Management of ca lung - early stage -Dr Sumanth.pptx

Management of ca lung. Early stage

1. Management of Stage I-III NSCLC Dr Sumanth kumar mallupattu Medical Oncology

2. Stage I,II Tumors Surgical resection is widely accepted as the optimal treatment of stage I and II NSCLC over no treatment. Based on such retrospective series of resected stage I and stage II NSCLC, the prognoses for stage I and II NSCLC, expressed in terms of 5-year survival rates, are commonly accepted to be 60% to 80% for stage I and 30% to 50% for stage II NSCLC. In contrast, data on the natural history of untreated clinical stage I or II NSCLC consistently shows poor survival (2-year survival of approximately 20% and 15% 5-year survival ).

3. Preoperative physiologic pulmonary evaluation for lung resection Algorithm for pulmonary preoperative assessment of patients requiring lung resection-- American College of Chest Physicians (ACCP)

4. Algorithm for assessment of cardiopulmonary reserve before lung resection in lung cancer patients. European respiratory Society/European Society of thoracic surgeons (ERS/ESTS)

5. Importance of surgical expertise and Volume of disease at centres The studies have consistently noted better long-term survival after surgery performed by a thoracic or cardiac surgeon vs a general surgeon. The rate of mediastinal node dissection is twofold to threefold higher among specialty-trained surgeons. Other measures, such as the use of PET scanning and videoassisted thoracic surgery (VATS) resections , are more commonly done by thoracic and cardiac surgeons, whereas the use of neoadjuvant or adjuvant therapy is not different.

6. Lobectomy—Surgical Issues Minimally Invasive vs Open Surgical Resection: VATS lobectomy is associated with fewer complications, l ower estimated blood loss or transfusion rates a nd shorter hospital LOS. Two meta-analyses and two systematic reviews--VATS vs open lobectomy. These studies all found VATS is associated with a short-term benefit (reduced complications, perioperative mortality, pain) and long-term recurrence and survival rates that are at least as high as after thoracotomy

7. Outcomes of thoracoscopic vs open lung cancer resection. Results of a meta-analysis of comparative studies. Most of the included studies were cohort studies , not randomized studies.

8. For patients with clinical stage I NSCLC, a minimally invasive approach such as video assisted thoracic surgery (thoracoscopy) is preferred over a thoracotomy for anatomic pulmonary resection

9. Mediastinal Lymph Node Dissection vs Systematic Sampling Selective biopsy or sampling (involving only selected suspicious or representative nodes), A systematic sampling (exploration and biopsy of a standard set of lymph node stations in each case), Formal mediastinal lymph node dissection (MLND)/ lymphadenectomy----involves removal of all node-bearing tissue within defined landmarks for a standard set of lymph node stations.

10. The median survival for MLNS is8.1 years, and 8.5 years for MLND ( p=0.25 ). There was no difference for local (p=0.52), regional (p=0.10), or distant (p=0.76) recurrence between the two groups.

11. Safety of Lymphadenectomy for Stage I/II NSCLC As might be expected, MLND dissection adds operative time, blood loss, and postoperative chest drainage when compared with sampling, but the effect is minor and does not translate into increased morbidity. In the American College of Surgeons Oncology Group (ACOSOG) Z0030 trial, the two randomized arms had very similar morbidity profiles and were equivalently safe.

12. Sublobar Resection The standard extent of resection for lung cancer has been lobectomy with systematic lymph node sampling or mediastinal node dissection. Most series reporting the results of sublobar resection ( wedge resection or segmentectomy ) have no comparison group with lobectomy. The rational use of sublobar resection can thus be divided into three groups of patients : T hose deemed not able to tolerate lobectomy (compromised patients), G ood-risk patients in general who could tolerate lobectomy, W ho could tolerate lobectomy but who have tumors for which lobectomy may not be necessary

13. Lobar vs Elective Sublobar Resection

14. For patients with clinical stage I and II NSCLC, who are medically fit for surgical resection a lobectomy rather than sublobar resection is recommended, For patients with a clinical stage I predominantly GGO lesion 2 cm, a sublobar resection with negative margins is suggested over Lobectomy.

15. Surgical Margins It becomes a greater issue when considering sublobar resection. A retrospective analysis of 428 stage I NSCLC registry cases of sublobar resection found that 89% (24 of 27) of local recurrences were seen in those with margins 2 cm . A margin to tumor diameter ratio , 1.0 was associated with a much higher rate of local recurrence (25% vs 6.2%, P = .0014). Another retrospective review of 81 patients undergoing segmentectomy (n = 26) or wedge resection (n 5= 55) found that local recurrence was frequently associated with margins , 1 cm. Finally, many prospective protocols involving sublobar resections have arbitrarily set a margin of 2 cm.

16. During sublobar resection of solid tumors in compromised patients, it is recommended that margins greater than the maximal tumor diameter for lesions less than 2 cm should be a chieved . F or tumors larger than 2 cm at least 2 cm gross margins should be sought to minimize the likelihood of a positive margin and/or local recurrence.

17. Segmentectomy vs Wedge Resection

18. S egmentectomy offers ---  the potential advantage of complete resection of lymphatic and vascular drainage basins and frequently provides a better parenchymal margin . T hese are uncontrolled, mostly retrospective comparisons -  Therefore it is not possible to draw definitive conclusions. Nevertheless, the survival and recurrence rates suggest that wedge resection should be used very cautiously , and in general only in patients in whom a larger resection is not deemed to be an option

19. Postoperative (Adjuvant) Therapy Adjuvant Chemotherapy for Resected Stage I -IIIA NSCLC: Background: A significant number of patients with NSCLC undergoing “curative resection”--  die of systemic recurrence Need for adjuvant therapies. Most studies demonstrate no benefit of adjuvant chemotherapy for T1 (3 cm) N0, stage IA NSCLC, and the Lung Adjuvant Cisplatin Evaluation (LACE) meta-analysis suggests a possible deleterious effect of chemotherapy

20. A few Japanese trials have suggested that an oral agent (tegafur/uracil [UFT]) given continuously for up to 2 years might be beneficial as an adjuvant for patients with resected stage IA disease. The poor response rate of patients with advanced NSCLC to UFT raises questions about the usefulness of UFT in the adjuvant setting for resected patients. Consequently, adjuvant chemotherapy currently is not indicated for patients with completely resected stage IA disease.

21. There is no clear consensus regarding benefi t of adjuvant therapy for patients with stage IB disease based on current randomized data. Two trials -  on earlier-stage patients (JBR10 and CALGB 9633) --  initially reported to favor use of adjuvant chemotherapy for patients with IB disease and temporarily defined a standard of care for patients with stage IB disease when analyzed. However, on late follow-up and subsequent reanalysis --  changed both JBR10 and CALGB 9633 to negative trials for patients with stage IB disease. It has been suggested that patients with IB disease with tumors 4 cm might benefit from adjuvant chemotherapy , but this is not a consistent finding among trials in late follow-up reanalysis.

22. IALT-International Adjuvant Lung Cancer Trial

23. The analysis of non-lung cancer deaths for the whole period showed an HR of 1.34 (95% CI, 0.99 to 1.81; P = .06).

24. Median follow-up is currently >70 months.  5-year survival by stage I/II/IIIA were 62%/52%/42% in NP and 63%/39%/26% in OBS. The ANITA results demonstrate that NP significantly improves survival in completely resected stage II and IIIA NSCLC pts, although no benefit was observed in stage I.

25. In JBR.10, IB patients with tumors 4 cm or greater in size did appear to derive a clinically meaningful benefit, with a similar HR of 0.66 ( v  HR 0.68 in stage II patients). The lack of statistical significance may be due to the small sample size , with only 99 and 120 patients in the less than 4 cm and 4 cm or greater subgroups respectively.

26. LACE- Meta Analysis

27. Role of Post Op RT Meta-analysis of postoperative radiotherapy on overall survival Patient data from nine studies This represented 2,000 randomized patients from whom data were available. PORT dose varied from 30 to 60 Gy

28. For patients with completely resected pathologic stage I,II NSCLC, it is recommended that postoperative radiation therapy should not be used. For a positive bronchial margin (R1 resection), postoperative radiation therapy is suggested.

29. Nonsurgical Treatment Approaches to Stage I NSCLC-SBRT, RFA SBRT: SBRT is defined as a method of external beam radiotherapy (EBRT) that accurately delivers a high irradiation dose to an extracranial target in one or few treatment fractions.

30. SBRT versus surgery  —  The results from nonrandomized phase I and II studies have led to comparisons of stereotactic body radiation therapy (SBRT) with surgery in patients who are surgical candidates. Prior to 2010, three randomized trials were designed to compare the efficacy of SBRT with surgical resection for the operable patient population (American College of Surgeons Oncology Group Z4099, the ROSEL trial, and the Accuray trial). Unfortunately, all of these trials were closed prematurely due to poor accrual.

31. A combined analysis of two of these trials looked at outcomes in 58 patients: 31 treated with SBRT and 27 with surgery. At a median follow-up of 40 months, the overall survival was better at three years in patients treated with SBRT compared with surgery (95 versus 79 percent, hazard ratio [HR] 0.14, 95% CI 0.02-1.19 ). No significant differences in rates of locoregional or distant recurrence or progression-free survival, and the improved overall survival may be attributable to a better safety profile with SBRT compared with surgery. To be interpreted with caution given the very limited number of patients.

32. At least two other trials are now randomizing patients with operable stage I NSCLC to surgery or stereotactic ablative radiotherapy . T he Joint Lung Cancer Trialist's Coalition STABLE-MATES trial and The Veterans Affairs Lung Cancer Surgery or Stereotactic Radiotherapy trial.

33. T hree fractions over 1.5 to 2 weeks, using fractions of 18 Gy for peripherally situated tumors based on Radiation Therapy Oncology Group (RTOG) 0236. Alternatively, a single fraction of 34 Gy has been evaluated with acceptable five-year outcomes, although larger studies are needed. For central tumors , 5 fractions over 2.0 to 2.5 weeks is better tolerated, using fractions of 10 to 12 Gy . In a phase I/II study of patients with T1 to 2, node-negative, centrally located NSCLC, Two-year rates of local control in the 11.5- and 12.0-Gy/fraction cohorts were 89 and 88 percent , respectively.

34. For patients with clinical stage I NSCLC who cannot tolerate a lobectomy or segmentectomy, SBRT is recommended over no therapy . Surgical resection has the potential benefit of definitive histologic analysis ( eg , adenocarcinoma subtype) and pathologic nodal information. In compromised patients for whom such information would not change management SBRT is a preferred option. Also, SBRT is favored in patients for whom an adequate margin in unlikely with a surgical wedge resection

35. RFA for patients with Ia NSCLC who are not candidates for any surgical intervention appears to be better than no treatment. The data are more limited than for SBRT, and the rate of short-term complications may be slightly higher. Nevertheless, RFA appears to be a reasonable alternative to SBRT, with the advantage that it involves only one treatment and likely is associated with less cost. RFA may be considered for peripheral tumors , 3 cm in inoperable patients.

36. Stage III

37. Definition of Subgroups: I nterpretation of data for stage III by separating the discussion into three readily identify able groups: (1 ) patients with infiltrative stage III (N2/N3) tumors,- Grp A (2) patients with discrete clinically evident (by CT or CT-PET scan) N2 involvement. – Grp B & C (3) patients with occult N2 node involvement despite thorough preoperative staging, and

38. Patients with infiltrative N2/N3 involvement have N2 or N3 disease where discrete nodes can no longer be clearly distinguished and measured . T his corresponds to the radiographic group A in the stage evaluation. These patients have fairly : extensive mediastinal involvement, with tumor infiltration in the mediastinum partially surrounding the major structures ( ie , great vessels, trachea). T he term “infiltrative N2/N3 involvement”has not been in widespread use. Nevertheless, from a practical, clinical standpoint, this way seems to distinguish a recognizable subgroup of patients with stage III disease.

39. Discrete N2 involvement denotes patients in whom individual mediastinal nodes can be distinguished. These nodes may be enlarged or normal sized and may be suspected by PET uptake or by other clinical characteristics ( eg , size, a central tumor). Thus, these patients correspond to the radiographic groups B and C in the stage evaluation. The mediastinal stage suggested by imaging in these patients must be confirmed through thorough invasive Staging.

40. Patients with occult N2 disease despite thorough preoperative staging are found intraoperatively or postoperatively to have positive N2 nodes. The thoroughness of the preoperative staging and intraoperative mediastinal assessment is critical. Nevertheless, this group of patients with N2 involvement is distinct and identifiable.

41. Infiltrative Stage III (N 2 /N 3 ) Disease Combined Chemotherapy With Radiotherapy: T he use of radiotherapy alone as a curative mode of therapy for stage IIIA or IIIB disease yields ---  poor survival at 5 years (5%-10%) with traditional dose and fractionation schedules (1.8-2.0 Gy per fraction per day to 60-70 Gy in 6-7 weeks). Chemotherapy has been combined with radiotherapy in different ways chemotherapy followed sequentially by radiotherapy, concurrent chemoradiation, induction chemotherapy followed by concurrent chemoradiation, or concurrent chemoradiation followed by consolidation chemotherapy) in multiple phase 2/3 trials

42. Goal -  in treating the patient with stage III lung cancer: T o eradicate both visible, intrathoracic disease and T o reduce the incidence of subsequent systemic, extrathoracic metastases. Local control can be achieved through radiotherapy , with higher doses generally resulting in higher rates of disease control and higher and eventually unacceptable rates of toxicity that limit the dose that can be delivered. Systemic chemotherapy is used to achieve two aims. As a radiosensitizing agent , the aim is to increase the therapeutic index of radiation therapy, A s a cytotoxic agent , the aim is to eradicate unsuspected or prevent de novo development of systemic metastasis,

43. Concurrent Chemoradiotherapy The definitive chemotherapy and radiotherapy trials included patients with infiltrative disease as well as discrete nodal involvement. Therefore, the results of these studies are applicable to the patients with discrete nodal involvement as well. With combined chemotherapy and radiotherapy demonstrating improved survival over radiotherapy alone in locally advanced, unresectable stage III NSCLC, this combination became the standard of care . Two meta-analyses reviewing 50 trials confirmed the survival benefit of combined platinum- based chemotherapy with radiotherapy over radiotherapy alone in locally advanced, unresectable NSCLC.

44. Addition of cisplatin-based chemotherapy to radiotherapy improves survival in stage III NSCLC. Inclusion criteria: randomized controlled trial of cisplatin-based chemotherapy and RT vs RT alone in 100 patients with stage III NSCLC.

45. C oncurrent chemoradiation had a significant absolute survival benefit of 5.7% at 3 years and 4.5% at 5 years (HR, 0.84; 95% CI, 0.74-0.95; P = .004 )

46. Concurrent chemoradiotherapy vs sequential chemoradiotherapy Inclusion criteria: randomized controlled trial of concurrent vs sequential chemotherapy and RT in stage III NSCLC.

47. A Cochrane meta-analysis

48. Concurrent chemoradiotherapy has several drawbacks : D ifficulty in maintaining full-dose chemotherapy sufficient to treat systemic disease, especially with some of the newer agents such as gemcitabine, docetaxel, and paclitaxel of which all require dose reductions when given concurrently with radiotherapy. Concurrent chemoradiotherapy also has increased local adverse effects (esophagitis and pneumonitis). Finally, although concurrent is superior to sequential therapy, the long-term survival for patients with stage III NSCLC remains low.

49. Role of sequential chemo-radiotherapy: Sequential chemotherapy followed by radiation or radiation alone can still be used for patients: W ith very large radiation ports or S ignificantly decreased performance status, each of which puts patients at higher risk for severe toxicity

50. Any role of systemic chemotherapy either before (induction) or after (consolidation) concurrent chemoradiotherapy ? Rationale: Even with the increased survival and improved local disease control that comes with combining chemotherapy and radiotherapy concurrently, the rate of systemic metastasis remains high . To reduce the incidence of extrathoracic disease, investigators have conducted trials with these approaches.

51. Studies : Induction chemo-  Conc ChemoRT CALGB French Lung Cancer Study Group

52. Conclusion:  The addition of induction chemotherapy to concurrent chemoradiotherapy added toxicity and provided no survival benefit over concurrent chemoradiotherapy alone. 

53. Conc ChemoRT -  Consolidation chemo Conclusion:  Consolidation docetaxel after PE/XRT results in increased toxicities but does not further improve survival compared with PE/XRT alone in patients with stage III inoperable NSCLC.

54. ? Role of PCI after chemoRT –Stage III Patients with stage III NSCLC without disease progression after treatment with surgery and/or radiation therapy (RT) with or without chemotherapy were eligible. Conclusion:  In patients with stage III disease without progression of disease after therapy, PCI decreased the rate of BM but did not improve OS or DFS .

55. In patients with infiltrative stage III (N2,3) with good performance status , combination platinum-based chemotherapy and radiotherapy (60-66 Gy ) are recommended. Dose esclation of radiotherapy is not recommended concurrent chemoradiotherapy is recommended over sequential chemoradiotherapy. In patients with a complte response after treatment with concurrent chemoradiotherapy, PCI should not be given. In patients with symptomatic stage III (N2,3) NSCLC and either performance status 3-4, comorbidities, or disease too extensive to treat with curative intent, palliative radiotherapy is recommended.

56. Discrete Mediastinal Node Involvement Several RCTs compared the outcomes of primary surgery vs preoperative (induction or neoadjuvant) therapy followed by surgery. These trials demonstrated a fairly consistent trend to better 2- and 5-year survival after preoperative therapy vs primary surgery. Discrete N2 involvement denotes patients in whom individual mediastinal nodes can be distinguished. These nodes may be enlarged or normal sized and may be suspected by PET uptake or by other clinical characteristics ( eg , size, a central tumor

57. Meta-analysis- Sx alone Vs NACT Sx A 2007 Cochrane meta-analysis (for stages I-III) revealed a benefit of platinum-based neoadjuvant chemotherapy over surgery alone (HR, 0.82; 95% CI, 0.69-0.97; P = .022 ), corresponding to an absolute benefit of 6% to 7% in stages IB to IIIA and 3% to 5% in IIIb . D ata demonstrate that surgery as the primary therapy (for preoperatively identified N2 involvement) is inferior to approaches involving neoadjuvant treatment.

58. Any specific subgroups that could benefit from primary surgery in preoperatively identified N2 disease? In general, the data show that the outcomes are poor even among highly selected patients in centers that believed they were able to select the patients with good prognosis ( 5-year survival of 10%-15%).

59. P reoperative therapy followed by surgery vs chemoradiotherapy for stage III NSCLC Overall, the results are fairly consistent that preoperative therapy, and surgical resection offers long-term outcomes that are similar to chemoradiotherapy alone .

60. The apparent equivalence between neoadjuvant therapy followed by surgery, and definitive chemoradiation has several implications: First , patient preferences and characteristics should be considered. Second-  importance of minimizing harms. If surgery is to be undertaken, it should be done in a center with experience, that tracks its results, and that can demonstrate a low operative mortality rate for resection after neoadjuvant therapy. Third, if concerns about the ability of radiotherapy to achieve local control ( ie , large treatment field, reduced dose), surgery may have a benefit provided that a complete R0 resection is likely to be achieved.

61. Any favorable subgroups that benefit with preopchemo+Sx than Concurrent ChemoRT Despite the results of RCTs, the question remains--  whether certain subgroups of patients exist for whom surgical resection after preoperative therapy is superior to definitive chemoradiotherapy. S ubgroups have been suggested, including patients with : Nonenlarged N2 nodes, nonbulky nodes and single-node-station involvement. patients with nodal downstaging or other signs of good response to neoadjuvant therapy ( eg , tumor shrinkage, decrease in intensity of uptake on PET scan); patients in whom a pneumonectomy is not necessary.

62. Selection criteria for trimodality therapy with surgery in patients with stage III (N2) lung cancer

63. For potentially resectable superior sulcus tumours , concurrent chemoradiotherapy induction followed by surgery has become the standard of care . As randomized trials are dif fi cult to perform because of rarity of these tumours , this recommendation is based on a multicentre prospective phase II Southwest Oncology Group (SWOG) trial in North America, which demonstrated an excellent complete resection rate and markedly improved 5-year survival rates. A comparable strategy using concurrent chemoradiotherapy to downsize the primary tumour and down-stage centrally located tumours may be applied to certain T3 N2 or T4 N0-1 tumours

64. In patients with discrete N2 involvement by NSCLC identified preoperatively (IIIA), it is recommended that the treatment plan should be made with the input from a multidisciplinary team . The multidisciplinary team should include at a minimum a thoracic surgeon, medical oncologist, and radiation oncologist. E ither definitive chemoradiation therapy or induction therapy followed by surgery is recommended over either surgery or radiation alone. P rimary surgical resection followed by adjuvant therapy is not recommended.

65. Occult N 2 Involvement Despite Thorough Preoperative Staging (Stage IIIA) Recent reports of patients with thorough staging indicate that true unsuspected N2 disease occurs in about 10% of surgical patients (5%-16%). In the case of intraoperatively identified N2 involvement, it is suggested that a complete MLND be performed, even though survival data are not available -  morbidity of MLND has been consistently found to be minimal).

66. Adjuvant Chemotherapy Typically, the RCTs have required that chemotherapy be started within 8 to 12 weeks of surgery. adjuvant chemotherapy involve cisplatin-based doublets for three to four cycles started within 12 weeks of surgery.

67. In patients with NSCLC who have incidental (occult) N2 disease (IIIA) found at surgical resection despite thorough preoperative staging and in whom complete resection of the lymph nodes and primary tumor is technically possible , completion of the planned lung resection and mediastinal lymphadenectomy is suggested . In those patiets , adjuvant platinum-based chemotherapy is recommended. It should typically involve a doublet regimen for 3 to 4 cycles initiated within 12 weeks .

68. Adjuvant Radiotherapy Although it appears that PORT might benefit some patients with N2 disease, presently, it i s not recommended for unselected patients. It should be considered in selected patients at risk for local recurrence, especially as assessed by the surgeon performing the resection. S equential adjuvant radiotherapy is suggested when concern for a local recurrence is high . Adjuvant PORT reduces the incidence of local recurrence, but it is unclear whether it improves survival. Incompletely resected (R1,2), combined postoperative concurrent chemotherapy and radiotherapy is given.

69. Superior sulcus or Pancoast tumors are a special and unique subset of lung carcinomas which are located in the apex of the lung and invade through tissue contiguity the apical chest wall and the structures of the thoracic inlet (parietal pleura, 1 st  and 2 nd  ribs or periosteum and adjacent 1 st  and 2 nd  vertebral bodies, the lower nerve roots of the brachial plexus, the upper sympathetic chain and stellate ganglion, the subclavian vein and artery) Superior sulcus or Pancoast tumors Chest CT scan displaying an apical chest wall tumor that was associated with Horner’s syndrome

70. According to the results of SWOG 9416 and JCO 9806 trials and few retrospective studies , the standard of care for Pancoast tumors is currently induction chemo-radiotherapy followed by surgical resection .

71. Role of TKI’s, Immunotherapy

72. Conclusion:  Adjuvant erlotinib did not prolong DFS in patients with EGFR-expressing NSCLC or in the EGFRm-positive subgroup.

73. The DFS advantage with adjuvant gefitinib did not translate to a significant difference in OS. However, adjuvant therapy with gefitinib is an important treatment option for patients with resected stage II-IIIA (N1-N2) NSCLC, demonstrating improved DFS over standard-of-care chemotherapy.

74. Thank You