重离子束放射治疗肿瘤的临床进展-6

3.16其它复发转移性癌  Makishima H等人于2019年1月报告了确定单次CIRT治疗结直肠癌肝转移最佳剂量研究，纳入31例结直肠癌肝转移患者，29名患者接受单次CIRT，将剂量从36 GyE开始，按5%至10%的增量，直到观察到不可接受的剂量限制毒性发生率，剂量限制毒性定义为放射治疗引起的≥3级急性毒性，处方剂量为:36GyE/Fr(3例)、40GyE/Fr(2例)、44GyE/Fr(4例)、46GyE/Fr(6例)、48GyE/Fr(3例)、53GyE/Fr(8例)、58GyE/Fr戈瑞(3例)，未观察到剂量限制毒性，但2例患者在53 GyE时观察到因胆道梗阻而引起的3级肝脏毒性，两例患者均有靠近肝门静脉区域的病灶，因此仅限于周围病灶将剂量上升至58戈瑞(RBE)，29例患者3年总生存率为78%，中位生存时间为65个月，局部控制率在≥53GyE时显著提高，3年局部控制率为82%，而低剂量时为28%，报告认为单组分CIRT治疗结直肠癌肝转移，只要避开肝中心门静脉区域，其安全剂量可达58 GyE[51]。2019年4月Okonogi N报告CIRT治疗少数淋巴结复发的的疗效，收集了1996年12月至2015年12月在4个机构少数淋巴结复发接受CIRT治疗并符合以下条件的患者：(i) 组织学或临床诊断LN复发；(ii)原发病变受控；(iii)除淋巴结外无其它复发；(iv)单处淋巴结复发；(v) 年龄≥20岁。结果:共纳入323例患者，存活患者的平均随访时间为34个月，CIRT的处方剂量为48.0 GyE/12Fr，其中47例复发部位有放射治疗史，CIRT治疗后2年的局部控制率(LC)和总生存率(OS)分别为85%和63%，仅有1例患者出现3级毒性，多因素分析显示淋巴结直径、组织学、既往放疗病史等因素与局部控制率无关；较小直径(< 30mm)和≤3个淋巴结转移，以及较长的无病间隔(≥16个月)与较好的OS显著相关。结论:CIRT治疗少数淋巴结复发是安全有效的。CIRT治疗可能对少数淋巴结复发患者有生存益处，特别是对LN转移少、LN直径小、无病程较长的患者[52]。2019年6月Hayashi, Kazuhiko报告了2007-2016年收治的48例复发性头颈部恶性肿瘤患者的资料，粘膜恶性黑色素瘤21例(43.8%)，腺样囊性癌17例(35.4%)，骨、软组织肉瘤6例(12.5%)，其他疾病4例(8.3%)，再次照射时肿瘤复发的部位依次为副鼻窦(18.37.5%)、鼻腔(9.18.8%)、鼻咽(4.8.3%)、眼眶(3.6.3%)、海绵窦(3.6.3%)和其他部位(11.22.9%)，初始CIRT的中位剂量为57.6 Gy，再照射时的中位剂量为54.0 GyE。所有患者均未同时接受化疗，再照射后中位随访时间为27.1个月，5例(10.4%)出现3级急性毒性，18例(37.5%)出现≥3级晚期毒性，其中1例出现5级中枢神经系统坏死，2年局部对照、局部共区对照、无进展生存率、总生存率分别为40.5、33.5%、29.4%、59.6%；表明对于复发性头颈部恶性肿瘤患者,使用CIRT是头颈部肿瘤复发的一种可行治疗方案，具有可耐受的毒性[53]。

4 小结

随着技术及设备越来越成熟，CIRT病例量不断扩大，治疗病种也在不断扩大，其治疗原发及复发鼻咽癌、脂肪肉瘤、视网膜色素瘤、滑膜肉瘤等等都取得了显著的效果，因篇幅所限，在此不一一列举。在碳离子临床实践中，放射并发症的发生率远远低于X线，而且少数严重的放射并发症均发生在临床研究的初始探索阶段，随着剂量体积直方图的应用(DVH)及对风险器官做了严格限定，以及呼吸门控、主动扫描等技术的进展，严重的并发症的发生率已很低[54]。虽然CIRT的临床应用仍在探索中,但不断报道的临床试验越来越多的支持其显著的疗效，尤其在难治性肿瘤、抗拒射线肿瘤、复杂部位肿瘤方面疗效喜人，并有望显著缩短治疗时间，患者甚至可以在门诊完成治疗等必将对现有的肿瘤治疗格局产生巨大的影响。

参考文献

[1]张雁山， 王慧娟， 叶延程 ，张红．碳离子束放射治疗肿瘤的临床进展［J］．医学综述，  2017；20：4033-4038,4044 .

[2]Tsujii H,Kamada T,Shirai T,et al. Carbon-Ion Radiotherapy:Principles, Practices, and Treatment Planning[M].Tokyo:Springer,2014:14,34,197-202, 221-228, 256-261,263-267.

[3]Kubota N , Suzuki M, Furusawa Y, et al. A compari son of biological effects of modulated carbon-ions and fast neut rons in human osteosarcoma cells[J]. Int J Radiat Oncol Biol Phys , 1995 , 33 :135-141 .

[4]Kraft G. Tumour therapy with heavy charged ions[J]. Progr Part Nucl Phys , 2000 ,45 :473-544 .

[5]https://www.ptcog.ch/index.php/patient-statistics

[6]Schulz-Ertner D, Nikoghosyan A, Thilmann C, et al. Results of carbon ion radiotherapy in 152 patients[J]. Int J Radiat Oncol Biol Phys 2004; 58: 631–40.

[7]Mizoe JE, Hasegawa A, Jingu K,et al. Results of carbon ion radiotherapy for head and neck cancer[J]. Journal Of The European Society For Therapeutic Radiology And Oncology , 2012 ,103 (1): 32-7.

[8]Shirai K; Saitoh JI; Musha A;et al. Prospective observational study of carbon-ion radiotherapy for non-squamous cell carcinoma of the head and neck[J].Cancer Science [Cancer Sci]，2017，108 (10)：2039-2044.

[9]Miyamoto T, Yamamoto N, Nishimura H, et al. Carbon ion radiotherapy for stage I non-small cell lung cancer[J]. Radiother Oncol. 2003;66:127–40.

[10]Miyamoto T, Baba M, Yamamoto N, et al. Curative treatment of stage I non-small-cell lung cancer with carbon ion beams using a hypofractionated regimen[J]. Int J Radiat Oncol Biol Phys. 2007;67:750–8.

[11]Miyamoto T, Baba M, Sugane T, et al. Carbon ion  radiotherapy  for stage I non-small cell lung cancer using a regimen of four fractions during 1 week[J]. J Thorac Oncol. 2007;2:916–26.

[12]Yamamoto N,Miyamoto T,Nakajima M,et al. A Dose Escalation Clinical Trial of Single-Fraction Carbon Ion Radiotherapy for Peripheral Stage I Non-Small Cell Lung Cancer[J]. Journal Of Thoracic Oncology. 2017,12 (4): 673-680.

[13]Karube M; Yamamoto N; Shioyama Y;et al. Carbon-ion radiotherapy for patients with advanced stage non-small-cell lung cancer at multicenters [J].  Journal Of Radiation Research [J] Radiat Res, 2017 ,58 (5):761-764;

[14]Sugane, Toshio, Baba, Masayuki, Imai Reiko,et al. Carbon ion radiotherapy for elderly patients 80 years and older with stage I non-small cell lung cancer[J]. Lung Cancer ,2009,  64( 1), 45-50.

[15]Hayashi K, Yamamoto N, Nakajima M,et al. Clinical outcomes of carbon-ion radiotherapy for locally advanced non-small-cell lung cancer[J].Cancer Science, 2019,110 (2): 734-741.

[16]Karube M, Yamamoto N, Tsuji H,et al.（Carbon-ion re-irradiation for recurrences after initial treatment of stage I non-small cell lung cancer with carbon-ion radiotherapy[J].   Radiotherapy And Oncology, 2017,125 (1): 31-35.

[17]Kato H, Tsujii H, Miyamoto T, et al. Results of the fi rst prospective study of carbon ion radiotherapy for hepatocellular carcinoma with liver cirrhosis[J]. Int J Radiat Oncol Biol Phys. 2004;59:1468–76.

[18] Kasuya G,Kato H, Yasuda S, et al. Progressive hypofractionated carbon-ion radiotherapy for hepatocellular carcinoma: Combined analyses of 2 prospective trials[J].Cancer, ISSN: 2017 ,123 (20), 3955-3965.

[19]Shiba S; Abe T; Shibuya K;et al. Carbon ion radiotherapy for 80 years or older patients with hepatocellular carcinoma[J]. BMC Cancer , 2017 17 (1): 721.

[20]Shibuya K, Ohno T, Terashima K，et al. Short-course carbon-ion radiotherapy for hepatocellular carcinoma: A multi-institutional retrospective study[J].Liver Int. 2018，38(12)：2239-2247.

[21]Ishikawa H,Tsuji H,Kamada T,et al. Carbon-ion radiation therapy for prostate cancer[J].Int J Urol,2012,19(4):296-305.

[22]Akakura K, Tsujii H, Morita S, et al. Phase I/II clinical trials of carbon ion therapy for prostate cancer[J]. Prostate. 2004;58:252–8.

[23]Okada T, Tsuji H, Kamada T, et al. Carbon ion radiotherapy in advanced hypofractionated  regimens for prostate cancer: from 20 to 16 fractions[J]. Int J Radiat Oncol Biol Phys. 2012;84:968–72.

[24]Nobuteru Kubo，Takuma Nomiya, Hiroshi Tsuji.et al. Multi-Institutional Retrospective Analysis Of Carbon Ion Radiotherapy For Prostate Cancer[J]. Journal of Cancer Research & Therapeutics. 2017,（13）:48-49.

[25]Saito N, Koda K, Takiguchi N, et al. Curative surgery for local pelvic recurrence of rectal cancer[J]. Dig Surg,2003,20:192–200.

[26]Yamada S, Kamada T, Ebner DK, et al.(Carbon-Ion Radiation Therapy for Pelvic Recurrence of Rectal Cancer[J].International Journal of Radiation Oncology, Biology, Physics, 2016， 96(1): 93-101.

[27]Hayashi K; Koto M; Ikawa H; et al. Feasibility of Re-irradiation using carbon ions for recurrent head and neck malignancies after carbon-ion radiotherapy[J]. Radiotherapy & Oncology. 2019, 136, 148-153.

[28]Shinoto M;Terashima K; Suefuji H;et al.A single institutional experience of combined carbon-ion radiotherapy and chemotherapy for unresectable locally advanced pancreatic cancer[J].Radiotherapy And Oncology:  2018 ,129 (2): 333-339.

[29]Kawashiro S, Yamada S, Okamoto M,et al. Multi-institutional Study of Carbon-ion Radiotherapy for Locally Advanced Pancreatic Cancer: Japan Carbon-ion Radiation Oncology Study Group (J-CROS) Study 1403 Pancreas[J]. International Journal Of Radiation Oncology, Biology, Physics,2018 ,101 (5):  1212-1221. 

 [30]Toita T, Ohno T, Kaneyasu Y, Uno T, Yoshimura R,et al. A consensus-based guideline defi ning the clinical target volume for pelvic lymph nodes in external beam radiotherapy for uterine cervical cancer[J]. Jpn J Clin Oncol. 2010;40(5):456–63.

[31]Kato S, et al. Dose escalation study of carbon ion radiotherapy for locally advanced carcinoma of the uterine cervix[J]. Int J Radiat Oncol Biol Phys. 2006;65(2):388–97.

[32]Yanagi T, Mizoe JE, Hasegawa A, et al. Mucosal malignant melanoma of the head and neck treated by carbon ion radiotherapy[J]. Int J Radiat Oncol Biol Phys. 2009;74(1):15–20.

[33]Mohr A; Chaudhri N; Hassel JC; et al. Raster-scanned intensity-controlled carbon ion therapy for mucosal melanoma of the paranasal sinus[J]. Head & Neck，2016，38 （1） 1445-51.

[35]Matsunobu A, Imai R, Kamada T, et al. Impact of carbon ion radiotherapy for unresectable osteosarcoma of the trunk[J]. Cancer，2012，118:4555–6.

[34]杨立娜,冉俊涛,张红,等.重离子束治疗肿瘤临床研究[J].原子核物理评论,2013,30(2):166-173..

[35]Mizoe JE, Hasegawa A, Takagi R, et al .Carbon ion radiotherapy for skull base chordoma[J]. Skull Base.2009;19:219–24.

[36]Uhl M,Mattke M,Welzel T,et al. Highly effective treatment of skull base chordoma with carbon ion irradiation using a raster scan technique in 155 patients: first long-term results[J].Cancer, 2014, 120(21): 3410-7;

[37]Yusuke Suzuki,Azusa Hasegawa,Masaru Aoyagi,et al.Carbon Ion Beam Radiotherapy for Sinonasal Malignant Tumors Invading Skull Base[J].Case Reports in Otolaryngology. 2014:1-4.

[38]Imai R, Kamada T, Sugahara S, et al. Carbon ion radiotherapy for sacral chordoma[J]. Br J Radiol ,2011, 84: 48–54.

[39]Matsunobu A,Imai R,Kamada T,et al.Impact of carbon ion radiotherapy for unresectable osteosarcoma of the trunk[J].Cancer,2012,118(18):4555-4556.

[40]Imai R; Kamada T; Araki N; et al. Carbon Ion Radiation Therapy for Unresectable Sacral Chordoma: An Analysis of 188 Cases[J]. International Journal Of Radiation Oncology, Biology, Physics,2016. 95: 322-7.

[41]Maruyama K, Imai R, Kamada T, et al. Carbon ion radiation therapy for chondrosarcoma[J]. Int J Radiat Oncol Biol Phys. 2012;84:S139.

[42]Tsuji H, Ishikawa H, Yanagi T, et al. Carbon-ion radiotherapy for locally advanced or unfavorably located choroidal melanoma: a phase I/II dose-escalation study[J]. Int J Radiat Oncol Biol Phys.2007;67:857–62.

[43]THirasawa N, Tsuji H, Ishikawa H, et al. Risk factors for neovascular glaucoma after carbon ion radiotherapy of choroidal melanoma using dose-volume histogram analysis[J]. Int J Radiat Oncol Biol Phys. 2007;67:538–43.

[44]TToyama S, Tsuji H, Mizoguchi N, et al. Long-term results of carbon ion radiation therapy for locally advanced or unfavorably located choroidal melanoma: usefulness of CT-based 2-port orthogonal therapy for reducing the incidence of neovascular glaucoma[J]. Int J Radiat Oncol Biol Phys. 2013;86:270–6.

[45]Nomiya T, Tsuji H, Hirasawa N, et al. Carbon ion radiation therapy for primary renal cell carcinoma: initial clinical experience[J]. Int J Radiat Oncol Biol Phys. 2008;72(3):828–33.

[46]Kasuya G, Tsuji H, Nomiya T, et al.Updated long-term outcomes after carbon-ion adiotherapy for primary renal cell carcinoma[J].Cancer Science,2018, 109 (9):2873-2880.

[47]Akamatsu H; Karasawa K; Omatsu,et al.First experience of carbon-ion radiotherapy for early breast cancer[J]. Japanese Journal Of Radiology ,2014 ,32 (5):288-95.

[48] Yamamoto N; Ishikawa T; Saito M; et al. Phase I clinical trial of carbon ion radiotherapy for Stage I breast cancer: clinical and pathological evaluation[J]. Journal Of Radiation Research, 2019; 60 (3): 342-347.

[49] Mizoe JE, Tsujii H, Hasegawa A, et al.. Phase I/II clinical trial of carbon ion radiotherapy for malignant gliomas: combined X-ray radiotherapy, chemotherapy, and carbon ion radiotherapy[J]. Int J Radiat Oncol Biol Phys. 2007;69:390–6.

[50]Kong L, Gao J, Hu J, et al.Carbon ion radiotherapy boost in the treatment of glioblastoma: a randomized phase I/III clinical trial[J].Cancer Communications (London, England), 2019, 39 (1).

[51]Makishima H; Yasuda S; Isozaki Y;  et al.Single fraction carbon ion radiotherapy for colorectal cancer liver metastasis: A dose escalation study[J]. Cancer Science,2019.110 (1):303-309;

[52]Okonogi  N,  Kaminuma T,  Okimoto T,et al.Carbon-ion radiotherapy for lymph node oligo-recurrence: a multi-institutional study by the Japan Carbon-Ion Radiation Oncology Study Group (J-CROS)[J]. International Journal Of Clinical Oncology,2019 Apr;[Epub ahead of print]

[53]Koto, Masashi，Ikawa, Hiroaki，Hagiwara, Yasuhito,et al.Feasibility of Re-irradiation using carbon ions for recurrent head and neck malignancies after carbon-ion radiotherapy[J]. Radiotherapy & Oncology. 2019, 136:148-153.

[54]乐紫妤,刘勇.重离子肿瘤放射生物学的研究进展[J].中华放射肿瘤学杂志,2015,24(5):600-60.