CHEMORADIOTHERAPY RADIOTHERAPY CONVENTIONAL 3DCRT IMRT IGRT SBRT PROTON THERAPY

1. MANAGEMENT OF
EARLY STAGE
NON SMALL CELL CANCER LUNG
Made by: Dr Isha Jaiswal
Guided by: Prof. Kamal Sahni
Date: 19th January 2016

2. 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

4. TREATMENT ALOHORITHM FOR EARLY STAGE LUNG CANCER
Cardiorespiratory assessment Cardiorespiratory assessment
NCI Treatment guidelines for Early stage NSCLC

5. 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

6. Preop assessment :Cardiopulmonary Evaluation
• to determine
preoperative cardiac clearance.
expected reduction in lung function after resection.
• Includes
pulmonary function testing, including spirometry, diffusion capacity, and arterial blood
gases.
Imaging studies include ventilation-perfusion scan

7. Surgery : Indications in early NSCLC
gold standard treatment
1. Indicated in all Stage I , II
2. Medically fit
3. Good performance scale

8. Extent of Surgery
Primary surgery
Wedge Resection
Segmentectomy
Lobectomy (preferable)
Pneumonectomy
Lymphadenectomy
 LN sampling
 LN dissection
depends on
Patients factors
Tumor related factors
Surgical expertise

9. 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):615–623
2. 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, 2014
3. Amgad El-Sherif,Outcomes of Sublobar Resection Versus Lobectomy for Stage I Non–Small Cell Lung Cancer: A 13-Year
Analysis, Ann Thorac Surg 2006; 82:408 –16
4.Okada M et al. Radical sublobar resection for small-sized NSCLC: a multicenter study. J Thorac Cardiovasc Surg 2006;132:769-75
5. 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)

10. • .

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

13. 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.

14. Extent of lymphadenectomy
sampling 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

15. • 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.

16. 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.

17. 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

21. 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.

22. VATS vs open lung resections

23. Posterolateral thoracotomy
Video assisted thoracoscopic
surgery (VATS) :Learning curve

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

25. Oncologic control Five year survival

26. All cause mortality improved 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

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

28. 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,

29. 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

30. 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.

31. 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.

32. Lung ART trial: in completely resected NSCLC with pN2
The trial is ongoing, and results are not yet available.

33. Postoperative chemotherapy
• Indication
• pT2N0M0
• pT1-2N1M0
• pT3N0-1M0
• Not indicated in
• pT1N0M0

34. • 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

36. • 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.

37. Adjuvant chemotherapy: regimen
• Cisplatin based chemotherapy
• Preferred
• Cisplatin +vinrolebine
• Other
• Cisplatin + etoposide
• Cisplatin +gemcitabine
• Cisplatin +doceteaxel
• Paclitaxel+ carboplatin

38. 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.

39.  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

40. INOPERABLE EARLY STAGE NSCLC

41. INOPERABLE Stage I/II Non–Small Cell Lung Cancer
Radiotherapy technique
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
Good KPS
 N+ Disease: consider definitive CTRT
 N- disease : consider definitive RT
Poor KPS
 Palliative treatment
 Best supportive care

42. 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

43. 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

44. • 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.

45. 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

46. 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

47. 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

48. 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 filter
depending upon location of the tumour
• Modality : Linac beam 6-10 MeV or cobalt beam
• Dose
60-66 GY @1.8-2 GY/#

49. 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.

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

51. 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.

52. 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-hold
automatic breathing control,
respiratory gating
tumor tracking

53. 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

54. 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
Microscopicextension Adeno Squamos
meanvalue 2.69mm 1.48mm
5mmmargincovers: 80% 91%
margintocover95% 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):1015–1024
2. 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

55. 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)

56. 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

57. TARGET DOSE PRESCRIPTION & OAR CONSTRAINTS
NCCN Guidelines Version 4.2016 Non-Small Cell Lung Cancer
For conventional fractionated RT

59. 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

60. THANKYOU