Radiation Oncology/NSCLC/Protons

Proton Therapy in NSCLC

Clinical Literature

 * Hyogo Ion Beam; 2010 (2003-2007) PMID 20225229 -- "High-dose proton therapy and carbon-ion therapy for stage I nonsmall cell lung cancer." (Iwata H, Cancer. 2010 Mar 11. [Epub ahead of print])
 * Retrospective. 80 patients, Stage I NSCLC. Proton (n=57) or carbon ion (n=23) RT. Inoperable 46%, refused surgery 54%. T1 52%, T2 48%.  Three protocols: protons 80/20, protons 60/10, carbon 52.8/4. Since 2005, both carbon and proton plan made and the superior adopted. Median F/U 3 years
 * Outcome: 3-year OS 75% (IA 74%, IB 76%), 3-years CSS 86% (84%, 88%), 3-year local control 82% (87%, 77%)
 * Toxicity: Grade 3 in 1 patient
 * Conclusion: Particle therapy safe and effective for Stage I NSCLC


 * Tsukuba
 * 2010 (2001-2008) PMID 20056349 -- Proton Beam Therapy for Patients with Medically Inoperable Stage I Non-Small-Cell Lung Cancer at the University of Tsukuba." (Nakayama H, Int J Radiat Oncol Biol Phys. 2010 Jan 5. [Epub ahead of print])
 * Retrospective. 55 inoperable Stage I NSCLC, 58 tumors. Proton therapy. T1 52%, T2 48%. Peripheral tumors 66/10, central tumors 72.6/22
 * Outcome: 2-year local control 97%, 2-year OS 98%. No difference between T1 and T2
 * Toxicity: Grade 3 pneumonitis 4%, deterioration in pulmonary function 4%
 * Conclusion: Proton beam therapy effective and well tolerated
 * 2007 PMID 17379439 -- "Hypofractionated high-dose proton beam therapy for stage I non-small-cell lung cancer: preliminary results of a phase I/II clinical study." (Hata M, Int J Radiat Oncol Biol Phys. 2007 Jul 1;68(3):786-93. Epub 2007 Mar 26.)
 * Retrospective. 21 patients, Stage I NSCLC (Stage IA 11, Stage IB 10). Median tumor size 2.5 cm. PT 50/10 (n=3) and 60/10 (n=18). Median F/U 2.1 years
 * Outcome: 2-year OS 74%, CSS 86%, LC 95%, local DFS 79% (new lung lesions outside treated volume)
 * Toxicity: No Grade 3+
 * Conclusion: Hypofractionated proton beam therapy feasible and effective for Stage I
 * 2003 (1983-2000) PMID 12694818 -- "Clinical evaluation of proton radiotherapy for non-small-cell lung cancer." (Shioyama Y, Int J Radiat Oncol Biol Phys. 2003 May 1;56(1):7-13.)
 * Retrospective. 51 patients with NSCLC (Stage I 28, Stage II 9, Stage III 8, Stage IV 1, recurrent 5). Median dose 76 Gy (49.0-93.0), median fraction 3.0 Gy/fx (2.0-6.0)
 * Outcome: 5-year OS Stage IA 70%, Stage IB 16%, overall 29%. 5-year LC Stage IA 89%, Stage IB 39%
 * Toxicity: Acute Grade 2 in 6%, Grade 3 in 2%, no Grade 4-5; minimal late
 * Conclusion: Proton therapy safe and effective, especially for early stage
 * 1998 PMID 9645836 -- "Proton irradiation for non-small cell lung cancer." (Satoh H, Arch Intern Med. 1998 Jun 22;158(12):1379-80.)
 * 1993 (1983-1990) PMID 8380147 -- "Clinical results of fractionated proton therapy." (Tsujii H, Int J Radiat Oncol Biol Phys. 1993 Jan;25(1):49-60.)
 * Preliminary review of Tsukuba experience. 147 patients
 * Conclusion: Proton therapy has potential advantage in lung, esophagus, liver, cervix, prostate, and H&N


 * Chiba; 2006 (1999-2003) PMID 16458447 -- "High-dose proton beam therapy for Stage I non-small-cell lung cancer." (Nihei K, Int J Radiat Oncol Biol Phys. 2006 May 1;65(1):107-11. Epub 2006 Feb 3.)
 * Dose escalation, then retrospective. 37 patients, clinical Stage I, tumor size <=5cm. Initial 10 patients dose escalation, 3 per level. RT 70/20 (n=3), 80/20 (n=17), 88/20 (n=16), 94/20 (n=1). Median F/U 2 years
 * Dose escalation: Stopped at 94/20, as first patient developed symptomatic pneumonitis. Subsequent 27 patients treated at 88/20 or 80/20 if poor pulmonary function
 * Outcome: 2-year LC 80%, LRC Stage IA 79%, LRC Stage IB 60%, OS 84%
 * Toxicity: Late pulmonary G2 in 8%, G3 in 8% (5/6 patients had Stage IB disease)
 * Conclusion: Proton beam therapy promising, though locoregional relapse and late pulmonary toxicity substantial in Stage IB


 * Loma Linda
 * 2004 PMID 15486383 -- "Hypofractionated proton beam radiotherapy for stage I lung cancer." (Bush DA, Chest. 2004 Oct;126(4):1198-203.)
 * Phase II. 68 patients with Stage I NSCLC. Initial 22 patients 51 CGE/10, then 46 patients 60 CGE/10. Median F/U 2.5 years
 * Outcome: 3-year LC 74%, DSS 72%. T1 tumors 87% vs. T2 tumors 49%
 * Toxicity: No symptomatic pneumonitis, or late esophageal or cardiac toxicity
 * Conclusion: Safe; local control improved compared to conventional RT
 * 2001 PMID 11742905 -- "Effects of proton and combined proton/photon beam radiation on pulmonary function in patients with resectable but medically inoperable non-small cell lung cancer." (Bonnet RB, Chest. 2001 Dec;120(6):1803-10.)
 * Prospective. 25 patients with NSCLC. Protocol 1) Stage I-II (n=10), FEV1 <=1.0 L, given protons 51/10. Protocol 2) Stage I-III, FEV1 >1.0 L, given 45 Gy photons + 28.8 proton boost.
 * Outcome: Protocol 1 patients - no change in pulmonary function. Protocol 2 patients - DLCO declined from 61% to 45% (SS), TLC 114% to 95% (SS), airway resistance increased 3.8 to 5.2 mmH20/L/S (SS). No change in VC, FEV1 or PaO2
 * Conclusion: Feasible to apply higher-than-conventional RT, without excess pulmonary toxicity
 * 1999 (1994-1998) PMID 10559093 -- "Proton-beam radiotherapy for early-stage lung cancer." (Bush DA, Chest. 1999 Nov;116(5):1313-9.)
 * Retrospective. 37 patients with Stage I-IIIA NSCLC (Stage I 27, II 2, IIIA 8). Photons 45/25 + concurrent proton boost 28.8 CGE/16, total dose 73.8 CGE (n=18). If poor cardiopulmonary function, protons only 51 CGE/10 (n=19)
 * Outcome: 2-year DFS 63%; Stage I DFS 86%. LC 87%
 * Conclusion: PT can be used safely; DFS and LC appear good
 * 1999 PMID 10063871 -- "Pulmonary injury from proton and conventional radiotherapy as revealed by CT." (Bush DA, AJR Am J Roentgenol. 1999 Mar;172(3):735-9.)
 * Comparison of pulmonary injury by CT in patients with limited volume proton therapy vs. larger volume combined photon/proton therapy
 * Conclusion: Proton RT associated with lower frequency of pulmonary injury

Dosimetry

 * Southern Tohoku PTC, Japan; 2010 PMID 20732759 -- "Dose-Volume Comparison of Proton Radiotherapy and Stereotactic Body Radiotherapy for Non-Small-Cell Lung Cancer." (Kadoya N, Int J Radiat Oncol Biol Phys. 2010 Aug 21. [Epub ahead of print])
 * Plan comparison. 21 patients, Stage I NSCLC, peripheral. Dose 66/10. SBRT vs proton therapy.
 * Outcome: Dosimetric values lower with PT. Correlation between volume parameters and PTV
 * Conclusion: PT may be more advantageous for large PTV or several tumors


 * Tsukuba; 2009 PMID 19370425 -- "Comparisons of dose-volume histograms for proton-beam versus 3-D conformal x-ray therapy in patients with stage I non-small cell lung cancer." (Wang C, Strahlenther Onkol. 2009 Apr;185(4):231-4. Epub 2009 Apr 16.)
 * Planning comparison. 24 patients, Stage I NSCLC, treated with PT. 3DCRT plans developed. Prescribed 66 Gy at isocenter.
 * Outcome: 90% isodose line covered >99% of CTV in both PT and 3DCRT. 95% isodose line covered PT 86% and 3DCRT 43% of CTV (SS).
 * NTCP: Lung V5 PT 10% vs 3DCRT 26%, V10 8% vs 14%, V20 5% vs 7%, mean lung dose 2.6 Gy vs 4.6 Gy. Heart, esophagus, and spinal cord also lower
 * Conslusion: PBT reduces doses to lung, heart, esophagus, and spinal cord over 3D-CRT


 * Mayo Clinic; 2009 PMID 19801106 -- "Proton beam radiotherapy versus three-dimensional conformal stereotactic body radiotherapy in primary peripheral, early-stage non-small-cell lung carcinoma: a comparative dosimetric analysis." (Macdonald OK, Int J Radiat Oncol Biol Phys. 2009 Nov 1;75(3):950-8.)
 * Treatment comparison. 8 patients treated with non-corrected SBRT. Replanned using corrected SBRT and proton beams
 * Outcome: Comparable PTV coverage. For lung volume, PT resulted in higher high dose but lower low dose. V20 and V13 comparable
 * Conclusion: Clinical significance remains to be determined


 * Purdue University
 * 2008 PMID 18523345 -- "Dosimetric impact of intrafraction motion for compensator-based proton therapy of lung cancer." (Zhao L, Phys Med Biol. 2008 Jun 21;53(12):3343-64. Epub 2008 Jun 3.)
 * Use of MIP images for designing patient-specific composite compensators
 * 2008 PMID 18274078 -- "Patient-specific margins for proton therapy of lung." (Zhao L, Australas Phys Eng Sci Med. 2007 Dec;30(4):344-8.)
 * MIP method compared with end-of-inhale and middle-of-exhale plans
 * Conclusion: MIP method provides superior tumor dose distribution


 * MD Anderson
 * 2009 PMID 19660879 -- "Intensity-Modulated Proton Therapy Reduces the Dose to Normal Tissue Compared with Intensity-Modulated Radiation Therapy or Passive Scattering Proton Therapy and Enables Individualized Radical Radiotherapy for Extensive Stage IIIB Non-Small-Cell Lung Cancer: A Virtual Clinical Study." (Zhang X, Int J Radiat Oncol Biol Phys. 2009 Aug 4. [Epub ahead of print])
 * Planning comparison. 10 patients, bulky Stage IIIB NSCLC. IMRT 60-63 Gy, passive scatter PT and IMPT at 74 Gy. Constraints lung V20 <35%, mean lung <20 Gy, cord <45 Gy.
 * Outcome: IMPT spared more lung, heart, spinal cord, and esophagus than IMRT; allowed dose escalation to 83.5 Gy
 * Conclusion: IMPT spared more normal tissues compared with IMRT, and allowed dose escalation
 * 2008 PMID 18486357 -- "Effects of Interfractional Motion and Anatomic Changes on Proton Therapy Dose Distribution in Lung Cancer." (Hui Z, Int J Radiat Oncol Biol Phys. 2008 May 15. [Epub ahead of print])
 * 8 patients treated with IMRT for mobile Stage III NSCLC. Weekly 4D-CT scans acquired. Conformal proton passive scattering plan designed for each patient. dose distributions recalculated on each weekly 4D-CT scan, using bone registration
 * Outcome: CTV coverage compromised in 1/8 patients (99% to 91%); remaining 7/8 sufficient CTV coverage (99% to 98%).
 * Toxicity: 8/8 patients mean 4% increase in contralateral lung V5, and mean spinal cord max increase 4.4 Gy
 * Conclusion: For most patients, CTV coverage is adequate if tumor motion is taken into consideration in the original plan
 * 2007 PMID 17293240 -- "4D Proton treatment planning strategy for mobile lung tumors." (Kang Y, Int J Radiat Oncol Biol Phys. 2007 Mar 1;67(3):906-14.)
 * Strategies for designing compensator-based 3D proton treatment plans for mobile lung tumors using 4D-CT. Used Average CT, Free-breathing CT, MIP CT, and modified Average CT with IGTV constant density voxels (AVE_RIGHTV)
 * Conclusion: AVE_RIGHTV effective strategy for mobile lung tumors
 * 2006 PMID 16682145 -- "Significant reduction of normal tissue dose by proton radiotherapy compared with three-dimensional conformal or intensity-modulated radiation therapy in Stage I or Stage III non-small-cell lung cancer." (Chang JY, Int J Radiat Oncol Biol Phys. 2006 Jul 15;65(4):1087-96. Epub 2006 May 6.)
 * Comparison of 3D-CRT, IMRT, and proton plans. 15 plants. Stage I (66 Gy and 87.5 Gy) and Stage III (60-63 Gy and 74 Gy)
 * Conclusion: Proton therapy reduced normal tissu dose compared with 3D-CRT or IMRT, even with dose escalation
 * Comment and author reply (PMID 17637400): Discussion of conformality index
 * 2006 PMID 16580508 -- "Four-dimensional proton treatment planning for lung tumors." (Engelsman M, Int J Radiat Oncol Biol Phys. 2006 Apr 1;64(5):1589-95.)
 * Planning comparison for 4D-CT
 * Outcome: 4D-CT decreased mean lung dose by up to 16%, and V20 by up to 15%
 * Conclusion: 4D-CT guarantees delivery of prescribed dose throughout respiratory cycle
 * 2005 PMID 16475753 -- "Target volume dose considerations in proton beam treatment planning for lung tumors." (Engelsman M, Med Phys. 2005 Dec;32(12):3549-57.)
 * Treatment planning study to evaluate effect of setup error and breathing motion


 * Tubingen; 2008 (Germany) PMID 18491552 -- "Comparison of fixed-beam IMRT, helical tomotherapy, and IMPT for selected cases." (Muzik J, Med Phys. 2008 Apr;35(4):1580-92.)
 * Comparison of static MLC, dynamic MLC, conventional IMRT, helical tomotherapy, and spot-scanning proton therapy. Monte Carlo dose computation. Five cases: prostate, pediatric case, H&N case, lung tumor, and optical neurinoma
 * Conclusion: Each technique excels for certain classes of highly complex cases, and the modalities should be viewed as complementary


 * Vienna; 2008 PMID 18405986 -- "Can protons improve SBRT for lung lesions? Dosimetric considerations." (Georg D, Radiother Oncol. 2008 Apr 9. [Epub ahead of print])
 * Treatment plan comparison for 12 SBRT patients: scattered protons (SPT), intensity modulated protons (IMPT), and 3D-CRT. RT 45/3 prescribed at 65% isodose
 * Conclusion: Only small dosimetric differences between photons and protons for SBRT


 * Insbruck; 2007 (Austria) PMID 18166995 -- "Photons or protons: precision radiotherapy of lung cancer" (Auberger T, Strahlenther Onkol. 2007 Dec;183 Spec No 2:3-6.)
 * Treatment plan comparison, 6 patients (3 Stage I, 3 Stage III). 3D-CRT vs. IMRT vs. passive PT
 * Outcome: No difference between IMRT and passive PT for tumor coverage; passive PT better for OAR (lung, esophagus, heart). 3D-CRT worse.


 * Harvard; 2007 PMID 17879790 -- "A respiratory-gated treatment system for proton therapy." (Lu HM, Med Phys. 2007 Aug;34(8):3273-8.)
 * Description of a gating system


 * Wisconsin; 2003 PMID 12602558 -- "What can we expect from dose escalation using proton beams?" (Fowler JF, Clin Oncol (R Coll Radiol). 2003 Feb;15(1):S10-5.)
 * Review of dose escalation potential in prostate and NSCLC


 * Loma Linda; 2001 PMID 11286851 -- "Methodologies and tools for proton beam design for lung tumors." (Moyers MF, Int J Radiat Oncol Biol Phys. 2001 Apr 1;49(5):1429-38.)
 * Evaluation of planning strategies


 * Surrey; 1999 (UK) PMID 10700825 -- "Comparison of proton therapy and conformal X-ray therapy in non-small cell lung cancer (NSCLC)." (Lee CH, Br J Radiol. 1999 Nov;72(863):1078-84.)
 * Treatment plan comparison. Proton and four x-ray plans
 * Conclusion: Proton plan superior, diferent performance among photon plans

Animal Models

 * Groningen; 2005 (Netherlands) PMID 16061627 -- "Radiation damage to the heart enhances early radiation-induced lung function loss." (van Luijk P, Cancer Res. 2005 Aug 1;65(15):6509-11.)
 * Rate model. Dependence of lung tolerance on heart dose. 50% lung irradiated, including or excluding the heart, using proton beam. Lung toxicity scored using breathing rate assay
 * Conclusion: Concomitant RT of the heart severely reduces tolerance of the lung


 * South Africa; 2000 PMID 10863078 -- "Proton relative biological effectiveness (RBE) for survival in mice after thoracic irradiation with fractionated doses." (Gueulette J, Int J Radiat Oncol Biol Phys. 2000 Jul 1;47(4):1051-8.)
 * Evaluation of "clinical RBE" using 200 MeV proton beam. Selective irradiation of thorax in mice (n=1008). Control gamma irradiation.
 * Outcome: RBEs did not vary significantly with fractionation (2-20 Gy). They increase with time: 180 days 1.00; 210 days 1.08; 240 days 1.14; 270 days 1.25. Alpha/beta similar for protons and gamma rays (~2.3). Control crypt irradiation RBE 1.14, same as previously
 * Conclusion: No need to raise clinical RBE of protons

Economics

 * Also please see the general proton economics page


 * MAASTRO; 2010 PMID 20303217 -- "The cost-effectiveness of particle therapy in non-small cell lung cancer: Exploring decision uncertainty and areas for future research." (Grutters JP, Cancer Treat Rev. 2010 Mar 17. [Epub ahead of print])
 * Markov model. Comparative treatments carbon-ion, protons, conventional RT, and SBRT for Stage I NSCLC
 * Outcome: For inoperable NSCLC, Carbon cost euro 67,257 per QALY compared to SBRT; both carbon and SBRT dominated protons and conventional RT. For operable NSCLC, SBRT dominated carbon ion. Considerable uncertainity in estimates
 * Conclusion: It is recommended not to adopt particle therapy in Stage I NSCLC until more evidence is available


 * Malmo; 2005 (Sweden) PMID 16332596 -- "The potential of proton beam radiation therapy in lung cancer (including mesothelioma)." (Bjelkengren G, Acta Oncol. 2005;44(8):881-3.)
 * Estimate ~350 patients with lung cancer and ~20 patients with mesothelioma annually may benefit from proton beam therapy

Meta-Analysis

 * Maastricht, The Netherlands
 * Systematic review; 2008 PMID 18226466 -- "Particle therapy in lung cancer: Where do we stand?" (Pijls-Johannesma, Cancer Treat Rev. 2008 May;34(3):259-67. Epub 2008 Jan 15.)
 * Review. 10 reports. No phase III trials. Mainly Stage I.
 * Outcome: 2-year OS 31-74%, 5-year OS ~23%
 * Toxicity: 10%
 * Conclusion: Results seem promising; particle therapy safe and feasible, but more evidence required
 * Systematic review; 2010 PMID 20067947 -- "Do we have enough evidence to implement particle therapy as standard treatment in lung cancer? A systematic literature review." (Pijls-Johannesma M, Oncologist. 2010;15(1):93-103. Epub 2010 Jan 12.)
 * Literature review update. 11 studies. No phase III trials. Mainly Stage I
 * Outcome: local control 57%-87%. 2-year CSS 58%-86%; 5-year CSS 46%. 2-year OS 31%-74%, 5-year OS 23%. For carbon ion, overall local control 77%, but 95% when hypofractionated
 * Toxicity: radiation induced pneumonitis ~10%
 * Conclusion: Results are promising, but for now charged particle therapy should be considered experimental
 * Meta-analysis; 2010 PMID 19733410 -- "Comparison of the effectiveness of radiotherapy with photons, protons and carbon-ions for non-small cell lung cancer: a meta-analysis." (Grutters JP, Radiother Oncol. 2010 Apr;95(1):32-40. Epub 2009 Sep 3.)
 * Meta-analysis, conventional RT, SBRT, chemo-RT, proton therapy and carbon ion therapy.
 * Outcome: Inoperable STage I NSCLC 5-year OS conventional RT 20%, SBRT 42%, protons 40%, carbon ion 42%. Limited number of patients and limited follow up
 * Conclusion: Survival rates for particle therapy similar to SBRT for Stage I. Particle therapy may be more beneficial in Stage III


 * Trento; 2008 (Italy) PMID 18241945 -- "Proton therapy in lung cancer: clinical outcomes and technical issues. A systematic review." (Widesott L, Radiother Oncol. 2008 Feb;86(2):154-64. Epub 2008 Jan 31.)
 * Review. 17 reports, 214 patients. None prospective. Mostly related to stage I-II
 * Outcome: Results comparable to surgery, without significant toxicity. 2 dosimetric studies showing potential for dose escalation, 6 dosimetric studies underlying difficulties
 * Conclusion: Outcomes good, but limited data available, and technical challenges significant


 * MD Anderson; 2005 PMID 15946583 -- "Intensity modulated radiation therapy and proton radiotherapy for non-small cell lung cancer." (Chang JY, Curr Oncol Rep. 2005 Jul;7(4):255-9.)
 * Preliminary data reviewed

Heavy Ions

 * HIMAC Chiba
 * Elderly; 2008 (1999-2003) PMID 18762351 -- "Carbon ion radiotherapy for elderly patients 80 years and older with stage I non-small cell lung cancer." (Sugane T, Lung Cancer. 2008 Aug 30. [Epub ahead of print])
 * Retrospective. 28 patients, Stage I NSCLC, age >=80. Treated with carbon ion radiotherapy
 * Outcome: 5-year LC 96%; 5-year OS 31%. No patients started home O2 or had decreased ADL
 * Conclusion: Carbon ion RT effective in treating elderly
 * Dosimetry; 2007 PMID 17917408 -- "Dosimetric factors used for thoracic X-ray radiotherapy are not predictive of the occurrence of radiation pneumonitis after carbon-ion radiotherapy." (Koto M, Tohoku J Exp Med. 2007 Oct;213(2):149-56.)
 * Retrospective. 80 patients on dose escalation protocols
 * Outcome: V4, V20, V30, and mean lung dose not predictive for developing radiation pneumonitis after carbon-ion therapy
 * Conclusion: Dosimetric factors used for XRT not applicable for carbon ion therapy
 * Protocol 0001; 2007 (2000-2003) PMID 17909354 -- "Carbon ion radiotherapy for stage I non-small cell lung cancer using a regimen of four fractions during 1 week." (Miyamoto T, J Thorac Oncol. 2007 Oct;2(10):916-26.)
 * Phase II. 79 patients, 80 primary lesions. Average age 75 years. Stage IA using carbon ion 52.8/4 and Stage IB 60/4 delivered in 1 week. Median F/U 3.2 years (minimum 3 years or death)
 * Outcome: 5-year LC 90% (T1 98%, T2 80%). 5-year CSS 68% (87%, 42%). 5-year OS 45% (62%, 25%).
 * Toxicity: No Grade 4-5 toxicity
 * Conclusion: Carbon ion given 4 fractions over 1 week valid alternative to surgery for Stage I NSCLC, especially for elderly patients
 * Protocol 9802; 2007 (1999-2000) PMID 17293232 -- "Curative treatment of Stage I non-small-cell lung cancer with carbon ion beams using a hypofractionated regimen." (Miyamoto T, Int J Radiat Oncol Biol Phys. 2007 Mar 1;67(3):750-8.)
 * Phase II. 50 patients, 51 primary lesions. Peripheral Stage I NSCLC (T1 59%, T2 41%), medically inoperable 66%. RT 72/9 over 3 weeks. Median F/U 5 years
 * Outcome: 5-year LC 95%; 5-year CSS 76% (IA 89%, IB 55%); 5-year OS 50% (IA 55%, IB 43%)
 * Late Toxicity: Grade 3-4 pulmonary 0%; Grade 3-4 skin 2%
 * Conclusion: Carbon ion therapy is a valid alternative to surgery for Stage I NSCLC
 * Chromosome Aberrations; 2004 PMID 15304960 -- "Chromosomal aberrations in lymphocytes of lung cancer patients treated with carbon ions." (Lee R, J Radiat Res (Tokyo). 2004 Jun;45(2):195-9.)
 * Retrospective. 22 patients. FISH evaluation of aberrations in peripheral blood lymphocytes in chromosome 2 and 4
 * Outcome: Fraction of aberrant cells no correlation with total tumor dose, but significant (and linear) correlation with clinical target volume. Median increase from 0.8% to 2.6%
 * Conclusion: Chromosomal aberrations dependent on target volume size
 * Local control; 2004 PMID 15110447 -- "Local control and recurrence of stage I non-small cell lung cancer after carbon ion radiotherapy." (Koto M, Radiother Oncol. 2004 May;71(2):147-56.)
 * Retrospective. Two Phase I dose-escalation protocols (9303 and 9701) analyzed
 * Outcome: LR 23%. Patterns of failure analyzed
 * Conclusion: Local control shows dose-dependence
 * Protocol 9303 and Protocol 9701; 2003 (1994-1999) PMID 12648784 -- "Carbon ion radiotherapy for stage I non-small cell lung cancer." (Miyamoto T, Radiother Oncol. 2003 Feb;66(2):127-40.)
 * Protocol 9303: Phase I. 1994-1998. 48 lesions. Carbon ion dose escalation 59.4/18 - 64.8/18 - 72.0/18 - 79.2/18 - 86.4/18 - 90.0/18 - 95.4/18 (tentative MTD, 2/3 patients developed Grade II pneumonitis)
 * Protocol 9701: Phase I/II. 34 lesions. Dose escalation. 68.4/9 - 72.0/9 - 75.6/9 - 79.2/9 (tentative MTD, 3/5 patients developed Grade II pneumonitis)
 * Outcome: 5-year OS 42%, 5-year CSS 60%. If dose >86.4/18 and >72/9, LC 90% and 95%
 * Toxicity: Grade III pneumonitis in 3/81 (4%), but not dose-limiting
 * Conclusion: Optimum safety and efficacy dose of carbon ion beams determined
 * Radiographic changes; 2003 PMID 12605963 -- "Radiographic pulmonary and pleural changes after carbon ion irradiation." (Nishimura H, Int J Radiat Oncol Biol Phys. 2003 Mar 15;55(4):861-6.)
 * Retrospective. 43 patients on dose-escalating protocol
 * Outcome: median appearance of pulmonary reactions 3 months; maximum 6 months. Severity correlated with V20 and V40 GyE
 * Conclusion: Lung damage observed in parenchyma and pleura; severity correlated with dose-volume factors
 * Pulmonary function; 2002 PMID 12475828 -- "Effect of heavy-ion radiotherapy on pulmonary function in stage I non-small cell lung cancer patients." (Kadono K, Chest. 2002 Dec;122(6):1925-32.)
 * Retrospective. 52/81 patients treated 1994-1999 who had repeat PFTs
 * Outcome: Significant decrease in FEV1 and TLC at 6 and 12 months; no change in other PFT indices
 * Conclusion: Heavy ion RT is feasible without a severe loss of pulmonary function