2023年8月現在、コロナ禍は終息していないものの、新型コロナウイルス感染症が5月8日に5類感染症に移行され、世の中は日常を取り戻しつつあります。一方で病院内はマスク装着の義務付けが継続され、このウイルスの感染者ならびに感染疑いの方の隔離も継続されています。このコロナ禍の3年半の間にも、世間の耳目は集めませんでしたが乳癌診療をめぐる様々な進歩が見られました。これらの進歩は明らかに患者さんの利益に直結していますが、益々現場はやるべきことが増え、患者さんの方も理解が不十分なまま追い立てられるように検査や治療が進んでいき、結果として現場は疲弊し患者さんの診療に関する満足度は逆に低下しているのではないかという懸念を持っています。私が乳癌治療に携わるようになって30年が経過し、この間明らかに患者さんの治癒率は改善し、治癒が困難な遠隔再発後の生存期間も延長されています。一方で医療者がやるべきことが本当に増え、日々頭を悩ませることになっています。それでは今回は2020年以降の3つの変化を取り上げてみたいと思います。
世の中がコロナ問題一色になり、イタリアやニューヨークの惨状が報道され日本でも緊急事態宣言が発令されたこの時期に、HBOCの遺伝子検査、リスク低減を目的とした予防的手術が保険適応になりました。この遺伝子検査や予防的手術は以前から、自費で行うことは可能であり、検査や手術自体が画期的だったわけではありません。しかしながら遺伝子検査を行い、予防切除を実施する一連の過程は200~300万円程度の自己負担が必要で、実施できる方はある程度限られていたために、今回の保険適応は多くの方にとって福音となりました。しかしながら乳癌の診断が下った直後に遺伝子検査を行い、乳癌の手術と共に、対側の予防的切除を行う必要について考え、実施するかどうかの決断を迫られることは多くの患者さんにとって強いストレスを強いることになったと思います。保険適応に至るには多くの方の貢献があったわけですが、専門医としてはありがたいと思う反面大変だなというのは偽らざる気持ちです。
この技術は2019年3月厚労省で薬事承認たことで、国内での導入が増加してきました。これに関しては昨年度の本誌(2022年の東都クリニックの出版物)で紹介させていただいた内容のため詳細は省略しますが、2010年代の初期の日本への臨床導入に関しては四国がんセンターの大住省三先生(現・松山市民病院)や国立がん研究センターの木下貴之先生(現、東京医療センター)の役割が大きくこの薬事承認に繋がっています。薬事承認以降は各地の病院で保険適応外の自費診療として広がっていきましたが、実施する現場への負担が大きく、自己負担(15万~35万円程度)をしてもらっても運用が困難で、国内での実施施設は100以下にとどまり、かつ積極的に対応できている施設は限られています。虎の門病院は新病院建設に際して外来化学療法室のスペースが確保できていたこと(43室)や院内の様々な部署の協力もあり、現在年間の新規導入患者数が100例程度まで拡大されました(全国一位の実施数:国内代理店のデータ)。頭皮冷却の効果のイメージは50%以上の脱毛を患者さんの50%程度の割合に抑えることができ、ウイッグの使用期間をかなり短縮でき、場合により使用なしで済ませることも可能です。また患者さんの20%程度にみられた永久脱毛(生涯ウイッグが必要)をかなり確実に回避できることが大きなメリットで、費用・点滴時間の延長・冷却中の苦痛があっても患者さんの50%程度が選択されています。
抗PD-1抗体薬であるキイトルーダ(一般名:ペムブロリズマブ)がトリプルネガティブ(TNBC)乳癌の治療薬として国内で適応拡大承認されました。これまでも進行再発例には承認されていましたが、StageⅡ~Ⅲのいわゆる早期乳癌の術前、術後療法にも適応拡大されたことで、対象患者さんが一気に拡大されました。この承認はKEYNOTE-522試験の結果に基づくものです。キイトルーダは免疫チェックポイント阻害薬の1つで、免疫に関与する活性化T細胞上に発現するPD-1と結合することで、がん細胞上のPD-L1/2とPD-1が結合するのを阻害します。これによりがん細胞がT細胞の働きを抑制するのを阻害し、T細胞が再活性化されることによりがん細胞を排除することにより効果を発揮します。キートルーダの併用によってこれまでの標準治療をかなり上回る成績が示されましたが、免疫チェックポイント阻害剤はなかなか厄介な治療薬で、間質性肺炎、重症筋無力症、神経障害、肝障害、甲状腺機能障害、下垂体機能障害、副腎機能障害など多彩な副作用が発生する可能性があり、時に重篤化し、機能不全を引き起こすなどのリスクがあります。使用対象がこれまでの標準治療でもかなりの治癒が期待された症例に使用するわけで、より慎重な対応が求められることはもちろん、呼吸器内科、内分泌内科、神経内科など多くの専門家の支援が必要で、こうした各診療科が常設されている総合病院でないと治療が安全に実施できないという傾向がますます強まると思います。このキートルーダに関してはホルモン受容体陽性のいわゆるルミナルタイプの乳癌に対しても有望とされ(KEYNOTE-756試験)国内導入は2年後くらいと期待されています。
最近の乳癌治療の話題を挙げてみましたが、進行再発例でのゲノム診療、免疫チェックポイント阻害剤以外の複雑な管理を要する分子標的薬、局所治療に関してもこれから早期乳癌に対するラジオ波焼灼療法が導入されてきます。この30年を振り返って手術療法は縮小され、薬物療法もバイオマーカーなどによってより的確に対象を絞ることで患者さんの負担は軽減されたと思います。また治癒が期待できない進行再発乳癌でも5年以上の生存期間が期待できる場合も多く、10年以上の意味のある延命ができることも少なくありません。一方でこうした先進医療をすべて提供できる病院は本当に限られており、このことから中核病院、中堅病院、クリニックの間の有機的な連携が必要でで、また病院内での職種間でのタスクシフトも必須だと実感しています。
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As of 8 August 2023, although the coronary scourge has not ended, new coronavirus infection was moved to category 5 infection on 8 May, and the world is returning to normal. Meanwhile, the wearing of masks in hospitals continues to be mandatory and the isolation of people infected or suspected to be infected with the virus continues. During the three and a half years of the coronary disaster, there have been many advances in breast cancer care, although they have not attracted much public attention. Although these advances have clearly directly benefited patients, there is concern that more and more work is being done in the field and patients are being rushed through tests and treatments with insufficient understanding, resulting in exhaustion in the field and a decline in patients’ satisfaction with their treatment. I am concerned that the result of this is a decline in patient satisfaction with medical care. During the 30 years that I have been involved in breast cancer treatment, the cure rate for patients has clearly improved and the survival period after distant recurrence, which is difficult to cure, has also been prolonged. On the other hand, the number of things that the medical profession has to do has really increased, and it is a daily headache for me. Now I would like to focus on three changes for 2020 and beyond.
At a time when the world was in the throes of the Corona crisis, and a state of emergency was declared in Japan after reports of devastation in Italy and New York, genetic testing for HBOC and preventive surgery to reduce the risk of the disease became covered by insurance. Genetic testing and prophylactic surgery had been available for some time at private expense, and the tests and surgery themselves were not groundbreaking. However, the series of steps involved in carrying out the genetic test and preventive resection required an out-of-pocket expense of around 2-3 million yen, and the number of people who could afford it was limited to a certain extent. However, I believe that many patients would have been highly stressed if they had to make the decision whether or not to have the genetic test immediately after the diagnosis of breast cancer, and whether or not to have a contralateral prophylactic resection along with the breast cancer operation. Many people contributed to the insurance approval of the procedure, and as a specialist, I am grateful for this, but at the same time I feel that it is a difficult task.
The introduction of this technology in Japan has been increasing since it was approved by the Ministry of Health, Labour and Welfare in March 2019. The details of this are omitted as they were introduced in last year’s edition of this journal (Toto Clinic publication in 2022), but Dr Shozo Osumi of the Shikoku Cancer Centre (now Matsuyama Municipal Hospital) and Dr Takayuki Kinoshita of the National Cancer Centre (now Tokyo Medical Centre) played a major role in the clinical introduction of this technology in Japan in the early 2010s. However, the burden on the site where the treatment is carried out is heavy and it is difficult to operate even if the patient bears the cost (around 150,000-350,000 yen), so the number of facilities in Japan that carry out the treatment is limited to less than 100, and the number of facilities that are proactive in dealing with the problem is also limited. Toranomon Hospital was able to secure space for an outpatient chemotherapy room when the new hospital was built (43 rooms), and with the cooperation of various departments within the hospital, the number of new cases per year has now expanded to around 100 (the highest number of cases in the country: data from a domestic agency). The image of the effect of scalp cooling is that it can reduce hair loss from more than 50% of patients to about 50% of patients, considerably shortening the period of wig use and in some cases even eliminating its use. Another major advantage is that permanent hair loss (requiring a wig for life), which is seen in about 20% of patients, can be avoided with a high degree of certainty, and about 50% of patients choose this option, despite the cost, prolonged infusion time and pain during cooling.
The anti-PD-1 antibody drug Keytruda (generic name: pembrolizumab) was approved for an expanded indication in Japan for the treatment of triple negative (TNBC) breast cancer. Although it had previously been approved for advanced recurrence, the indication has now been expanded to include pre- and post-operative treatment of Stage II-III so-called early-stage breast cancer, which means that the number of eligible patients has suddenly increased. This approval is based on the results of the KEYNOTE-522 study. Keytruda is an immune checkpoint inhibitor that binds to PD-1, which is expressed on activated T cells involved in immunity, thereby preventing PD-L1/2 on cancer cells from binding to PD-1. This inhibits cancer cells from suppressing T-cell function, and the T-cells are reactivated, thereby eliminating the cancer cells, thereby demonstrating efficacy. Although the combination of Keytruda has shown considerably better results than previous standard treatments, immune checkpoint inhibitors are quite troublesome treatments and can cause a wide variety of side effects, including interstitial pneumonia, myasthenia gravis, neuropathy, liver damage, thyroid dysfunction, pituitary gland dysfunction and adrenal dysfunction, There is a risk of sometimes severe and dysfunctional effects. The use of the drug is targeted at patients who were expected to be cured by conventional standard treatment, so it is necessary to take a more careful approach and requires the support of many specialists, including respiratory medicine, endocrinology and neurology, and treatment can only be carried out safely in general hospitals where these departments are permanently located. This trend is likely to intensify. Keytruda is also promising for hormone receptor-positive luminal type breast cancer (KEYNOTE-756 trial) and is expected to be introduced in Japan in about two years’ time.
The topics of recent breast cancer treatment are listed here, but genomic treatment for advanced recurrence, molecular targeted drugs requiring complex management other than immune checkpoint inhibitors, and radiofrequency ablation for local treatment of early-stage breast cancer will be introduced in the future. Looking back over the past 30 years, surgical treatment has been reduced and drug therapy has been more precisely targeted using biomarkers and other methods, which has reduced the burden on patients. In addition, even in advanced recurrent breast cancer, where a cure is not expected, a survival period of five years or more can often be expected, and in many cases, a meaningful life extension of 10 years or more can be achieved. On the other hand, the number of hospitals that can provide all these advanced medical services is really limited, and this makes me realise that organic collaboration between core hospitals, medium-sized hospitals and clinics is necessary, as well as task shifting between professions within hospitals is also essential.
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