今日の臨床サポート

放射線肺障害

著者: 馬屋原博1) 神戸低侵襲がん医療センター 放射線治療科

著者: 冨岡洋海2) 神戸市立医療センター 西市民病院 呼吸器内科

監修: 杉山幸比古 練馬光が丘病院 呼吸器内科

著者校正/監修レビュー済:2020/07/16
参考ガイドライン:
  1. 日本肺癌学会(https://www.haigan.gr.jp/modules/guideline/index.php?content_id=3):肺癌診療ガイドライン 2019年版
  1. 日本放射線腫瘍学会(https://www.jastro.or.jp/medicalpersonnel/guideline/jastro/2016.html):放射線治療計画ガイドライン 2016年版
患者向け説明資料

概要・推奨   

  1. 放射線照射開始後早期に発症した放射線肺臓炎は重症化しやすい
  1. 放射線治療によって器質化肺炎(OP, BOOP)が起こることがある
  1. 高精度放射線治療においても放射線肺炎の発症頻度は低くはない。
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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:
馬屋原博 : 特に申告事項無し[2021年]
冨岡洋海 : 特に申告事項無し[2021年]
監修:杉山幸比古 : 特に申告事項無し[2021年]

改訂のポイント:
  1. 切除不能Ⅲ期非小細胞肺癌に対する同時併用化学放射線療法後に、免疫チェックポイント阻害薬の投与による地固め療法が標準的治療となり、このような症例における放射線肺炎のエビデンスも追加した。

病態・疫学・診察

疾患情報(疫学・病態)  
  1. 放射線肺炎は、胸部への放射線照射後、照射野内を主体として、ときに照射野外にも拡大する非感染性の肺障害である。臨床的には放射線肺臓炎と感染性肺炎が併発する場合もしばしばみられる。
  1. 肺癌をはじめとする胸部腫瘍性病変に対する放射線治療に伴う最も重篤で、また頻度も高い有害事象である。
  1. 照射後、1~3カ月後の比較的早期に起こる放射線肺臓炎(radiation pneumonitis)と、6~12カ月後に起こり、晩期障害として治癒することなく継続する放射線肺線維症(radiation-induced pulmonary fibrosis)の2つの病態に分けられる。
  1. 古典的な2次元照射においては、症状を伴う放射線肺臓炎、線維症の発症頻度はそれぞれ14.6%、28%、近年行われている高精度放射線治療である3次元照射においても、ステロイド治療を要する放射線肺臓炎の発症頻度は2~31%と報告されている[1]
  1. 2005年に行われたわが国の全国調査では、3次元放射線治療例1,111例のうち11例が放射線肺炎で死亡したと報告されている[2]
  1. 2004年から2008年にかけてわが国で行われた169例のcT1N0M0 非小細胞肺癌に対するSBRTの第II相試験では、Grade 5の死亡例はなかったが、Grade 3、4の放射線肺臓炎は11例(6.5%)と報告されている[3]
  1. 切除不能Ⅲ期非小細胞肺癌に対する同時併用化学放射線療法後に、免疫チェックポイント阻害薬の投与による地固め療法が標準的治療として推奨されている(日本肺癌学会肺癌診療ガイドライン2019年版)。デュルバルマブによる地固め療法(デュルバルマブ群)を、プラセボ群と比較する第Ⅲ相試験では放射線肺臓炎/肺炎はデュルバルマブ群32.8%、プラセボ群23.5%で認められ、Grade 3以上の放射線肺臓炎/肺炎については、デュルバルマブ群4.4%、プラセボ群4.3%で認められた[4][5]。デュルバルマブ群において全体の放射線肺臓炎の頻度は増加するものの、そのうちの重篤な放射線肺臓炎の頻度は変わらないと評価されている。放射線肺臓炎の発症時期に関しても、両群で地固め療法開始後中央値55日と不変であった[6]。日本人サブセット解析(日本人集団/全体集団:112/713例)における放射線肺臓炎は、デュルバルマブ群73.6%、プラセボ群60.0%であった[7]。そのうち、Grade 3~4の放射線肺臓炎は、デュルバルマブ群5.6%、プラセボ群2.5%、Grade 5の放射線肺臓炎については、デュルバルマブ群1.4%、プラセボ群2.5%で認められた。化学放射線療法そのものはプロトコール治療外で行われたため、照射技術や肺照射体積の詳細については明らかにされていない。評価方法の違いが考えられるものの、欧米人と比較して、日本人では放射線肺臓炎の発症率がもともと高い可能性があり、デュルバルマブの投与に伴うGrade 3~4の重篤な放射線肺臓炎の発症頻度についても、わずかながら増加する可能性もあることが示唆される。
  1. 照射により、放射線感受性の高いⅡ型肺胞上皮細胞と血管内皮細胞が傷害され、膜の透過性が亢進し、TNF-α、IL-1α、IL-1β、TGF-β等のサイトカインが誘導され、間質の浮腫や炎症が惹起されると考えられている。
 
  1. 放射線肺炎の予防薬として確立されたものはない
  1. 臨床的な有効性は確立されていないが、放射線肺炎を予防する薬剤(radioprotector, radiation mitigator)として、pentoxifylline[8]、amifostine[8]や、カプトプリルなどのACE阻害薬[9][10]、BIO300[11]が研究段階にある。また、マクロライド系抗生剤であるクラリスロマイシンが、SBRTにおける放射線肺臓炎の重症化を抑制する可能性が報告されている[12]。さらに、抗線維化薬であるニンテダニブの放射線線維症への有効性が検討されている[13]
 
  1. 高精度放射線治療においても放射線肺炎の発症頻度は低くはないO
  1. 近年、正常組織への照射を減らし、標的組織への効果的な照射が可能な3次元照射体放射線治療(3D-CRT)、体幹部定位放射線治療(SBRT)、強度変調放射線治療(IMRT)といった高精度放射線治療が行われるようになってきたが、広範な正常肺が照射野に含まれることになり、肺障害のリスクは低いわけではない。3D—CRTにおいても、ステロイド治療を要する放射線肺炎の発症頻度は2~31%[1]、放射線線維症の頻度は51.4%、重症放射線線維症発症頻度は8.3%と報告されている[14]
  1. 2005年に行われたわが国の全国調査で、3次元放射線治療例1,111例のうち11例が放射線肺炎で死亡したと報告されている[2]。また、2004年から2008年にかけてわが国で行われた169例のcT1N0M0 非小細胞肺癌に対するSBRTの第II相試験では、Grade 5の死亡例はなかったが、Grade 3、4の放射線肺臓炎は11例(6.5%)と報告されている[3]
  1. 非小細胞肺癌に対する同時併用化学放射線療法症例836例の国際的なメタアナリシスによると、有症状放射線肺炎の発症率は30%、致死的放射線肺炎の発症率は2%であった[15]
  1. 非小細胞肺癌化学放射線療法において3D-CRTとIMRTを比較したメタアナリシスでは、症候性放射線肺臓炎の頻度は3D-CRTで24~35%、IMRTで9~32%であり、IMRTにより頻度低減が得られる可能性が示唆されている[16]
  1. 非小細胞肺癌化学放射線療法における線量増加の意義を検証した臨床試験のなかで3D-CRTとIMRTを比較したサブセット解析では、IMRTによりCTCAE Grade 3以上の重篤な放射線肺臓炎の頻度が低減できることが示唆された[17]
 
  1. 予防的リンパ節照射の省略により、放射線肺炎の発症頻度が低減できるR
  1. 予防的リンパ節照射(elective nodal irradiation:ENI)とは、臨床上は明らかなリンパ節転移は認められないものの、腫瘍の進展形式から微小転移が高頻度に起こりうるリンパ節領域への予防的な照射のことを指す。肺癌の原発部位により、ENIの領域が異なってくる。日本肺癌学会と日本放射線腫瘍学会の共同で、『肺癌放射線治療計画のためのリンパ節部位のCTアトラス』が作成されている[18]。近年ではENIを設定せず、画像上の肉眼的病巣の進展範囲のみを照射する病巣部照射(involved field irradiation:IFI)が行われることがある。切除不能Ⅲ期非小細胞肺癌に対してIFIを用いた化学放射線療法の線量増加を検証する第Ⅲ相比較試験の結果、IFIにより線量増加が可能であること、ENI群に対するIFI群による放射線肺臓炎の発症頻度低減(29% vs. 17%, p=0.044)が得られたことが報告されている[19]。しかしながら、後に行われたIFIを用いた線量増加の意義を検証する第Ⅲ相比較試験にて、線量増加の意義が否定されたことより(RTOG 0617試験)[20]、最近では肺毒性を低減させることを意図してIFIによる化学放射線療法が行われることが多い。腫瘍の進展範囲が大きいために照射野が広くなる場合にはIFIによる放射線治療が推奨される。一般的にIFIによる領域照射の省略に伴う明らかなリンパ節転移再発の増加や生存期間への影響は生じにくいと考えられている[21]
 
  1. 放射線治療計画において、線量体積ヒストグラム(Dose Volume HistogramDVH)を用い肺照射体積計算を行うことで、放射線肺臓炎の頻度をある程度予測可能であるO
  1. 胸部腫瘍に対するCT画像に基づく3次元放射線治療計画を行う場合、DVHを用いることで、ある線量以上が照射される肺体積の、全肺に対する比率を正確に計算することができる。DVHから導かれるさまざまなパラメータと放射線肺臓炎発症の相関性が検討されている。なかでもV20(20Gy以上照射される肺体積の全肺体積に占める割合)と平均肺線量(mean lung dose:MLD)の有症状放射線肺臓炎との関連性がよく知られている[22][23][24]。Tsujinoらは非小細胞肺癌71例に対する化学放射線療法におけるV20とCTCAE Grade 2以上の放射線肺臓炎発症率の関係を解析し、V20≤20%,21~25%,26~30%,≧31% での発症率はそれぞれ8、18、50、85%でV20が高くなるほど発症率が高かった[22]。これらの報告から日本放射線腫瘍学会のガイドラインでは、通常分割60Gy/30回程度の同時併用化学放射線療法においては両肺のV20を35%以下、MLDを20Gy以下にするよう放射線治療計画を行うことが推奨されている[25]
  1. 日本人を対象とした化学放射線療法の臨床試験では放射線肺臓炎の発症頻度が海外からの報告と比較して、やや多い傾向がみられることが知られている。V20が30〜35%の症例で致死的放射線肺臓炎の発症がみられたという報告もあり[26]、V20が30%を超える治療計画は臨床的に許容されるものの、治療経過には十分な注意が必要である。
  1. 強度変調放射線治療(IMRT)などの高精度放射線治療技術の普及に伴い、最近ではごく低線量の肺照射体積も重篤な放射線肺臓炎発症へ関与していることが指摘されている。YomらはIMRTを用いることで従来の照射(3D-CRT)と比較してGrade 3以上の重篤な放射線肺臓炎の頻度低減が期待できることを報告しているが、IMRT群においてV5が70%超の場合には逆に重篤な放射線肺臓炎が増加することを報告している[27]。KhalilらはIMRTにおいて従来の線量制約に対して、さらにV5≦60%の制約を加えることにより、致死的な放射線肺臓炎の頻度が大幅に低減できることを報告している[28]。また、同側あるいは対側肺のまったく照射されずに、スペアされる肺体積(Vs5)が放射線肺臓炎の予測に有用であるという報告もある[29]
  1. 臨床的Ⅰ期非小細胞肺癌に対するSBRTにおいても、肺照射体積V25が症候性放射線肺臓炎を予測する因子であると報告されている[30]
  1. NTCP(normal tissue complication probability)と呼ばれる数理モデルを用いた放射線肺臓炎の予測法もあるものの、まだ十分に確立されたものではない[31][32][33]
 
線量体積ヒストグラム(DVH)における肺線量の見かた

非小細胞肺癌に対して60Gy/30分割の化学放射線療法を行った症例におけるDVHを上記に例示する。横軸(X軸:Gy)は線量を示し、縦軸(X軸:%)は各臓器あるいは標的における相対的な体積割合を示す。紺色で示す曲線が全肺のDVH曲線である。肺V(XGy)%は肺においてXGy以上の線量照射される領域の全肺における割合を示す。本症例におけるV20は、20Gyから上方に伸ばし、肺DVH曲線との交点のY座標を読み取ることで、38%と見積もられる。

出典

img1:  著者提供
 
 
 
  1. KL-6は放射線肺炎の血清マーカーとして有用である(推奨度2C)。
  1. 胸部放射線治療を受けた肺癌患者における血清マーカーをprospectiveに検討した報告では、40Gy照射の時点におけるKL-6値が照射前値より上昇している場合には、放射線肺炎の発症を予測できる可能性があるとされている。なお、SP-Dに関しては有意な結果は得られなかった[34]
  1. 同様に体幹部定位放射線治療(stereotactic body radiotherapy、SBRT)における検討でも、照射開始2カ月後にKL-6が照射前値の1.5倍以上であれば放射線肺炎の発症を予測できる、との報告[35]や、KL-6照射前値が300U/ml以上であればgrade 2以上の放射線肺炎の発症が予測されるとの報告がある[36]。また、予後に関しても、KL-6が照射前値の1.5倍以上に上昇した放射線肺炎(放射線肺臓炎)では、致死的になる可能性が高い[37]。なお、放射線治療後の器質化肺炎(radiation-induced organizing pneumonia)においては、一般的にKL-6の有用性は乏しい。その他、放射線肺炎に関する血清マーカーとして、TGF-β1, IL-1, IL-6などが検討されている[38]。 間質性肺炎 
問診・診察のポイント  
  1. 放射線治療についての情報(開始日、照射方法、照射範囲、照射スケジュール)を確認する。

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11月30日(火)までにお申込みいただくと、
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文献 

著者: Feng-Ming Kong, Randall Ten Haken, Avraham Eisbruch, Theodore S Lawrence
雑誌名: Semin Oncol. 2005 Apr;32(2 Suppl 3):S42-54.
Abstract/Text Successful treatment of non-small cell lung cancer requires adequate local and systemic disease control. Although it has been shown to have superior results, high-dose radiation therapy is not a current practice largely because of concerns of normal tissue toxicity. This article reviews and updates the possible mechanism of radiation-induced pneumonitis and fibrosis, their associations with dose intensity, and the role they may play in making treatment decisions. The commonly used clinical terminology and grading systems are summarized. Pneumonitis and fibrosis after 3-dimensional conformal high-dose radiation are reviewed, including recent updates from radiation dose escalation trials. Chemotherapy- and chemoradiation-related lung toxicities are also discussed. Individual susceptibility and potential predictive models are examined; dose and 3-dimensional dosimetric parameters are reviewed along with estimation of normal tissue complication probability and biologic predictive assays. Based on the risk levels of toxicity for each patient, future clinical trials may be designed to maximize individual therapeutic gain.

PMID 16015535  Semin Oncol. 2005 Apr;32(2 Suppl 3):S42-54.
著者: Yasushi Nagata, Masahiro Hiraoka, Takashi Mizowaki, Yuichiro Narita, Yukinori Matsuo, Yoshiki Norihisa, Hiroshi Onishi, Hiroki Shirato
雑誌名: Int J Radiat Oncol Biol Phys. 2009 Oct 1;75(2):343-7. doi: 10.1016/j.ijrobp.2009.02.087.
Abstract/Text PURPOSE: To recognize the current status of stereotactic body radiotherapy (SBRT) in Japan, using a nationwide survey conducted by the Japan 3-D Conformal External Beam Radiotherapy Group.
METHODS AND MATERIALS: The questionnaire was sent by mail to 117 institutions. Ninety-four institutions (80%) responded by the end of November 2005. Fifty-three institutions indicated that they have already started SBRT, and 38 institutions had been reimbursed by insurance.
RESULTS: A total of 1111 patients with histologically confirmed lung cancer were treated. Among these patients, 637 had T1N0M0 and 272 had T2N0M0 lung cancer. Metastatic lung cancer was found in 702 and histologically unconfirmed lung tumor in 291 patients. Primary liver cancer was found in 207 and metastatic liver cancer in 76 patients. The most frequent schedule used for primary lung cancer was 48 Gy in 4 fractions at 22 institutions (52%), followed by 50 Gy in 5 fractions at 11 institutions (26%) and 60 Gy in 8 fractions at 4 institutions (10%). The tendency was the same for metastatic lung cancer. The average number of personnel involved in SBRT was 1.8 radiation oncologists, including 1.1 certified radiation oncologists, 2.8 technologists, 0.7 nurses, and 0.6 certified quality assurance personnel and 0.3 physicists. The most frequent amount of time for treatment planning was 61-120 min, for quality assurance was 50-60 min, and for treatment was 30 min. There were 14 (0.6% of all cases) reported Grade 5 complications: 11 cases of radiation pneumonitis, 2 cases of hemoptysis, and 1 case of radiation esophagitis.
CONCLUSION: The current status of SBRT in Japan was surveyed.

PMID 19735861  Int J Radiat Oncol Biol Phys. 2009 Oct 1;75(2):343-7. d・・・
著者: Yasushi Nagata, Masahiro Hiraoka, Taro Shibata, Hiroshi Onishi, Masaki Kokubo, Katsuyuki Karasawa, Yoshiyuki Shioyama, Rikiya Onimaru, Takuyo Kozuka, Etsuo Kunieda, Tsutomu Saito, Keiichi Nakagawa, Masato Hareyama, Yoshihiro Takai, Kazushige Hayakawa, Norio Mitsuhashi, Satoshi Ishikura
雑誌名: Int J Radiat Oncol Biol Phys. 2015 Dec 1;93(5):989-96. doi: 10.1016/j.ijrobp.2015.07.2278. Epub 2015 Nov 11.
Abstract/Text PURPOSE: To evaluate, in Japan Clinical Oncology Group study 0403, the safety and efficacy of stereotactic body radiation therapy (SBRT) in patients with T1N0M0 non-small cell lung cancer (NSCLC).
METHODS AND MATERIALS: Eligibility criteria included histologically or cytologically proven NSCLC, clinical T1N0M0. Prescribed dose was 48 Gy at the isocenter in 4 fractions. The primary endpoint was the percent (%) 3-year overall survival. The threshold % 3-year survival to be rejected was set at 35% for inoperable patients, whereas the expected % 3-year survival was 80% for operable patients.
RESULTS: Between July 2004 and November 2008, 169 patients from 15 institutions were registered. One hundred inoperable and 64 operable patients (total 164) were eligible. Patients' characteristics were 122 male, 47 female; median age 78 years (range, 50-91 years); adenocarcinomas, 90; squamous cell carcinomas, 61; others, 18. Of the 100 inoperable patients, the % 3-year OS was 59.9% (95% confidence interval 49.6%-68.8%). Grade 3 and 4 toxicities were observed in 10 and 2 patients, respectively. No grade 5 toxicity was observed. Of the 64 operable patients, the % 3-year OS was 76.5% (95% confidence interval 64.0%-85.1%). Grade 3 toxicities were observed in 5 patients. No grade 4 and 5 toxicities were observed.
CONCLUSIONS: Stereotactic body radiation therapy for stage I NSCLC is effective, with low incidences of severe toxicity. This treatment can be considered a standard treatment for inoperable stage I NSCLC. This treatment is promising as an alternative to surgery for operable stage I NSCLC.

Copyright © 2015 Elsevier Inc. All rights reserved.
PMID 26581137  Int J Radiat Oncol Biol Phys. 2015 Dec 1;93(5):989-96. ・・・
著者: Scott J Antonia, Augusto Villegas, Davey Daniel, David Vicente, Shuji Murakami, Rina Hui, Takashi Yokoi, Alberto Chiappori, Ki H Lee, Maike de Wit, Byoung C Cho, Maryam Bourhaba, Xavier Quantin, Takaaki Tokito, Tarek Mekhail, David Planchard, Young-Chul Kim, Christos S Karapetis, Sandrine Hiret, Gyula Ostoros, Kaoru Kubota, Jhanelle E Gray, Luis Paz-Ares, Javier de Castro Carpeño, Catherine Wadsworth, Giovanni Melillo, Haiyi Jiang, Yifan Huang, Phillip A Dennis, Mustafa Özgüroğlu, PACIFIC Investigators
雑誌名: N Engl J Med. 2017 Nov 16;377(20):1919-1929. doi: 10.1056/NEJMoa1709937. Epub 2017 Sep 8.
Abstract/Text BACKGROUND: Most patients with locally advanced, unresectable, non-small-cell lung cancer (NSCLC) have disease progression despite definitive chemoradiotherapy (chemotherapy plus concurrent radiation therapy). This phase 3 study compared the anti-programmed death ligand 1 antibody durvalumab as consolidation therapy with placebo in patients with stage III NSCLC who did not have disease progression after two or more cycles of platinum-based chemoradiotherapy.
METHODS: We randomly assigned patients, in a 2:1 ratio, to receive durvalumab (at a dose of 10 mg per kilogram of body weight intravenously) or placebo every 2 weeks for up to 12 months. The study drug was administered 1 to 42 days after the patients had received chemoradiotherapy. The coprimary end points were progression-free survival (as assessed by means of blinded independent central review) and overall survival (unplanned for the interim analysis). Secondary end points included 12-month and 18-month progression-free survival rates, the objective response rate, the duration of response, the time to death or distant metastasis, and safety.
RESULTS: Of 713 patients who underwent randomization, 709 received consolidation therapy (473 received durvalumab and 236 received placebo). The median progression-free survival from randomization was 16.8 months (95% confidence interval [CI], 13.0 to 18.1) with durvalumab versus 5.6 months (95% CI, 4.6 to 7.8) with placebo (stratified hazard ratio for disease progression or death, 0.52; 95% CI, 0.42 to 0.65; P<0.001); the 12-month progression-free survival rate was 55.9% versus 35.3%, and the 18-month progression-free survival rate was 44.2% versus 27.0%. The response rate was higher with durvalumab than with placebo (28.4% vs. 16.0%; P<0.001), and the median duration of response was longer (72.8% vs. 46.8% of the patients had an ongoing response at 18 months). The median time to death or distant metastasis was longer with durvalumab than with placebo (23.2 months vs. 14.6 months; P<0.001). Grade 3 or 4 adverse events occurred in 29.9% of the patients who received durvalumab and 26.1% of those who received placebo; the most common adverse event of grade 3 or 4 was pneumonia (4.4% and 3.8%, respectively). A total of 15.4% of patients in the durvalumab group and 9.8% of those in the placebo group discontinued the study drug because of adverse events.
CONCLUSIONS: Progression-free survival was significantly longer with durvalumab than with placebo. The secondary end points also favored durvalumab, and safety was similar between the groups. (Funded by AstraZeneca; PACIFIC ClinicalTrials.gov number, NCT02125461 .).

PMID 28885881  N Engl J Med. 2017 Nov 16;377(20):1919-1929. doi: 10.10・・・
著者: Jhanelle E Gray, Augusto Villegas, Davey Daniel, David Vicente, Shuji Murakami, Rina Hui, Takayasu Kurata, Alberto Chiappori, Ki Hyeong Lee, Byoung Chul Cho, David Planchard, Luis Paz-Ares, Corinne Faivre-Finn, Johan F Vansteenkiste, David R Spigel, Catherine Wadsworth, Maria Taboada, Phillip A Dennis, Mustafa Özgüroğlu, Scott J Antonia
雑誌名: J Thorac Oncol. 2020 Feb;15(2):288-293. doi: 10.1016/j.jtho.2019.10.002. Epub 2019 Oct 14.
Abstract/Text INTRODUCTION: In the phase 3 PACIFIC study of patients with unresectable stage III NSCLC without progression after chemoradiotherapy, durvalumab demonstrated significant improvements versus placebo in the primary end points of progression-free survival (hazard ratio [HR] = 0.52, 95% confidence interval [CI]: 0.42-65, p < 0.0001) and overall survival (OS) (HR = 0.68, 95% CI: 0.53-0.87, p = 0.00251), with manageable safety and no detrimental effect on patient-reported outcomes. Here, we report 3-year OS rates for all patients randomized in the PACIFIC study.
METHODS: Patients, stratified by age, sex, and smoking history, were randomized (2:1) to receive durvalumab, 10 mg/kg intravenously every 2 weeks, or placebo for up to 12 months. OS was analyzed by using a stratified log-rank test in the intention-to-treat population. Medians and rates at 12, 24, and 36 months were estimated by the Kaplan-Meier method.
RESULTS: As of January 31, 2019, 48.2% of patients had died (44.1% and 56.5% in the durvalumab and placebo groups, respectively). The median duration of follow-up was 33.3 months. The updated OS remained consistent with that previously reported (stratified HR = 0.69 [95% CI: 0.55-0.86]); the median OS was not reached with durvalumab but was 29.1 months with placebo. The 12-, 24- and 36-month OS rates with durvalumab and placebo were 83.1% versus 74.6%, 66.3% versus 55.3%, and 57.0% versus 43.5%, respectively. All secondary outcomes examined showed improvements consistent with previous analyses.
CONCLUSIONS: Updated OS data from PACIFIC, including 3-year survival rates, demonstrate the long-term clinical benefit with durvalumab after chemoradiotherapy and further establish the PACIFIC regimen as the standard of care in this population.

Copyright © 2019 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.
PMID 31622733  J Thorac Oncol. 2020 Feb;15(2):288-293. doi: 10.1016/j.・・・
著者: Deborah Citrin, Ana P Cotrim, Fuminori Hyodo, Bruce J Baum, Murali C Krishna, James B Mitchell
雑誌名: Oncologist. 2010;15(4):360-71. doi: 10.1634/theoncologist.2009-S104.
Abstract/Text Radiation is used in the treatment of a broad range of malignancies. Exposure of normal tissue to radiation may result in both acute and chronic toxicities that can result in an inability to deliver the intended therapy, a range of symptoms, and a decrease in quality of life. Radioprotectors are compounds that are designed to reduce the damage in normal tissues caused by radiation. These compounds are often antioxidants and must be present before or at the time of radiation for effectiveness. Other agents, termed mitigators, may be used to minimize toxicity even after radiation has been delivered. Herein, we review agents in clinical use or in development as radioprotectors and mitigators of radiation-induced normal tissue injury. Few agents are approved for clinical use, but many new compounds show promising results in preclinical testing.

PMID 20413641  Oncologist. 2010;15(4):360-71. doi: 10.1634/theoncologi・・・
著者: Lakhan Kma, Feng Gao, Brian L Fish, John E Moulder, Elizabeth R Jacobs, Meetha Medhora
雑誌名: J Radiat Res. 2012;53(1):10-7.
Abstract/Text Our long-term goal is to use angiotensin converting enzyme (ACE) inhibitors to mitigate the increase in lung collagen synthesis that is induced by irradiation to the lung, which could result from accidental exposure or radiological terrorism. Rats (WAG/RijCmcr) were given a single dose of 13 Gy (dose rate of 1.43 Gy/min) of X-irradiation to the thorax. Three structurally-different ACE inhibitors, captopril, enalapril and fosinopril were provided in drinking water beginning 1 week after irradiation. Rats that survived acute pneumonitis (at 6-12 weeks) were evaluated monthly for synthesis of lung collagen. Other endpoints included breathing rate, wet to dry lung weight ratio, and analysis of lung structure. Treatment with captopril (145-207 mg/m(2)/day) or enalapril (19-28 mg/m(2)/day), but not fosinopril (19-28 mg/m(2)/day), decreased morbidity from acute pneumonitis. Lung collagen in the surviving irradiated rats was increased over that of controls by 7 months after irradiation. This increase in collagen synthesis was not observed in rats treated with any of the three ACE inhibitors. Analysis of the lung morphology at 7 months supports the efficacy of ACE inhibitors against radiation-induced fibrosis. The effectiveness of fosinopril against fibrosis, but not against acute pneumonitis, suggests that pulmonary fibrosis may not be a simple consequence of injury during acute pneumonitis. In summary, three structurally-different ACE inhibitors mitigate the increase in collagen synthesis 7 months following irradiation of the whole thorax and do so, even when therapy is started one week after irradiation.

PMID 22302041  J Radiat Res. 2012;53(1):10-7.
著者: Peter Jenkins, Anne Welsh
雑誌名: Int J Radiat Oncol Biol Phys. 2011 Sep 1;81(1):97-103. doi: 10.1016/j.ijrobp.2010.05.017. Epub 2011 May 3.
Abstract/Text PURPOSE: To systematically assess the spectrum of radiologic changes in the lung after radiation therapy for non-small-cell lung cancer.
METHODS AND MATERIALS: We reviewed the cases of 146 patients treated with radical radiotherapy at our institution. All patients had computed tomography (CT) scans performed 3 months after completion of therapy. Radiographic appearances were categorized using a standard grading system. The association of these abnormalities with pretreatment factors and clinical radiation pneumonitis (RP) was investigated.
RESULTS: New intrapulmonary abnormalities were seen in 92 patients (63%). These were ground-glass opacity in 16 (11%), patchy consolidation in 19 (13%), and diffuse consolidation in 57 (39%). Twenty-five patients (17%) developed clinical symptoms of RP. Although 80% of the patients with RP had areas of consolidation seen on the posttreatment CT scan, the majority (74%) of patients with such radiographic changes were asymptomatic. For patients with lung infiltrates, the minimum isodose encompassing the volume of radiologic abnormality was usually ≥27 Gy. Traditional dose-volume metrics, pulmonary function tests, and the coadministration of angiotensin converting enzyme inhibitors (ACE-I) were all strongly correlated with the presence of radiologic injury on univariate analysis (p≤0.002). There was also an inverse correlation between prior smoking history and CT scan changes (p=0.02). On multivariate analysis, dosimetric parameters and the use of ACE-I retained significance (p=0.005).
CONCLUSIONS: Our findings suggest that there is substantial interindividual variation in lung radiosensitivity. ACE-I prevented the radiologic changes seen after high-dose radiation therapy, and their role as radioprotectants warrants further investigation.

Copyright © 2011 Elsevier Inc. All rights reserved.
PMID 21543163  Int J Radiat Oncol Biol Phys. 2011 Sep 1;81(1):97-103. ・・・
著者: Renaud Mazeron, Bénédicte Etienne-Mastroianni, David Pérol, Dominique Arpin, Michel Vincent, Lionel Falchero, Isabelle Martel-Lafay, Christian Carrie, Line Claude
雑誌名: Int J Radiat Oncol Biol Phys. 2010 May 1;77(1):38-43. doi: 10.1016/j.ijrobp.2009.04.019. Epub 2010 Feb 18.
Abstract/Text PURPOSE: To determine predictive factors of late radiation fibrosis (RF) after conformal radiotherapy (3D-RT) in non-small cell lung cancer (NSCLC).
METHODS AND MATERIALS: Ninety-six patients with Stage IA-IIIB NSCLC were included in a prospective trial. Clinical evaluation, chest X-ray, and pulmonary functional tests including diffusion parameters were performed before and 6 months after radiotherapy. An independent panel of experts prospectively analyzed RF, using Late Effects in Normal Tissues-Subjective, Objective, Management and Analytic scales classification. Logistic regression analysis was performed to identify relationships between clinical, functional, or treatment parameters and incidence of RF. Variations of circulating serum levels of pro-inflammatory (interleukin-6, tumor necrosis factor alpha, tumor growth factor beta1) and anti-inflammatory (interleukin-10) cytokines during 3D-RT were examined to identify correlations with RF.
RESULTS: Of the 96 patients included, 72 were evaluable for RF at 6 months. Thirty-seven (51.4%) developed RF (Grade >or=1), including six severe RF (Grades 2-3; 8.3%). In univariate analysis, only poor Karnofsky Performance Status and previous acute radiation pneumonitis were associated with RF (p < 0.05). Dosimetric factors (mean lung dose, percentage of lung volume receiving more than 10, 20, 30, 40, and 50 Gy) were highly correlated with RF (p < 0.001). In multivariate analysis, previous acute radiation pneumonitis and dosimetric parameters were significantly correlated with RF occurrence. It was not significantly correlated either with cytokines at baseline or with their variation during 3D-RT.
CONCLUSIONS: This study confirms the importance of dosimetric parameters to limit the risk of RF. Contrary to acute radiation pneumonitis, RF was not correlated to cytokine variations during 3D-RT.

PMID 20171801  Int J Radiat Oncol Biol Phys. 2010 May 1;77(1):38-43. d・・・
著者: Jeffrey D Bradley, Rebecca Paulus, Ritsuko Komaki, Gregory Masters, George Blumenschein, Steven Schild, Jeffrey Bogart, Chen Hu, Kenneth Forster, Anthony Magliocco, Vivek Kavadi, Yolanda I Garces, Samir Narayan, Puneeth Iyengar, Cliff Robinson, Raymond B Wynn, Christopher Koprowski, Joanne Meng, Jonathan Beitler, Rakesh Gaur, Walter Curran, Hak Choy
雑誌名: Lancet Oncol. 2015 Feb;16(2):187-99. doi: 10.1016/S1470-2045(14)71207-0. Epub 2015 Jan 16.
Abstract/Text BACKGROUND: We aimed to compare overall survival after standard-dose versus high-dose conformal radiotherapy with concurrent chemotherapy and the addition of cetuximab to concurrent chemoradiation for patients with inoperable stage III non-small-cell lung cancer.
METHODS: In this open-label randomised, two-by-two factorial phase 3 study in 185 institutions in the USA and Canada, we enrolled patients (aged ≥ 18 years) with unresectable stage III non-small-cell lung cancer, a Zubrod performance status of 0-1, adequate pulmonary function, and no evidence of supraclavicular or contralateral hilar adenopathy. We randomly assigned (1:1:1:1) patients to receive either 60 Gy (standard dose), 74 Gy (high dose), 60 Gy plus cetuximab, or 74 Gy plus cetuximab. All patients also received concurrent chemotherapy with 45 mg/m(2) paclitaxel and carboplatin once a week (AUC 2); 2 weeks after chemoradiation, two cycles of consolidation chemotherapy separated by 3 weeks were given consisting of paclitaxel (200 mg/m(2)) and carboplatin (AUC 6). Randomisation was done with permuted block randomisation methods, stratified by radiotherapy technique, Zubrod performance status, use of PET during staging, and histology; treatment group assignments were not masked. Radiation dose was prescribed to the planning target volume and was given in 2 Gy daily fractions with either intensity-modulated radiation therapy or three-dimensional conformal radiation therapy. The use of four-dimensional CT and image-guided radiation therapy were encouraged but not necessary. For patients assigned to receive cetuximab, 400 mg/m(2) cetuximab was given on day 1 followed by weekly doses of 250 mg/m(2), and was continued through consolidation therapy. The primary endpoint was overall survival. All analyses were done by modified intention-to-treat. The study is registered with ClinicalTrials.gov, number NCT00533949.
FINDINGS: Between Nov 27, 2007, and Nov 22, 2011, 166 patients were randomly assigned to receive standard-dose chemoradiotherapy, 121 to high-dose chemoradiotherapy, 147 to standard-dose chemoradiotherapy and cetuximab, and 110 to high-dose chemoradiotherapy and cetuximab. Median follow-up for the radiotherapy comparison was 22.9 months (IQR 27.5-33.3). Median overall survival was 28.7 months (95% CI 24.1-36.9) for patients who received standard-dose radiotherapy and 20.3 months (17.7-25.0) for those who received high-dose radiotherapy (hazard ratio [HR] 1.38, 95% CI 1.09-1.76; p=0.004). Median follow-up for the cetuximab comparison was 21.3 months (IQR 23.5-29.8). Median overall survival in patients who received cetuximab was 25.0 months (95% CI 20.2-30.5) compared with 24.0 months (19.8-28.6) in those who did not (HR 1.07, 95% CI 0.84-1.35; p=0.29). Both the radiation-dose and cetuximab results crossed protocol-specified futility boundaries. We recorded no statistical differences in grade 3 or worse toxic effects between radiotherapy groups. By contrast, the use of cetuximab was associated with a higher rate of grade 3 or worse toxic effects (205 [86%] of 237 vs 160 [70%] of 228 patients; p<0.0001). There were more treatment-related deaths in the high-dose chemoradiotherapy and cetuximab groups (radiotherapy comparison: eight vs three patients; cetuximab comparison: ten vs five patients). There were no differences in severe pulmonary events between treatment groups. Severe oesophagitis was more common in patients who received high-dose chemoradiotherapy than in those who received standard-dose treatment (43 [21%] of 207 patients vs 16 [7%] of 217 patients; p<0.0001).
INTERPRETATION: 74 Gy radiation given in 2 Gy fractions with concurrent chemotherapy was not better than 60 Gy plus concurrent chemotherapy for patients with stage III non-small-cell lung cancer, and might be potentially harmful. Addition of cetuximab to concurrent chemoradiation and consolidation treatment provided no benefit in overall survival for these patients.
FUNDING: National Cancer Institute and Bristol-Myers Squibb.

Copyright © 2015 Elsevier Ltd. All rights reserved.
PMID 25601342  Lancet Oncol. 2015 Feb;16(2):187-99. doi: 10.1016/S1470・・・
著者: M V Graham, J A Purdy, B Emami, W Harms, W Bosch, M A Lockett, C A Perez
雑誌名: Int J Radiat Oncol Biol Phys. 1999 Sep 1;45(2):323-9.
Abstract/Text PURPOSE: To identify a clinically relevant and available parameter upon which to identify non-small cell lung cancer (NSCLC) patients at risk for pneumonitis when treated with three-dimensional (3D) radiation therapy.
METHODS AND MATERIALS: Between January 1991 and October 1995, 99 patients were treated definitively for inoperable NSCLC. Patients were selected for good performance status (96%) and absence of weight loss (82%). All patients had full 3D treatment planning (including total lung dose-volume histograms [DVHs]) prior to treatment delivery. The total lung DVH parameters were compared with the incidence and grade of pneumonitis after treatment.
RESULTS: Univariate analysis revealed the percent of the total lung volume exceeding 20 Gy (V20), the effective volume (Veff) and the total lung volume mean dose, and location of the tumor primary (upper versus lower lobes) to be statistically significant relative to the development of > or = Grade 2 pneumonitis. Multivariate analysis revealed the V20 to be the single independent predictor of pneumonitis.
CONCLUSIONS: The V20 from the total lung DVH is a useful parameter easily obtained from most 3D treatment planning systems. The V20 may be useful in comparing competing treatment plans to evaluate the risk of pneumonitis for our individual patient treatment and may also be a useful parameter upon which to stratify patients or prospective dose escalation trials.

PMID 10487552  Int J Radiat Oncol Biol Phys. 1999 Sep 1;45(2):323-9.
著者: Kayoko Tsujino, Saeko Hirota, Masahiro Endo, Kayoko Obayashi, Yoshikazu Kotani, Miyako Satouchi, Tetsuji Kado, Yoshiki Takada
雑誌名: Int J Radiat Oncol Biol Phys. 2003 Jan 1;55(1):110-5. doi: 10.1016/s0360-3016(02)03807-5.
Abstract/Text PURPOSE: To clarify whether the percentage of pulmonary volume irradiated to >20 Gy (V20) is related to the incidence and grade of radiation pneumonitis (RP) in cases of lung cancer treated with concurrent chemoradiation.
METHODS AND MATERIALS: The subjects comprised 71 patients with lung cancer who were treated with conventionally fractionated definitive concurrent chemoradiation. The chemotherapy agents were carboplatin or cisplatin combined with taxane for most patients. Radiotherapy was delivered at 1.8-2.0 Gy fractions once daily to a total of 48-66 Gy (median 60). We analyzed the relation between RP grade and V20. Univariate and multivariate analyses were performed to assess patient- and treatment-related factors, including age, gender, smoking history, pulmonary function (forced expiratory volume in 1 s), tumor location (upper lobe vs. middle/lower lobe), chemotherapy regimen (platinum + taxane vs. other), total dose, overall radiation periods in addition to V20.
RESULTS: With a median follow-up of 7.5 months, an RP grade of 0, 1, 2, 3, and 5 was observed in 16, 35, 17, 1, and 2 patients, respectively; the corresponding mean V20 values were 20.1%, 22.0%, 26.3%, 27.0%, and 34.5%. The 6-month cumulative incidence of RP greater than Grade 2 was 8.7%, 18.3%, 51%, and 85% in patients with a V20 of or=31%, respectively (p <0.0001). According to both univariate and multivariate analyses, V20 was the only factor associated with RP of Grade 2 or greater.
CONCLUSION: The incidence and grade of RP are significantly related to the V20 value. Thus, V20 appears to be a factor that can be used to predict RP after concurrent chemoradiation for lung cancer.

PMID 12504042  Int J Radiat Oncol Biol Phys. 2003 Jan 1;55(1):110-5. d・・・
著者: Susan L Tucker, H Helen Liu, Shulian Wang, Xiong Wei, Zhongxing Liao, Ritsuko Komaki, James D Cox, Radhe Mohan
雑誌名: Int J Radiat Oncol Biol Phys. 2006 Nov 1;66(3):754-61. doi: 10.1016/j.ijrobp.2006.06.002. Epub 2006 Sep 11.
Abstract/Text PURPOSE: The aim of this study was to investigate the effect of radiation dose distribution in the lung on the risk of postoperative pulmonary complications among esophageal cancer patients.
METHODS AND MATERIALS: We analyzed data from 110 patients with esophageal cancer treated with concurrent chemoradiotherapy followed by surgery at our institution from 1998 to 2003. The endpoint for analysis was postsurgical pneumonia or acute respiratory distress syndrome. Dose-volume histograms (DVHs) and dose-mass histograms (DMHs) for the whole lung were used to fit normal-tissue complication probability (NTCP) models, and the quality of fits were compared using bootstrap analysis.
RESULTS: Normal-tissue complication probability modeling identified that the risk of postoperative pulmonary complications was most significantly associated with small absolute volumes of lung spared from doses > or = 5 Gy (VS5), that is, exposed to doses < 5 Gy. However, bootstrap analysis found no significant difference between the quality of this model and fits based on other dosimetric parameters, including mean lung dose, effective dose, and relative volume of lung receiving > or = 5 Gy, probably because of correlations among these factors. The choice of DVH vs. DMH or the use of fractionation correction did not significantly affect the results of the NTCP modeling. The parameter values estimated for the Lyman NTCP model were as follows (with 95% confidence intervals in parentheses): n = 1.85 (0.04, infinity), m = 0.55 (0.22, 1.02), and D50 = 17.5 Gy (9.4 Gy, 102 Gy).
CONCLUSIONS: In this cohort of esophageal cancer patients, several dosimetric parameters including mean lung dose, effective dose, and absolute volume of lung receiving < 5 Gy provided similar descriptions of the risk of postoperative pulmonary complications as a function of the radiation dose distribution in the lung.

PMID 16965865  Int J Radiat Oncol Biol Phys. 2006 Nov 1;66(3):754-61. ・・・
著者: Yosuke Matsuno, Hiroaki Satoh, Hiroichi Ishikawa, Takahide Kodama, Morio Ohtsuka, Kiyohisa Sekizawa
雑誌名: Med Oncol. 2006;23(1):75-82. doi: 10.1385/MO:23:1:75.
Abstract/Text PURPOSE: Radiation pneumonitis (RP) is a serious complication in patients undergoing thoracic radiotherapy (TRT). Serum KL-6 and SP-D have been shown to increase in several kinds of interstitial pneumonia. To evaluate their clinical usefulness in detecting RP, we serially measured them in patients receiving TRT.
MATERIALS AND METHODS: Thirty-nine patients, who received TRT for lung cancer between July 1999 and April 2004, were prospectively studied. Serum levels of KL-6 and SP-D were measured using enzyme-linked immunosorbent assays. Patients were followed up until August 2004 or their deaths.
RESULTS: During the period, RP occurred in 19 patients. In five patients with diffuse RP extended outside the radiation field, serum KL-6 levels increased, reaching more than 1,000 U/mL. Serum KL-6 levels at 40 Gy in patients who developed RP were higher than those without it (p = 0.0363, Mann-Whitney U test). In addition, serum KL-6 levels at 40 Gy in patients who developed RP were higher than those of pretreatment (p = 0.0126, Wilcoxon signed rank test). On the other hand, there were no statistical differences between sp-d at 40 Gy and those before TRT (P = 0.1165).
CONCLUSIONS: Increased KL-6 at 40 Gy compared with those before treatment in patients undergoing TRT may be of clinical significance. KL-6 proved to be a useful indicator for estimating RP, while usefulness of SP-D was not confirmed in this study.

PMID 16645232  Med Oncol. 2006;23(1):75-82. doi: 10.1385/MO:23:1:75.
著者: Ryusuke Hara, Jun Itami, Takafumi Komiyama, Daiki Katoh, Tatsuya Kondo
雑誌名: Chest. 2004 Jan;125(1):340-4.
Abstract/Text To determine the usefulness of serum KL-6 levels for predicting the occurrence of radiation pneumonitis (RP) after the application of single high-dose stereotactic radiation therapy for lung tumors, the serum KL-6 levels were measured in 16 patients before irradiation and every 1 or 2 months thereafter. Three of the 16 patients experienced RP of grade 3 severity according to the European Organization for Research and Treatment of Cancer/Radiation Therapy Oncology Group toxicity criteria. RP occurred 3 months after the completion of radiation therapy in two patients, and 4 months after completion in one patient. RP occurred at significantly increased frequencies in patients with primary lung cancer (p = 0.01) and adenocarcinoma (p = 0.01), and in those undergoing the concurrent irinotecan therapy (p = 0.02). In all 16 patients, the lactate dehydrogenase level remained normal during the follow-up period. In all three of the patients with RP, KL-6 levels increased by > 1.5-fold compared to the pretreatment value and over the cutoff level of 500 IU. The ratio of the increase in serum KL-6 values 2 months after the patient had undergone irradiation showed a significant correlation with the occurrence of RP (p = 0.04). In conclusion, KL-6 is a useful marker for prediction of the occurrence of RP after single, fractional, high-dose stereotactic irradiation of lung tumors.

PMID 14718465  Chest. 2004 Jan;125(1):340-4.
著者: Hiromitsu Iwata, Yuta Shibamoto, Fumiya Baba, Chikao Sugie, Hiroyuki Ogino, Rumi Murata, Takeshi Yanagi, Shinya Otsuka, Katsura Kosaki, Taro Murai, Akifumi Miyakawa
雑誌名: Radiother Oncol. 2011 Nov;101(2):267-70. doi: 10.1016/j.radonc.2011.05.031. Epub 2011 Jun 2.
Abstract/Text
PMID 21640420  Radiother Oncol. 2011 Nov;101(2):267-70. doi: 10.1016/j・・・
著者: K Goto, T Kodama, I Sekine, R Kakinuma, K Kubota, F Hojo, T Matsumoto, H Ohmatsu, H Ikeda, M Ando, Y Nishiwaki
雑誌名: Lung Cancer. 2001 Oct;34(1):141-8.
Abstract/Text The antigen KL-6, a mucin-like high-molecular-weight glycoprotein, is expressed on type-2 pneumocytes and bronchiolar epithelial cells. Serum levels of KL-6 have been shown to correlate well with the activities of several different kinds of interstitial pneumonia. The purpose of this study was to assess the usefulness of monitoring serum KL-6 levels in patients who had received thoracic radiotherapy (TRT). In particular, the usefulness of such a protocol for the early diagnosis of severe radiation pneumonitis (RP) and the evaluation of its progress and severity was examined. Serum KL-6 levels were retrospectively monitored in 16 patients with lung cancer who had received TRT with or without chemotherapy. Eight of these patients had developed severe RP and eight had developed localized (within the irradiated field) RP. Serum KL-6 levels were measured using a modified sandwich-type enzyme-linked immunosorbent assay. In patients who developed severe RP, serum KL-6 levels showed a consistent tendency to increase after the clinical diagnosis of RP. In four patients, serum KL-6 levels even began to rise before a clinical diagnosis of severe RP had been made. In the patients with localized RP, on the other hand, the serum levels did not show any tendency to increase during or after TRT. Moreover, patients whose serum KL-6 levels rose more than 1.5 times higher than their pre-treatment serum KL-6 level, had a large chance of developing severe RP that was unresponsive to steroid hormones and resulted in death. Serum KL-6 levels, therefore, should be useful indicators for the early diagnosis of severe RP and for estimating its progress and severity in patients treated with TRT.

PMID 11557124  Lung Cancer. 2001 Oct;34(1):141-8.
著者: Feng-Ming Kong, Xiaoping Ao, Li Wang, Theodore S Lawrence
雑誌名: Cancer Control. 2008 Apr;15(2):140-50.
Abstract/Text BACKGROUND: Radiation-induced lung toxicity (RILT) is an important dose-limiting toxicity during thoracic radiotherapy. Early prediction of radiation lung toxicity will allow physicians to determine a customized treatment regimen for each patient and deliver a radiation dose tailored to that individual's normal tissue sensitivity profile rather than to the average tolerance of the whole population.
METHODS: This review focuses on blood biomarkers in predicting radiation-induced lung toxicity. We searched the literature for data associated with cytokines, and we review the updates of proteomic and genetic polymorphisms in radiation lung toxicity.
RESULTS: Studies from single institutions have demonstrated the significant values of cytokines such as TGF-beta1, IL-6, KL-6, surfactant proteins, and IL-1ra on predicting RILT. The majority of studies focus on the values prior to and at the end of radiation therapy. There is limited data from proteomics and specific genomic single nucleotide polymorphism studies that target individualized radiation therapy for patients with lung cancer.
CONCLUSIONS: Biomarkers or models that can accurately predict radiation-induced lung damage at an early stage, before completion of chemoradiation, would allow physicians to monitor and customize remaining treatment for each patient.

PMID 18376381  Cancer Control. 2008 Apr;15(2):140-50.
著者: Anhui Shi, Guangying Zhu, Hao Wu, Rong Yu, Fuhai Li, Bo Xu
雑誌名: Radiat Oncol. 2010 May 12;5:35. doi: 10.1186/1748-717X-5-35. Epub 2010 May 12.
Abstract/Text BACKGROUND: To evaluate the association between the clinical, dosimetric factors and severe acute radiation pneumonitis (SARP) in patients with locally advanced non-small cell lung cancer (LANSCLC) treated with concurrent chemotherapy and intensity-modulated radiotherapy (IMRT).
METHODS: We analyzed 94 LANSCLC patients treated with concurrent chemotherapy and IMRT between May 2005 and September 2006. SARP was defined as greater than or equal 3 side effects and graded according to Common Terminology Criteria for Adverse Events (CTCAE) version 3.0. The clinical and dosimetric factors were analyzed. Univariate and multivariate logistic regression analyses were performed to evaluate the relationship between clinical, dosimetric factors and SARP.
RESULTS: Median follow-up was 10.5 months (range 6.5-24). Of 94 patients, 11 (11.7%) developed SARP. Univariate analyses showed that the normal tissue complication probability (NTCP), mean lung dose (MLD), relative volumes of lung receiving more than a threshold dose of 5-60 Gy at increments of 5 Gy (V5-V60), chronic obstructive pulmonary disease (COPD) and Forced Expiratory Volume in the first second (FEV1) were associated with SARP (p < 0.05). In multivariate analysis, NTCP value (p = 0.001) and V10 (p = 0.015) were the most significant factors associated with SARP. The incidences of SARP in the group with NTCP > 4.2% and NTCP 50% were 5.7% and 29.2%, respectively (p < 0.01).
CONCLUSIONS: NTCP value and V10 are the useful indicators for predicting SARP in NSCLC patients treated with concurrent chemotherapy and IMRT.

PMID 20462424  Radiat Oncol. 2010 May 12;5:35. doi: 10.1186/1748-717X-・・・
著者: Vivek Mehta
雑誌名: Int J Radiat Oncol Biol Phys. 2005 Sep 1;63(1):5-24. doi: 10.1016/j.ijrobp.2005.03.047.
Abstract/Text Although radiotherapy improves locoregional control and survival in patients with non-small-cell lung cancer, radiation pneumonitis is a common treatment-related toxicity. Many pulmonary function tests are not significantly altered by pulmonary toxicity of irradiation, but reductions in D(L(CO)), the diffusing capacity of carbon monoxide, are more commonly associated with pneumonitis. Several patient-specific factors (e.g. age, smoking history, tumor location, performance score, gender) and treatment-specific factors (e.g. chemotherapy regimen and dose) have been proposed as potential predictors of the risk of radiation pneumonitis, but these have not been consistently demonstrated across different studies. The risk of radiation pneumonitis also seems to increase as the cumulative dose of radiation to normal lung tissue increases, as measured by dose-volume histograms. However, controversy persists about which dosimetric parameter optimally predicts the risk of radiation pneumonitis, and whether the volume of lung or the dose of radiation is more important. Radiation oncologists ought to consider these dosimetric factors when designing radiation treatment plans for all patients who receive thoracic radiotherapy. Newer radiotherapy techniques and technologies may reduce the exposure of normal lung to irradiation. Several medications have also been evaluated for their ability to reduce radiation pneumonitis in animals and humans, including corticosteroids, amifostine, ACE inhibitors or angiotensin II type 1 receptor blockers, pentoxifylline, melatonin, carvedilol, and manganese superoxide dismutase-plasmid/liposome. Additional research is warranted to determine the efficacy of these medications and identify nonpharmacologic strategies to predict and prevent radiation pneumonitis.

PMID 15963660  Int J Radiat Oncol Biol Phys. 2005 Sep 1;63(1):5-24. do・・・
著者: Naoko Sanuki, Asami Ono, Eiji Komatsu, Noritaka Kamei, Shinji Akamine, Tohru Yamazaki, Syunji Mizunoe, Toru Maeda
雑誌名: J Radiat Res. 2012;53(1):110-6.
Abstract/Text We evaluated associations of interstitial changes with radiation pneumonitis (RP) for patients treated with thoracic radiotherapy. Between 2005 and 2009, patients who received thoracic radiotherapy of 40 Gy or more for lung cancer or thymic tumors and were followed-up for more than 6 months were eligible for this study. Possible risk factors for RP included the presence of interstitial changes on computed tomography before radiotherapy, and elevated C-reactive protein (CRP) and lactate dehydrogenase (LDH) levels; these were compared with the incidences of severe RP. A total of 106 patients were included. The incidences of RP were 4 (4%), 0 (0%), and 5 (5%) for grades 3, 4, and 5, respectively. For those with interstitial changes, the incidence of RP ≥ grade 3 was significantly increased from 3% (2/79) to 26% (7/27) (p < 0.001). CRP and LDH levels were also associated with increased RP, as were pulmonary emphysema and performance status ≥ 2. Among 91 patients with RP ≥ grade 1, RP grade ≥ 3 occurred significantly earlier than grades 1 and 2. In conclusion, pulmonary interstitial changes, LDH and CRP levels, pulmonary emphysema, and performance status ≥ 2 were significantly associated with RP ≥ grade 3. RP grade ≥ 3 occurred significantly earlier than grades 1 and 2. The early appearance of interstitial changes requires careful management due to the possibility of severe RP.

PMID 22302051  J Radiat Res. 2012;53(1):110-6.
著者: Hideomi Yamashita, Shino Kobayashi-Shibata, Atsuro Terahara, Kae Okuma, Akihiro Haga, Reiko Wakui, Kuni Ohtomo, Keiichi Nakagawa
雑誌名: Radiat Oncol. 2010 May 9;5:32. doi: 10.1186/1748-717X-5-32. Epub 2010 May 9.
Abstract/Text PURPOSE: To determine the risk factors of severe radiation pneumonitis (RP) after stereotactic body radiation therapy (SBRT) for primary or secondary lung tumors.
MATERIALS AND METHODS: From January 2003 to March 2009, SBRT was performed on 117 patients (32 patients before 2005 and 85 patients after 2006) with lung tumors (primary = 74 patients and metastatic/recurrent = 43 patients) in our institution. In the current study, the results on cases with severe RP (grades 4-5) were evaluated. Serum Krebs von den Lungen-6 (KL-6) and serum Surfactant protein-D (SP-D) were used to predict the incidence of RP. A shadow of interstitial pneumonitis (IP) on the CT image before performing SBRT was also used as an indicator for RP. Since 2006, patients have been prescreened for biological markers (KL-6 & SP-D) as well as checking for an IP-shadow in CT.
RESULTS: Grades 4-5 RP was observed in nine patients (7.7%) after SBRT and seven of these cases (6.0%) were grade 5 in our institution. A correlation was found between the incidence of RP and higher serum KL-6 & SP-D levels. IP-shadow in patient's CT was also found to correlate well with the severe RP. Severe RP was reduced from 18.8% before 2005 to 3.5% after 2006 (p = 0.042). There was no correlation between the dose volume histogram parameters and these severe RP patients.
CONCLUSION: Patients presenting with an IP shadow in the CT and a high value of the serum KL-6 & SP-D before SBRT treatment developed severe radiation pneumonitis at a high rate. The reduction of RP incidence in patients treated after 2006 may have been attributed to prescreening of the patients. Therefore, pre-screening before SBRT for an IP shadow in CT and serum KL-6 & SP-D is recommended in the management and treatment of patients with primary or secondary lung tumors.

PMID 20459699  Radiat Oncol. 2010 May 9;5:32. doi: 10.1186/1748-717X-5・・・
著者: Jing Zhao, Ellen D Yorke, Ling Li, Brian D Kavanagh, X Allen Li, Shiva Das, Moyed Miften, Andreas Rimner, Jeffrey Campbell, Jinyu Xue, Andrew Jackson, Jimm Grimm, Michael T Milano, Feng-Ming Spring Kong
雑誌名: Int J Radiat Oncol Biol Phys. 2016 Aug 1;95(5):1357-66. doi: 10.1016/j.ijrobp.2016.03.024. Epub 2016 Mar 25.
Abstract/Text PURPOSE: To study the risk factors for radiation-induced lung toxicity (RILT) after stereotactic body radiation therapy (SBRT) of the thorax.
METHODS AND MATERIALS: Published studies on lung toxicity in patients with early-stage non-small cell lung cancer (NSCLC) or metastatic lung tumors treated with SBRT were pooled and analyzed. The primary endpoint was RILT, including pneumonitis and fibrosis. Data of RILT and risk factors were extracted from each study, and rates of grade 2 to 5 (G2+) and grade 3 to 5 (G3+) RILT were computed. Patient, tumor, and dosimetric factors were analyzed for their correlation with RILT.
RESULTS: Eighty-eight studies (7752 patients) that reported RILT incidence were eligible. The pooled rates of G2+ and G3+ RILT from all 88 studies were 9.1% (95% confidence interval [CI]: 7.15-11.4) and 1.8% (95% CI: 1.3-2.5), respectively. The median of median tumor sizes was 2.3 (range, 1.4-4.1) cm. Among the factors analyzed, older patient age (P=.044) and larger tumor size (the greatest diameter) were significantly correlated with higher rates of G2+ (P=.049) and G3+ RILT (P=.001). Patients with stage IA versus stage IB NSCLC had significantly lower risks of G2+ RILT (8.3% vs 17.1%, odds ratio = 0.43, 95% CI: 0.29-0.64, P<.0001). Among studies that provided detailed dosimetric data, the pooled analysis demonstrated a significantly higher mean lung dose (MLD) (P=.027) and V20 (P=.019) in patients with G2+ RILT than in those with grade 0 to 1 RILT.
CONCLUSIONS: The overall rate of RILT is relatively low after thoracic SBRT. Older age and larger tumor size are significant adverse risk factors for RILT. Lung dosimetry, specifically lung V20 and MLD, also significantly affect RILT risk.

Copyright © 2016. Published by Elsevier Inc.
PMID 27325482  Int J Radiat Oncol Biol Phys. 2016 Aug 1;95(5):1357-66.・・・
著者: Raymond H Mak, Brian M Alexander, Kofi Asomaning, Rebecca S Heist, Chen-yu Liu, Li Su, Rihong Zhai, Marek Ancukiewicz, Brian Napolitano, Andrzej Niemierko, Henning Willers, Noah C Choi, David C Christiani
雑誌名: Cancer. 2012 Jul 15;118(14):3654-65. doi: 10.1002/cncr.26667. Epub 2011 Dec 5.
Abstract/Text BACKGROUND: This study examined the association between functional single-nucleotide polymorphisms in candidate genes from oxidative stress pathways and risk of radiation pneumonitis (RP) in patients treated with thoracic radiation therapy for locally advanced lung cancer.
METHODS: A review was conducted of 136 patients treated with radiation therapy for lung cancer between 2001 and 2007, and who had prior genotyping of functional single-nucleotide polymorphisms in oxidative stress genes including superoxide dismutase 2 (SOD2; rs4880) and methylene tetrahydrofolate reductase (MTHFR; rs1801131, rs1801133). RP events were retrospectively scored using the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0. Cox proportional hazard regression was performed to identify clinical variables and genotypes associated with risk of RP of grades ≥2 and ≥3 on univariate and multivariate analysis, respectively. P values were corrected for multiple hypothesis esting.
RESULTS: With a median follow-up of 21.4 months, the incidence of grade ≥2 RP was 29% and grade ≥3 RP was 14%. On multivariate analysis, after adjusting for clinical factors such as concurrent chemotherapy and consolidation docetaxel, and lung dosimetric parameters such as volume receiving greater than 20 Gy and mean lung dose, MTHFR genotype (rs1801131; AA versus AC/CC) was significantly associated with risk of grade ≥2 RP (hazard ratio: 0.37; 95% confidence interval: 0.18-0.76; P = .006, corrected P = .018) and grade ≥3 RP (hazard ratio: 0.21; 95% confidence interval: 0.06-0.70; P = .01; corrected P = .03). SOD2 genotype was not associated with RP.
CONCLUSIONS: This study showed an association between MTHFR genotype and risk of clinically significant RP. Further study of MTHFR-related pathways may provide insight into the mechanisms behind RP.

Copyright © 2011 American Cancer Society.
PMID 22144047  Cancer. 2012 Jul 15;118(14):3654-65. doi: 10.1002/cncr.・・・
著者: Matthew R McCurdy, Mohamad W Wazni, Josue Martinez, Mary Frances McAleer, Thomas Guerrero
雑誌名: Radiother Oncol. 2011 Dec;101(3):443-8. doi: 10.1016/j.radonc.2011.08.035. Epub 2011 Oct 6.
Abstract/Text BACKGROUND AND PURPOSE: Radiation pneumonitis is a significant toxicity following thoracic radiotherapy with no method to predict individual risk.
MATERIALS AND METHODS: Sixty-five patients receiving thoracic radiation for lung or esophageal cancer were enrolled in a phase II study. Each patient received respiratory surveys and exhaled nitric oxide measurements before, on the last day of, and 30-60 days after completing radiotherapy (RT). Pneumonitis toxicity was scored using the common terminology criteria for adverse events, version 4.0. The demographics, dosimetric factors, and nitric oxide ratio (NOR) of end RT/pre-RT were evaluated for correlation with symptomatic patients (Grade ≥ 2).
RESULTS: Fifty patients completed the trial. The pneumonitis toxicity score was: Grade 3 for 1 patient, Grade 2 for 6 patients, Grade 1 for 18 patients, and Grade 0 for 25 patients. Dosimetric factors were not predictive of symptoms. The NOR was 3.0 ± 1.8 (range 1.47-6.73) for the symptomatic and 0.78 ± 0.29 (range 0.33-1.37) for the asymptomatic patients (p=0.006). A threshold NOR of 1.4 separated symptomatic and asymptomatic patients (p<0.001). The average error was 4%.
CONCLUSIONS: Elevation in eNO on the last day of radiotherapy predicted subsequent symptomatic radiation pneumonitis weeks to months after treatment.

Copyright © 2011. Published by Elsevier Ireland Ltd.
PMID 21981878  Radiother Oncol. 2011 Dec;101(3):443-8. doi: 10.1016/j.・・・
著者: Thomas Guerrero, Josue Martinez, Matthew R McCurdy, Michael Wolski, Mary Francis McAleer
雑誌名: Int J Radiat Oncol Biol Phys. 2012 Feb 1;82(2):981-8. doi: 10.1016/j.ijrobp.2010.08.041. Epub 2011 Mar 4.
Abstract/Text PURPOSE: Radiation pneumonitis is a major toxicity after thoracic radiotherapy (RT), with no method available to accurately predict the individual risk. This was a prospective study to evaluate exhaled nitric oxide as a predictive biomarker for radiation pneumonitis in esophageal cancer patients.
PATIENTS AND METHODS: A total of 34 patients prescribed neoadjuvant chemoradiotherapy for esophageal cancer were enrolled in the present trial. Each patient underwent respiratory surveys and exhaled nitric oxide (NO) measurements before, at the end of, and 1 to 2 months after completing RT. Pneumonitis toxicity was scored using the Common Terminology Criteria for Adverse Events, version 4.0. The demographics, dosimetric factors, and exhaled NO levels were evaluated for correlation with symptomatic patients (scores ≥ 2).
RESULTS: Of the 34 patients, 28 were evaluable. All had received 50.4 Gy RT with concurrent chemotherapy. The pneumonitis toxicity score was Grade 3 for 1, Grade 2 for 3, Grade 1 for 7, and Grade 0 for 17. The dosimetric factors were not predictive of symptoms. The mean exhaled NO level measured before, at completion, and at restaging was 17.3 ± 8.5 (range, 5.5-36.7), 16.0 ± 14.2 (range, 5.8-67.7), and 14.7 ± 6.2 (range, 5.5-28.0) parts per billion, respectively. The ratio of exhaled NO at the end of RT vs. before treatment was 3.4 (range, 1.7-6.7) for the symptomatic and 0.8 (range, 0.3-1.3) for the asymptomatic (p = .0017) patients. The elevation in exhaled NO preceded the peak symptoms by 33 days (range, 21-50). The interval to peak symptoms was inversely related to the exhaled NO elevation.
CONCLUSIONS: Elevations in exhaled NO at the end of RT was found to predict for radiation pneumonitis symptoms.

Copyright © 2012 Elsevier Inc. All rights reserved.
PMID 21377296  Int J Radiat Oncol Biol Phys. 2012 Feb 1;82(2):981-8. d・・・
著者: Aadel A Chaudhuri, Michael S Binkley, Joseph Rigdon, Justin N Carter, Sonya Aggarwal, Sara A Dudley, Yushen Qian, Kiran A Kumar, Wendy Y Hara, Michael Gensheimer, Viswam S Nair, Peter G Maxim, David B Shultz, Karl Bush, Nicholas Trakul, Quynh-Thu Le, Maximilian Diehn, Billy W Loo, Haiwei Henry Guo
雑誌名: Radiother Oncol. 2016 Jun;119(3):454-60. doi: 10.1016/j.radonc.2016.05.007. Epub 2016 Jun 3.
Abstract/Text PURPOSE: To determine if pre-treatment non-target lung FDG-PET uptake predicts for symptomatic radiation pneumonitis (RP) following lung stereotactic ablative radiotherapy (SABR).
METHODS: We reviewed a 258 patient database from our institution to identify 28 patients who experienced symptomatic (grade ⩾ 2) RP after SABR, and compared them to 57 controls who did not develop symptomatic RP. We compared clinical, dosimetric and functional imaging characteristics between the 2 cohorts including pre-treatment non-target lung FDG-PET uptake.
RESULTS: Median follow-up time was 26.9 months. Patients who experienced symptomatic RP had significantly higher non-target lung FDG-PET uptake as measured by mean SUV (p < 0.0001) than controls. ROC analysis for symptomatic RP revealed area under the curve (AUC) of 0.74, with sensitivity 82.1% and specificity 57.9% with cutoff mean non-target lung SUV > 0.56. Predictive value increased (AUC of 0.82) when mean non-target lung SUV was combined with mean lung dose (MLD). We developed a 0-2 point model using these 2 variables, 1 point each for SUV > 0.56 or MLD > 5.88 Gy equivalent dose in 2 Gy per fraction (EQD2), predictive for symptomatic RP in our cohort with hazard ratio 10.01 for score 2 versus 0 (p < 0.001).
CONCLUSIONS: Patients with elevated pre-SABR non-target lung FDG-PET uptake are at increased risk of symptomatic RP after lung SABR. Our predictive model suggests patients with mean non-target lung SUV > 0.56 and MLD > 5.88 Gy EQD2 are at highest risk. Our predictive model should be validated in an external cohort before clinical implementation.

Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.
PMID 27267049  Radiother Oncol. 2016 Jun;119(3):454-60. doi: 10.1016/j・・・
著者: Richard Castillo, Ngoc Pham, Edward Castillo, Samantha Aso-Gonzalez, Sobiya Ansari, Brian Hobbs, Diana Palacio, Heath Skinner, Thomas M Guerrero
雑誌名: Radiology. 2015 Jun;275(3):822-31. doi: 10.1148/radiol.14140457. Epub 2015 Jan 13.
Abstract/Text PURPOSE: To examine the association between pre-radiation therapy (RT) fluorine 18 fluorodeoxyglucose (FDG) uptake and post-RT symptomatic radiation pneumonitis (RP).
MATERIALS AND METHODS: In accordance with the retrospective study protocol approved by the institutional review board, 228 esophageal cancer patients who underwent FDG PET/CT before chemotherapy and RT were examined. RP symptoms were evaluated by using the Common Terminology Criteria for Adverse Events, version 4.0, from the consensus of five clinicians. By using the cumulative distribution of standardized uptake values (SUVs) within the lungs, those values greater than 80%-95% of the total lung voxels were determined for each patient. The effect of pre-chemotherapy and RT FDG uptake, dose, and patient or treatment characteristics on RP toxicity was studied by using logistic regression.
RESULTS: The study subjects were treated with three-dimensional conformal RT (n = 36), intensity-modulated RT (n = 135), or proton therapy (n = 57). Logistic regression analysis demonstrated elevated FDG uptake at pre-chemotherapy and RT was related to expression of RP symptoms. Study subjects with elevated 95% percentile of the SUV (SUV95) were more likely to develop symptomatic RP (P < .000012); each 0.1 unit increase in SUV95 was associated with a 1.36-fold increase in the odds of symptomatic RP. Receiver operating characteristic (ROC) curve analysis resulted in area under the ROC curve of 0.676 (95% confidence interval: 0.58, 0.77), sensitivity of 60%, and specificity of 71% at the 1.17 SUV95 threshold. CT imaging and dosimetric parameters were found to be poor predictors of RP symptoms.
CONCLUSION: The SUV95, a biomarker of pretreatment pulmonary metabolic activity, was shown to be prognostic of symptomatic RP. Elevation in this pretreatment biomarker identifies patients at high risk for posttreatment symptomatic RP.

RSNA, 2015
PMID 25584706  Radiology. 2015 Jun;275(3):822-31. doi: 10.1148/radiol.・・・
著者: R Shibaki, H Akamatsu, M Fujimoto, Y Koh, N Yamamoto
雑誌名: Ann Oncol. 2017 Jun 1;28(6):1404-1405. doi: 10.1093/annonc/mdx115.
Abstract/Text
PMID 28383674  Ann Oncol. 2017 Jun 1;28(6):1404-1405. doi: 10.1093/ann・・・
著者: Xiao Ding, Wei Ji, Junling Li, Xiangru Zhang, Luhua Wang
雑誌名: Radiat Oncol. 2011 Mar 6;6:24. doi: 10.1186/1748-717X-6-24. Epub 2011 Mar 6.
Abstract/Text BACKGROUND: Radiation recall pneumonitis (RRP) describes a rare reaction in previously irradiated area of pulmonary tissue after application of triggering agents. RRP remains loosely characterized and poorly understood since it has so far only been depicted in 8 cases in the literature. The objective of the study is to disclose the general characteristics of RRP induced by chemotherapy after thoracic irradiation for lung cancer, and to draw attention to the potential toxicity even after a long time interval from the previous irradiation.
METHODS: Medical records were reviewed. RRP induced by chemotherapy was diagnosed by the history of chemotherapy after radiotherapy, clinical presentation and radiographic abnormalities including ground-glass opacity, attenuation, or consolidation changes within the radiation field, plus that radiographic examination of the thorax before showed no radiation pneumonitis. RRP was graded according to Common Terminology Criteria for Adverse Events version 3.0. The characteristics of the 12 RRP cases were analyzed.
RESULTS: Twelve patients were diagnosed of RRP, of who 8 received taxanes. The median time interval between end of radiotherapy and RRP, between end of radiotherapy and beginning of chemotherapy, and between beginning of chemotherapy and RRP was 95 days, 42 days and 47 days, respectively. Marked symptomatic and radiographic improvement was observed in the 12 patients after withdrawal of chemotherapy and application of systemic corticosteroids. Seven patients were rechallenged with chemotherapy, of whom four with the same kind of agents, and showed no recurrence with steroid cover.
CONCLUSIONS: Doctors should pay attention to RRP even after a long time from the previous radiotherapy or after several cycles of consolidation chemotherapy. Taxanes are likely to be associated with radiation recall more frequently. Withdrawal of causative agent and application of steroids are the treatment of choice. Patients may be rechallenged safely with steroid cover and careful observation, which needs to be validated.

PMID 21375774  Radiat Oncol. 2011 Mar 6;6:24. doi: 10.1186/1748-717X-6・・・
著者: J F Cordier, J F Mornex, Y Lasne, J P Gérard, G Cordier, R Creyssel, R Touraine
雑誌名: Bull Eur Physiopathol Respir. 1984 Jul-Aug;20(4):369-74.
Abstract/Text Bronchoalveolar lavage (BAL) was carried out in six patients with radiation pneumonitis, the early radiation-induced lung damage that usually leads to radiation fibrosis. Protein analysis by immuno-electrophoresis and polyacrylamide gel electrophoresis of BAL fluid revealed leakage of circulatory proteins, including high molecular weight components. Cell count of BAL fluid showed an increased number of lymphocytes; these proved to be activated on cell cycle analysis in one patient. Collagenolytic activity, assessed by degradation of radiolabelled type I human collagen, was present in BAL fluid of all six patients. The following mechanisms are therefore considered to participate in the pathogenesis of radiation-induced lung damage: 1) permeability oedema, which led to acute respiratory distress syndrome in one case of hyperacute radiation pneumonitis, 2) lymphocyte alveolitis possibly perpetuated by activated lymphocytes, and 3) release of collagenolytic enzymes in alveolar structures contributing to fibrotic processes.

PMID 6478094  Bull Eur Physiopathol Respir. 1984 Jul-Aug;20(4):369-74・・・
著者: C M Roberts, E Foulcher, J J Zaunders, D H Bryant, J Freund, D Cairns, R Penny, G W Morgan, S N Breit
雑誌名: Ann Intern Med. 1993 May 1;118(9):696-700.
Abstract/Text OBJECTIVE: To determine if unilateral thoracic irradiation results in a lymphoid alveolitis in both irradiated and unirradiated lung fields.
DESIGN: A prospective, nonrandomized study.
PATIENTS: Women receiving postoperative radiotherapy for carcinoma of the breast were evaluated both before and 4 to 6 weeks after radiotherapy. Findings after radiotherapy in 15 asymptomatic patients were compared with findings in a group of patients with clinical radiation pneumonitis.
MEASUREMENTS: History, physical examination, chest radiograph, quantitative gallium lung scanning, respiratory function tests, bronchoalveolar lavage, and lavage lymphocyte subset analysis.
RESULTS: After irradiation, lavage lymphocytes increased significantly (34.5% versus 46.8%; P = 0.01) in the 17 patients studied prospectively. There was an associated reduction in vital capacity (102.5% versus 95.5%; P = 0.04). Comparison of results in patients before treatment, after treatment without clinical pneumonitis, and after treatment with clinical pneumonitis showed a dramatic increase in total lymphocytes after irradiation (6.3 versus 9.4 versus 35.2 million, respectively; P = 0.005), particularly in those with clinical pneumonitis. Only in those with clinical pneumonitis was this accompanied by an increase in the gallium index (3.7 versus 3.4 versus 9.0, respectively; P < 0.001). Vital capacity was also progressively reduced (102.5% versus 96.9% versus 76.7%, respectively; P = 0.04), as was diffusing capacity (98.6% versus 91.4% versus 72.6%, respectively; P = 0.003). No statistical differences existed between irradiated and unirradiated sides of the chest in either lavage or gallium lung scan studies.
CONCLUSION: In most patients, a lymphocytic alveolitis develops in both lung fields after strictly unilateral thoracic irradiation; this is more pronounced in patients developing clinical pneumonitis. These findings suggest that radiotherapy may cause a generalized lymphocyte-mediated hypersensitivity reaction.

PMID 8460855  Ann Intern Med. 1993 May 1;118(9):696-700.
著者: Claudia Lucia Toma, Aneta Serbescu, Mihai Alexe, Luminita Cervis, Diana Ionita, Miron Alexandru Bogdan
雑誌名: Maedica (Buchar). 2010 Dec;5(4):250-7.
Abstract/Text Background and purpose: Radiotherapy in breast cancer patients is limited by lung tissue tolerance. Two complications involving the lung are known: radiation pneumonitis (RP) and radiation fibrosis. The aim of the study was to evaluate the pattern of bronchoalveolar lavage (BAL) in patients with RP after radiotherapy for breast cancer in symptomatic and asymptomatic patients.Material and methods: Sixty-five female patients (mean age 58.3 yrs) with RP after radiotherapy for breast cancer were included in the study. The majority of patients had previous breast surgery (mastectomy or lumpectomy and axillary dissection) and received doses of radiations of 45-50Gy. All patients had adjuvant chemotherapy with cyclophosphamide, 5-fluorouracil, and epirubicin or methotrexate.Results: All patients had an infiltrate or consolidation on chest radiography confined to the upper lobe of the irradiated lung, as marker of RP. Based on the presence or absence of symptoms, we divided the patients in 2 groups: 49 patients (75.4%) with symptomatic RP (fever, cough, dyspnea, chest pain and fatigue) and 16 patients (24.6%) without any symptom. Symptomatic RP patients had a BAL with significant increase in total cells (18.0±12.2 x10(6) cells•100mL-1) when compared to BAL in asymptomatic patients (11.9±6.2 x10(6) cells•100mL-1), p=0.01. Lymphocytosis in BAL was significantly increased in symptomatic group, compared with asymptomatic one (35.4±18.7% vs. 26.1±14.3%, p=0.045), with predominance of T lymphocytes (CD3). It was also a predominance of CD4 lymphocytes in all patients, but the CD4/CD8 ratio was inside normal range in the majority of cases. Five patients had clinical features of bronchiolitis obliterans organizing pneumonia (BOOP) secondary to irradiation with increased percentages of lymphocytes, neutrophils, eosinophils, and mast cells in BAL and one patient without history of atopic disease had a percentage of 40% eosinophils. Only a mild reduction in diffusing capacity for carbon monoxide was seen in both groups on pulmonary function tests. The lung volumes were normal in all patients.Conclusions: Lymphocytic alveolitis was the marker of radiation pneumonitis in all patients. The degree of the inflammatory reaction of the lungs was correlated with the presence of symptoms. The lymphocytic alveolitis consisted mainly of T lymphocytes, with a predominance of CD4 subset in both groups, but the CD4/CD8 ratio remained mostly into normal range.

PMID 21977166  Maedica (Buchar). 2010 Dec;5(4):250-7.
著者: A Frank, D Lefkowitz, S Jaeger, L Gobar, J Sunderland, N Gupta, W Scott, J Mailliard, H Lynch, J Bishop
雑誌名: Int J Radiat Oncol Biol Phys. 1995 Jul 30;32(5):1495-512. doi: 10.1016/0360-3016(94)00622-R.
Abstract/Text PURPOSE: The purpose of the study was to determine if Positron emission tomography (PET) 2-[F-18] fluoro-2-deoxy-D-glucose (FDG) imaging could detect subclinical local lung cancer recurrence and whether retreatment of such recurrence was feasible and beneficial.
METHODS AND MATERIALS: Twenty patients with biopsy proven lung cancer were studied with Positron emission tomography for the purpose of detecting subclinical lung cancer recurrence over a period of 4.25 years. All patients were treated with external radiation as part or all of their therapy. Twenty patients had baseline PET and computed tomography (CT) studies for comparison with later studies. Surviving patients had a total of 40 sequential PET scans and 35 CT scans. The follow-up interval ranged from 5 to 40 months posttreatment. The differential uptake ratio (DUR) was determined for regions of interest of increased FDG uptake.
RESULTS: The median DUR value of the 20 baseline PET studies was 5.59. The DUR value of greater than 3 was empirically selected as being positive for tumor detection. On baseline studies, PET had a 100% correlation with the CT findings in regard to detection of the site of primary tumor involvement. Four of 20 patients showed areas of discordance in the mediastinal and hilar areas on initial PET and CT studies. Seven of 17 patients showed discordant posttreatment PET-CT findings. Two false positive PET studies were due to radiation pneumonitis and one to macrophage glycolysis in tumor necrosis. For detection of asymptomatic tumor recurrence, analysis of sequential PET and CT studies, biopsy results, and the patient's clinical course suggested that PET had a sensitivity of 100%, specificity of 89.3%, and accuracy of 92.5%. Computerized Tomography was found to have a sensitivity of 67%, specificity of 85%, and accuracy of 82% for detection of such early-stage recurrence. Five patients went on to have retreatment with external irradiation based upon the PET evidence. Four retreated patients had biopsies that corroborated the positive PET findings, and one patient was retreated on the basis of the qualitative appearance of the posttreatment PET study. Two of the five retreated patients remain alive without evidence of tumor to 34 months following initial therapy.
CONCLUSION: Positron emission tomography scanning appears to be effective in detecting and following the progression of recurrent lung cancer. Retreatment of patients with asymptomatic recurrent tumor has resulted in absent or decreased FDG activity. Monitoring of patients with PET may provide prolonged survival in patients who otherwise would fail treatment because of local tumor recurrence.

PMID 7635795  Int J Radiat Oncol Biol Phys. 1995 Jul 30;32(5):1495-51・・・
著者: Yo Won Choi, Reginald F Munden, Jeremy J Erasmus, Kyung Joo Park, Woo Kyung Chung, Seok Chol Jeon, Choong-Ki Park
雑誌名: Radiographics. 2004 Jul-Aug;24(4):985-97; discussion 998. doi: 10.1148/rg.244035160.
Abstract/Text Radiation-induced lung disease (RILD) due to radiation therapy is common. Radiologic manifestations are usually confined to the lung tissue within the radiation port and are dependent on the interval after completion of treatment. In the acute phase, RILD typically manifests as ground-glass opacity or attenuation or as consolidation; in the late phase, it typically manifests as traction bronchiectasis, volume loss, and scarring. However, the use of oblique beam angles and the development of newer irradiation techniques such as three-dimensional conformal radiation therapy can result in an unusual distribution of these findings. Awareness of the atypical manifestations of RILD can be useful in preventing confusion with infection, recurrent malignancy, lymphangitic carcinomatosis, and radiation-induced tumors. In addition, knowledge of radiologic findings that are outside the expected pattern for RILD can be useful in diagnosis of infection or recurrent malignancy. Such findings include the late appearance or enlargement of a pleural effusion; development of consolidation, a mass, or cavitation; and occlusion of bronchi within an area of radiation-induced fibrosis. A comprehensive understanding of the full spectrum of these manifestations is important to facilitate diagnosis and management in cancer patients treated with radiation therapy.

Copyright RSNA, 2004
PMID 15256622  Radiographics. 2004 Jul-Aug;24(4):985-97; discussion 99・・・
著者: Michael P Mac Manus, Zhe Ding, Annette Hogg, Alan Herschtal, David Binns, David L Ball, Rodney J Hicks
雑誌名: Int J Radiat Oncol Biol Phys. 2011 Aug 1;80(5):1365-71. doi: 10.1016/j.ijrobp.2010.04.021. Epub 2010 Aug 2.
Abstract/Text PURPOSE: To study the relationship between fluorodeoxyglucose (FDG) uptake in pulmonary tissue after radical radiation therapy (RT) and the presence and severity of radiation pneumonitis.
METHODS AND MATERIALS: In 88 consecutive patients, (18)F-FDG-positron emission tomography was performed at a median of 70 days after completion of RT. Patients received 60 Gy in 30 fractions, and all but 15 had concurrent platinum-based chemotherapy. RT-induced pulmonary inflammatory changes occurring within the radiation treatment volume were scored, using a visual (0 to 3) radiotoxicity grading scale, by an observer blinded to the presence or absence of clinical radiation pneumonitis. Radiation pneumonitis was retrospectively graded using the Radiation Therapy Oncology Group (RTOG) scale by an observer blinded to the PET radiotoxicity score.
RESULTS: There was a significant association between the worst RTOG pneumonitis grade occurring at any time after RT and the positron emission tomograph (PET) radiotoxicity grade (one-sided p = 0.033). The worst RTOG pneumonitis grade occurring after the PET scan was also associated with the PET radiotoxicity grade (one-sided p = 0.035). For every one-level increase in the PET toxicity scale, the risk of a higher RTOG radiation pneumonitis score increased by approximately 40%. The PET radiotoxicity score showed no significant correlation with the duration of radiation pneumonitis.
CONCLUSIONS: The intensity of FDG uptake in pulmonary tissue after RT determined using a simple visual scoring system showed significant correlation with the presence and severity of radiation pneumonitis. (18)F-FDG-PET may be useful in the prediction, diagnosis and therapeutic monitoring of radiation pneumonitis.

Copyright © 2011 Elsevier Inc. All rights reserved.
PMID 20675076  Int J Radiat Oncol Biol Phys. 2011 Aug 1;80(5):1365-71.・・・
著者: Atsuya Takeda, Etsuo Kunieda, Hirofumi Fujii, Noriko Yokosuka, Yousuke Aoki, Yoshikazu Oooka, Yohei Oku, Toshio Ohashi, Naoko Sanuki, Tomikazu Mizuno, Yukihiko Ozawa
雑誌名: Lung Cancer. 2013 Mar;79(3):248-53. doi: 10.1016/j.lungcan.2012.11.008. Epub 2012 Dec 11.
Abstract/Text PURPOSE: Stereotactic body radiotherapy (SBRT) is the standard care for medically inoperable early non-small-cell lung cancer (NSCLC). However, it can be difficult to differentiate local recurrence from non-recurrence radiation-induced lung opacity. We retrospectively assessed (18)F-FDG PET/CT to detect local recurrence after SBRT for NSCLC.
METHODS: Between 2005 and 2011, 273 NSCLCs in 257 patients were treated with SBRT. Prescribed doses were 50Gy and 40Gy per 5 fractions for peripheral and central lesions, respectively. Tri-monthly follow-up CT scans were acquired. (18)F-FDG PET/CT scans were scheduled for screening at one year after SBRT or when recurrence was highly suspected. The dual-time-point maximum standardized uptake values (SUVmaxs) and their retention indexes (RIs) were obtained.
RESULTS: A total of 214 (18)F-FDG PET/CT scans were obtained for 164 localized NSCLC tumors in 154 patients. The median follow-up period was 24.9 months (range: 6.3-72.1). Among these, 21 scans of 17 tumors were diagnosed as local recurrence. The median SUVmaxs on early and late images of recurrence and their RI were 5.0 (range: 3.2-10.7), 6.3 (range: 4.2-13.4), and 0.20 (range; 0-0.41), respectively. These were significantly higher than the respective values of non-recurrence images of 1.8 (range: 0.5-4.6), 1.7 (range: 0.5-6.1), and 0.00 (range: -0.37-0.41) (all p<0.05). For SUVmaxs on early and late images, optimal thresholds were identified as 3.2 and 4.2. Using each threshold, the sensitivity and specificity were 100% and 96-98%, respectively. CT findings were classified into ground-glass opacity (N=9), scar or fibrotic change (N=96), consolidation with air-bronchogram (N=34), consolidation only (N=22), and nodule (N=17); the respective numbers of recurrence were 0, 0, 1, 3, and 17.
CONCLUSION: SUVmaxs of (18)F-FDG PET/CT could detect local recurrence after SBRT for localized NSCLC. In contrast, CT scan results had a limited ability to diagnose local recurrence.

Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.
PMID 23246123  Lung Cancer. 2013 Mar;79(3):248-53. doi: 10.1016/j.lung・・・
著者: Neal E Dunlap, Wensha Yang, Alyson McIntosh, Ke Sheng, Stanley H Benedict, Paul W Read, James M Larner
雑誌名: Int J Radiat Oncol Biol Phys. 2012 Dec 1;84(5):1071-7. doi: 10.1016/j.ijrobp.2012.01.088. Epub 2012 Aug 14.
Abstract/Text PURPOSE: To investigate pulmonary radiologic changes after lung stereotactic body radiotherapy (SBRT), to distinguish between mass-like fibrosis and tumor recurrence.
METHODS AND MATERIALS: Eighty consecutive patients treated with 3- to 5-fraction SBRT for early-stage peripheral non-small cell lung cancer with a minimum follow-up of 12 months were reviewed. The mean biologic equivalent dose received was 150 Gy (range, 78-180 Gy). Patients were followed with serial CT imaging every 3 months. The CT appearance of consolidation was defined as diffuse or mass-like. Progressive disease on CT was defined according to Response Evaluation Criteria in Solid Tumors 1.1. Positron emission tomography (PET) CT was used as an adjunct test. Tumor recurrence was defined as a standardized uptake value equal to or greater than the pretreatment value. Biopsy was used to further assess consolidation in select patients.
RESULTS: Median follow-up was 24 months (range, 12.0-36.0 months). Abnormal mass-like consolidation was identified in 44 patients (55%), whereas diffuse consolidation was identified in 12 patients (15%), at a median time from end of treatment of 10.3 months and 11.5 months, respectively. Tumor recurrence was found in 35 of 44 patients with mass-like consolidation using CT alone. Combined with PET, 10 of the 44 patients had tumor recurrence. Tumor size (hazard ratio 1.12, P=.05) and time to consolidation (hazard ratio 0.622, P=.03) were predictors for tumor recurrence. Three consecutive increases in volume and increasing volume at 12 months after treatment in mass-like consolidation were highly specific for tumor recurrence (100% and 80%, respectively). Patients with diffuse consolidation were more likely to develop grade ≥ 2 pneumonitis (odds ratio 26.5, P=.02) than those with mass-like consolidation (odds ratio 0.42, P=.07).
CONCLUSION: Incorporating the kinetics of mass-like consolidation and PET to the current criteria for evaluating posttreatment response will increase the likelihood of correctly identifying patients with progressive disease after lung SBRT.

Copyright © 2012 Elsevier Inc. All rights reserved.
PMID 22898383  Int J Radiat Oncol Biol Phys. 2012 Dec 1;84(5):1071-7. ・・・
著者: Atsuya Takeda, Etsuo Kunieda, Toshiaki Takeda, Michio Tanaka, Naoko Sanuki, Hirofumi Fujii, Naoyuki Shigematsu, Atsushi Kubo
雑誌名: Int J Radiat Oncol Biol Phys. 2008 Mar 15;70(4):1057-65. doi: 10.1016/j.ijrobp.2007.07.2383. Epub 2007 Oct 1.
Abstract/Text PURPOSE: To retrospectively analyze opacity changes near primary lung cancer tumors irradiated by using hypofractionated stereotactic radiotherapy (HSRT) to determine the presence or absence of tumor recurrence.
METHODS AND MATERIALS: After review-board approval for a retrospective study, we examined data from 50 patients treated with curative intent for proven or highly suspected localized peripheral-lung cancer and followed up for at least 12 months. All patients had received 50 Gy in five fractions (80% isodose) and were followed up monthly with chest X-ray until clinical and X-ray findings stabilized. Follow-up computed tomography scans were performed 1 and 3 months after HSRT and thereafter at 3-month intervals during the first 2 years.
RESULTS: Median follow-up was 30.4 months (range, 12.0-73.8 months). Abnormal opacities that were suspicious for recurrent tumor appeared in 20 patients at a median of 20.7 months (range, 5.9-61.4 months). Only 3 patients were finally found to have recurrence; 14 were recurrence free but were suspected to have fibrosis, and findings for the other 3 patients were considered equivocal because of a short follow-up period (CONCLUSION: Radiation fibrosis, which may occur 1 year or longer after completion of HSRT, is difficult to distinguish from tumor recurrence. Even when opacities increase on follow-up radiologic scans, recurrence cannot be diagnosed conclusively based on image findings; biopsy occasionally is warranted.

PMID 17905527  Int J Radiat Oncol Biol Phys. 2008 Mar 15;70(4):1057-65・・・
著者: B Crestani, D Valeyre, S Roden, B Wallaert, J C Dalphin, J F Cordier
雑誌名: Am J Respir Crit Care Med. 1998 Dec;158(6):1929-35. doi: 10.1164/ajrccm.158.6.9711036.
Abstract/Text Reports of bronchiolitis obliterans organizing pneumonia (BOOP) occurring in women after radiation therapy for breast cancer have suggested that radiation to the lung could participate in the development of BOOP. We now describe the clinical, radiographic, functional, and bronchoalveolar lavage characteristics of this syndrome in a series of 15 patients reported to the Groupe d'Etudes et de Recherche sur les Maladies "Orphelines" Pulmonaires (GERM"O"P) in France. All 15 women (60 +/- 6 yr of age) fulfilled the following inclusion criteria: (1) radiation therapy to the breast within 12 mo, (2) general and/or respiratory symptoms lasting for at least 2 wk, (3) lung infiltrates outside the radiation port, and (4) no specific cause. The patients presented with fever, nonproductive cough, mild dyspnea, and peripheral alveolar opacities on chest radiograph with a characteristic migratory pattern. In five patients, BOOP was found at lung pathologic analysis. In all the patients dramatic improvement was obtained with corticosteroids, but relapses occurred in 12 patients while tapering or after stopping corticosteroids. This report demonstrates that a characteristic BOOP syndrome may occur after radiation therapy to the breast, including tangential radiation to the lung, thus suggesting that radiation therapy may prime the development of BOOP.

PMID 9847288  Am J Respir Crit Care Med. 1998 Dec;158(6):1929-35. doi・・・
著者: Etsuyo Ogo, Ritsuko Komaki, Kiminori Fujimoto, Masafumi Uchida, Toshi Abe, Katsumasa Nakamura, Michihide Mitsumori, Kenji Sekiguchi, Yuko Kaneyasu, Naofumi Hayabuchi
雑誌名: Int J Radiat Oncol Biol Phys. 2008 May 1;71(1):123-31. doi: 10.1016/j.ijrobp.2007.09.003. Epub 2007 Dec 3.
Abstract/Text PURPOSE: We observed a rare and unique occurrence of radiation-induced pulmonary injury outside the tangential field for early breast cancer treatment. The findings appeared to be idiopathic and were called radiation-induced bronchiolitis obliterans organizing pneumonia (BOOP) syndrome. We surveyed major hospitals in Japan to review their findings of radiation-induced BOOP, in particular the clinical and pictorial characteristics of the entity.
METHODS AND MATERIALS: We reviewed surveys completed and returned by 20 institutions. The survey responses were based on a total of 37 cases of BOOP syndrome. We also reviewed X-ray and computed tomography scans provided by these institutions. We discussed the information derived from the questionnaire and analyzed patients' characteristics, methods used in the treatment of BOOP syndrome, and prognosis.
RESULTS: The incidence of the radiation-induced BOOP syndrome was about 1.8% (37 of 2,056). We did not find a relationship between the characteristics of patients and the occurrence of radiation-induced BOOP syndrome. The pulmonary findings were classified into four patterns on chest computed tomography scans. Progression of the pulmonary lesions observed on chest X-ray was classified into three patterns. Pneumonitis appeared within 6 months after radiotherapy was completed and disappeared within 6-12 months after its onset. At 5-year follow-up, 2 patients had died, 1 of breast cancer and the other of interstitial pneumonitis, which seemed to be idiopathic and unrelated to the radiation-induced BOOP syndrome.
CONCLUSIONS: Although the incidence of BOOP syndrome and its associated prognosis are not significant, the patients' clinical condition must be carefully followed.

PMID 18060702  Int J Radiat Oncol Biol Phys. 2008 May 1;71(1):123-31. ・・・
著者: Norihisa Katayama, Shuhei Sato, Kuniaki Katsui, Mitsuhiro Takemoto, Toshihide Tsuda, Atsushi Yoshida, Tsuneharu Morito, Tomio Nakagawa, Akifumi Mizuta, Takahiro Waki, Harutaka Niiya, Susumu Kanazawa
雑誌名: Int J Radiat Oncol Biol Phys. 2009 Mar 15;73(4):1049-54. doi: 10.1016/j.ijrobp.2008.05.050. Epub 2008 Aug 26.
Abstract/Text PURPOSE: To evaluate factors associated with radiation-induced bronchiolitis obliterans organizing pneumonia (BOOP) syndrome after breast-conserving therapy.
METHODS AND MATERIALS: A total of 702 women with breast cancer who received radiotherapy after breast-conserving surgery at seven institutions between July 1995 and December 2006 were analyzed. In all patients, the whole breast was irradiated with two tangential photon beams. The criteria used for the diagnosis of radiation-induced BOOP syndrome were as follows: (1) radiotherapy to the breast within 12 months, (2) general and/or respiratory symptoms lasting for >or=2 weeks, (3) radiographs showing lung infiltration outside the radiation port, and (4) no evidence of a specific cause.
RESULTS: Radiation-induced BOOP syndrome was seen in 16 patients (2.3%). Eleven patients (68.8%) were administered steroids. The duration of steroid administration ranged from 1 week to 3.7 years (median, 1.1 years). Multivariate analysis revealed that age (>or=50 years; odds ratio [OR] 8.88; 95% confidence interval [CI] 1.16-67.76; p = 0.04) and concurrent endocrine therapy (OR 3.05; 95% CI 1.09-8.54; p = 0.03) were significantly associated with BOOP syndrome. Of the 161 patients whose age was >or=50 years and who received concurrent endocrine therapy, 10 (6.2%) developed BOOP syndrome.
CONCLUSIONS: Age (>or=50 years) and concurrent endocrine therapy can promote the development of radiation-induced BOOP syndrome after breast-conserving therapy. Physicians should carefully follow patients who received breast-conserving therapy, especially those who are older than 50 years and received concurrent endocrine therapy during radiotherapy.

PMID 18755559  Int J Radiat Oncol Biol Phys. 2009 Mar 15;73(4):1049-54・・・
著者: Hyun Jin Park, Ki Jun Kim, Seog Hee Park, Chul-Seung Kay, Jung Suk Oh
雑誌名: AJR Am J Roentgenol. 2009 Sep;193(3):W209-13. doi: 10.2214/AJR.08.2298.
Abstract/Text OBJECTIVE: The objective of our study was to evaluate the early CT findings of tomotherapy-induced radiation pneumonitis.
MATERIALS AND METHODS: Tomotherapy was performed during the study period in 31 patients with peripheral pulmonary malignancies, 25 of whom underwent follow-up CT within the first 3 months after tomotherapy. These 25 patients, with a total of 77 target lesions, were enrolled for the analysis. We evaluated pulmonary toxicity by the Common Toxicity Criteria for Adverse Events (CTCAE) method and retrospectively analyzed the CT findings of radiation pneumonitis, focusing on the appearance (attenuation, shape, degree of fibrosis) and location (concentric vs eccentric, centrifugal vs centripetal) of radiation pneumonitis relative to the target lesions.
RESULTS: Radiation pneumonitis developed around 34 target lesions (34/77, 44%) in 13 patients (13/25, 52%) during the first 3 months after tomotherapy. Five patients needed steroid therapy (CTCAE grade 2, 5/25 [20%]) and the remaining eight patients required no additional treatment (CTCAE grade 0 or 1, 20/25 [80%]). In appearance, the common CT findings were irregular shape (18/34), ground-glass attenuation (19/34), and no or minimal fibrosis (33/34). The location of the radiation pneumonitis was eccentric (22/34) and centrifugal (19/34) relative to the target lesions.
CONCLUSION: Radiation pneumonitis commonly developed with minimal clinical findings within 3 months after tomotherapy. The CT findings were nonspecific: focal, irregular-shaped ground-glass opacities with minimal fibrosis. However, the location of the radiation pneumonitis tended not to correspond to the planned target volume and had a centrifugal distribution. In addition, the immediate area around the target tended to be spared.

PMID 19696261  AJR Am J Roentgenol. 2009 Sep;193(3):W209-13. doi: 10.2・・・
著者: Anna Linda, Marco Trovo, Jeffrey D Bradley
雑誌名: Eur J Radiol. 2011 Jul;79(1):147-54. doi: 10.1016/j.ejrad.2009.10.029. Epub 2009 Dec 1.
Abstract/Text Stereotactic body radiation therapy (SBRT) is a new radiotherapy treatment method that has been applied to the treatment of Stage I lung cancers in medically inoperable patients, with excellent clinical results. SBRT allows the delivery of a very high radiation dose to the target volume, while minimizing the dose to the adjacent normal tissues. As a consequence, CT findings after SBRT have different appearance, geographic extent and progression timeline compared to those following conventional radiation therapy for lung cancer. In particular, SBRT-induced changes are limited to the "shell" of normal tissue outside the tumor and have a complex shape. When SBRT-induced CT changes have a consolidation/mass-like appearance, the differentiation from tumor recurrence can be very difficult. An understanding of SBRT technique as it relates to the development of SBRT-induced lung injury and familiarity with the full spectrum of CT manifestations are important to facilitate diagnosis and management of lung cancer patients treated with this newly emerging radiotherapy method.

Copyright © 2009 Elsevier Ireland Ltd. All rights reserved.
PMID 19954913  Eur J Radiol. 2011 Jul;79(1):147-54. doi: 10.1016/j.ejr・・・
著者: Shinsaku Yamaguchi, Takayuki Ohguri, Satoru Ide, Takatoshi Aoki, Hajime Imada, Katsuya Yahara, Hiroyuki Narisada, Yukunori Korogi
雑誌名: Lung Cancer. 2013 Nov;82(2):260-5. doi: 10.1016/j.lungcan.2013.08.024. Epub 2013 Sep 7.
Abstract/Text PURPOSE: To evaluate the toxicity and efficacy of thoracic stereotactic body radiotherapy (SBRT) in patients with subclinical interstitial lung disease (ILD).
METHODS AND MATERIALS: One hundred patients with 124 lung tumors were treated with SBRT at our institution according to our own protocols; patients with subclinical (untreated and oxygen-free) ILD were treated with SBRT, while those with clinical ILD (post- or under treatment) were not. The administration of 48 Gy in four fractions was used in 103 (83%) of the 124 tumors. The presence of subclinical ILD in the pre-SBRT CT findings was reviewed by two chest radiologists. The relationships between radiation pneumonitis (RP) and clinical factors were investigated.
RESULTS: Subclinical ILD was recognized in 16 (16%) of 100 patients. Grade 2-5 RP was recognized in 13 (13%) of 100 patients. Grade 2-5 RP was observed in three (19%) of 16 patients with subclinical ILD. Subclinical ILD was not found to be a significant factor influencing Grade 2-5 RP; however, extensive RP beyond the irradiated field, including the contralateral lung, was recognized in only three patients with subclinical ILD, and the rate of extensive RP was significantly high in the patients with subclinical ILD. Grade 4 or 5 extensive RP was recognized in only two patients with subclinical ILD. Dosimetric factors of the lungs (V5, V10, V15, V20, V25, MLD) were significantly associated with Grade 2-5 RP. The three-year overall survival and local control rates of all patients were 53% and 86%, respectively. No significant differences were seen in either overall survival or local control rates between the patients with ILD and those without ILD.
CONCLUSIONS: Subclinical ILD was not found to be a significant factor for Grade 2-5 RP or clinical outcomes in the current study; however, uncommon extensive RP can occur in patients with subclinical ILD.

Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.
PMID 24054547  Lung Cancer. 2013 Nov;82(2):260-5. doi: 10.1016/j.lungc・・・
著者: Jann-Yuan Wang, Kuan-Yu Chen, Jann-Tay Wang, Jen-Hau Chen, Jou-Wei Lin, Hao-Chien Wang, Li-Na Lee, Pan-Chyr Yang
雑誌名: Int J Radiat Oncol Biol Phys. 2002 Nov 1;54(3):735-41.
Abstract/Text PURPOSE: Radiation pneumonitis is a serious complication that develops after thoracic irradiation. The purpose of this study was to identify prognostic factors for severe radiation pneumonitis in patients with non-small-cell lung cancer.
METHODS AND MATERIALS: The medical records of patients with non-small-cell lung cancer and severe radiation pneumonitis were reviewed. Variables were analyzed by univariate and stepwise multivariate analysis using the Cox regression model.
RESULTS: Among the 31 patients, the mortality rate approached 50% in the first 2 months after the onset of radiation pneumonitis. The variables significantly associated with survival in the univariate analysis were tumor histologic feature, grade and extent (out-of-field or in-field) of radiation pneumonitis, oxygenation index, and serum albumin (<35 g/L or >or=35 g/L), and uric acid levels at the onset of radiation pneumonitis. Only the extent of radiation pneumonitis and serum albumin level were independently associated with survival in the multivariate analysis.
CONCLUSION: The mortality rate of non-small-cell lung cancer patients with severe radiation pneumonitis is extremely high, and survival is much shorter in patients with out-of-field radiation pneumonitis or a low serum albumin level at the onset. Additional studies to investigate the factors precipitating out-of-field radiation pneumonitis should improve the management of irradiation complications.

PMID 12377325  Int J Radiat Oncol Biol Phys. 2002 Nov 1;54(3):735-41.
著者: N J Gross
雑誌名: Ann Intern Med. 1977 Jan;86(1):81-92.
Abstract/Text The cellular effects of irradiating the lungs are rleated to the histologic and clinical sequelae. The occurrence and severity of damage rare semiquantitatively related to the volume of lung irradiated, and the dose rate of irradiation. The clinical syndrome occurs in up to about 10% of patients and consists of an acute transient phase, radiation pneumonitis, usually occurring 6 to 12 weeks after radiation therapy. This is followed by clinical remission except in the most severe cases and gradula radiologic progression to the stage of radiation fibrosis over the next 6 to 12 months. Concommittant chemotherapy, repeat courses of radiation, and steroid wihtdrawal are exacerbating factors. Characteristic changes in pulmonary function and radiographic appearance are described, and management is reviewed.

PMID 319723  Ann Intern Med. 1977 Jan;86(1):81-92.
著者: Ikuo Sekine, Minako Sumi, Yoshinori Ito, Hiroshi Nokihara, Noboru Yamamoto, Hideo Kunitoh, Yuichiro Ohe, Tetsuro Kodama, Nagahiro Saijo, Tomohide Tamura
雑誌名: Radiother Oncol. 2006 Jul;80(1):93-7. doi: 10.1016/j.radonc.2006.06.007. Epub 2006 Jul 3.
Abstract/Text PURPOSE: To disclose characteristics of lung cancer patients developing radiation-induced lung injury treated with or without corticosteroid therapy.
METHODS AND MATERIALS: Radiographic changes, symptoms, history of corticosteroid prescription, and clinical course after 50-70 Gy of thoracic radiotherapy were retrospectively evaluated in 385 lung cancer patients.
RESULTS: Radiation-induced lung injury was stable without corticosteroid in 307 patients (Group 1), stable with corticosteroid in 64 patients (Group 2), and progressive to death despite corticosteroid in 14 patients (Group 3). Fever and dyspnea were noted in 11%, 50% and 86% (p<0.001), and in 13%, 44% and 57% (p<0.001) patients in Groups 1-3, respectively. Median weeks between the end of radiotherapy and the first radiographic change were 9.9, 6.7 and 2.4 for Groups 1-3, respectively (p<0.001). The initial prednisolone equivalent dose was 30-40 mg daily in 52 (67%) patients. A total of 16 (4.2%) patients died of radiation pneumonitis or steroid complication with a median survival of 45 (range, 8-107) days.
CONCLUSION: Development of fever and dyspnea, and short interval between the end of radiotherapy and the first radiographic change were associated with fatal radiation-induced lung injury. Prednisolone 30-40 mg daily was selected for the treatment in many patients.

PMID 16820236  Radiother Oncol. 2006 Jul;80(1):93-7. doi: 10.1016/j.ra・・・
著者: B Movsas, T A Raffin, A H Epstein, C J Link
雑誌名: Chest. 1997 Apr;111(4):1061-76.
Abstract/Text
PMID 9106589  Chest. 1997 Apr;111(4):1061-76.
著者: Taiju Shimbo, Taisuke Inomata, Masatsugu Takahashi, Toshiaki Tatsumi, Yasuo Uesugi, Isamu Narabayashi, Hiroshi Sonobe
雑誌名: Int J Mol Med. 2007 Dec;20(6):817-22.
Abstract/Text In this study, we irradiated the murine lung and analyzed the inhibitory effects of sivelestat sodium hydrate, a neutrophil elastase (NE) inhibitor, on lung injury in mice. Sivelestat sodium hydrate (3 mg/kg) was administered by intraperitoneal injection immediately, 3, 6, and 12 h after irradiation in groups RE-0, RE-3, RE-6, and RE-12, respectively. A control group and a group receiving radiation without sivelestat (group R) were also used. NE activity was measured 24 and 48 h after irradiation. The lungs were simultaneously extirpated and stained with hematoxylin and eosin and a naphthol AS-D chloroacetate esterase stain (N-ASDCLA). NE activity increased in the groups in which the murine lungs were irradiated. There was no increase in NE activity in the control group. Among the sivelestat-administered groups, NE activity was slightly elevated in group RE-0 and was suppressed, compared to group R, in groups RE-3, RE-6, and RE-12 at 24 h after irradiation. In the irradiated groups, intra-alveolar neutrophil infiltration, perivascular edema, and alveolar wall thickness were observed, but these changes were mild in the sivelestat-administered groups. The number of N-ASDCLA-positive cells increased in the sivelestat-administered groups, while group R had low values. This indicated that sivelestat sodium hydrate blocked the release of NE from the neutrophils in the irradiated lungs. NE plays an important role in the development of radiation-induced lung injury. Sivelestat is thus expected to decrease radiation-induced lung toxicity by suppressing NE release from neutrophils.

PMID 17982688  Int J Mol Med. 2007 Dec;20(6):817-22.
著者: Tomie Muraoka, Shuji Bandoh, Jiro Fujita, Atsushi Horiike, Tomoya Ishii, Yasunori Tojo, Akihito Kubo, Toshihiko Ishida
雑誌名: Intern Med. 2002 Sep;41(9):730-3.
Abstract/Text Radiation therapy is commonly used for the treatment of lung cancer. However, radiation pneumonitis frequently occurs as a complication of the radiation therapy. Although corticosteroids are widely used for the treatment of radiation pneumonitis, they are not always effective. In this report, we used cyclosporin A in the treatment of a patient suffering from steroid-refractory radiation pneumonitis. To our knowledge, this is the first report in which cyclosporin A was successfully used in the treatment of radiation pneumonitis.

PMID 12322802  Intern Med. 2002 Sep;41(9):730-3.
著者: M J McCarty, P Lillis, S J Vukelja
雑誌名: Chest. 1996 May;109(5):1397-400.
Abstract/Text Radiation therapy is commonly used for treatment of neoplastic disease involving the thorax. Treatment complications include radiation pneumonitis that may require therapy with corticosteroids which possess significant side effects. We report the use of azathioprine as a steroid-sparing agent in a patient with severe radiation pneumonitis and steroid-induced myopathy.

PMID 8625698  Chest. 1996 May;109(5):1397-400.

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