steven D Trocha, Frances Wright, David R Byrd, Maurice Matter, Eddy Hsueh, Alastair MacKenzie-Ross, Douglas B Johnson, Patrick Terheyden, Adam C Berger, Tara L Huston, Jeffrey D Wayne, B Mark Smithers, Heather B Neuman, Schlomo Schneebaum, Jeffrey E Gershenwald, Charlotte E Ariyan, Darius C Desai, Lisa Jacobs, Kelly M McMasters, Anja Gesierich, Peter Hersey, Steven D Bines, John M Kane, Richard J Barth, Gregory McKinnon, Jeffrey M Farma, Erwin Schultz, Sergi Vidal-Sicart, Richard A Hoefer, James M Lewis, Randall Scheri, Mark C Kelley, Omgo E Nieweg, R Dirk Noyes, Dave S B Hoon, He-Jing Wang, David A Elashoff, Robert M Elashoff
雑誌名: N Engl J Med. 2017 Jun 8;376(23):2211-2222. doi: 10.1056/NEJMoa1613210.
Abstract/Text BACKGROUND: Sentinel-lymph-node biopsy is associated with increased melanoma-specific survival (i.e., survival until death from melanoma) among patients with node-positive intermediate-thickness melanomas (1.2 to 3.5 mm). The value of completion lymph-node dissection for patients with sentinel-node metastases is not clear.
METHODS: In an international trial, we randomly assigned patients with sentinel-node metastases detected by means of standard pathological assessment or a multimarker molecular assay to immediate completion lymph-node dissection (dissection group) or nodal observation with ultrasonography (observation group). The primary end point was melanoma-specific survival. Secondary end points included disease-free survival and the cumulative rate of nonsentinel-node metastasis.
RESULTS: Immediate completion lymph-node dissection was not associated with increased melanoma-specific survival among 1934 patients with data that could be evaluated in an intention-to-treat analysis or among 1755 patients in the per-protocol analysis. In the per-protocol analysis, the mean (±SE) 3-year rate of melanoma-specific survival was similar in the dissection group and the observation group (86±1.3% and 86±1.2%, respectively; P=0.42 by the log-rank test) at a median follow-up of 43 months. The rate of disease-free survival was slightly higher in the dissection group than in the observation group (68±1.7% and 63±1.7%, respectively; P=0.05 by the log-rank test) at 3 years, based on an increased rate of disease control in the regional nodes at 3 years (92±1.0% vs. 77±1.5%; P<0.001 by the log-rank test); these results must be interpreted with caution. Nonsentinel-node metastases, identified in 11.5% of the patients in the dissection group, were a strong, independent prognostic factor for recurrence (hazard ratio, 1.78; P=0.005). Lymphedema was observed in 24.1% of the patients in the dissection group and in 6.3% of those in the observation group.
CONCLUSIONS: Immediate completion lymph-node dissection increased the rate of regional disease control and provided prognostic information but did not increase melanoma-specific survival among patients with melanoma and sentinel-node metastases. (Funded by the National Cancer Institute and others; MSLT-II ClinicalTrials.gov number, NCT00297895 .).

PMID 28591523  N Engl J Med. 2017 Jun 8;376(23):2211-2222. doi: 10.105・・・
著者: Donald L Morton, John F Thompson, Alistair J Cochran, Nicola Mozzillo, Omgo E Nieweg, Daniel F Roses, Harold J Hoekstra, Constantine P Karakousis, Christopher A Puleo, Brendon J Coventry, Mohammed Kashani-Sabet, B Mark Smithers, Eberhard Paul, William G Kraybill, J Gregory McKinnon, He-Jing Wang, Robert Elashoff, Mark B Faries, MSLT Group
雑誌名: N Engl J Med. 2014 Feb 13;370(7):599-609. doi: 10.1056/NEJMoa1310460.
Abstract/Text BACKGROUND: Sentinel-node biopsy, a minimally invasive procedure for regional melanoma staging, was evaluated in a phase 3 trial.
METHODS: We evaluated outcomes in 2001 patients with primary cutaneous melanomas randomly assigned to undergo wide excision and nodal observation, with lymphadenectomy for nodal relapse (observation group), or wide excision and sentinel-node biopsy, with immediate lymphadenectomy for nodal metastases detected on biopsy (biopsy group). Results No significant treatment-related difference in the 10-year melanoma-specific survival rate was seen in the overall study population (20.8% with and 79.2% without nodal metastases). Mean (± SE) 10-year disease-free survival rates were significantly improved in the biopsy group, as compared with the observation group, among patients with intermediate-thickness melanomas, defined as 1.20 to 3.50 mm (71.3 ± 1.8% vs. 64.7 ± 2.3%; hazard ratio for recurrence or metastasis, 0.76; P=0.01), and those with thick melanomas, defined as >3.50 mm (50.7 ± 4.0% vs. 40.5 ± 4.7%; hazard ratio, 0.70; P=0.03). Among patients with intermediate-thickness melanomas, the 10-year melanoma-specific survival rate was 62.1 ± 4.8% among those with metastasis versus 85.1 ± 1.5% for those without metastasis (hazard ratio for death from melanoma, 3.09; P<0.001); among patients with thick melanomas, the respective rates were 48.0 ± 7.0% and 64.6 ± 4.9% (hazard ratio, 1.75; P=0.03). Biopsy-based management improved the 10-year rate of distant disease-free survival (hazard ratio for distant metastasis, 0.62; P=0.02) and the 10-year rate of melanoma-specific survival (hazard ratio for death from melanoma, 0.56; P=0.006) for patients with intermediate-thickness melanomas and nodal metastases. Accelerated-failure-time latent-subgroup analysis was performed to account for the fact that nodal status was initially known only in the biopsy group, and a significant treatment benefit persisted.
CONCLUSIONS: Biopsy-based staging of intermediate-thickness or thick primary melanomas provides important prognostic information and identifies patients with nodal metastases who may benefit from immediate complete lymphadenectomy. Biopsy-based management prolongs disease-free survival for all patients and prolongs distant disease-free survival and melanoma-specific survival for patients with nodal metastases from intermediate-thickness melanomas. (Funded by the National Cancer Institute, National Institutes of Health, and the Australia and New Zealand Melanoma Trials Group; ClinicalTrials.gov number, NCT00275496.).

PMID 24521106  N Engl J Med. 2014 Feb 13;370(7):599-609. doi: 10.1056/・・・
著者: Ulrike Leiter, Rudolf Stadler, Cornelia Mauch, Werner Hohenberger, Norbert Brockmeyer, Carola Berking, Cord Sunderkötter, Martin Kaatz, Klaus-Werner Schulte, Percy Lehmann, Thomas Vogt, Jens Ulrich, Rudolf Herbst, Wolfgang Gehring, Jan-Christoph Simon, Ulrike Keim, Peter Martus, Claus Garbe, German Dermatologic Cooperative Oncology Group (DeCOG)
雑誌名: Lancet Oncol. 2016 Jun;17(6):757-767. doi: 10.1016/S1470-2045(16)00141-8. Epub 2016 May 5.
Abstract/Text BACKGROUND: Complete lymph node dissection is recommended in patients with positive sentinel lymph node biopsy results. To date, the effect of complete lymph node dissection on prognosis is controversial. In the DeCOG-SLT trial, we assessed whether complete lymph node dissection resulted in increased survival compared with observation.
METHODS: In this multicentre, randomised, phase 3 trial, we enrolled patients with cutaneous melanoma of the torso, arms, or legs from 41 German skin cancer centres. Patients with positive sentinel lymph node biopsy results were eligible. Patients were randomly assigned (1:1) to undergo complete lymph node dissection or observation with permuted blocks of variable size and stratified by primary tumour thickness, ulceration of primary tumour, and intended adjuvant interferon therapy. Treatment assignment was not masked. The primary endpoint was distant metastasis-free survival and analysed by intention to treat. All patients in the intention-to-treat population of the complete lymph node dissection group were included in the safety analysis. This trial is registered with ClinicalTrials.gov, number NCT02434107. Follow-up is ongoing, but the trial no longer recruiting patients.
FINDINGS: Between Jan 1, 2006, and Dec 1, 2014, 5547 patients were screened with sentinel lymph node biopsy and 1269 (23%) patients were positive for micrometastasis. Of these, 483 (39%) agreed to randomisation into the clinical trial; due to difficulties enrolling and a low event rate the trial closed early on Dec 1, 2014. 241 patients were randomly assigned to the observation group and 242 to the complete lymph node dissection group. Ten patients did not meet the inclusion criteria, so 233 patients were analysed in the observation group and 240 patients were analysed in the complete lymph node dissection group, as the intention-to-treat population. 311 (66%) patients (158 in the observation group and 153 in the dissection group) had sentinel lymph node metastases of 1 mm or less. Median follow-up was 35 months (IQR 20-54). Distant metastasis-free survival at 3 years was 77·0% (90% CI 71·9-82·1; 55 events) in the observation group and 74·9% (69·5-80·3; 54 events) in the complete lymph node dissection group. In the complete lymph node dissection group, grade 3 and 4 events occurred in 15 patients (6%) and 19 patients (8%) patients, respectively. Adverse events included lymph oedema (grade 3 in seven patients, grade 4 in 13 patients), lymph fistula (grade 3 in one patient, grade 4 in two patients), seroma (grade 3 in three patients, no grade 4), infection (grade 3 in three patients, no grade 4), and delayed wound healing (grade 3 in one patient, grade 4 in four patients); no serious adverse events were reported.
INTERPRETATION: Although we did not achieve the required number of events, leading to the trial being underpowered, our results showed no difference in survival in patients treated with complete lymph node dissection compared with observation only. Consequently, complete lymph node dissection should not be recommended in patients with melanoma with lymph node micrometastases of at least a diameter of 1 mm or smaller.
FUNDING: German Cancer Aid.

Copyright © 2016 Elsevier Ltd. All rights reserved.
PMID 27161539  Lancet Oncol. 2016 Jun;17(6):757-767. doi: 10.1016/S147・・・
著者: Georgina V Long, Axel Hauschild, Mario Santinami, Victoria Atkinson, Mario Mandalà, Vanna Chiarion-Sileni, James Larkin, Marta Nyakas, Caroline Dutriaux, Andrew Haydon, Caroline Robert, Laurent Mortier, Jacob Schachter, Dirk Schadendorf, Thierry Lesimple, Ruth Plummer, Ran Ji, Pingkuan Zhang, Bijoyesh Mookerjee, Jeff Legos, Richard Kefford, Reinhard Dummer, John M Kirkwood
雑誌名: N Engl J Med. 2017 Nov 9;377(19):1813-1823. doi: 10.1056/NEJMoa1708539. Epub 2017 Sep 10.
Abstract/Text BACKGROUND: Combination therapy with the BRAF inhibitor dabrafenib plus the MEK inhibitor trametinib improved survival in patients with advanced melanoma with BRAF V600 mutations. We sought to determine whether adjuvant dabrafenib plus trametinib would improve outcomes in patients with resected, stage III melanoma with BRAF V600 mutations.
METHODS: In this double-blind, placebo-controlled, phase 3 trial, we randomly assigned 870 patients with completely resected, stage III melanoma with BRAF V600E or V600K mutations to receive oral dabrafenib at a dose of 150 mg twice daily plus trametinib at a dose of 2 mg once daily (combination therapy, 438 patients) or two matched placebo tablets (432 patients) for 12 months. The primary end point was relapse-free survival. Secondary end points included overall survival, distant metastasis-free survival, freedom from relapse, and safety.
RESULTS: At a median follow-up of 2.8 years, the estimated 3-year rate of relapse-free survival was 58% in the combination-therapy group and 39% in the placebo group (hazard ratio for relapse or death, 0.47; 95% confidence interval [CI], 0.39 to 0.58; P<0.001). The 3-year overall survival rate was 86% in the combination-therapy group and 77% in the placebo group (hazard ratio for death, 0.57; 95% CI, 0.42 to 0.79; P=0.0006), but this level of improvement did not cross the prespecified interim analysis boundary of P=0.000019. Rates of distant metastasis-free survival and freedom from relapse were also higher in the combination-therapy group than in the placebo group. The safety profile of dabrafenib plus trametinib was consistent with that observed with the combination in patients with metastatic melanoma.
CONCLUSIONS: Adjuvant use of combination therapy with dabrafenib plus trametinib resulted in a significantly lower risk of recurrence in patients with stage III melanoma with BRAF V600E or V600K mutations than the adjuvant use of placebo and was not associated with new toxic effects. (Funded by GlaxoSmithKline and Novartis; COMBI-AD ClinicalTrials.gov, NCT01682083 ; EudraCT number, 2012-001266-15 .).

PMID 28891408  N Engl J Med. 2017 Nov 9;377(19):1813-1823. doi: 10.105・・・
著者: Axel Hauschild, Reinhard Dummer, Dirk Schadendorf, Mario Santinami, Victoria Atkinson, Mario Mandalà, Vanna Chiarion-Sileni, James Larkin, Marta Nyakas, Caroline Dutriaux, Andrew Haydon, Caroline Robert, Laurent Mortier, Jacob Schachter, Thierry Lesimple, Ruth Plummer, Kohinoor Dasgupta, Tomas Haas, Mark Shilkrut, Eduard Gasal, Richard Kefford, John M Kirkwood, Georgina V Long
雑誌名: J Clin Oncol. 2018 Oct 22;:JCO1801219. doi: 10.1200/JCO.18.01219. Epub 2018 Oct 22.
Abstract/Text PURPOSE: Dabrafenib plus trametinib improved relapse-free survival (RFS) versus placebo (hazard ratio [HR], 0.47; P < .001) in patients with resected BRAF V600-mutant stage III melanoma (BRF115532; COMBI-AD; ClinicalTrials.gov identifier: NCT01682083). We present an updated RFS analysis on the basis of extended study follow-up and a cure-rate model analysis to estimate the fraction of patients expected to remain relapse free long term.
METHODS: In this phase III trial, patients with resected BRAF V600-mutant stage III melanoma were randomly assigned to 12 months of adjuvant dabrafenib plus trametinib versus placebo. We report updated RFS (primary end point) and distant metastasis-free survival. RFS was also analyzed by subgroups defined by baseline disease stage (American Joint Committee on Cancer 7th and 8th editions), nodal metastatic burden, and ulceration status. The fraction of patients who remained relapse free long term was estimated using a Weibull mixture cure-rate model.
RESULTS: At median follow-up of 44 months (dabrafenib plus trametinib) and 42 months (placebo), 3- and 4-year RFS rates were 59% (95% CI, 55% to 64%) and 54% (95% CI, 49% to 59%) in the dabrafenib plus trametinib arm and 40% (95% CI, 35% to 45%) and 38% (95% CI, 34% to 44%) in the placebo arm, respectively (HR, 0.49; 95% CI, 0.40 to 0.59). Distant metastasis-free survival also favored dabrafenib plus trametinib (HR, 0.53; 95% CI, 0.42 to 0.67). The estimated cure rate was 54% (95% CI, 49% to 59%) in the dabrafenib plus trametinib arm compared with 37% (95% CI, 32% to 42%) in the placebo arm. Subgroup analysis of RFS demonstrated similar treatment benefit regardless of baseline factors, including disease stage, nodal metastatic burden, and ulceration.
CONCLUSION: Longer follow-up confirmed RFS benefit with dabrafenib plus trametinib. Subgroup analysis suggested that dabrafenib plus trametinib benefited patients regardless of baseline factors.

PMID 30343620  J Clin Oncol. 2018 Oct 22;:JCO1801219. doi: 10.1200/JCO・・・
著者: Jeffrey Weber, Mario Mandala, Michele Del Vecchio, Helen J Gogas, Ana M Arance, C Lance Cowey, Stéphane Dalle, Michael Schenker, Vanna Chiarion-Sileni, Ivan Marquez-Rodas, Jean-Jacques Grob, Marcus O Butler, Mark R Middleton, Michele Maio, Victoria Atkinson, Paola Queirolo, Rene Gonzalez, Ragini R Kudchadkar, Michael Smylie, Nicolas Meyer, Laurent Mortier, Michael B Atkins, Georgina V Long, Shailender Bhatia, Celeste Lebbé, Piotr Rutkowski, Kenji Yokota, Naoya Yamazaki, Tae M Kim, Veerle de Pril, Javier Sabater, Anila Qureshi, James Larkin, Paolo A Ascierto, CheckMate 238 Collaborators
雑誌名: N Engl J Med. 2017 Nov 9;377(19):1824-1835. doi: 10.1056/NEJMoa1709030. Epub 2017 Sep 10.
Abstract/Text BACKGROUND: Nivolumab and ipilimumab are immune checkpoint inhibitors that have been approved for the treatment of advanced melanoma. In the United States, ipilimumab has also been approved as adjuvant therapy for melanoma on the basis of recurrence-free and overall survival rates that were higher than those with placebo in a phase 3 trial. We wanted to determine the efficacy of nivolumab versus ipilimumab for adjuvant therapy in patients with resected advanced melanoma.
METHODS: In this randomized, double-blind, phase 3 trial, we randomly assigned 906 patients (≥15 years of age) who were undergoing complete resection of stage IIIB, IIIC, or IV melanoma to receive an intravenous infusion of either nivolumab at a dose of 3 mg per kilogram of body weight every 2 weeks (453 patients) or ipilimumab at a dose of 10 mg per kilogram every 3 weeks for four doses and then every 12 weeks (453 patients). The patients were treated for a period of up to 1 year or until disease recurrence, a report of unacceptable toxic effects, or withdrawal of consent. The primary end point was recurrence-free survival in the intention-to-treat population.
RESULTS: At a minimum follow-up of 18 months, the 12-month rate of recurrence-free survival was 70.5% (95% confidence interval [CI], 66.1 to 74.5) in the nivolumab group and 60.8% (95% CI, 56.0 to 65.2) in the ipilimumab group (hazard ratio for disease recurrence or death, 0.65; 97.56% CI, 0.51 to 0.83; P<0.001). Treatment-related grade 3 or 4 adverse events were reported in 14.4% of the patients in the nivolumab group and in 45.9% of those in the ipilimumab group; treatment was discontinued because of any adverse event in 9.7% and 42.6% of the patients, respectively. Two deaths (0.4%) related to toxic effects were reported in the ipilimumab group more than 100 days after treatment.
CONCLUSIONS: Among patients undergoing resection of stage IIIB, IIIC, or IV melanoma, adjuvant therapy with nivolumab resulted in significantly longer recurrence-free survival and a lower rate of grade 3 or 4 adverse events than adjuvant therapy with ipilimumab. (Funded by Bristol-Myers Squibb and Ono Pharmaceutical; CheckMate 238 ClinicalTrials.gov number, NCT02388906 ; Eudra-CT number, 2014-002351-26 .).

PMID 28891423  N Engl J Med. 2017 Nov 9;377(19):1824-1835. doi: 10.105・・・
著者: Alexander M M Eggermont, Christian U Blank, Mario Mandala, Georgina V Long, Victoria Atkinson, Stéphane Dalle, Andrew Haydon, Mikhail Lichinitser, Adnan Khattak, Matteo S Carlino, Shahneen Sandhu, James Larkin, Susana Puig, Paolo A Ascierto, Piotr Rutkowski, Dirk Schadendorf, Rutger Koornstra, Leonel Hernandez-Aya, Michele Maio, Alfonsus J M van den Eertwegh, Jean-Jacques Grob, Ralf Gutzmer, Rahima Jamal, Paul Lorigan, Nageatte Ibrahim, Sandrine Marreaud, Alexander C J van Akkooi, Stefan Suciu, Caroline Robert
雑誌名: N Engl J Med. 2018 May 10;378(19):1789-1801. doi: 10.1056/NEJMoa1802357. Epub 2018 Apr 15.
Abstract/Text BACKGROUND: The programmed death 1 (PD-1) inhibitor pembrolizumab has been found to prolong progression-free and overall survival among patients with advanced melanoma. We conducted a phase 3 double-blind trial to evaluate pembrolizumab as adjuvant therapy in patients with resected, high-risk stage III melanoma.
METHODS: Patients with completely resected stage III melanoma were randomly assigned (with stratification according to cancer stage and geographic region) to receive 200 mg of pembrolizumab (514 patients) or placebo (505 patients) intravenously every 3 weeks for a total of 18 doses (approximately 1 year) or until disease recurrence or unacceptable toxic effects occurred. Recurrence-free survival in the overall intention-to-treat population and in the subgroup of patients with cancer that was positive for the PD-1 ligand (PD-L1) were the primary end points. Safety was also evaluated.
RESULTS: At a median follow-up of 15 months, pembrolizumab was associated with significantly longer recurrence-free survival than placebo in the overall intention-to-treat population (1-year rate of recurrence-free survival, 75.4% [95% confidence interval {CI}, 71.3 to 78.9] vs. 61.0% [95% CI, 56.5 to 65.1]; hazard ratio for recurrence or death, 0.57; 98.4% CI, 0.43 to 0.74; P<0.001) and in the subgroup of 853 patients with PD-L1-positive tumors (1-year rate of recurrence-free survival, 77.1% [95% CI, 72.7 to 80.9] in the pembrolizumab group and 62.6% [95% CI, 57.7 to 67.0] in the placebo group; hazard ratio, 0.54; 95% CI, 0.42 to 0.69; P<0.001). Adverse events of grades 3 to 5 that were related to the trial regimen were reported in 14.7% of the patients in the pembrolizumab group and in 3.4% of patients in the placebo group. There was one treatment-related death due to myositis in the pembrolizumab group.
CONCLUSIONS: As adjuvant therapy for high-risk stage III melanoma, 200 mg of pembrolizumab administered every 3 weeks for up to 1 year resulted in significantly longer recurrence-free survival than placebo, with no new toxic effects identified. (Funded by Merck; ClinicalTrials.gov number, NCT02362594 ; EudraCT number, 2014-004944-37 .).

PMID 29658430  N Engl J Med. 2018 May 10;378(19):1789-1801. doi: 10.10・・・
著者: G J Hill, E T Krementz, H Z Hill
雑誌名: Cancer. 1984 Mar 15;53(6):1299-305.
Abstract/Text The results of three Phase III studies of DTIC in 580 patients with metastatic melanoma were reviewed to evaluate the subsequent course of 26 patients who achieved a complete response (CR) to chemotherapy. The majority (17 of 26) of these patients had soft tissue metastases. Six of the 26 patients remained in CR at last report (30-259 weeks), two died of other causes while remaining free of melanoma, and 18 relapsed and died. Ninety-five percent of the 26 patients were alive at 1 year, and survival was 31.1% at 72 months. Seven of the eight patients with sustained remission received chemotherapy for at least 6 months after CR developed, whereas 10 of 18 relapsing patients were treated for less than 6 months after CR was achieved. Long-term sustained CR to chemotherapy occurs in 1% to 2% of patients treated with DTIC, and late relapse is rare in patients who remain in CR for 2 years.

PMID 6362841  Cancer. 1984 Mar 15;53(6):1299-305.

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