MANAGEMENT OF EARLY STAGE NON SMALL CELL LUNG CARCINOMA

MANAGEMENT OF EARLY STAGE

NON SMALL CELL CANCER LUNG

Made by: Dr Isha JaiswalGuided by: Prof. Kamal Sahni

Date: 19th January 2016

Early-stage NSCLC: Stages I and II

• Stage IA: T1aN0, T1bN0• Stage IB: T2aN0• Stage IIA: T2bN0 or T1–2aN1• Stage IIB: T2bN1 or T3N0

TREATMENT ALOHORITHM FOR EARLY STAGE LUNG CANCER

Cardiorespiratory assessment Cardiorespiratory assessment

NCI Treatment guidelines for Early stage NSCLC

TREATMENT OPTIONS

OPERABLE PATIENT INOPERABLE PATIENT

SURGERY• WEDGE RESECTION• SEGMENTECTOMY• LOBECTOMY• PNEUMENECTOMY

± ADJUVANT TREATMENT CHEMOTHERAPY RADIOTHERAPY CHEMORADIOTHERAPY

GOOD PS POOR PS

CHEMORADIOTHERAPY RADIOTHERAPY

• CONVENTIONAL• 3DCRT• IMRT• IGRT• SBRT• PROTON THERAPY

PALLIATIVE TREATEMNT CHEMOTHERAPY RADIOTHERAPY

BEST SUPPORTIVE CARE

Preop assessment :Cardiopulmonary Evaluation

• to determine preoperative cardiac clearance.expected reduction in lung function after resection.

• Includespulmonary function testing, including spirometry, diffusion capacity, and arterial blood

gases.Imaging studies include ventilation-perfusion scan

Surgery : Indications in early NSCLC

gold standard treatment1. Indicated in all Stage I , II 2. Medically fit3. Good performance scale

Extent of SurgeryPrimary surgery

Wedge Resection Segmentectomy Lobectomy (preferable)Pneumonectomy

Lymphadenectomy LN sampling LN dissection

depends onPatients factorsTumor related factors Surgical expertise

1. Ginsberg RJ, Rubinstein LV. Randomized trial of lobectomy versus limited resection for T1 N0 non-small cell lung cancer. Lung Cancer Study Group. Ann Thorac Surg 1995;60(3):615–6232. Christopher Cao et al.Meta-analysis of intentional sublobar resections versus lobectomy for early stage non-small cell lung cancer : CORE group STUDY, Ann cardiothoracic surgery, 20143. Amgad El-Sherif,Outcomes of Sublobar Resection Versus Lobectomy for Stage I Non–Small Cell Lung Cancer: A 13-YearAnalysis, Ann Thorac Surg 2006; 82:408 –164.Okada M et al. Radical sublobar resection for small-sized NSCLC: a multicenter study. J Thorac Cardiovasc Surg 2006;132:769-755. Watanabe A et al. Feasibility of VATS segmentectomy for selected peripheral lung carcinomas. Eur J Cardiothorac Surg 2009;35:775-80

Lobectomy is the standard surgery for operable NSCLC. Various randomizes /non randomized studies has shown survival advantage over limited

resection (1)

however several recent studies and metanalysis have compared sub lobar resection with lobectomy in appropriately selected early-stage NSCLC with mixed results (2-5)

• .

Conclusion: sublobectomy (including wedge resection and segmentectomy) causes lower OS in stage IA (T1a) NSCLC patients. Hence lobectomy is the best optimal choice

FUTURE….• Two currently active prospective randomized trials are examining the role of sublobar

resection in early-stage disease: • the Cancer and Leukemia Group B (CALGB) 140503, a randomized trial of sublobar

resection versus lobectomy in small, peripheral early-stage operable NSCLC, • ACOSOG Z4032, a prospective randomized trial of sublobar resection with or

without brachytherapy for high-risk early-stage NSCLC.

• These trials will delineate the role of sublobar resection in the management of early-stage NSCLC.

Extent of lymphadenectomysampling vs dissection

Several Studies address survival benefit of mediastinal lymph node dissection (MLND) vs sampling

Pros:• MLND remove occult N+ disease, would decrease recurrence and increase survival.

Cons:• Increased morbidity• Improved sampling techniques

• 1111 pts NSCLC randomized, • undergoing resection for N0 or non hilar N1, T1, or T2 NSCLC• underwent sampling of 2R, 4R, 7, and 10R for right-sided tumors and 5, 6, 7, and 10L for

left-sided tumors. • sampling by mediastinoscopy ,thoracotomy, or VATS• If all tumors were negative for malignancy, randomized to

no further L.N sampling (mediastinal lymph node sampling Arm MLNS) complete mediastinal lymph node dissection (MLND)

• 1023 evaluable Sampling:498 pts, vs. Dissection:525pts.

Darling GE, Allen MS, Decker PA, et al. Randomized trial of mediastinal lymph node sampling versus complete lymphadenectomy during pulmonary resection in the patient with N0 or N1 (less than hilar) non-small cell carcinoma: results of the American College of Surgery Oncology Group Z0030 Trial. J Thorac Cardiovasc Surg 2011;141(3):662–670.

RESULTS:• Previous reports from this trial showed no increase in morbidity or mortality with the

addition of MLND*• At a median follow-up of 6.5 years, • 435 patients (43%) have died: MLNS:44% and MLND:42%). • median survival is 8.1 years for MLNS and 8.5 years MLND (P = .25). • 5-year DFS was 69% in the MLNS and 68% in the MLND group (p = .92). • no difference in local (P = .52), regional (P = .10), or distant (P = .76) recurrence

*Allen MS, Darling GE, Pechet TT, et al. Morbidity and mortality of major pulmonary resections in patients with early-stage lung cancer: initial results of the randomized, prospective ACOSOG Z0030 trial. Ann Thorac Surg. 2006;81:1013-20.

CONCLUSIONS: If systematic and thorough pre-resection sampling of mediastinal and hilar lymph nodes

is negative, MLND does not improve survival in patients with early stage NSCLC , but these results are not generalizable to patients staged radio graphically or those

with higher stage tumors

conclusion• there was no statistically significant difference in overall survival, local

recurrence, and distant metastasis between MLND and MLNS in early stage NSCLC patients.

• Furthermore, no evidence was found that MLND increased complications compared with MLNS.

• However, due to significant staging heterogeneity between RCTs, whether or not MLND is superior to MLNS remains to be determined.

VATS vs open lung resections

Posterolateral thoracotomyVideo assisted thoracoscopic surgery (VATS) :Learning curve

VATS vs open thoracic surgery meta analysis• 21 studies; 2641 patients• Two randomized trials • 1391 VATS resections• 1250 open resections

Oncologic control Five year survival

All cause mortalityimproved 5-year mortality rate of VATS (P = .04).

CONCLUSION:Both randomized and nonrandomized trials suggest that VATS lobectomy is an appropriate procedure for selected patients with early-stage NSCLC when compared with open surgery

Adjuvant therapy• Postoperative Radiotherapy• Postoperative Chemotherapy• postoperative Chemo-radiotherapy

 Patterns of failure. Sites of locoregional recurrence after surgical resection

• Locoregional recurrence after resection of NSCLC is common, occurring in 20% of pts. with stage I compared to 50% of pts with stage III disease.

• The predominant pattern of intrathoracic failure is along the surgical stump or in the mediastinal nodes

. Patterns of failure after resection of NSCLC. IJROBO 2006;65(4):1097–1105,

INDICATIONS - PORT• Completely resected R0• Stage I & II –no role.• Stage IIIA- may benefit

• Other indications• Stage I & II – close/positive margins.• Stage IIIA• Close margin (<5mm),• Positive margin, • N2 disease,• Nodal ECE

Port meta-analysis Trialist Group

• 2128 patients. • 9 randomised trials of S +PORT vs Surgery• 21% relative increase in the risk of death with RT• 2 yr reduced OS from 55% to 48% • Adverse effect was greatest for Stage I,II• Stage.III (N2): no clear evidence of an adverse effect• CRITICISM:

• 25% pts were pN0 • no quality control in the radiotherapy

Role Of Port Called Into Question

 Postoperative radiotherapy in non-small-cell lung cancer: systematic review and meta-analysis of individual patient data from nine randomised controlled trials. PORT Meta-analysis Trialists Group. Lancet 1998;352(9124):257–263.

SEER (JCO 2006)7,400 patients, stage II–III NSCLC post op + PORT• T3-T4 advanced nodal stage• On multivariate analysis following had negative impact on survival

• older age T3,T4 N2 stage male, • fewer sampled LN • greater no of LN involved.

• 5-year OS for • N2 patients (20→27%, HR 0.85) IMPROVED SURVIVAL• N0 (41 → 31%, HR 1.2) REDUCED SURVIVAL• N1 (34 → 30%, HR 1.1) REDUCED SURVIVAL

Lally BE, Zelterman D, Colasanto JM, et al. Postoperative radiotherapy for stage II or III non-small-cell lung cancer using the surveillance, epidemiology, and end results database. J Clin Oncol 2006;24(19):2998–3006.

Lung ART trial: in completely resected NSCLC with pN2The trial is ongoing, and results are not yet available.

Postoperative chemotherapy

• Indication• pT2N0M0 • pT1-2N1M0 • pT3N0-1M0

• Not indicated in• pT1N0M0

• pooling data from five large randomized trials • 4,584 patients stage I-IIIA to examine the role of cisplatin-based adjuvant chemotherapy in

completely resected patients. • With a median follow-up time of 5.2 years• demonstrated a statistically significant 5.4% absolute survival benefit favouring adjuvant. cisplatin-

based chemotherapy

• LACE-vinorelbine cohort included 1888 patients • Baseline characteristics similar to LACE-other but had fewer patients with stage IA

(2% versus 11%). Survival improvement at 5 years was 8.9% with cisplatin-vinorelbine versus observation (HR 0.80, 95% confidence interval: 0.70-0.91, p <0.001).

• Stage was a significant predictor for survival (test for trend, p = 0.02;• benefit at 5 years: 14.7% [stage III], 11.6% [stage II], and 1.8% [stage I]). • Similar benefits were seen for disease-free survival (HR 0.75 [0.67-0.85, p <0.001],

stage III [HR 0.62, 0.50-0.76], stage II [HR 0.69, 0.57-0.83], and stage I [HR 0.95, 0.767-1.19]).

• The overall result was statistically superior to LACE-other (LACE other HR 0.95, 0.86-1.05, interaction p = 0.04).

CONCLUSION:In subgroup analyses, adjuvant cisplatin-vinorelbine provides a superior survival benefit and can be recommended in completely resected stages II and III non-small cell lung cancer.

Adjuvant chemotherapy: regimen

• Cisplatin based chemotherapy• Preferred• Cisplatin +vinrolebine• Other

• Cisplatin + etoposide• Cisplatin +gemcitabine• Cisplatin +doceteaxel• Paclitaxel+ carboplatin

Postoperative chemo-radiotherapy Role of post op CTRT has been studied in few phase II/III trials RT – 50.4Gy/28Fr ± Boost 10.8Gy/6Fr for ECE + or or R1 resections in

stage II & III NSCLC with concurrent pacli+carbo CT Shown trend towards improvement in OS & PFS Further trials with modern chemotherapy regimen and radiotherapy

techniques needed

can be considered for medically fit patients at high risk for local recurrence

positive microscopic margin residual macroscopic disease Node + with ECE• Keller SM, Adak S, Wagner H, et al. A randomized trial of postoperative adjuvant therapy in patients with completely resected stage II or IIIA non-small-cell

lung cancer. Eastern Cooperative Oncology Group. N Engl J Med 2000;343(17):1217–1222 • Bradley JD, Paulus R, Graham MV, et al. Phase II trial of postoperative adjuvant paclitaxel/carboplatin and thoracic radiotherapy in resected stage II and IIIA

non-small-cell lung cancer: promising long-term results of the Radiation Therapy Oncology Group—RTOG 9705. J Clin Oncol 2005;23(15):3480–3487.• Feigenberg SJ, Hanlon AL, Langer C, et al. A phase II study of concurrent carboplatin and paclitaxel and thoracic radiotherapy for completely resected stage II

and IIIA non-small cell lung cancer. J Thorac Oncol 2007;2(4):287–292.

Adjuvant chemotherapy is accepted as standard of care for patients T2/N+ PORT /CTRT might be beneficial in R1 resection,pN2/ECE patients

Conclusion On Adjuvant Treatment In Post Op Cases

INOPERABLE EARLY STAGE NSCLC

INOPERABLE Stage I/II Non–Small Cell Lung Cancer

Radiotherapy technique1. Conventional radiotherapy2. 3-Dimentional Conformal Therapy.3. Intensity Modulated Radiation Therapy.4. IGRT and Gated Radiotherapy.5. Stereotactic body radiotherapy6. Particle beam therapy

Good KPS N+ Disease: consider definitive CTRT N- disease : consider definitive RT

Poor KPS Palliative treatment Best supportive care

Outcome By Radiation Therapy Dose And Treatment Volume For Patients With stage I-IIIA Non–small Cell Lung Cancer

Perez & Brady's Principles and Practice of Radiation Oncology

Surgery vs radiotherapy

Surgery

5 yr survival• T1 N0 70-90%• T2 N0 45-68%• T1 N1 40-57%• T2 N1 33-45%

Radiotherapy:3DCRT Median dose:60Gy

5 yr survival

• Stages I, II 6-36%

NON RANDOMIZED COMPARISION

• The 5-year survival with definitive RT range from 10% to 40% • possible explanations for poorer results

• poorer health of medically inoperable pt.• most patients are clinically staged.• limitation in the maximum dose that can be delivered to the tumor

• Fletcher* predicted that using 1.8 to 2 Gy/#, doses of 100 Gy or higher required for the sterilization of most NSCLC tumors.

• These doses are not routinely achievable with conventionally # RT without excessive toxicity.

Fletcher GH. Clinical dose-response curves of human malignant epithelial tumours. Br J Radiol 1973;46(541):1–12.

Stereotactic Body Radiotherapy• stereo taxis refers to targeting, planning, and directing of therapy using beams of

radiation toward a target of known 3-D coordinates. • Allows delivery of large doses of radiation, in small number of fractions (usually

≤5) to a small treatment volume, employing multiple non overlapping, non coplanar beams, with advanced imaging & treatment delivery techniques

• INDICATIONS Accurately staged AJCC stage I or II TNM staging: T1N0M0, T2 (≤ 5 cm)N0 M0, T3 (≤ 5 cm)N0M0 ECOG 0-2

Outcome For Patients With Early-stage Non–small Cell Lung Cancer Receiving Stereotactic Body Radiation Therapy

Perez & Brady's Principles and Practice of Radiation Oncology

RADIOTHERAPY TECHNIQUES

1. Conventional radiotherapy

2. 3-Dimentional Conformal Therapy.

3. Intensity Modulated Radiation Therapy.

4. IGRT and Gated Radiotherapy.

5. Stereotactic body radiotherapy

6. Particle beam therapy

Conventional External beam radiotherapy

• Position: supine ,hands above head• Simulation :Xray, CT based• Volume:• Radiologically visible tumour with 2 cm margin all around

the tumour.• Adjacent lymph nodes and mediastinum included.

• Fields : 2-3 fields with or without wedge filterdepending upon location of the tumour• Modality : Linac beam 6-10 MeV or cobalt beam

• Dose60-66 GY @1.8-2 GY/#

CONFORMAL RT IN LUNG CANCER

Conformal RT Allows• Volumetric image acquisition• Tumour and normal tissue delineation.• Fusion of different image modalities.• Ability to manipulate beam geometry• Accurate dose calculations • Image guidance ,motion management• IMRT,SBRT offers benefit of dose escalation

Advantages over conventional RT• Better conformity of radiation dose to the tumour.• Sparing of vital structures around tumour-Reduced morbidity.• Escalation of dose- Better control of disease.

RT PLANNING STEPS• Immobilization• Simulation scan• Contouring• Dose constraints to both target and OAR’s• Daily verification of treatment setup• Plan execution• Weekly review

SIMULATION• Positioning: Supine position, hands above the head• Immobilization: wing board, alpha cradle, stereotactic body

frame. Abdominal compression• I.v Contrast• Serial CT Thickness <5mm(1-3mm for SBRT) from the level of

the cricoid cartilage to the second lumbar vertebra.

Management of Tumor Motion during Simulation• AAPM Task Group Report No. 76 recommends that motion management strategies be considered

when the range of tumor motion is >5 mm (lesser for SBRT) in any direction. • Tumor and organ motion, should be assessed or accounted for at simulation. • To assess the range of mobility of tumors options include

fluoroscopy, inhale/exhale or slow scan CT (4sec/slice), 4D-CT generate multiple data sets at different phases of the respiratory cycle

• Methods to limit motion shallow breathing using abdominal compression devices, deep inspiration breath-holdautomatic breathing control,respiratory gatingtumor tracking

Delineation: GTV• lung windowing should be used for delineation of primary tumor GTV. • soft tissue windows with contrast used to avoid inclusion of adjacent vessels, atelectasis,

or mediastinal or chest wall structures within GTV. • FDG-PET may be of additional value in the setting of atelectasis and nodal volumes• GTVp: clinical macroscopic disease defined on any imaging modality usually derived from a

treatment planning CT &/or PET-CT • GTVn:information from CECT ,FDG-PET-CT, mediastinoscpoy ,endobronchial ultrasound

should be incorporated into delineating the nodal GTV

CTV: volumetric expansion of the GTV to encompass microscopic disease.• CTV-p• For the primary tumor, pathologically derived correlative data have shown that CTV varies with histologic

type 1

• CTV-n• surgical series have shown that a 3-mm margin will encompass 95% of the microscopic extra nodal

extension in lymph nodes <2 cm 2

• However, larger margins may be required for lymph nodes >2 cm• No CTV for SBRT planning

Microscopic extension Adeno Squamos mean value 2.69mm 1.48mm 5mm margin covers: 80% 91% margin to cover 95% 8mm 6mm

1. Giraud P, Antoine M, Larrouy A, et al. Evaluation of microscopic tumor extension in non-small-cell lung cancer for three-dimensional conformal radiotherapy planning. Int J Radiat Oncol Biol Phys 2000;48(4):1015–10242. Yuan S, Meng X, Yu J, et al. Determining optimal clinical target volume margins on the basis of microscopic extracapsular extension of metastatic nodes in patients with non-small-cell lung cancer. Int J Radiat Oncol Biol Phys 2007;67(3):727–73

PTV• volumetric expansion of the CTV to account for tumor motion & setup

variability• PTV margin can be decreased by immobilization, motion management, and

IGRT techniques.

• With motion management & IGRT PTV ranges 5-10mm (3-6mm for SBRT)

Image Guided Treatment delivery

Radiation delivery for lung cancer treatment is generally performed using IGRT-which can be acquired using • megavoltage (MV)- or kilovoltage (kV)-based planar imaging, • volumetric, cone-beam CT imaging • Gating :treatment delivery within a particular portion of the patient’s breathing cycle ie

preset Window commonly referred to as the “gate”• Tracking: fiducials used to track the tumor in real time

TARGET DOSE PRESCRIPTION & OAR CONSTRAINTS

NCCN Guidelines Version 4.2016 Non-Small Cell Lung Cancer

For conventional fractionated RT

PROTON BEAM THERAPY

• Proton beam has a Bragg peak which can be modulated to deliver uniform dose to tumor site while sparing surrounding normal tissues.

• It reduces dose to normal lung Oesophagus Heart and spinal cord• Higher dose of radiation-87-88 Greys can be delivered compared to only 66 Gys with

conventional radiation• Limited availability

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