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10th ESO-ESMO Masterclass in Clinical Oncology
         02-07 April 2011, Ermatingen




                 NSCLC:
                 Surgery

                 Walter Weder MD
               Professor of Surgery
             University Hospital Zurich
Case 1




   59 y, female, 40 py,
   incidental finding on
   chest X-ray
Questions

• What is your diagnosis?

• Further staging?

• Lobectomy or sublobar resection?

• Radiotherapy

• Adjuvant therapy indicated?
NSCLC - stages at presentation


            7%
          Stage II       31%
                       Stage III


         24%
        Stage I

                       38%
                     Stage IV




                                   Fry, Cancer 1996
Stage-dependent survival for NSCLC

5-y survival after state-of-the-art treatment

     • Stage I 54-80%
     • Stage II     38-60%
     • Stage IIIA   10-30%
     • Stage IIIB   <10%
     • Stage IV     <5%
                               Tsuboi, World Conference IASLC 2009
Personalized therapy




                                                   • Local extension
                                    Surgery
                        TNM                        • Timing
                                    Radiotherapy
                                                   • Undetermined




Paradigm shift from empiric to integrated therapy
                      adapted from D. Gandara, World Conference IASLC 2009
Lung cancer - treatment concepts


T 1- 3 N 0         Curative surgery
                        ± adjuvant therapy
      T 1 -3 N 1

T 1 -3 N2          Chemo-/(radio-)therapy
                   and surgery
  T 4 N 0-1
     T 1 -2 N 3
T 4 N3       M1    Palliative therapy
Surgical procedures

• Standard lobectomy (pneumonectomy)
  + mediastinal lymphadenectomy
  Modifications:
• Minimally invasive lobectomy (VATS)
• Sublobar resections
• Sleeve resections
Minimally invasive (VATS) resections




               2-4 incisions

               30 – 70% of all lobectomies
               in experienced centers

       may preserve immunologic response and
       better compliance for adjuvant therapy
Limited resection vs lobectomy

                „Limited“
               Resections         Lobectomy
               n=122 (%)           n=125 (%)         p-value
Recurrence      38 (31.1)           23 (18.4)        0.02

Locoregional    21 (17.2)             8 (6.4)        0.01
recurrence
Distant         17 (13.9)           15 (12.0)        0.67
metastases
Death           48 (39.3)           38 (30.4)        0.08



                 Lung Cancer Study Group: Ann. Thorac. Surg., 60, 615, 1995
Limited resection vs lobectomy




                Nakamura H. et al. Brit. J. Cancer 2005; 92, 1033
The role of Tumor size


                              5-Year-survival
                        according to tumor diameter

                  < 20mm       21-30 mm                > 30 mm


Lobectomy         92%              87%                    81%

Segmentectomy     96%              85%                    63%

Wedge resection   86%              39%                     0%


                        Okada et al. J. Thorac. Cardiovasc. Surg. 2005; 129, 87
Tumor histology and Grading


                    5-Y- survival after
                   sublobar resection p-value
Adenocarcinoma            66 %
(n=76)
Squamous cell             59 %                 0.75
carcinoma (n=21)
G1 (=52)                  84 %

G2-3 (n=45)               46 %                 0.001


                       Nakamura H. et. al., Lung Cancer, 2004; 44, 61
Consequences of limited resection


 • Small functional advantage after
   limited resection (<10 %)

 • More local recurrences after sublobar
   resections

 • Small survival disadvantage (3.6%)
Lung saving (sleeve-) resections
T-stage
New staging system




 68000 NSCLC,
 1000 SCLC




          World Conference
          IASLC 2009
Chest wall infiltration ?
Chest wall infiltration

• important only for planning of the
   surgical procedure
• 5-year survival up to 40% in T3N1with
  adjuvant chemotherapy     Burkhardt, JTCVS 2002



• similar success rates in pancoast tumors
  following induction radio-chemotherapy
  and complete resection               Rusch, JCO 2007
Pancoast tumors
            (superior sulcus tumors)
Tumor of the apex of the lung
with possible infiltration of the
chest wall brachial plexus,
stellate ganglion, ribs, vertebae

< 5% of all bronchogenic
carcinoma
       PET/CT for staging
       (mediastinum,
        distant metastases)

       Determination of the
       radiation field
N-stage


Microscopic
 infiltration
       or
    bulky
 multilevel
  disease?




                S.P.1940 cT3N2
Lymph node status predicts outcome




                         Naruke, Ann Thorac Surg 2001
Survival of patients with resected N2


 Subgroups           Patients   5-yr Survival
 Minimal N2            354          29,5%
 - One Level           244           34%
 - Multiple Levels      78           11%
 Clinical N2           332            7%
 - One Level           118            8%
 - Multiple N2         122            3%


                                         Andre, JCO 2000
Incidental (occult) N2 disease
          adjuvant treatment


• adjuvant cisplantin – based chemotherapy is
  recommended

• adjuvant postoperative radiotherapy should
  be considered to reduce local recurrence


                                ACCP Guidelines, Chest 2007
N-stage


Multilevel N2
 disease –

  primary
surgery not
 indicated
The stage III disease


                              CT* + RT (61 Gy)
                   N=194
Pts with NSCLC,
    IIIA, pN2
   resectable

                   N=202
                              CT* + RT (45 Gy)     Surgery          CT*




                     * Cisplatin 50 mg/m2 d1/8/29/36
                       Etopophos 50 mg/m2 d1-5, d29-33

                                                             Albain, Lancet 2009
RTOG 9309: Efficacy

               100                                                                  100                                               Death/total
                                                        Death/total
Survival probability (%)




                                                  CT/RT/C 145/202                                                             CT/RT/S     57/90




                                                                      Survival probability (%)
                           75                     CT/RT 155/194
                                                                                                 75                           CT/RT       74/90

                           50
                                                                                                                                           p=0.002
                                                                                                 50
                           25       p=0.24


                           0
                                0   12       24    36     48     60                              25
                                                                                                                 CT/RT/S      CT/RT
                                                                                                          MS 34 months 22 months
                                                                                                      5-year S     36%         18%
                     RR=0.87 (0.70; 1.10)                  Months                                 0
                                                                                                      0      12          24    36        48         60

                                                                                                                         Months


                                                                                                                               Albain, Lancet, 2009
RTOG 9309: operative mortality


• Lobectomy versus pneumonectomy

• Mortality (n=15):
   – Lobectomy 1% versus pneumonectomy 26%
   – Right pneumonectomy (n=11; 79%)
   – Etiology: ARDS (n=11)



                                   Albain, Lancet, 2009
Pneumonectomy after neoadjuvant
      chemo- and radiotherapy
176 patients, 122 males (69%) 56 years (33-74)

3 cycles of cisplatin-doublets (n=35, 20%)

3 cycles of cisplatin-doublets (n=141, 80%)
  +45 Gy (1.5 Gy, bi-daily) to primary tumor and
  mediastinum
  (fourth cycle cisplatin-doublets in Essen)

• pneumonectomy (n=176), 86 (49%) right
                 138 (78%) extended
                                          Weder JTCS 2010
Morbidity and Mortality

• 6 patients died (3%) (30 d mortality)
         (3 pulmonary embolism, 2 ARDS, 2 cardiac
failure)
• 23 major complications (13%) in 22 patients
      6 pneumonia / ARDS
      5 broncho-pleural fistula (4R, 1L)
      5 empyema
      3 pulmonary embolism
      2 hemothorax
      1 heart failure
      1 gastric hernia                      Weder, JTCS 2010
Survival according to clinical stage




                              Weder, JTCS 2010
65 year old obese (BMI 25) female of RLL with metastases to
lymph nodes # 10, 7, 4 R (tracheal infiltration)

Patient received 2 cycles of induction with CDDP/GEM. Tolerated
chemotherapy very poorly
Restaging with PET/CT SD (± PD)
MRI of brain without metastasis
Patient is alive after 5 years with
NED, assessed clinically and by CT
‘Resectable N2‘ – which questions
       have to be answered?
• Is ‘N2‘ technically resectable?
• Is surgery complete?
• Is surgery indicated from an oncological point
  of view?
• What is the risk for the patient?
• Does the patient tolerate pulmonary resection?

    risk-benefit ratio
Role of highest level N2 node




                        Sakao, Ann Thorac Surg 2006
Single vs multilevel N2




                          Decaluwé, EJCTS 2009
Role of mediastinal downstaging




                         Betticher et al. , JCO 2003
Take home message I

• NSCLC remains to be the cancer with the highest
  cancer related mortality
• Appropriate clinical and pathological staging
  (including tissue diagnosis) is key to an
  “individualized“ treatment
• Lobectomy with systematic mediastinal lymph node
  dissection is the standard surgical procedure for
  most T1 – T3, N0 – N1 tumors
• Minimal invasive lobectomy by VATS is performed
  more and more frequent in specialized centers since
  morbidity and mortality is reduced and adjuvant
  therapy better tolerated
Take home message II

• Adjuvant chemotherapy is indicated for “fit patients“
  with stages ≥ T2, N1
• Patients with ipsilateral mediastinal lymph node
  metastasis (N2 disease) are best treated with
  neaoadjuvant chemo(-radio)therapy followed by
  surgery preferentially as part of “clinical trial“
• surgical resection after induction
  chemoradiotherapy should be limited to a lobectomy
  - whenever possible
• surgical resection for NSCLC should be complete
  and the treatment related mortality within an
  acceptable range.

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MON 2011 - Slide 22 - W. Weder - Surgery

  • 1. 10th ESO-ESMO Masterclass in Clinical Oncology 02-07 April 2011, Ermatingen NSCLC: Surgery Walter Weder MD Professor of Surgery University Hospital Zurich
  • 2. Case 1 59 y, female, 40 py, incidental finding on chest X-ray
  • 3. Questions • What is your diagnosis? • Further staging? • Lobectomy or sublobar resection? • Radiotherapy • Adjuvant therapy indicated?
  • 4. NSCLC - stages at presentation 7% Stage II 31% Stage III 24% Stage I 38% Stage IV Fry, Cancer 1996
  • 5. Stage-dependent survival for NSCLC 5-y survival after state-of-the-art treatment • Stage I 54-80% • Stage II 38-60% • Stage IIIA 10-30% • Stage IIIB <10% • Stage IV <5% Tsuboi, World Conference IASLC 2009
  • 6. Personalized therapy • Local extension Surgery TNM • Timing Radiotherapy • Undetermined Paradigm shift from empiric to integrated therapy adapted from D. Gandara, World Conference IASLC 2009
  • 7. Lung cancer - treatment concepts T 1- 3 N 0 Curative surgery ± adjuvant therapy T 1 -3 N 1 T 1 -3 N2 Chemo-/(radio-)therapy and surgery T 4 N 0-1 T 1 -2 N 3 T 4 N3 M1 Palliative therapy
  • 8. Surgical procedures • Standard lobectomy (pneumonectomy) + mediastinal lymphadenectomy Modifications: • Minimally invasive lobectomy (VATS) • Sublobar resections • Sleeve resections
  • 9. Minimally invasive (VATS) resections 2-4 incisions 30 – 70% of all lobectomies in experienced centers may preserve immunologic response and better compliance for adjuvant therapy
  • 10. Limited resection vs lobectomy „Limited“ Resections Lobectomy n=122 (%) n=125 (%) p-value Recurrence 38 (31.1) 23 (18.4) 0.02 Locoregional 21 (17.2) 8 (6.4) 0.01 recurrence Distant 17 (13.9) 15 (12.0) 0.67 metastases Death 48 (39.3) 38 (30.4) 0.08 Lung Cancer Study Group: Ann. Thorac. Surg., 60, 615, 1995
  • 11. Limited resection vs lobectomy Nakamura H. et al. Brit. J. Cancer 2005; 92, 1033
  • 12. The role of Tumor size 5-Year-survival according to tumor diameter < 20mm 21-30 mm > 30 mm Lobectomy 92% 87% 81% Segmentectomy 96% 85% 63% Wedge resection 86% 39% 0% Okada et al. J. Thorac. Cardiovasc. Surg. 2005; 129, 87
  • 13. Tumor histology and Grading 5-Y- survival after sublobar resection p-value Adenocarcinoma 66 % (n=76) Squamous cell 59 % 0.75 carcinoma (n=21) G1 (=52) 84 % G2-3 (n=45) 46 % 0.001 Nakamura H. et. al., Lung Cancer, 2004; 44, 61
  • 14. Consequences of limited resection • Small functional advantage after limited resection (<10 %) • More local recurrences after sublobar resections • Small survival disadvantage (3.6%)
  • 15. Lung saving (sleeve-) resections
  • 17. New staging system  68000 NSCLC,  1000 SCLC World Conference IASLC 2009
  • 19. Chest wall infiltration • important only for planning of the surgical procedure • 5-year survival up to 40% in T3N1with adjuvant chemotherapy Burkhardt, JTCVS 2002 • similar success rates in pancoast tumors following induction radio-chemotherapy and complete resection Rusch, JCO 2007
  • 20. Pancoast tumors (superior sulcus tumors) Tumor of the apex of the lung with possible infiltration of the chest wall brachial plexus, stellate ganglion, ribs, vertebae < 5% of all bronchogenic carcinoma PET/CT for staging (mediastinum, distant metastases) Determination of the radiation field
  • 21. N-stage Microscopic infiltration or bulky multilevel disease? S.P.1940 cT3N2
  • 22. Lymph node status predicts outcome Naruke, Ann Thorac Surg 2001
  • 23. Survival of patients with resected N2 Subgroups Patients 5-yr Survival Minimal N2 354 29,5% - One Level 244 34% - Multiple Levels 78 11% Clinical N2 332 7% - One Level 118 8% - Multiple N2 122 3% Andre, JCO 2000
  • 24. Incidental (occult) N2 disease adjuvant treatment • adjuvant cisplantin – based chemotherapy is recommended • adjuvant postoperative radiotherapy should be considered to reduce local recurrence ACCP Guidelines, Chest 2007
  • 25. N-stage Multilevel N2 disease – primary surgery not indicated
  • 26. The stage III disease CT* + RT (61 Gy) N=194 Pts with NSCLC, IIIA, pN2 resectable N=202 CT* + RT (45 Gy) Surgery CT* * Cisplatin 50 mg/m2 d1/8/29/36 Etopophos 50 mg/m2 d1-5, d29-33 Albain, Lancet 2009
  • 27. RTOG 9309: Efficacy 100 100 Death/total Death/total Survival probability (%) CT/RT/C 145/202 CT/RT/S 57/90 Survival probability (%) 75 CT/RT 155/194 75 CT/RT 74/90 50 p=0.002 50 25 p=0.24 0 0 12 24 36 48 60 25 CT/RT/S CT/RT MS 34 months 22 months 5-year S 36% 18% RR=0.87 (0.70; 1.10) Months 0 0 12 24 36 48 60 Months Albain, Lancet, 2009
  • 28. RTOG 9309: operative mortality • Lobectomy versus pneumonectomy • Mortality (n=15): – Lobectomy 1% versus pneumonectomy 26% – Right pneumonectomy (n=11; 79%) – Etiology: ARDS (n=11) Albain, Lancet, 2009
  • 29. Pneumonectomy after neoadjuvant chemo- and radiotherapy 176 patients, 122 males (69%) 56 years (33-74) 3 cycles of cisplatin-doublets (n=35, 20%) 3 cycles of cisplatin-doublets (n=141, 80%) +45 Gy (1.5 Gy, bi-daily) to primary tumor and mediastinum (fourth cycle cisplatin-doublets in Essen) • pneumonectomy (n=176), 86 (49%) right 138 (78%) extended Weder JTCS 2010
  • 30. Morbidity and Mortality • 6 patients died (3%) (30 d mortality) (3 pulmonary embolism, 2 ARDS, 2 cardiac failure) • 23 major complications (13%) in 22 patients 6 pneumonia / ARDS 5 broncho-pleural fistula (4R, 1L) 5 empyema 3 pulmonary embolism 2 hemothorax 1 heart failure 1 gastric hernia Weder, JTCS 2010
  • 31. Survival according to clinical stage Weder, JTCS 2010
  • 32. 65 year old obese (BMI 25) female of RLL with metastases to lymph nodes # 10, 7, 4 R (tracheal infiltration) Patient received 2 cycles of induction with CDDP/GEM. Tolerated chemotherapy very poorly Restaging with PET/CT SD (± PD) MRI of brain without metastasis
  • 33. Patient is alive after 5 years with NED, assessed clinically and by CT
  • 34. ‘Resectable N2‘ – which questions have to be answered? • Is ‘N2‘ technically resectable? • Is surgery complete? • Is surgery indicated from an oncological point of view? • What is the risk for the patient? • Does the patient tolerate pulmonary resection?  risk-benefit ratio
  • 35. Role of highest level N2 node Sakao, Ann Thorac Surg 2006
  • 36. Single vs multilevel N2 Decaluwé, EJCTS 2009
  • 37. Role of mediastinal downstaging Betticher et al. , JCO 2003
  • 38. Take home message I • NSCLC remains to be the cancer with the highest cancer related mortality • Appropriate clinical and pathological staging (including tissue diagnosis) is key to an “individualized“ treatment • Lobectomy with systematic mediastinal lymph node dissection is the standard surgical procedure for most T1 – T3, N0 – N1 tumors • Minimal invasive lobectomy by VATS is performed more and more frequent in specialized centers since morbidity and mortality is reduced and adjuvant therapy better tolerated
  • 39. Take home message II • Adjuvant chemotherapy is indicated for “fit patients“ with stages ≥ T2, N1 • Patients with ipsilateral mediastinal lymph node metastasis (N2 disease) are best treated with neaoadjuvant chemo(-radio)therapy followed by surgery preferentially as part of “clinical trial“ • surgical resection after induction chemoradiotherapy should be limited to a lobectomy - whenever possible • surgical resection for NSCLC should be complete and the treatment related mortality within an acceptable range.