Radiation Oncology/NSCLC/Early Stage Inoperable

Early Stage Inoperable NSCLC

Upstaging

• Patients treated with RT are clinically staged
• Approximately 25% of patients with clinical Stage I are pathologically higher Stage
• Evaluation of PET for mediastinal LN staging is ongoing

• CALGB 9761 PMID 15829324 -- "Poor correspondence between clinical and pathologic staging in stage I non-small cell lung cancer: results from CALGB 9761, a prospective trial." (D'Cunha J, Lung Cancer. 2005 May;48(2):241-6. Epub 2005 Jan 4.)
  • Prospective. 502 patients with suspected or biopsy-proven NSCLC, clinical Stage I (T1-2N0) by CT or mediastinoscopy
  • Outcome: In biopsy proven NSCLC, pathologic Stage I 72%, pII 14%, pIII 13%, pIV 1%
  • Conclusion: Poor predictive value of current clinical staging techniques

No treatment

• Stage I-II patients, who were not treated with surgery, RT or chemotherapy have median OS ~1 year and 5-year OS ~10%
• Their 5-year lung cancer disease specific survival is ~25% for Stage IA and ~10% for Stage IB, suggesting that vast majority die of their cancer, even though they typically have severe comorbidities that preclude surgery (median 5-year OS for patients with severe COPD is ~40%)
• Even patients who are surgical candidates, but refuse surgery, have poor outcomes. Their median OS ~1.2 years, and 5-year cancer specific survival is ~20%

• California Cancer Registry; 2007 (1989-2003) PMID 17505036 -- "Natural history of stage I non-small cell lung cancer: implications for early detection." (Raz DJ, Chest. 2007 Jul;132(1):193-9. Epub 2007 May 15.)
  • Registry study. 19,702 patients with Stage I NSCLC, 1432 did not undergo surgery, chemotherapy or RT (Stage IA 40%, Stage IB 60%). Surgery refused in 32%
  • Outcome: Median OS 9 months, Stage IA 13 months, Stage IB 8 months. 5-year OS 7%, Stage IA 9%, Stage IB 5%. Median lung CSS Stage IA 2.1 years, Stage IB 10 months. 5-year lung CSS Stage IA 23%, Stage IB 12%.
  • "Refused" subgroup analysis: median OS 1.2 years, 5-year OS 6%; median CSS 1.7 years, 5-year CSS 22%.
  • Conclusion: Long-term survival with untreated Stage I NSCLC is uncommon, and vast majority die of lung cancer. Therapy shouldn't be delayed even in patients with small lung cancers

• SEER data; 2005 (1988-2001) PMID 16162744 -- "Radiation therapy for the treatment of unresected stage I-II non-small cell lung cancer." (Wisnivesky JP, Chest. 2005 Sep;128(3):1461-7.)
  • Population analysis. 4,357 patients with Stage I-II, who did not undergo surgery. Stage I 88%, Stage II 12%. RT delivered in 63%, no RT in 27% (chemotherapy not tracked).
  • Outcome: 75% died from cancer. On multivariate analysis, RT significantly associated with improved lung cancer survival
    • Stage I: median OS RT 1.7 years vs. no RT 1.2; 5-year OS 15% vs. 14% (NS)
    • Stage II: median OS RT 1.2 years vs. no RT 9 months; 5-year OS 11% vs. 10% (NS)
  • Conclusion: RT is associated with improved survival in unresected Stage I-II NSCLC, benefit 5-7 months. RT not curative, since 5-year OS same

• Japan National Chest Hospital Study Group; 2002 (1982-1991) PMID 11891035 -- "Prognosis of non-surgically treated, clinical stage I lung cancer patients in Japan." (Motohiro A, Lung Cancer. 2002 Apr;36(1):65-9.)
  • Retrospective. 799 patients with clinical Stage I lung cancer, not treated with surgery (reason not stated).
  • Outcome: 5-year OS 17%, 10-year OS 7%
  • Conclusion: There are long-term survivors in non-surgically treated stage I, but the rate is low

• Indiana; 2002 (1994-1999) PMID 11948046 -- "Observation-only management of early stage, medically inoperable lung cancer: poor outcome." (McGarry RC, Chest. 2002 Apr;121(4):1155-8.)
  • Retrospective. 128 patients with Stage I and II NSCLC. Surgery 34%, (mostly palliative) RT 28%, no cancer treatment 38%. RT delivered via 20 different fractionation schemes, ranging from 20/10 to 70.5/39, some BID.
  • Outcome: Median OS surgery 3.8 years vs. RT 1.7 years vs. no treatment 1.2 years. By retrospective RT intent: curative 1.7 years vs. palliative 1.3 years (small numbers, NS). Cancer as cause of death: RT group 43%, no treatment 53%, surgery not specified.
  • Conclusion: Untreated lung cancer has a poor outcome

• Split; 1994 (Croatia)(1980-1987) PMID 7988203 — "Survival analysis of untreated patients with non-small-cell lung cancer." (Vrdoljak E, Chest. 1994 Dec;106(6):1797-800.)
  • Retrospective. 130 patients not treated with anti-cancer therapy
  • Outcome: Median OS T2N0 17 months, T2N1 11 months, T2N2 10 months, other groups <8 months. Overall median OS 9 months. No patient (including T2N0) survived >3 years
  • Subgroup analysis: Stage I (T2N0) better survival, all other stages comparable (worse) survival
  • Conclusion: Lymph node involvement crucial factor in determining length of survival

COPD Outcome Comparison

• Colorado; 1980 (1966-1968) PMID 7357926 -- "Ten year follow-up of a comprehensive rehabilitation program for severe COPD." (Sahn SA, Chest. 1980 Feb;77(2 Suppl):311-4.)
  • Retrospective. 182 patients, severe COPD (clinical dx of emphysema/chronic bronchitis, FEV1 <50% predicted, symptoms interfering with ADLs), accepted into Colorado Rehabilitation Program. Mean age 61 years. Mean FEV1 0.9 L, mean FVC 2.8 L
  • Outcome: 5-year OS 41%, 10-year OS 17%; compared with life tables for white men same age 5-year OS 86%, 10-year OS 69% (SS)

Conventional (2D/3D) RT

Overview

• Outcomes are better than no treatment, but quite poor
  • Median OS: ~1.5 years
  • 5-year OS: ~20% (range 15-30%)
  • Based on SEER data analysis, RT offers 5-7 month median survival benefit. Given that there is no difference in 5-year OS with or without RT, conventional RT does not result in cure but only delays progression
• These outcomes are considerably worse than surgery (Stage I 60-80%, Stage II 40-50%), but the patients have significantly worse medical comorbidities
• 3D conformal RT improved outcomes, despite comparable dose, in a retrospective study from MD Anderson
• Traditionally curative doses using 2D/3D planning were 60-66 Gy (without heterogeneity correction)
• 3D-CRT with dose >80 Gy (MSKCC data) suggests median OS ~3.5 years and 5-year OS ~35%

Historical Outcomes

• MD Anderson; 2006 (1978-2003) PMID 16904517 -- "Comparison of outcomes for patients with medically inoperable Stage I non-small-cell lung cancer treated with two-dimensional vs. three-dimensional radiotherapy." (Fang LC, Int J Radiat Oncol Biol Phys. 2006 Sep 1;66(1):108-16.)
  • Retrospective. 200 patients with Stage I NSCLC, treated with RT alone. 2D planning (n=115), or 3D planning (n=85). Median RT dose 64 Gy vs. 66 Gy (NS). Age 69 vs 73 (SS). Median F/U 1.7 years vs. 1.6 years (NS).
  • Outcome: 5-year OS 2D 10% vs. 3D 36% (SS); 5-year DSS 29% vs. 68% (SS). 5-year LC 34% vs. 70% (SS).
  • Negative predictors: male, age >=70, weight loss >=5%, tumor >=4 cm
  • Conclusion: 3D conformal RT improves outcomes compared with 2D treatment

• SEER data; 2005 (1988-2001) PMID 16162744 -- "Radiation therapy for the treatment of unresected stage I-II non-small cell lung cancer." (Wisnivesky JP, Chest. 2005 Sep;128(3):1461-7.)
  • Population analysis. 4,357 patients with Stage I-II, who did not undergo surgery. Stage I 88%, Stage II 12%. RT delivered in 63%, no RT in 27% (chemotherapy not tracked).
  • Outcome: 75% died from cancer. On multivariate analysis, RT significantly associated with improved lung cancer survival
    • Stage I: median OS RT 1.7 years vs. no RT 1.2; 5-year OS 15% vs. 14% (NS)
    • Stage II: median OS RT 1.2 years vs. no RT 9 months; 5-year OS 11% vs. 10% (NS)
  • Conclusion: RT is associated with improved survival in unresected Stage I-II NSCLC, benefit 5-7 months. RT not curative, since 5-year OS same

• Karolinska; 2003 PMID 12826306 -- "The role of radiotherapy in treatment of stage I non-small cell lung cancer." (Qiao X, Lung Cancer. 2003 Jul;41(1):1-11.)
  • Literature review. 18 studies published 1988-2000.
  • Outcome: LR most common reason for failure (median 40%, range 6-70%). Regional recurrence low (0-3%). 5-year OS 21%; DSS 25%
  • Conclusion: Dose escalation should be the focus to improve local control and survival

• Munich; 2003 PMID 14508859 -- "Radiation therapy alone in early stage non-small cell lung cancer." (Zimmermann FB, Semin Surg Oncol. 2003;21(2):91-7.)
  • Literature review. Median OS up to 2.5 years and 5-year OS up to 42%. Dose >=65 Gy with standard fractionation necessary for long-term control. Elective nodal irradiation controversial
  • Conclusion: RT effective treatment modality in medically inoperable patients with early stage NSCLC

• Tubingen; 2002 PMID 12182981 -- "Radiotherapy alone in technically operable, medically inoperable, early-stage (I/II) non-small-cell lung cancer." (Jeremic B, Int J Radiat Oncol Biol Phys. 2002 Sep 1;54(1):119-130.)
  • Literature review. 26 studies published 1963-2000.
  • Outcome: Median OS >30 months, 5-year OS 30% achieved. Dose >65 Gy necessary. Local failure predominant (average 31%); elective nodal RT controversial (initial nodal failure 2%), average distant failure 17%
  • Conclusion: High-dose curative RT (dose 65-70 Gy) effective treatment modality in medically inoperable NSCLC.

• Indiana; 2002 (1994-1999) PMID 11948046 -- "Observation-only management of early stage, medically inoperable lung cancer: poor outcome." (McGarry RC, Chest. 2002 Apr;121(4):1155-8.)
  • Retrospective. 128 patients with Stage I and II NSCLC. Surgery 34%, (mostly palliative) RT 28%, no cancer treatment 38%. RT delivered via 20 different fractionation schemes, ranging from 20/10 to 70.5/39, some BID.
  • Outcome: Median OS surgery 3.8 years vs. RT 1.7 years vs. no treatment 1.2 years. By retrospective RT intent: curative 1.7 years vs. palliative 1.3 years (small numbers, NS). Cancer as cause of death: RT group 43%, no treatment 53%, surgery not specified.
  • Conclusion: Untreated lung cancer has a poor outcome

Dose escalation

• Memorial Sloan Kettering
  • 2007 PMID 17762758 -- "High-dose radiotherapy for the treatment of inoperable non-small cell lung cancer." (Sura S, Cancer J. 2007 Jul-Aug;13(4):238-42.)
    • Retrospective. 82 patients, inoperable NSCLC Stage I-IIIB (I-II n=55; III n=27). Dose >= 80 Gy using 3D-CRT with sequential chemotherapy
    • 5-year Outcome:
      • Stage I/II LC 67%, OS 36%, median OS 3.4 years
      • Stage III LC 39%, OS 31%, median OS 2.7 years
    • Conclusion: OS and LC comparable with other dose-escalation studies
  • Phase I, 2005 (1991-2003) PMID 15830346 -- "Results of a phase I dose-escalation study using three-dimensional conformal radiotherapy in the treatment of inoperable nonsmall cell lung carcinoma." (Rosenzweig KE, Cancer. 2005 May 15;103(10):2118-27.)
    • Phase I. 104 patients, inoperable. Stage I-II 28%, Stage IIIA 33%, Stage IIIB 32%, Recurrent 6%. 3D-CRT (inhomogeneity corrected) 70.2/39, 75.6/42, 81.0/45, 84.0/42, 90.0/45 Gy. NTCP planning used.
    • Maximum tolerated dose: 84.0 Gy in 2 Gy/fx. Overall survival significantly increased if >= 80 Gy
    • Toxicity: Unacceptable pulmonary toxicity at 90.0 Gy; 84 Gy level: 5% Grade 3-4; 90 Gy level: 29% Grade 3-4, 14% Grade 5
    • Conclusion: MTD of 3D-CRT with NTCP constraint of 25% was 84.0 Gy, with suggestion of improved survival

• RTOG 0117 (closed) -- dose escalation with concurrent chemotherapy
  • Phase I/II. Stage I-IIIB NSCLC. RT + concurrent paclitaxel 50 mg/m2 + carboplatin AUC 2. Arm I 75.25/35 (8 patients) -> dose limiting toxicity (acute Grade 5 pneumonitis, acute Grade 3 pneumonitis; also late Grade 3 pneumonitis and Grade 4 pain) -> de-escalated to 74/37 (Arm II; 9 pts) + concurrent carbo/taxol. Phase II accrued at 74/37 dose level.
  • Rx at ICRU pt; PTV must be covered by 93% isodose. Calculations without heterogeneity corrections.
  • 2005 ASCO Abstract
    • Conclusion: MTD 74/37 using 3D-CRT + concurrent paclitaxel/carboplatin. Phase II component not yet reported.
  • 2010 PMID 20368547 -- "Primary Analysis of the Phase II Component of a Phase I/II Dose Intensification Study Using Three-Dimensional Conformal Radiation Therapy and Concurrent Chemotherapy for Patients With Inoperable Non–Small-Cell Lung Cancer: RTOG 0117." (Bradley JD, J Clin Oncol. 2010 May 10;28(14):2475-80.)
    • Total of 55 pts (53 evaluable) treated to 74/37 dose level in Phase I (9) and Phase II (46) portions of study. Median f/u 19.3 months. Median survival 25.9 months. 1 yr OS 75%. For Stage III pts (n=44), MS 21.6 months and PFS 10.8 months, 1 yr OS 72%.
    • Conclusion: encouraging results for 74 Gy dose + chemo.
  • 2010 PMID 20457350 -- "A phase I/II radiation dose escalation study with concurrent chemotherapy for patients with inoperable stages I to III non-small-cell lung cancer: phase I results of RTOG 0117." (Bradley JD, Int J Radiat Oncol Biol Phys. 2010 Jun 1;77(2):367-72.)
    • Conclusion: MTD 74 Gy in 37 fractions using concurrent carbo/taxol.

• RTOG 93-11 (1995-2001) -- dose escalation
  • Phase I/II dose escalation. 176 patients. Stage I-III NSCLC, SCV LN+ excluded ( Prior chemotherapy allowed, concurrent chemotherapy not allowed. 3D treatement planning . GTV = primary tumor and enlarged LN. No elective nodal irradiation. PTV = GTV + 1 cm minimum; verified on fluoroscopy because of breathing motion. Dose prescribed to ICRU reference point within GTV, 93% isodose line to cover PTV, maximum PTV dose <=107%, no heterogeneity correction. Patients grouped based on V20 value using 2.15 Gy/fx:
    • Group 1 (V20 <25%): 70.9/33 -> 77.4/36 -> 83.8/39 -> 90.3/42 (Stage I 53%, Stage III 38%)
    • Group 2 (V20 25-36%): 70.9/33 -> 77.4/36 -> 83.8/39 (Stage I 21%, Stage III 75%) (accrual stopped after 77.4 Gy due to opening of RTOG 0117)
    • Group 3 (V20 >36%): 64.5/30 -> 70.9/33 -> 77.4/36 (accrual stopped after 2 patients)
  • 2005 PMID 15667949 — "Toxicity and outcome results of RTOG 9311: a phase I-II dose-escalation study using three-dimensional conformal radiotherapy in patients with inoperable non-small-cell lung carcinoma." (Bradley J, Int J Radiat Oncol Biol Phys. 2005 Feb 1;61(2):318-28.) Minimum median F/U 13.4 months
    • Acute toxicity: minimal. Group 1 had 9% Grade 3 pneumonitis at 90.3 Gy; Group 2 had 8% Grade 3 pneumonitis at 77.4 Gy. Acute dose-limiting toxicity not reached
    • Late toxicity. Predictors for pulmonary toxicity: mean lung dose, V20
      • Group 1 had 13% Grade 3-5 lung and 6% Grade 3-5 esophageal toxicity (1 death of hemoptysis, 1 death of tracheoesophageal fistula) at 90.3 Gy; tolerable otherwise. Late dose-limiting toxicity at 90.3 Gy level.
      • Group 2 had 16% Grade 3-4 lung toxicity, and 4% esophagus toxicity. Late dose-limiting toxicity not reached.
    • Outcome: 2-year LR 50-78% (but small individual group sizes); LR sole site 18%, component 38%. Elective nodal failure <10%
    • Conclusion: For Group 1 (V20 <25%), 83.8 Gy safe; for Group 2 (V20 25-36%), 77.4 Gy safe using 2.15 Gy/fx

Hypofractionation

• CALGB 39904; 2009 (2000-2005) PMID 19933904 -- "Phase I Study of Accelerated Conformal Radiotherapy for Stage I Non-Small-Cell Lung Cancer in Patients With Pulmonary Dysfunction: CALGB 39904." (Bogart JA, J Clin Oncol. 2009 Nov 23. [Epub ahead of print])
  • Phase I. 39 patients, medically inoperable Stage I (<4 cm). Eligibility: FEV1 <40%, DLCO <50%, PCO >45 mmHg, VO2max <15 mL, or O2 dependent (28%). 3D-CRT, nominal dose 70 Gy, accelerated stepwise: 70/29 (@2.41) -> 70/26 (@2.69) -> 70/23 (@3.04) -> 70/20 (@3.5) -> 70/17 (@4.11). Median age 75, 28% on supplemental O2. Median F/U 4.4 years
  • Outcome: MTD not defined. LC 92%, distant failure rate 26%, median OS 3.2 years.
  • Toxicity: No Grade 3+ late toxicity
  • Conclusion: Accelerated 3D-CRT well tolerated, with less apparent severe toxicity compared with SBRT

• Amsterdam; 1996 (The Netherlands)(1988-1993) PMID 8961366 -- "Limited field irradiation in early stage (T1-2N0) non-small cell lung cancer." (Slotman BJ, Radiother Oncol. 1996 Oct;41(1):41-4.)
  • Retrospective. 31 patients with operable T1-2N0 NSCLC. RT 48/12 to 'postage stamp' field, no mediastinum/hilum
  • Outcome: 3-year OS 42%; DSS 76%. LF 6%
  • Conclusion: Limited 'postage stamp' irradiation effective alternative to surgery

Stereotactic Body Radiation Therapy (SBRT)

• SBRT is an area under active research. Dose schedules have not yet been established
• Japanese data suggests that BED10 >100 Gy results in superior local control and overall survival
• Indiana University dose escalation didn't reach MTD at 60/3 (BED10 = 180 Gy) for Stage IA tumors, and reached MTD at 72/3 (BED10 = 245 Gy); however, some toxicity was experienced at lower doses with central tumors. It is not clear what is the appropriate ablative dose
• Several studies have now reported 5-year OS, ranging from 30% to 83%
• ASTRO Emerging Technology Committee Report (2010)

Ongoing Trials

• Operable
  • Dutch ROSEL - Trial Info Overview - Phase III. Operable Stage T1N0. Surgery vs SBRT 60/3 or 60/5
  • Cyberknife - Trial Info - Phase III. Operable Stage I <4 cm. Surgery vs SBRT 60/3 or 60/4
  • RTOG 0618 - Protocol - Phase II. Operable Stage I. Dose 60/3
  • JCOG 0403 - Protocol - Phase II. Operable Stage T1N0

• Inoperable
  • TROG 09.02 - Trial Info - Phase III. 3D-CRT 60/30-66/33 vs SBRT 54/3
  • RTOG 0915 - Protocol - Phase III. Inoperable. Dose 34/1 vs 48/4
  • Scandinavian SPACE - Protocol - Phase II randomized. 3D-CRT 70/35 vs. SBRT 45/3
  • RTOG 0813 - Protocol - Phase II. Inoperable. Dose escalation 50/5 -> 60/5

Published Evidence

• RTOG 0236; 2010 (2004-2006) PMID 20233825 -- "Stereotactic body radiation therapy for inoperable early stage lung cancer." (Timmerman R, JAMA. 2010 Mar 17;303(11):1070-6.)
  • Phase II. 55 patients, peripheral T1-T2N0 NSCLC, <5 cm diameter, not surgical candidate. SBRT 54/3 over 1.5-2 weeks. Median F/U 2.9 years
  • Outcome: 3-year tumor control 98% (1 primary tumor failure); 3-year local (tumor+lobe) control 91%; 3-year loco-regional control 87%; 3-year DM 22%. Median OS 48 months
  • Toxicity: Grade 3 in 13%, Grade 4 in 4%, no Grade 5
  • Conclusion: Patients with inoperable NSCLC have high rates of local tumor control and moderate treatment-related morbidity

• Indiana University
  • Phase II; 2009 PMID 19251380 -- "Stereotactic body radiation therapy for early-stage non-small-cell lung carcinoma: four-year results of a prospective phase II study." (Fakiris AJ, Int J Radiat Oncol Biol Phys. 2009 Nov 1;75(3):677-82. Epub 2009 Feb 27.)
    • Phase II. 70 medically inoperable patients, cT1 (n=34) or cT2 (n=36), diameter <= 7 cm, biopsy proven NSCLC. Dose 60-66 Gy to 80% isodose in 3 fractions. Median F/U 4.2 years
    • Outcome: 3-year LC 88%, nodal failure 9%, DM 13%. 3-year OS 43%, CSS 82%. No difference in outcome between T1 and T2, by tumor volume, or by peripheral vs central location
    • Toxicity: Grade 3+ toxicity in peripheral 10% vs. central 27% (p=0.09)
    • Conclusion: SBRT results in high local control in medically inoperable Stage I patients
  • Phase I/II; 2007 PMID 17353064 -- "FDG-PET and stereotactic body radiotherapy (SBRT) for stage I non-small-cell lung cancer." (Hoopes DJ, Lung Cancer. 2007 May;56(2):229-34. Epub 2007 Mar 13.)
    • Phase I and II trials. 58 patients, Stage I NSCLC, inoperable. SBRT dose 24-72 Gy in 3 fractions. Pre-SBRT PET in 57. Post-SBRT PET performed in 28 patients, typically upon concern for recurrence. Min F/U 2 years, median F/U 3.5 years
    • Outcome: 3-year OS 49%; 3-year LC 75%. Isolated LN failure 10%, overall LN failure 25%
    • PET: Pre-SBRT PET didn't predict for OS or LC. However, 14% (4/28) had moderate SUV activity, but no evidence of disease recurrence
    • Conclusion: Isolated nodal recurrence uncommon; moderate PET activity may persist 2 years after treatment, without definitive evidence of recurrence
  • Phase II. 70 patients. Medically inoperable. Clinical T1N0 treated with SBRT 60/3; clinical T2N0 (<=7 cm) treated with 66/3.
    • 2006 PMID 17050868 -- "Excessive toxicity when treating central tumors in a phase II study of stereotactic body radiation therapy for medically inoperable early-stage lung cancer." (Timmerman R, J Clin Oncol. 2006 Oct 20;24(30):4833-9.) Median F/U 17 months
      • Outcome: 2-year LC 95%. Median OS 2.7 years, 2-year OS 55%.
      • Toxicity: Grade 3-5 in 20%; peripheral tumors 17% vs. central tumors 46%. Median time-to-toxicity 10 months. 6 deaths (4 pneumonia, 1 pericardial effusion, 1 local recurrence next to carina then hemoptysis)
      • Conclusion: High rate of local control, but also some late toxicity. This regimen should not be used for tumors near central airways (<2 cm) due to excessive toxicity
  • Phase I. (2000-2003) 47 patients, clinical Stage IA and IB (escalated separately), tumor size <=7 cm, NSCLC. Operable, but not surgical candidates. Dose escalation: 24/3 -> 30/3 -> 36/3 -> 42/3 -> 48/3 -> 54/3 -> 60/3. CTV = GTV. PTV = GTV + 0.5 cm radial and 1.0 cranio-caudal. Dose prescribed to 80% isodose.
    • 2003 PMID 14605072 -- "Extracranial stereotactic radioablation: results of a phase I study in medically inoperable stage I non-small cell lung cancer." (Timmerman R, Chest. 2003 Nov;124(5):1946-55.) Median F/U 15 months
      • Outcome: Both IA and IB reached 60/3; MTD yet to be reached. LF 16% (all dose <=48/3)
      • Toxicity: 1 Grade 3 pneumonitis, 1 Grade 3 hypoxia
      • Conclusion: Very high RT dose tolerated
    • 2005 PMID 16115740 -- "Stereotactic body radiation therapy of early-stage non-small-cell lung carcinoma: Phase I study." (McGarry RC, Int J Radiat Oncol Biol Phys. 2005 Nov 15;63(4):1010-5. Epub 2005 Aug 22.)
      • Outcome: Stage IA - MTD not reached (max=60/3). Stage IB (and tumors >5 cm) - MTD reached at 66/3. Local failure: 4/19 T1, 6/28 T2 patients, but only 1 failure at higher doses
      • Toxicity: Stage IB - At 72/3 level, 3/5 experienced Grade 3+ toxicity (pneumonitis x2, tracheal necrosis x1)
      • Conclusion: SBRT safe, effective. Excellent local control at higher doses. MTD reached for larger tumors

• Cleveland Clinic; 2009 (2004-2006) PMID 19765913 -- "Intensity-Modulated Radiotherapy-Based Stereotactic Body Radiotherapy for Medically Inoperable Early-Stage Lung Cancer: Excellent Local Control." (Videtic GM, Int J Radiat Oncol Biol Phys. 2009 Sep 16. [Epub ahead of print])
  • Retrospective. 26 patients with 28 lesions. T1 in 79%, T2 in 21%, no tissue diagnosis in 27%. SBRT IMRT 50/5 heterogeneity corrected. PTV = ITV + 3-5 mm. Median F/U 2.6 years
  • Outcome: Actuarial 3-year LC 94%, 3-year OS 52%
  • Toxicity: Acute Grade 3 dyspnea in 1 patient (4%), late Grade 2 chest wall pain 1 patient (4%)
  • Conclusion: SBRT excellent local control and favorable survival

• Scandinavian; 2009 (2003-2005) PMID 19414667 -- "Outcome in a prospective phase II trial of medically inoperable stage I non-small-cell lung cancer patients treated with stereotactic body radiotherapy." (Baumann P, J Clin Oncol. 2009 Jul 10;27(20):3290-6.)
  • Phase II. 57 patients with medically inoperable Stage I NSCLC (T1 70%, T2 30%) treated in Sweden, Norway, Denmark. SBRT 45/3 prescribed at 67% isodose. Median tumor diameter 2.5 cm. CTV = GTV + 1-2 mm. PTV = CTV + 5-10 mm. Median F/U 3 years
  • Outcome: 3-year PFS 52%; CSS 88%, OS 60%. No difference between T1 and T2. Local control 92%, regional relapse 5%, distant mets 16%
  • Conclusion: SBRT is state-of-the-art treatment for medically inoperable Stage I NSCLC

• Japanese Society of Radiation Oncology (1995-2003)
  • 2-years; 2004 PMID 15378503 -- "Stereotactic hypofractionated high-dose irradiation for stage I nonsmall cell lung carcinoma: clinical outcomes in 245 subjects in a Japanese multiinstitutional study." (Onishi H, Cancer. 2004 Oct 1;101(7):1623-31.)
    • Retrospective. 245 patients with Stage I NSCLC (T1N0 n=155, T2N0 n=90), tumor diameter < 6 cm, 65% inoperable/35% refused or chose RT. Hypofractionated SBRT (3-12 Gy dose/fx; 1-25 fractions; total dose 18-75 Gy; median BED10 108 Gy; BED10 range 57-180 Gy). Median F/U 2 years
    • Outcome: LF 14%, LF if BED10 <100 26% vs. BED10 >100 8% (SS). 3-year OS 69% vs. 88% (SS)
    • Toxicity: Grade 3 in 2%
    • Conclusion: Hypofractionated SBRT with BED10 <150 Gy feasible and beneficial; local control and survival better with BED10 >=100
  • 3-years; 2007 PMID 17603311 -- "Hypofractionated stereotactic radiotherapy (HypoFXSRT) for stage I non-small cell lung cancer: updated results of 257 patients in a Japanese multi-institutional study." (Onishi H, J Thorac Oncol. 2007 Jul;2(7 Suppl 3):S94-100.)
    • Retrospective. 275 patients, Stage I NSCLC (T1N0 n=164, T2N0 n=93). Hypofractionated SBRT, median BED10 = 111 Gy (57-180 Gy). Median F/U 3.2 years
    • Outcome: LF 14%, LF if BED10 <100 43% vs. BED10 >100 8% (SS); 5-year OS 30% vs. 71% (SS)
    • Operable: 5-year OS if BED10 <100 30% vs. BED10 >100 71% (SS)
    • Toxicity: Grade 3 pulmonary 5%
    • Conclusion: Hypofractionated SRT feasible for curative treatment of Stage I NSCLC; superior to conventional RT. Outcomes in operable patients are excellent

• Kyoto; 2005 (Japan)(1998-2004) PMID 16169670 -- "Clinical outcomes of a phase I/II study of 48 Gy of stereotactic body radiotherapy in 4 fractions for primary lung cancer using a stereotactic body frame." (Nagata Y, Int J Radiat Oncol Biol Phys. 2005 Dec 1;63(5):1427-31. Epub 2005 Sep 19.)
  • Retrospective. 45 patients with Stage I NSCLC (T1N0 n=32, T2N0 n=13). RT 48/4 over 12 days. Median F/U 2.5 years
  • Outcome: LC 98%; Stage IA 5-year DFS 72%, OS 83%. Stage IB 5-year DFS 71%, OS 72%
  • Toxicity: No Grade 3+ toxicity; 4% Grade 2 pneumonitis treated with steroids
  • Conclusion: Stereotactic RT useful for treatment of Stage I lung tumors

• Sahlgrenska University Hospital, Sweden; 2006 (1998-2003) PMID 16213059 -- "Stereotactic hypofractionated radiotherapy for stage I non-small cell lung cancer--mature results for medically inoperable patients." (Nyman J, Lung Cancer. 2006 Jan;51(1):97-103. Epub 2005 Oct 4.)
  • Retrospective. 45 Patients with Stage I (18 T1N0, 27 T2N0). RT 45/3 during 1 week (BED10 = 112 Gy). Median F/U 3.6 years
  • Outcome: LR 20% (9/45); 5-year OS 30%
  • Late toxicity: rib fracture 4%, atelectasis 7%
  • Conclusion: Encouraging survival and relatively low toxicity. Randomized trial underway

• National Defense Medical College, Japan; 1998 (1994-1997) PMID 9506350 -- "Focal, high dose, and fractionated modified stereotactic radiation therapy for lung carcinoma patients: a preliminary experience." (Uematsu M, Cancer. 1998 Mar 15;82(6):1062-70.)
  • Retrospective. 45 patients (23 primary and 43 metastatic lung carcinomas). RT 30-75 Gy in 5-15 fractions, prescribed to 80% isodose line, with/without conventional RT. Median F/U 11 months
  • Outcome: LF 3%
  • Toxicity: minimal
  • Conclusion: Focal RT similar to cranial SRS possible for extracranial sites

Elderly patients

• VU University, The Netherlands; 2009 PMID 19950125 -- "Stage I nonsmall cell lung cancer in patients aged >/=75 years: outcomes after stereotactic radiotherapy." (Haasbeek CJ, Cancer. 2009 Nov 30. [Epub ahead of print])
  • Retrospective. 203 tumors in 193 patints (T1 118, T2 85), age >=75, 80% inoperable 20% declined surgery. Median Charlson comorbidity score 4, severe COPD 25%. Risk-adapted SRT dose 60 Gy in 3 fractions (33%), 5 fractions (50%) or 8 fractions (17%)
  • Outcome: OS 1-year 86%, 3-year 45% and correlated with performance score (SS) and lung function. 3-year LC 89%
  • Toxicity: Late Grade 3+ in <10% patients
  • Conclusion: High LC rates, minimal toxicity, despite significant medical comorbidities

Dose

• There are currently multiple dose regimens available
• Initial dose-escalation at Indiana University established 20 Gy x3 fractions as a "standard" regimen in the U.S. for peripheral lesions. This was adopted by RTOG
• Commonly used Japanese regimen tends to be 12 Gy x4 fractions
• RTOG is now randomizing patients in a Phase II study between 34 Gy single fraction and the Japanese regimen of 12 Gy x4 fraction, to serve as an arm in a future Phase III between the current reference 20 Gy x3 fractions and the winner
• RTOG is also carrying out a dose-escalation protocol for central lesions starting at 10 Gy x5 fractions going to 12 Gy x5 fractions

• Colorado; 2009 (1999-2005) PMID 1878678 -- "Observation of a dose-control relationship for lung and liver tumors after stereotactic body radiation therapy." (McCammon R, Int J Radiat Oncol Biol Phys. 2009 Jan 1;73(1):112-8. Epub 2008 Sep 9.)
  • Retrospective. 141 patients, 246 lesions with lung or liver tumors. SBRT in 3 fractions
  • Outcome: 3-year LC if dose <36/3 (< 12 Gy/fx) 8% vs. 36/3-53.9/3 (12-17.9 Gy/fx) 59% vs. >=54/3 (>= 18 Gy/fx) 89%
  • Toxicity: Grade 3+ in 6%
  • Conclusion: Dose-control relationship exists, with excellent control rates at >= 54 Gy in 3 fractions

• University of Virginia; 2007 PMID 17513066 -- "Dose as a function of lung volume and planned treatment volume in helical tomotherapy intensity-modulated radiation therapy-based stereotactic body radiation therapy for small lung tumors." (Baisden JM, Int J Radiat Oncol Biol Phys. 2007 Jul 15;68(4):1229-37. Epub 2007 May 21.)
  • Treatment planning. 7 patients. Helical tomotherapy. Regression analysis of correlation of maximum acceptable dose to PTV and lung volume
  • Outcome: Linear relationship between maximum dose, PTV, and lung volume.
  • Conclusion: Maximum dose can be predicted by PTV and lung volume

Set Up

• University of Toronto (2008-2009) -- abdominal compression vs Body fix immobilization
  • Randomized. 24 patients, 25 lesions (16 upper lobe, 2 middle lobe, 7 lower lobe), medically inoperable Stage I NSCLC or pulmonary mets. All patients underwent 4D-CRT with free breathing, Bodyfix, and abdominal compression plate (ACP). After sim randomized to immobilization with Arm 1) Bodyfix or Arm 2) ACP. CBCT acquired before and after each treatment
  • 2010 PMID 20189669 -- "A comparison of two immobilization systems for stereotactic body radiation therapy of lung tumors." (Han K, Radiother Oncol. 2010 Feb 26. [Epub ahead of print])
    • Outcome: Both Bodyfix and ACP reduced sup-inf (4.6 mm vs 4.0 mm vs 5.3 mm) and overall tumor motion (5.3 mm vs 4.7 mm vs 6.1 mm) compared to free-breathing (SS). ACP further reduced sup-inf (SS) and overall tumor motion (SS) compared to Bodyfix
    • Toxicity: ACP faster to set up and more comfortable by patients (SS)
    • Conclusion: Abdominal compression superior to Bodyfix in immobilization and patient comfort

Proton Therapy

• Please see the NSCLC Protons page

Primary RT Technique Comparison

• Maastricht; 2009 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. 2009 Sep 3. [Epub ahead of print])
  • Meta-analysis. 41 studies (22 conventional, 11 SBRT, 5 proton, 3 carbon)
  • Outcome: Pooled 5-year OS estimate conventional RT 19% vs. SBRT 42% vs. protons 40% vs. carbon ion 42% (NS for SBRT vs protons vs carbon). 5-year DSS 43% vs 63% vs 52% vs 64% (SBRT significantly better than conventional)
  • Conclusion: Conventional RT outcome significantly worse than SBRT, protons, and carbon, though limited number of patients and limited follow-up

RT and chemotherapy

Hyperfractionated RT + chemo

• Jeremic (Yugoslavia), 2005 (1996-98) - PMID 16192579 — "Concurrent Hyperfractionated Radiotherapy and Low-Dose Daily Carboplatin/Paclitaxel in Patients With Early-Stage (I/II) Non-Small-Cell Lung Cancer: Long-Term Results of a Phase II Study." Jeremic B et al. J Clin Oncol. 2005 Oct 1;23(28):6873-80.
  • 56 pts, Stage I-II. Taxol on day 1 (30 mg/m2) then RT beginning on day 2 to 67.6 Gy at 1.3 Gy BID with concurrent daily chemotherapy with carboplatin 25 mg/m2 and paclitaxel 10 mg/m2.
  • Conclusion: feasible with low toxicity.

Radiofrequency Ablation (RFA)

• RAPTURE (2001-2005) PMID 18565793 -- "Response to radiofrequency ablation of pulmonary tumours: a prospective, intention-to-treat, multicentre clinical trial (the RAPTURE study)." (Lencioni R, Lancet Oncol. 2008 Jul;9(7):621-8. Epub 2008 Jun 17.)
  • Multinational prospective trial (Europe, USA, Australia). 106 patients, 183 lung tumors, <3.5cm diameter. Unsuitable for surgery, RT or chemo. NSCLC (n=33), CRC mets (n=53), other mets (n=20).
  • Outcome: Technical success 99%. 1-year CR 88%. 1-year OS NSCLC 70%, CRC mets 89%, other mets 92%. 2-year OS Stage I NSCLC 72%
  • Toxicity: Pneumothorax 1%; no significant worsening of pulmonary function
  • Conclusion: Percutaneous RFA high sustained CR, acceptable morbidity