# Radiation Oncology/NSCLC/Early Stage Inoperable

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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, although recent data suggests that the optimal dose may be dependent on the histologic classification of the treated tumor (sqaume v. adeno)
* 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. Terminated secondary to slow accrual.
** Cyberknife STARS - Trial Info - Phase III. Operable Stage I <4 cm. Surgery vs SBRT 60/3 or 60/4. Terminated secondary to slow accrual.
** 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 II. 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

* Pooled analysis of STARS (MD Anderson CC) and ROSEL (Dutch) trials; 2015 (2008-2013)) PMID 25981812 -- "Stereotactic ablative radiotherapy versus lobectomy for operable stage I non-small-cell lung cancer: a pooled analysis of two randomised trials" (Chang J et al., Lancet Oncology. 2015 Jun;16(6):630-7)
** Pooled analysis of 2 Phase III studies that both did not meet accrural goals. 58 patients, operable T1-T2a N0 M0 NSCLC, <4 cm diameter, 1:1 randomization SBRT vs surgery. STARS: SBRT 54/3 Gy peripheral, 50/4 Gy central lesions over 5 days; ROSEL: SBRT 54/3 Gy peripheral (5 -8 days), 60/5 Gy central lesions (10-14 days); . Median F/U 3.4 years
** Outcome: 3-year OAS 95% (SBRT) vs 79% (Surgery) (p<0.05)
** Toxicity: SBRT: Grade 3 in 10%, no grade 4/5; Surgery: grade 3/4 44%; 1pt Grade 5
** Conclusion: SBRT is better tolerated than surgery, SBRT might lead to better OAS; SBRT could be an option for operable Stage I NSCLC.
* 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