Early stage lung_cancer- jtl

Early Stage Lung Cancer

Wake Forest Baptist Medical CenterRadiation Oncology Department

John T. Lucas Jr. MD, MSCR PGY2

OutlineManagementTreatment Options Surgery Alternative Ablative Modalities RadiotherapySBRT History Technique Dose, Fractionation Dose Constraints Side Effects/Complications Post Treatment Surveillance Outcomes Ongoing Trials

Surgery

- Types of Resection- Operability- Outcomes- QOL

Surgery - Types- Types of Resection - Pneumonectomy

- Lobectomy

- Sublobar: - Segmentectomy - Sleeve Segmentectomy

- Wedge Resection

"Sleeve"

Surgery - TypesOperability Min absolute FEV1 for: Pneumonectomy > 2L Lobectomy > 1.5L Wedge < 1.5L (variable) RTOG 0813 def: FEV1 50%, DLCO 50%

Morbidity Predictors: 1. pCO2 <45 mm Hg 2. pO2 <50 mm Hg 3. Preop FEV1 <40% of predicted value 4. Poor exercise tolerance 5. DLCO <50% of predicted value 6. Postop FEV1 <0.71 or <30% of predicted value 7. Cardiac problems (LV EF<40%, myocardial infarction within 6 mos, arrhythmias) 8. Obesity 9. Ongoing smoker pre and post surgery

Surgery - Morbidity

Lobectomy vs. Pneumonectomy

Tobias Schulte, Bodo Schniewind, Peter Dohrmann, Thomas Küchler and Roland Kurdow. The Extent of Lung Parenchyma Resection Significantly Impacts Long-Term Quality of Life in Patients With Non-Small Cell Lung Cancer. Chest 2009;135;322-329

Surgery - Morbidity

Tobias Schulte, Bodo Schniewind, Peter Dohrmann, Thomas Küchler and Roland Kurdow. The Extent of Lung Parenchyma Resection Significantly Impacts Long-Term Quality of Life in Patients With Non-Small Cell Lung Cancer. Chest 2009;135;322-329

Surgery - Types - Sublobar Resection

Errett LE et al J Thorac Cardiovasc Surg. 1985 Nov;90(5):656-61

- Not a new idea - 1985


RJ Ginsberg, LV Rubinstein and Lung Cancer Study Group Ann Thorac Surg 1995;60:615-23

- Prospective, multi-institutional randomized trial- Lobectomy vs. Sublobar for Early Stage NSCLC

= 1.26 & .016%

= 4.7 & 2.52%

= 3.83 & 1.3%


RJ Ginsberg, LV Rubinstein and Lung Cancer Study Group Ann Thorac Surg 1995;60:615-23

- Lobectomy vs. Sublobar for Early Stage NSCLC

Thermal AblationCryoablation (Cooltip)Microwave ablation

Alternative Ablative Modalities

• Retrospective Single Center

• 420 Patients

• 33% w/1o Lung, 67% w/Metastasis

• 1000 Cool-tip RFAs


AJR Am J Roentgenol. 2011 Oct;197(4):W576-80. Complications after 1000 lung radiofrequency ablation sessions in 420 patients: a single center's experiences. Kashima M, Yamakado K, Takaki H, Kodama H, Yamada T, Uraki J, Nakatsuka A.

• Complications


Radiotherapy- Historical Perspective-Standard approach involves giving approximately 45-66 Gy total dose in 1.8-2.0 Gy fractions.

- Relationship in both survival and local control in these patients. - Review of 156 medically inoperable stage I NSCLC patients at Duke University between 1980 and 1995 demonstrated a five-year, cause-specific survival of 32% with radiotherapy alone. Improved survival was significantly correlated with achieving local control and approached significance for higher radiotherapy dose (p=0.07).

- Historically treated area included regional lymphatics in the ipsilateral hilum and mediastinum. This “prophylactic” treatment was based on identified risk of occult nodal involvement from surgical series ranging up to 20%, and surgical data indicating better control with more extensive resections.

- Nonetheless, large radiotherapy fields are potentially poorly tolerated in this population with limited pulmonary reserve. (Curran WJ, Moldofsky PJ, Solin LJ. Analysis of the influence of elective nodal irradiation on postirradiation pulmonary function. Cancer. 65:2488-93, 1990.)

-Early technique used 1D-2D planning and didn’t:- visualize the target- had limitations in selection of beam directions- limitations in computational algorithms describing deposited dose.

Sibley GS, Jamieson TA, Marks LB, Anscher MS, Prosnitz LR. Radiotherapy alone for medically inoperable stage I non-small cell lung cancer: The Duke experience. Int J Radiat Oncol Biol Phys. 40(1): 149-54, 1998.

Radiotherapy- Historical Perspective

Researchers at the Karolinska Hospital in Stockholm, Sweden developed an extracranial stereotactic frame and began treatment with the device in 1992.

- Blomgren, et al., reported on 17 patients treated with stereotactic radiotherapy for intrathoracic metastases with follow-up of 3.5 to 25 months. 25 Tumors ranged in size from 1.8 cm to 7.2 cm. Margin doses ranges from 20 Gy in one fraction to 45 Gy in three fractions. Response was measured by repeat CT scans demonstrating:

Disappearance in 35%Reduction in 41%Stabilization in 18%Progression in only one patient (the largest tumor treated in the report).

SBRT - Rationale

-Conventionally fractionated RT (ie, cGy per fraction) operates on a portion of the cell survival curve describing the logarithm of clonagenic survival as a function of dose called the shoulder.

-In this shoulder region, an increasing dose per fraction corresponds to small decrements in cell survival dueto the ability of the tumor cell to repair modest damage (called sublethal damage).

-At some point with the increasing dose per fraction, these repair mechanisms become overwhelmed, and the logarithm of clonagenic survival becomes linear with increasing doses (called exponential cell killing).

-The dose per fraction and the total dose levels attained with ESR in this trial operated well beyond the shoulder, and its biological potency at disabling tumor clonogenicity should be significant.

SBRT

Dose, Fractionation Outcomes Technique Dose Constraints Side Effects/Complications Post Treatment Surveillance

SBRT Dose/Fractionation

Phase 1 Dose Finding Study

37 Stage 1 NSCLC Patients

1o Objective: Est DLT/MTD

8Gy x 3 to the 80% IDL

10Gy x 3

12Gy x 3

14Gy x 3

16Gy x 3

18Gy x 3

20Gy x 3

@ 14Gy stratifiedto escalate doseindependentlyfor T1 & T2tumors


- Didnt reach MTD

- No diff in Tox b/n T1 or T2

- No heterogeneity correction

- No significant cardiopulmonary toxicity

- 87% Objective RR, 27% CR

- 6 failures in patients all <18Gy/fx

8Gy x 3 to the 80% IDL

10Gy x 3

12Gy x 3

14Gy x 3

16Gy x 3

18Gy x 3

20Gy x 3


Retrospective Multicenter257 Stage 1 NSCLC PatientsWidely variable dose/fractionation: 18-75Gy, 1-22Fx


Phase II - Single Center

70 Patients w/ T1,T2 N0 M0

Tx: 60-66Gy / 3 Fx

Median f/u 17.5 mo

Robert Timmerman, and James Fletcher. J Clin Oncol 24:4833-4839. 2006

LC @ 2 years was 95%

Median OS 32.6 mo 2 yr OS 54.7%


2 yr freedom from toxicity-Central: 54%

-Peripheral: 83%

- Only additional predictor of toxicity was size of GTV, with > 10 cc tumors showing greater toxicity than smaller GTVs.

- G3/4 Toxicity events occurred a median of 7.6 mo after completion of SBRT.



Prospective Cohort27 Patients w/Central NSCLC (Recurrent (14) or Stage 1 (13)Median f/u of 17 mo - Prescribed dose of 40 Gy (n = 7) to the PTV- Escalated to 50 Gy (n = 20) in 4 consecutive days

1 patient experienced a brachial plexopathy w/20% of plexus recieving >40GyLC was poor w/<50Gy~ 3/7 failed

Not powered for any objectives, limited conclusions can be drawn - However 50Gy/4 fractions appears safe for central tumors - <50Gy is associated w/a higher failure rate

SBRT Dose/FractionationCentral Dose Question is currently being evaluated prospectively w/:

RTOG 0813 Phase I/II Study of SBRT in Medically Inoperable Patients w/Centrally Located Stage I NSCLC Dose Escalation: 50Gy/5fx --> 52.5/5 --> 55/5 --> 57.5/5 --> 60Gy/5fx

- Has high dose conformality index requirements that necessitate noncoplanar beam arrangement - OARs are limited to <105% of prescribed dose - Low and High Dose spillage are highly restrictive

SBRT Dose/Fractionation - RTOG 0236

Phase 2 Multi-center Trial

Peripheral Stage 1 NSCLC - Medically Inoperable

1o Objective: Eval Toxicity and Efficacy in high risk patients

Of 55 evaluable patients, 44 had T1 & 11 had T2 tumors.

Tx: 60Gy /3 fx --> Didnt correct for tissue inhomogeneity but retrospective analysis shows a total dose of 54Gy / 3 fx

Median f/u 34.4 mo

The study was activated in May 2004 and opened in 8 sites, after those sites had completed the credentialing process. RTOG 0236 was closed October 2006.

SBRT Dose/Fractionation - RTOG 0236

1o Failure = 2.4% @ 3yrs (CI 0.3-15.7%)1 patient

Involved Lobe Failure = Local failure - 1o Failure = 10.4%-2.4% = 8%

Local Failure = 1o failure + Involved lobe failure = 10.4% @ 3 yrs (CI 3.5-24%)3 patient (involved lobe 2nd 1o)

Regional Failure = hilum + mediastinum = local regional - local failure = 12.8%-10.4% = 2.4%2 involved lobe & mediastinum, 1 hilum alone Local-regional Failure=1o Failure+Involved lobe+hilum+mediastinum=12.8%@3yrs (CI 5.3%-29%)

Disseminated Failure = 22.1% @ 3yrs (CI 12.3%-37.8%)

11 patients 1 mediastinum & dissem 8 dissem alone 2 NOS - 30.7% Adeno, 6% SCC

SBRT Dose/Fractionation - RTOG 0236- 3yr DFS 48.3% (95% CI, 34.4%-60.8%) - 34.4 Mo (95% CI 34.4 mo-NA)

- 3 yr OS 55.8% (95% CI, 41.6%-67.9%) - Median OS 48.1 mo (95% CI, 29.6- NA) 10 patients died of lung cancer 16 patients died of other causes 5 of comorbid problems: - Stroke, MI, COPD exacerbation, & 2nd malignancy 2 of nonprotocol medical interventions 9 of unknown causes

SBRT Dose/Fractionation - RTOG 0236Toxicities

Median f/u of 38.7 mo- 1 (2%) G4 pulmonary- 2/7 reported PFT decrease- 1/7 reported cough/dyspnea- 1 reported hypoxia- 1 reported pneumonitis- 1 reported cough- 1 patient reported PNX - 1 G3 dermatitis - 1 G3 syncope reported as related to protocol treatment. - 7 (13%) G3 pulmonary/upper respiratory adverse events 2/2 protocol

*Median Time to Toxicity not evaluated

- No treatment related deaths have been reported.

SBRT Outcomes

Recently ClosedRTOG 0915 - Closed 3/22/2011 A Randomized Phase II Study Comparing 2 SBRT Schedules (48Gy/4fx vs. 34Gy/1) for Medically Inoperable Patients with Stage I Peripheral Non-Small Cell Lung Cancer

RTOG 0618 - Closed 5/17/10 - Analysis planned for 6/2012 A Phase II Trial of SBRT in the Treatment of Patients with Operable Stage I/II NSCLC

ROSEL - Closed 4/4/11 due to poor accrual Radiosurgery or Surgery for Operable Stage 1 NSCLC - Netherlands Trial

SBRT Outcomes

Current TrialsACOSOG RTOG 1021

Phase 3 Sublobar Resection +/- Brachytherapy vs. SBRT (54Gy/3fx)

STARS - Phase 3 Randomized Study to Compare Cyberknife to Surgical Resection (any) in Stage 1 NSCLC Central lesion: 15 Gy x 4 fractions = 60 Gy; Peripheral lesion: 20 Gy x 3 fractions = 60 Gy

SBRT Technique

SBRT Technique

SBRT Technique

Composite 4d (MIP)Breath Hold CT

SBRT Technique

Med Phys. 2004 Dec;31(12):3179-86. Four-dimensional (4D) PET/CT imaging of the thorax. Nehmeh SA, Erdi YE, Pan T, Pevsner A, Rosenzweig KE, Yorke E, Mageras GS, Schoder H, Vernon P, Squire O, Mostafavi H, Larson SM, Humm JL.

SBRT Technique

SBRT Technique - Constraints

AAPM Task Group 101

AAPM Task Group 101 SBRT Dose Constraints

SBRT Post Treatment Surveillance

Monitor for:- Early treatment effects- Late radiotherapy effects (median time to G3/4 tox ~8mo)- Appearance of occult disease- Failure at primary site- Failure at distant site


Early Stage- f/u visits Post Tx: @ 2 mo then q4mo thereafter for 2 yrs 2 mo visit to establish baseline CT prior to tx change q4mo visits: CT w/out contrast if no concerns 2 Yrs Post Tx: q6mo for 5 yrs w/CT 5 yrs Post Tx: q1yr w/CT

Monitor for: Early treatment effects- PFT changes - No SS change in FEV1 or DLCO - If <6 mo out, pneumonitis possible

J Thorac Oncol. 2009 Jul;4(7):838-44. Comprehensive analysis of PFT changes after SBRT for stage I lung cancer in medically inoperable patients. Stephans KL, Djemil T, Reddy CA, Gajdos SM, Kolar M, Machuzak M, Mazzone P, Videtic GM.



Monitor for: Early treatment effects - PFT changes

J Thorac Oncol. 2009 Jul;4(7):838-44. Comprehensive analysis of pulmonary function Test (PFT) changes after stereotactic body radiotherapy (SBRT) for stage I lung cancer in medically inoperable patients. Stephans KL, Djemil T, Reddy CA, Gajdos SM, Kolar M, Machuzak M, Mazzone P, Videtic GM.


Monitoring for Occult Disease - PET Sensitivity - 86% Specificity - 88% - Mediastinoscopy Sensitivity - 93% Specificity - 100% - EBUS Sensitivity - 76% Specificity - 97%

Chest. 2003 Jan;123(1 Suppl):137S-146S. Noninvasive staging of non-small cell lung cancer: a review of the current evidence. Toloza EM, Harpole L, McCrory DC.

PET


Monitoring for Primary Site Failure- Complicated by: - Post RT changes - Radiation pneumonitis - Radiation fibrosis - Effusion - Other disease processes w/in the lung - Infection/Pneumonia - Bronchiectasis - Atelectasis - Actual Treatment Failure - Local progression - Subclinical lyphmangitic spread

Larici. Lung Abnormalities at Multimodality Imaging after Radiation Therapy for NSCLC. May 2011 RadioGraphics, 31, 771-789.


Monitoring for Primary Site FailurePost Radiation Treatment Changes- 1-6 mo RT Pneumonitis - Ground glass opacities, consolidation w/in radiation port - Potential ipsiateral pleural effusion - 4 patterns (Ikezoe)

- ground glass opacities - patchy consolidation and ground glass opacities - patchy ground glass opacities - scar like

- 6-12 mo Radiation Fibrosis - Well defined area of volume loss w/linear scar or consolidation w/parenchymal distortiona and traction bronchiectasis conforming to treatment portals

Larici. Lung Abnormalities at Multimodality Imaging after Radiation Therapy for NSCLC. May 2011 RadioGraphics, 31, 771-789.

2 months

3 months 6 months

Before


Monitoring for Primary Site FailureAlgorithm for post treatment CT surveillance

Site Abnormality - after comparison to prior CT scans

Significant + in size w/no air

bronchograms

Moderate + in size

PET Scanvs. Biopsy

Short interval f/u w/CT

Empiric Tx w/ roids & abtx

Short interval f/u w/CT


Role of PET in f/u s/p SBRT Sensitivity and specificity of FDG-PET/CT for detecting recurrence has historically been estimated to range from 93% to 100% and 82% to 92%, respectively

More recently found to be controversial

Mac Manus MP, Ding Z, Hogg A, et al. Association between pulmonary uptake of fluorodeoxyglucose detected by positron emission tomography scanning after radiation therapy for nonsmall-cell lung cancer and radiation pneumonitis. Int J Radiat Oncol Biol Phys. [Epub ahead of print July 31, 2010].


Role of PET in f/u s/p SBRT- Hoopes et al demonstrated that moderate HM activity may persist for up to 2 yrs after completion of SBRT w/out definite evidence of recurrence.

Validated prospectively w/a small number of patients

Mac Manus MP, Ding Z, Hogg A, et al. Association between pulmonary uptake of fluorodeoxyglucose detected by positron emission tomography scanning after radiation therapy for nonsmall-cell lung cancer and radiation pneumonitis. Int J Radiat Oncol Biol Phys. [Epub ahead of print July 31, 2010].


A study from the University of Pittsburgh demonstrated a significant correlation with mean SUV and treatment response. (mean SUV decreases) Complete responders, 94%, Partial responders 48%, Stable disease 28%

Patients with progressive disease had an SUV decrease of only 0.4%.

However this study only had once LR, so their definition of CR, PR, SD is arbitrary and w/out clinical relevance

Clin Lung Cancer. 2008 Jul;9(4):217-21. Fractionated stereotactic body radiation therapy in the treatment of primary, recurrent, and metastatic lung tumors: the role of positron emission tomography/computed tomography-based treatment planning. Coon D, Gokhale AS, Burton SA, Heron DE, Ozhasoglu C, Christie N.


Monitoring for Distant FailureEvaluate bony, mediastinal windows for recurrence- Mediastinal changes suspicious include + size of LAD or loss of fatty hilum- Complicating factors can include associated comorbidities such as: - CHF exacerbation - Chronic Bronchitis - TB/MAC infection i.e. HIV patients

Algorithm for post treatment CT surveillance

High Suspicion @ Primary Site for recurrence

Restage w/PET C/A/P

Fin

SBRT Treatment Failure - Salvage

To be discussed at a later date…

1. maximal tolerated dose for peripheral primary tumors less than 7 cm is 60 to 66 Gy in three fractions.2. The maximal tolerated dose for centrally located primary tumors less than 7 cm is unknown but is exceeded by doses of 60 to 66 Gy in three fractions. 3. A prescription dose less than 54 Gy in three fractions is associated with maximal local control of approximately 70% to 80% for patients treated inprospective trials with adequate follow-up in North America and Europe.4. A prescription dose of 54 Gy or more in three fractions has been demonstrated to achieve local control in more than 90% of treated tumors in prospective testing.5. Despite clinical staging, isolated hilar and mediastinal nodal failures occur in less than 5% of patients after SBRT.6. Despite staging with whole body PET scans, approximately 20% of patients develop distant metastatic disease.7. Although it is well-known that toxicity after large dose per fraction treatment occurs late, it is also recognized that tumor recurrence likewise occurslate after treatment with the median time to recurrence of 16 to 24 months after therapy. 8. Despite excellent local control after SBRT, patient survival for medically inoperable early-stage lung cancer is very poor, mainly due to severe and life- threatening coexisting morbidities and the eventual appearance of metastatic disease.

How do we stage early stage lung cancer patients who are planned for surgical eval?

Why do PET only staged patients who go for SBRT have lower regional failures?

What is the most appropriate group for comparing surgical vs. nonsurgical (SBRT) intervention for early stage lung cancer?

- 20% to 25% of patients with earlystage lung cancer are not considered candidates for lobar resection because of concomitant severe cardiac or pulmonary comorbidities

- Varying modilty of choice by location? - Peripherally located tumors 3 cm, sublobar resection by an anatomic segmentectomy (rather than a wedge resection) may result in OS & CSS ~ to lobectomy

- Centrally located within a lobe or close to the lobar bronchi have no viable surgical option other than lobectomy which, in this patient population, may be associated with a prohibitive morbidity & higher mortality.

SBRT Outcomes

Timmerman, Journal of Thoracic Oncology • Vol. 2, No. 7, Supplement 3, July 2007

SBRT vs. Wedge Resection


A key issue that must be considered when comparing these modalities based on available literature is that the definitions of local recurrence, local control, and regional recurrence are not uniform. This has led todifferent perceptions and interpretations of the published literature relating to these modalities. In thesurgical literature, local recurrence variably includes recurrence occurring within the same lobe, sometimes another lobe within the same ipsilateral lung, hilar and sometimes ipsilateral mediastinal lymph nodes [2,18,102].

In the SBRT literature, local recurrence usually is synonymous with primary tumor control, i.e., limited to recurrence within and sometimes within 1cm of the planning treatment volume (PTV) [12,101]. The moreappropriate convention for characterizing recurrence definitions is a reflection on the original TNM staging.As such, a recurrence of the original primary tumor (originally characterized by the T of the TNM stagingincluding the primary tumor and involved lobe) is deemed a local recurrence. A recurrence in the primarytumors draining lymph nodes (hilar and mediastinal as originally characterized by the N of the TNM staging) is deemed a regional recurrence. Finally, a recurrence in distant sites (originally characterized by the M of the TNM staging) is deemed a disseminated recurrence. By this convention, both the more recent surgical literature and SBRT literature have been guilty of inappropriate recurrence definitions making comparisons difficult.

Surgery - -Lobectomy vs. Sublobar Resection

Sublobar resection for lung cancer. SERIES ‘‘LUNG CANCER’’ Number 2 in this Series. R. Rami-Porta* and M. Tsuboi# Edited by C. Brambilla.


At Indiana University, a phase I dose escalation protocol has been completed for the treatment ofmedically inoperable patients with AJCC Stage I lung cancer. 26 SBRT (a.k.a. extracranialstereotactic radioablation) with large doses per fraction was delivered in an extracranialstereotactic body frame, which includes a system to decrease respiratory motion. The startingdose was 8 Gy times 3 (24 Gy total), and fraction dose was escalated by 2 Gy per fraction foreach cohort. The target lesion was outlined by a physician and designated as the gross tumorvolume (GTV). An additional 0.5 cm in the axial plane and 1.0 cm in the longitudinal plane wasadded to the GTV to constitute the PTV based on validation measurements for this commerciallyavailable system.27-29 Typically, 7-10 non-coplanar beams were used to encompass the PTV.Dose was prescribed to the 80% line; however, higher isodoses (hotspots) occurred within thecentral core of the target mimicking the heterogenous dose profile common to intracranialstereotactic radiosurgery. The higher dose in the tumor core is intended to give extra dose inareas of presumed greatest tumor hypoxia and radioresistance. The treatment isocenter wasidentified with 3-D coordinates defined stereotactically and localized on verniers attached to theframe. No skin or bony landmarks were used to set the treatment isocenter, however; orthogonalport films were used on a daily basis for isocenter verification. 30 Separate dose escalations werecarried out independently for patients with T1 versus T2 small (< 5 cm) versus T2 large (5-7 cm)tumors at diagnosis.

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Early stage lung_cancer- jtl