Stereotactic Body Therapy Radiation for the Treatment of Early Stage Non Small Cell Lung Cancer

Judith Walsh, MD, MPH

CTAF

Abstract and Introduction

Introduction

The California Technology Assessment Forum (CTAF) was requested to review the scientific evidence for the use of Stereotactic Body Radiation Therapy (SBRT) for the treatment of early stage non small cell lung cancer (NSCLC) in medically inoperable patients. Given that the major treatment goal for non small cell lung cancer is to obtain local control, is SBRT a viable therapeutic option for patients who are medically inoperable? Secondarily, given its potentially less invasive approach, is it a viable option for patients who are potentially operable as an alternative to surgery?

CTAF evaluated this topic in June, 2008, but has been asked to readdress the topic in light of additional published evidence. Most of the available evidence focuses on the use of radiosurgery for treatment of medically inoperable patients who have few treatment options. However, SBRT is also being evaluated for patients who have operable cancers and its use in this patient population will be addressed as well.

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Table 1. Stereotactic Body Radiation Therapy for Early Non Small Cell Lung Cancer: Results of Retrospective Studies
STUDY	STUDY SITE	N	INTERVENTION	INCLUSION	DURATION OF FOLLOW UP	OUTCOMES FOR THOSE WITH NSCLC
Onishi, 2007^[12]	Multi-institutional in Japan	257 (158 medically inoperable)	18–75 Gy in 1–2 fractions	Stage 1 T1N0M0	38 months	5 year overall survival 56%; 3 year overall survival for medically operable 70.8% with BED >100 and 30.2% with BED <100
Pennathur, 2009^[13]	University of Pittsburgh	100 (19 had metastatic disease)	20 Gy single fraction increased to 60 Gy in 3 fractions	Primary, recurrent or metastatic lung cancer; all stages; medically inoperable, failure of prior therapies or refusal to have surgery	20 months	24 month median overall survival 50% probability of 2 year overall survival (44% for primary lung cancer)
Uematsu, 2001^[14]	National Defense Medical College, Japan	50	50–60 Gy 5–10 FX	T1–2N0M0 Medically inoperable or refused surgery	36 months	3 year survival 66%; 88% cause specific survival 86% in medically operable 94% local control
Wulf, 2004^[15]	U of Wuerzburg, Germany	20	3 x 10 G or 3 x 12–12.5 Gy	T1-T3N0M0 Medically inoperable	11 months	52% 1 year and 32% 2 year survival
Lee, 2003^[16]	University of Ulsan, South Korea	28 (9 primary lung cancers)	3–4 x 10 Gy	Primary lung cancer	18 months	39% showing complete response; 43% showed partial response; primary and metastatic disease not reported separately
Ricardi, 2010^[17]	University of Turin	62)	15 Gy x 3	Stage 1 NSCLC Medically inoperable	28 months	Local control at 3 years 87.8% Overall survival 57.1%
Scorsetti, 2007 Italy^[18]	Instituto Clinico Humanitas, Italy	43	30.5 Gy in 1–4 fractions	T1–2, N0M0	14 months	53% 2 year survival
Brown, 2007^[19]	CyberKnife Center in Miami	59	15–67.5 Gy in 1–5 fractions	Stage iA or 1 B	1–33 months Median not reported	86% alive at 1–33 month follow up
Baumann, 2006^[20]	Karolinska Hospital, Sweden	138	30–48 Gy in 2–4 fractions	Stage 1	33 months	3 year survival 52% 5 year survival 26%
Zimmerman, 2005^[21]	Technical University, Germany	30	24–37.5 Gy in 3–5 doses	Stage 1	18 months	80% 12 month survival 75% 24 month survival
Onimaru, 2003^[22]	Hokkaido University Japan	46 (26 with primary lung cancer)	48–60 GY in 8 doses	Stage 1	17 months	47% 2 year survival 60% 2 year cause specific survival
Hara, 2006^[23]	International Medical Center of Japan	59 (11 with primary lung cancer)	20–34 Gy single dose	Stage 1	12 months	76.5% 1 year survival 41% 2 year survival Primary lung cancer not analyzed separately
Fritz, 2006^[24]	Germany	58 (33 primary lung cancer)	30 Gy single dose	Stage 1	18 months	1 year survival 83% 3 year survival 53%
Grills, 2010^[25]	Michigan	124	48=60 Gy in 4–5 fractions or surgery	Stage 1 Borderline surgical candidates	2.5 years	No difference in regional recurrence, distant mets or freedom from any failure
Chang, 2008^[26]	University of Texas	27	40 or 50 Gy in 4 doses	Stage 1	17 months	Local control 100% for those receiving 50 GY 3/7 had local recurrences with 40 Gy
Videtic^[27]	Cleveland Clinic	26	10 Gy x 5 days	Sage I	40.9 months	3 year local control 94.4% 3 year overall survival 52%
Parashar, 2010^[28]	Cornell Medical Center, New york	55	SBRT or surgical resection with seed implantation	Malignant solitary lung nodule	17.5 months	No significant differences in local control, distant mets, survival or toxicity
Van Zyp, 2010^[29]	Netherlands	38	SBRT 45 or 60 Gy in 3 fractions	Age 80 or over Stage I	23 months	65% 1 year survival 44% 2 year survival
Oshiro, 2010^[30]	Japan	21	100 GY Median	Centrally located tumors	20 months	62.2% two year survival
Olsen, 2011^[31]	Missouri	19	18 Gy in 3 fractions 9 gy in 5 fractions 10 Gy in 5 fractions	Single primary lung lesion	11–16 months	Reduced local control in those who received 9 Gyx 5
Guckenberger, 2007^[32]	Europe	70 (38 primary lung cancer)	6–12.5 Gy in 3–8 fx or 26 gy x 1	Inoperable early stage NSCLC or metastatic disease	24 months	885 local control at 24 months

Gy, Gray; N0M0, No nodes and no metastatic disease; BED, Biologically Effective Dose; NSCLC, Non small cell lung cancer; Met, metastases; SBRT, Stereotactic Body Radiotherapy

Table 2. Prospective Studies of Stereotactic Body Radiation Therapy for Early Stage Non Small Cell Lung Cancer
STUDY	TYPE	LOCATION	N	INTERVENTION	INCLUSION	OUTCOMES
COMPLETED
Timmerman, 2010^[11]	Phase II	U.S. Multi-institutional	55	3 fractions 20 Gy each=60 Gy	Medically inoperable T1–3 tumors <5 cm ; no lymph nodes, peripheral (excludes tumors of proximal bronchial tree	Local control and toxicity
Fakiris, 2009^[8]	Phase II	University of Indiana, US	70	60–66 Gy in 3 fractions	Stage 1 Medically inoperable	Survival Local Control
Koto, 2007^[9]	Phase II	Japan	31	45 Gy in 3 fractions	T1–2, N0Mo	Survival
Nagata, 2005^[10]	Phase I/II	Japan	45	48 Gy in 4 fractions	Stage 1 A or 1B lung cancer	Survival Local Control
Le, 2006^[33]	Phase I Dose Escalation	Stanford, CA	32 (21 with NSCLC)	60–66 Gy in 20–22 Gy fracs 15–30 Gy single	Stage 1	Survival
Timmerman, 2003^[34]	Phase I Dose Escalation	U of Indiana, US	37	24–60 Gy in 3 fractions	T1 or T2 N0M0	Local Control
Bral, 2010^[35]	Phase II	Belgium	40	60 Gy in 3 fractions	T1–3N0M0	Local Control and survival
Bauman, 2009^[36]	Phase II	Sweden, Norway and Denmark	57	45–66 Gy	Stage I Medically inoperable	Progression free survival
Lagerwaard, 2008^[37]	Review of prospective database	Netherlands	206	Range: 20 Gy x 3 to 7.5 Gy x 8	Stage I or 2 81% medically inoperable	Overall survival and disease free survival
Bradley, 2010^[38]	Review of prospective database	Washington University, St. Louis	91	Median 54 Gy in 3 fractions	Medically inoperable or refused surgery	Local control
Stauder, 2011^[39]	Review of prospective database	U.S.	84 pts with 88 lesions (64 primary or recurrent	32–60 Gy in 3–5 fractions	Medically inoperable NSCLC or metastatic lung lesions	Pulmonary toxicity
ONGOING
RTOG 0618	U.S. Phase II multi-institutional	U.S. Multi-institutional	33 Accrual complete	20 Gy x 3 vs. surgery;	Tumor <5 Cm ; operable disease	Local control and toxicity
RTOG 0813	Phase I/II	U.S. Multi-institutional	48 of 94 as of 5/6/11	Goal to determine MTD Anticipated 11.5 Gy/FX	Medically inoperable centaly located tumors	Rate of tumor control
RTOG 0915	Phase II	U.s. multi-institutional	94 accrual complete	48 gy in 4 fx vs 34 Gy in 1 fx	Medically inoperable peripheral tumors	Toxicity
JCOG 0403 Recently completed results reported in abstract form	Single arm Phase II	Japan	Accrual plans 100 inoperable and 65 operable patients	48 Gy in 4 fractions over 4–8 days	Operable patients with clinical stage 1A	3 year survival
Washington University	Phase I/II	U.S.	Goal =75	MTD to be determined9range 9 GY x5 to 12 GY x 5)	Stage I or II Central tumors	Treatment related toxicity Local control rate
SPACE	Phase II two arms	Scandinavia	100	66 GY in 3 fractions vs. Conventional treatment 70 Gy with 2 Gy per fraction in 35 fractions	Stage 1 medically inoperable Peripheral tumors	3 year survival
CHISEL	Phase III	Australia	Goal of 100	Hypofractionated SBRT (total dose of 60–66 Gy vs conventional radiotherapy	Stage 1 medically inoperable Peripheral	Time to local failure
STARS	Phase III	U.S. multi-center	Goal of 1030	ecyberKnife stereotactic radiotherapy with surgical resection	Stage 1 Non small cell Operable	3 year survival

Gy,Gray; SPACE, Stereotactic Precision And Conventional Radiotherapy Evaluation; NSCLC, Non small cell lung cancer; JCOG, Japan Clinical Oncology Group; RTOG, Radiation Therapy Oncology Group; MTD, Maximum tolerated dose; N0M0, No nodes and no metastatic disease

Table 3. Results of Phase I and II Studies of Stereotactic Body Radiation Therapy for Early Stage Non Small Cell Lung Cancer
STUDY	TYPE	LOCATION	N	INTERVENTION	INCLUSION	DURATIO N OF FOLLOW UP	OUTCOMES
Timmerman, 2010^[11]	Phase II	U.S. multi-center	55	54 GY in 3 fractions	Stage 1 Medically inoperable Peripheral tumors	34.4 months	90.6% 3 year local control 55.8% 3 year survival
Fakiris, 2009^[8]	Phase II	U of Indiana, US	70	60–66 Gy in 3 fractions	Stage 1 Medically inoperable	50.2 months	3 year survival 42.7% 88.1% 3 year local control
Koto, 2007^[9]	Phase II	Japan	31	45 Gy in 3 fractions	T1–2, N0M0	32 months	3 year survival 71.7% 3 year cause specific survival 88.5%
Nagata, 2005^[10]	Phase I/II	Japan	45	48 Gy in 4 fractions	Stage 1 A or 1B lung cancer	30 months	98% local control survival for Stage 1 A:92%% 1 year and 83% 3 year Survival for Stage 1B:1 year 82% and 3 year 72%
Le, 2006^[33]	Phase I Dose Escalation	Stanford, CA	32 (21 with NSCLC)	60–66 Gy in 20–22 Gy fractions 15–30 Gy single	Stage 1	12 months	91% survival>20Gy 54% survival <20 Gy
Timmerman, 2003^[34]	Phase I Dose Escalation	U of Indiana, US	37	24–60 Gy in 3 fractions	T1 or T2 N0M0	15.2 months	6/37 local failure
Bauman, 2009^[36]	Phase II	Sweden, Norway and Denmark	57	45–66 Gy in 3 fractions	T1N0M0 and T2N0N0	35 months	92% local control at 3 years 75 local relapse 5% regional relapse 16% with distant mets
Bral, 2010^[35]	Phase II	Belbium	40	60 Gy in 3 fractions	T1–3N0M0	2 years	975 progression free survival at one year 84% progression free survival at two years

Gy, Gray; N0M0, No nodes and no metastatic disease; Met, metastases

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Stereotactic Body Therapy Radiation for the Treatment of Early Stage Non Small Cell Lung Cancer

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