Past, present and future of Radiotherapy of Lung Cancer

Transcription

1 Past, present and future of Radiotherapy of Lung Cancer Joaquin G Mira MD, FACR START center Clinical professor, Univers. Texas Health Science Center, San Antonio, Texas

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3 Small cell lung cancer past, present and future Non-small cell lung cancer Past,present and future

4 Past issues SCLC Radiotherapy

5 Because of good chemotherapy response, Med. Onc. thought they could eliminate chest XRT altogether

6 L. Einhorn second author

7 No chest RT!. I need to investigate patterns of relapse

8 Cancer 1982, 50, Chest relapse more than double without chest RT

9 Most relapses in primary area Do we treat if there is complete response to chemo?

10 Chest 1989,96:1s-78s Confirmation of lower chest failures with CT + RT

11 Median survival significantly increased in half of the studies

12 Studies on thoracic radiotherapy N Engl J Med Dec 3;327(23): A meta-analysis of thoracic radiotherapy for small-cell lung cancer. Pignon JP 1, Arriagada R, Ihde DC, Johnson DH, Perry MC, Souhami RL, Brodin O, Joss RA, Kies MS, Lebeau B, et al The meta-analysis included 13 trials and 2140 patients with limited disease The relative risk of death in the combined-therapy group as compared with the chemotherapy group was 0.86 (95 percent confidence interval, 0.78 to 0.94; P = 0.001), corresponding to a 14 percent reduction in the mortality rate. The benefit in terms of overall survival at three years (+/- SD) was 5.4 +/- 1.4 percent. CONCLUSIONS: Thoracic radiotherapy moderately improves survival in patients with limited small-cell lung cancer who are treated with combination chemotherapy. Identification of the optimal combination of chemotherapy and radiotherapy will require further trials. Thoracic XRT is now standard of care for limited SCLC

13 PCI to responders only? Central Nervous System Involvement and the Role of Prophylactic Cranial Irradiation in Small Cell Lung Cancer C.G. Alexopoulos, et al. Department of Medical Oncology, Evangelismos Hospital, Athens, Greece The oncologist, 1997 complete responders, by living longer, are exposed to a higher risk than either partial responders or the general SCLC population [17, 18]. significantly improved survival of complete responders after PCI. 9 of 11 published randomized trials which failed to demonstrate an improvement in survival with PCI did not take into consideration the type of response to chemotherapy

14 PCI started early in the studies, before evaluating response. Non-responders died quickly

15 PCI for responders in limited disease SCLC Prophylactic cranial irradiation for patients with small-cell lung cancer in complete remission. Prophylactic Cranial Irradiation Overview Collaborative Group. AUAupérin A, et al.n Engl J Med. 1999;341(7):476. meta-analysis of seven randomized trials that included 987 patients who achieved a complete remission with chemotherapy and received PCI between 1977 and The incidence of brain metastases was significantly decreased with PCI (relative risk [RR] 0.46; 95% CI ), and there was an absolute decrease in the three-year cumulative incidence of brain metastases (33 versus 59 percent). Furthermore, mortality was decreased with PCI (RR 0.84; 95% CI ), which corresponded to an increase in the three-year survival rate from 15.3 to 20.7 percent. 12 percent of patients in the PCI group and 17 percent of patients in the control group had extensive stage disease. CONCLUSIONS: Prophylactic cranial irradiation improves both overall survival and disease-free survival among patients with small-cell lung cancer in complete remission The effectiveness of PCI in patients with limited stage SCLC has been established by the results from numerous clinical trials. A second meta-analysis that evaluated 1547 patients from 12 randomized trials reported almost identical findings [6].( to date.com).

16 Prophylactic cranial irradiation in extensive small-cell lung cancer. Slotman B, EORTC Radiation Oncology Group and Lung Cancer Group N Engl J Med. 2007;357(7): patients with a response to chemotherapy as judged by the treating clinician were randomly assigned to PCI or to observation without PCI. Radiation doses and schedules ranged from 20 Gy in five fractions to 30 Gy in 12 fractions, depending upon the institution. Patients treated with PCI had a significantly decreased incidence of symptomatic brain metastases at one year (15 versus 40 percent without PCI, hazard ratio [HR] 0.27, 95% CI ). The median overall survival was increased in patients treated with PCI (6.7 versus 5.4 months, measured from randomization), and the one-year survival rate was significantly increased (27 versus 13 percent, HR % CI CONCLUSIONS: Prophylactic cranial irradiation reduces the incidence of symptomatic brain metastases and prolongs disease-free and overall survival. In a second trial that was conducted in Japan, 224 patients who had at least some response to their initial chemotherapy were randomly assigned to PCI or no PCI [8]. Preliminary results were presented at the 2014 American Society of Clinical Oncology (ASCO) meeting.the trial was stopped prematurely for futility, based upon an analysis after 111 deaths. Although not statistically significant, overall survival was shorter with PCI compared with no PCI (median 10.1 versus 15.1 months, HR 1.38, 95% CI ). significant decrease in the incidence of brain metastases with PCI (32 vs 58 % at one year, p<0.001), and fewer patients required RT for symptomatic brain metastases (31 vs 80 %) PCI decreases the incidence of brain metastases in patients with extensive SCLC with response to chemotherapy, although its effect on overall survival is uncertain.(

17 Dose for P.C.I. in SCLC Standard-dose versus higher-dose prophylactic cranial irradiation (PCI) in patients with limited-stage small-cell lung cancer in complete remission after chemotherapy and thoracic radiotherapy (PCI 99-01, EORTC , RTOG 0212, and IFCT 99-01): a randomised clinical trial. Le Péchoux et al. Lancet Oncol. 2009;10(5): patients with limited stage (LS)-SCLC and a CR to their initial treatment were randomly assigned to PCI at a dose of either 25 Gy in 10 fractions or a dose of 36 Gy (administered either as 18 fractions of 2 Gy each or 24 fractions of 1.5 Gy given twice-daily) [10]. At 2 years, brain met. were 23 % for the higher dose and 29 % with the lower dose. difference not statistically significant (HR 0.80, 95% CI ). However, the higher dose was associated with a significantly lower two-year survival rate (37 versus 42 percent, HR 1.20, 95% CI ). There was no obvious explanation for the increased mortality in the group treated with higher doses of PCI. Primary analysis of a phase II randomized trial Radiation Therapy Oncology Group (RTOG) 0212: impact of different total doses and schedules of prophylactic cranial irradiation on chronic neurotoxicity and quality of life for patients with limited-disease small-cell lung ca. Wolfson AH, et al. Int J Radiat Oncol Biol Phys. 2011;81(1): patients with limited stage SCLC and a CR after chemotherapy and thoracic RT were randomized for PCI with either 25 Gy in 10 fractions or 36 Gy. The 36 Gy cohort was secondarily randomized to receive their radiation either in 18 fractions of 2 Gy or 1.5 Gy twice daily in 24 fractions. At a median follow-up of 25 months, there was no significant difference in the incidence of brain metastases or overall survival between the treatment arms, but the study was not adequately powered to evaluate the impact of treatment on these parameters. No advantage to go higher than 250 cgyx 10 (

18 Toxicity of PCI Long-term toxicities are difficult to assess and quantify, and the data pertaining to these are limited. Potentially devastating neurologic and intellectual disabilities were seen with earlier treatment techniques that used concurrent chemotherapy, large fraction sizes (3.0 to 4.0 Gy), and/or a high total dose, all of which have been shown to be associated with severe late neurotoxicity [13-15]. There is significant neurotoxicity present in patients completing induction chemotherapy, prior to PCI Ongoing RTOG and EORTC trials will hopefully provide more information RTOG 0212: chronic neurotoxicity was significantly less frequent in patients treated with 25 Gy compared with 36 Gy (60 versus 85 and 89 percent, respectively, p = 0.02). Neurotoxicicy: decrease of one neurocognitive test The problem of neuropsychological toxicity remains unclear, leading to controversy about the indications of PCI in SCLC. So further studies about neuropsychological toxicity of the long-term PCI need studied by the researchers in the future.

19 Present recommendations SCLC Radiotherapy

20 NCCN History January 31, 1995, was the creation of a national alliance to develop and institute standards of care for the treatment of cancer and perform outcomes research With 13 original NCCN Member Institutions, the goal was to ensure delivery of high-quality, cost-effective services to people with cancer across the country. NCCN became a developer and promoter of national programs to facilitate the fulfillment of NCCN Member Institution missions in education, research, and patient care. Now an alliance of 26 of the world s leading cancer centers, NCCN develops and communicates scientific, evaluative information to better inform the decision-making process between patients and physicians, ultimately improving patient outcomes The American Society of Clinical Oncology (ASCO) began its guidelines program in 1993 following an ASCO strategic planning initiative. As part of this initiative, ASCO conducted a membership survey. Guideline development was ranked second among the priority areas for ASCO by the membership. In more recent ASCO Endorses ASTRO Guidelines for Radiation Therapy Insurance companies follow NCCN guidelines

21 UpToDate is an evidence-based, physician-authored clinical decision support resource which clinicians trust to make the right point-of-care decisions. More than 6,000 world-renowned physician authors, editors, and peer reviewers use a rigorous editorial process to synthesize the most recent medical information evidence-based recommendations that are proven to improve patient care and quality. More than 1 million clinicians in 174 countries and almost 90% of academic medical centers in the United States rely on UpToDate to provide the best care UpToDate is a Database, not a journal. Indexed within the UpToDate Database are topic reviews intended to help physicians make point of care dicisions. The topic reviews are not journal articles and are not peer reviewed. Developed in 1992 by Burton D. Rose MD

22 Limited and extensive most important definition

23 Limited can be treated with definite radiation fields and doses

24 2015 by American Society of Clinical Oncology Treatment of Small-Cell Lung Cancer: American Society of Clinical Oncology Endorsement of the American College of Chest Physicians Guideline Charles M. Rudin, et al. + Author Affiliations Alexandria, VA 22314; guidelines@asco.org Results The ASCO Endorsement Panel determined that the recommendations from the ACCP guideline, published in 2013, are clear, thorough, and based on current scientific evidence. ASCO endorses the ACCP guideline on the treatment of SCLC, with the addition of qualifying statements. Recommendations 1/ Surgery is indicated for selected stage I SCLC. 2/Limited-stage disease should be treated with concurrent chemoradiotherapy in patients with good performance status. 3/Thoracic radiotherapy should be administered early in the course of treatment, preferably beginning with cycle one or two of chemotherapy. ( important for radiotherapy volume) 4/Chemotherapy should consist of four cycles of a platinum agent and etoposide. 5/Extensive-stage disease should be treated primarily with chemotherapy consisting of a platinum agent plus etoposide or irinotecan. 6/Prophylactic cranial irradiation prolongs survival in patients with limited-stage disease who achieve a complete or partial response to initial therapy and may do so in similarly responding patients with extensive-stage disease as well. Additional information is available at Chest radiotherapy is now part of the treatment PCI is only given to complete or partial responders

25 PCI only to complete or partial responders

26 Use PET data for mediastinal nodes?. Optimal dose and schedules not stablished.do we treat lung primary in CR patients?. Better treat concomitant

27 BID for SCLC? N Engl J Med Jan 28;340(4): Twice-daily compared with once-daily thoracic radiotherapy in limited small-cell lung cancer treated concurrently with cisplatin and etoposide. Turrisi AT 3rd 1, Kim K, Blum R, Sause WT, Livingston RB, Komaki R, Wagner H, Aisner S, Johnson DH. 4500/ 1.8 / 25 fr. = 54.8 BED 4500/1.5bid/30 fr. = 61.4 BED 5040/ 1.8 /28 fr. = 61.4 BED Grimm-Jimm@CooperHealth.edu BED ( biological effective dose) is different for the two 4500 cgy regimens

28 The future SCLC Radiotherapy

29 Toxicity of PCI Long-term toxicities are difficult to assess and quantify, and the data pertaining to these are limited. Potentially devastating neurologic and intellectual disabilities were seen with earlier treatment techniques that used concurrent chemotherapy, large fraction sizes (3.0 to 4.0 Gy), and/or a high total dose, all of which have been shown to be associated with severe late neurotoxicity [13-15]. There is significant neurotoxicity present in patients completing induction chemotherapy, prior to PCI Ongoing RTOG and EORTC trials will hopefully provide more information RTOG 0212: chronic neurotoxicity was significantly less frequent in patients treated with 25 Gy compared with 36 Gy (60 versus 85 and 89 percent, respectively, p = 0.02). mild deterioration across time of communication deficit, weakness of legs, intellectual deficit and memory (all P < 0.005). The problem of neuropsychological toxicity remains unclear, leading to controversy about the indications of PCI in SCLC. So further studies about neuropsychological toxicity of the long-term PCI need studied by the researchers in the future. More than 250x10= 2500 is not recommended Do not give it while patient is getting chemotherapy

30 Possible methods to improve PCI toxicity Memantine Hydrochloride and Whole-Brain Radiotherapy With or Without Hippocampal Avoidance in Reducing Neurocognitive Decline in Patients With Brain Metastases This study is currently recruiting participants. (see Contacts and Locations) Verified August 2015 by NRG Oncology National Cancer Institute (NCI) Radiation Therapy Oncology Group Donepezil for Irradiated Brain Tumor Survivors: A Phase III Randomized Placebo-Controlled Clinical Trial:JCO JCO ; published online onapril 20, 2015; Donepezil Helps Some Patients Treated With Brain Irradiation Veronica Hackethal, MD April 30, 2015 It requires IMRT by American Society of Clinical Oncology Hippocampal-Avoidance Whole-Brain Radiation Therapy: A New Standard for Patients With Brain Metastases? : John H. Suh, MD, Cleveland Clinic, All these studies are in phase II-III. Are we ready to use them?

31 Optimal chest XRT for SCLC CALGB30610/RTOG0538:Phase III Comparison of Thoracic Radiotherapy Regimens in Patients With Limited Small Cell Lung Cancer Also Receiving Cisplatin and Etoposide. To determine whether administering high dose thoracic radiotherapy, 70 Gy (2 Gy once-daily over 7 weeks) or 61.2 Gy (1.8 Gy once-daily for 16 days followed by 1.8 Gy twice-daily for 9 days), will improve median and 2-year survival compared with 45 Gy (1.5 Gy twice-daily over 3 weeks) in patients with limited stage small cell lung cancer. Tumor volume on complete responders?. Do we treat volumes prior to chemotherapy?. Perhaps PET can help now better. Compare bid with much higher dose ( 70 GY)

32 North of Montreal, Canada, Mt. Tremblant

33 Past recommendations NSCLC Radiotherapy ( based on review articles)

34 Basel, Switzerland, company Roche. Perhaps best review article

35 XRT can produce good response and control If surgery is not possible

36 Post op XRT: can be detrimental?

37 Altered fractionation: Is CHART ( 3 times a day, 54 GY, 12 consecutive days) still used? Can you use it with chemotherapy?

38 CHT + XRT better than RT alone

39 Meta-analysis of multiple randomized trials( over 7500 patients) XRT-CHT usually better than XRT alone

40 Preoperative XRT and chemo: XRT before surgery hardly use

41 Much more complicated than small cell/,nsclc is less chemosensitive. New angiogenesis and EGFR inhibitors/ inmmunotherapy

42 Present recommendations NSCLC Radiotherapy Very complicated. Use NCCN guidelines

43 CCO and the ASCO Guideline for Adjuvant Chemotherapy and Adjuvant Radiation Therapy for Stages I-IIIA Resectable Non-Small Cell Lung Cancer Submitted by patchanan. owen on Thu, :06 Published in Journal of Clinical Oncology, Vol 25, Issue 34 (December), 2007: Katherine M. W. Pisters, Conclusion: Adjuvant cisplatin-based chemotherapy is recommended for routine use in patients with stages IIA, IIB, and IIIA disease. adjuvant chemotherapy in stage IB disease is not currently recommended for routine use. To date, very few patients with stage IA NSCLC have been enrolled onto RCTs of adjuvant therapy; adjuvant chemotherapy is not recommended in these cases Adjuvant radiation therapy appears detrimental to survival in stage IB and II, and may possibly confer a modest benefit in stage IIIA. - XRT, chemo or both only in patients borderline resectable or with advanced risk features

44 Definitive and Adjuvant Radiotherapy in Locally Advanced Non Small-Cell Lung Cancer: American Society of Clinical Oncology (ASCO) Clinical Practice Guideline Endorsement of the American Society for Radiation Oncology ( ASTRO) Evidence-Based Clinical Practice Guideline Submitted by shannon.mckernin on Tue, :23 Published online before print May 5, 2015, DOI /JCO Andrea Bezjak, Sarah Temin, Recommendations For curative-intent treatment of locally advanced NSCLC: 1/concurrent chemoradiotherapy improves local control and overall survival compared with sequential chemotherapy followed by radiation. 2/The standard dose-fractionation of radiation is 60 Gy given in 2-Gy once-daily fractions over 6 weeks. ( no altered fractionation recommended in US). 7/There is no role for the routine use of induction therapy before chemoradiotherapy. 8/Current data fail to support a clear role for consolidation therapy after chemoradiotherapy; however, consolidation therapy remains an option for patients who did not receive full systemic chemotherapy doses during radiotherapy. Important questions remain about the ideal concurrent chemotherapy regimen and optimal management of patients with resectable stage III disease. ASCO and ASTRO recommendations

45 T4 and N3 makes tumor unresectable Earlier stages are potencially resectable

46 Surgery :IA to IIIA: preop-postop XRT/Preop XRT not mentioned in NCCN guidelines No surgery possible : IIIB-IV: RT-chemo

47 Surgery: issue of margins. Early stage: XRT if margin positive./ No XRT if margins negative ( CHT in high risk) Unresectable: Chemo-XRT ( sequential or concurrent)

48 NSCLC Potentially resectable disease : preoperative chemoradiotherapy? Induction chemotherapy alone or induction concurrent chemoradiotherapy should be considered as the initial treatment for patients with clinically evident mediastinal lymph node involvement (N2 positive), when such disease is potentially resectable. It may have a role in carefully selected patients Improved survival associated with neoadjuvant chemoradiation in patients with clinical stage IIIA(N2) non-small-cell lung cancer. Koshy M, Fedewa et al. J Thorac Oncol Jul;8(7): Median follow-up was 11.8 months for 11,242 eligible patients. CONCLUSION: This large study demonstrates that patients with clinical stage IIIA-N2 NSCLC, who underwent neoadjuvant chemoradiation followed by lobectomy, were associated with an improved survival Radiotherapy plus chemotherapy with or without surgical resection for stage III non-small-cell lung cancer: a phase III randomised controlled trial. Limited dose for preop Albain KS et al. Lancet. 2009;374(9687):379. less effective post op ( vascular damage)? induction chemotherapy ( cisplatin and etoposide ) plus radiotherapy (45 Gy) in multiple academic and community hospitals. If no progression, patients in group 1 underwent resection and those in group 2 continued radiotherapy uninterrupted up to 61 Gy. OS was improved for patients who underwent lobectomy, but not pneumonectomy, versus chemotherapy plus radiotherapy Preop XRT might improve resectability and survival in selected cases. Danger if pneumonectomy required/some medical oncologist try chemo alone and post op XRT

49 NSCLC. PORT,Adjuvant Postop XRT 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. Data on 2128 patients from nine randomised trials. FINDINGS: significant adverse effect of postoperative radiotherapy on survival. Subgroup analyses suggest that this adverse effect was greatest for patients with stage I/II, N0- N1 disease, whereas for those with stage III, N2 disease there was no clear evidence of an adverse effect. Postoperative radiotherapy in non-small-cell lung cancer warrants further exploration in the era of adjuvant chemotherapy and conformal radiotherapy. Bonner JA, Spencer SA J Clin Oncol. 2006;24(19):2978./ Cobalt, old techniques, high daily dose, single daily field, cardiotoxicity etc Postoperative radiotherapy is associated with better survival in non-small cell lung cancer with involved N2 lymph nodes: results of an analysis of the National Cancer Data Base. Mikell JL, et al.j Thorac Oncol. 2015;10(3):462. PORT important for N2 disease. Use modern techniques. (dose-volume histograms, V-20, etc), careful with pneumonectomies. Not justified in early disease with negative margins

50 NSCLC, Post op. XRT, Positive margin Postoperative Radiation Therapy Is Associated With Improved Overall Survival in Incompletely Resected Stage II and III Non-Small-Cell Lung Cancer. Wang EH, et al. J Clin Oncol. 2015;33(25):2727. Method: Among 3,395 included patients, 1,207 (35.6%) received PORT. Total dose from 50 to 74 Gy using contemporary RT techniques. CONCLUSION: PORT is associated with improved overall survival in patients with incompletely resected stage II or III N0-2 NSCLC.

51 N2 disease: always chemo-xrt even with neg. margins. Neg. margins: sequential Chemo-XRT accepted. Pos. margins: concurrent Ch-XRT recommended ( more effective)

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53 Preop.XRT smaller dose single daily fraction ( CHART not mentioned)

54 Targeted lung cancer agents in current use While a very large number of agents targeting various molecular pathways are being developed and tested, the main classes and agents that are now being used in lung cancer treatment include: [8] Inhibitors of Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI's): [9] erlotinib (Tarceva)[10][unreliable medical source?] gefitinib (Iressa)[11][unreliable medical source?] monoclonal antibody against EGFR: cetuximab (Erbitux)[12][unreliable medical source?] Inhibitors of vascular endothelial growth factor (VEGF) [13] bevacizumab (Avastin)[14][unreliable medical source?] Inhibitor of EML4-ALK crizotinib shows benefit in a subset of non-small cell lung cancer that is characterized by the EML4-ALK fusion oncogene, [15][16] found in some relatively young, never or light smokers with adenocarcinoma. [17] Medscape Medical News: Immunotherapy: Backbone of Future Lung Cancer Treatment? Alexander M. Castellino et al. "I conceive that there will come a day when immunotherapy will be the standard of care and backbone therapy on which other treatment modalities will be added, especially for patients with no long-term benefits," Dr Herbst there is the problem of cost; the new immunotherapies have huge price tags, and will be unaffordable for many patients with copays. New Immunotherapy Costing $1 Million a Year. Gooder Than Gold Are they going to make radiotherapy obsolete?

55 The Future NSCLC Radiotherapy

56 Adjuvant post op XRT with negative margins Postoperative RT with negative margins may have a role in several situations: For patients with inadequate lymph node sampling in whom mediastinal node involvement was suspected but not confirmed. The use of postoperative RT in this scenario should not be prioritized over that of adjuvant chemotherapy. For patients with involvement of multiple stations of involved N2 lymph nodes Radiation Therapy in Treating Patients With Non Small Cell Lung Cancer That Has Been Completely Removed by Surgery (LUNG ART) This study is currently recruiting participants. (see Contacts and Locations) Verified September 2014 by Gustave Roussy, Cancer Campus, Grand Paris Sponsor: Gustave Roussy, Cancer Campus, Grand Paris PURPOSE: This randomized phase III trial is studying radiation therapy to see how well it works compared to no radiation therapy in treating patients with non-small cell lung cancer that has been completely removed by surgery.

57 SRS increasing in use for both intra and extracranial treatment

58 Stereotactic ablative radiotherapy versus lobectomy for operable stage I non-small-cell lung cancer: a pooled analysis of two randomised trials Prof Joe Y Chang, MD * et al. Lancet vol 16 number 6, p , June 2015 Findings 58 patients were enrolled and randomly assigned (31 to SABR and 27 to surgery). Median follow-up was 40 2 months (IQR ) for the SABR group and 35 4 months ( ) for the surgery group. 6 patients in the surgery group died compared with 1 patient in the SABR group. Estimated overall survival at 3 years was 95% (95% CI ) in the SABR group compared with 79% (64 97) in the surgery group. Recurrence-free survival at 3 years was 86% (95% CI ) in the SABR group and 80% (65 97) in the surgery group Three (10%) patients in the SABR group had grade 3 treatment-related adverse events No patients given SABR had grade 4 events or treatment-related death. In the surgery group, one (4%) patient died of surgical complications and 12 (44%) patients had grade 3 4 treatment-related adverse events. Interpretation SABR could be an option for treating operable stage I NSCLC. Because of the small patient sample size and short follow-up, additional randomised studies comparing SABR with surgery in operable patients are warranted. SBRT for stage 1: Better survival, less recurrence, less complications than surgery In practice, many stage I patients never reach a surgeon

59 Come and see me again SBRT in Oligometastasis Joaquin G Mira M.D. START center San Antonio, Texas More discussion on SBRT

60 SBRT and Inmunotherapy Stereotactic Radiation Therapy Combined With Immunotherapy: Augmenting the Role of Radiation in Local and Systemic Treatment Review Article May 15, 2015 Oncology Journal By AndrewB Sharabi et al Large radiation fields encompassing significant volumes of bone marrow or blood pool have been observed to result in decreases in white blood cell counts, giving rise to the notion that radiation may be generally immunosuppressive. Nonetheless, with the application of SRS and SBRT, there is the possibility of significantly limiting the volume of bone marrow and/or blood pool being irradiated, thereby minimizing these potentially consequential immunosuppressive effects. Accumulating preclinical data have documented that immunotherapy can augment radiationmediated local tumor response. Similarly, radiation can augment the systemic effects of immunotherapy Most preclinical data to date are from studies of high doses of radiation that, when translated to the clinic, may be best delivered with SBRT. carefully designed studies will be required to investigate the effects of radiation combined with immunotherapy on local tumor control in the definitive setting and on systemic tumor control in the metastatic setting. Lung Cancer 2015: A Shifting Paradigm with Focus on Immunotherapy and Newer Targeted Therapies.

61 Abscopal effect found in rats with radiosurgery/ Now approved clinical trials

62 Have we improved in the past 30 years?

63 One year survival almost double. Why? Effective treatments in the short term

64 Increase survival at 5 years but still poor results

65 Conclusions about XRT and lung cancer 1/Radiotherapy continues to be a very important tool in lung cancer. Medical oncologist recognize that many solid tumors relapse in spite of good early responses, and surgery or radiotherapy are needed to decrease local relapse and to prolong response. 2/Timing of surgery, radiotherapy and chemotherapy is important. We need to work together to offer the best results. Communication with other specialties 3/ Technologies to minimize normal tissue damage ( IMRT) and to increase daily accuracy ( On Board Imaging) allow us to increase dosages without increasing normal tissue complications. 3/ Radiosurgery is a revolutionary tool that allow us to increase dramatically tumor responses and local tumor control irrespective of histology. It is more frequently replacing surgery in early lung cancer It might enhance inmunotherapy and help systemic therapy. 4/ Although the general long term survival for lung cancer continues to be poor, definite improvement has been achieved, mainly in early survival statistics 5/ New internet tools ( NCCN, ASCO-ASTRO guidelines, search engines) allow knowledge to be available to almost anybody anywhere. Standards of therapy are becoming more available with benefits to patients and doctors.

66 Will radiation oncology become obsolete in the near future? Answer : no it will change as Medical Oncology and Surgical Oncology have changed After 40 years in practice, we lost a few indications, But we do things I never imagine we could do.

67 The end

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69 Neuro Oncol Oct;15(10): doi: /neuonc/not114. Epub 2013 Aug 16. Memantine for the prevention of cognitive dysfunction in patients receiving whole-brain radiotherapy: a randomized, double-blind, placebo-controlled trial. Brown PD 1, et al.(rtog). METHODS: Adult patients with brain metastases received WBRT and were randomized to receive placebo or memantine (20 mg/d), within 3 days of initiating radiotherapy for 24 weeks. Serial standardized tests of cognitive function were performed. 554 patients who were accrued, 508 were eligible. CONCLUSIONS: Although there was less decline in the primary endpoint of delayed recall at 24 weeks, this lacked statistical significance possibly due to significant patient loss

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72 Review 2013

73 Characteristics of the included studies using PORT. Abbreviatio n # Patients Stage Beam quality Dose/fractio n (Gy) EQD 2 (tumor) (Gy) EQD 2,T (Gy) Belgium [23] 224 I III Cobalt only 60/ CAMS [24] 317 II, III Cobalt and Linac 60/ GETCB 04CB86 [25] 189 I III Cobalt and Linac 60/ GETCB 05CB88 [26] 539 I III Cobalt and Linac 60/ LCSG 773 [27] 230 II, III Cobalt and Linac 50/ Lille 1985 [28] 163 I Cobalt and Linac 45 60/ MRC LUI I [29] 308 II, III Cobalt and Linac 40/ Slovenia 1988 [30] 74 III Linac only 30/ Austria [31] 155 III Linac only 50 56/ EORTC [32] 106 II, III Linac only 56/ Italy [33] 104 I Linac only 50.40/

74 2014 by American Society of Clinical Oncology Hippocampal-Avoidance Whole-Brain Radiation Therapy: A New Standard for Patients With Brain Metastases? John H. Suh + Author Affiliations Cleveland Clinic, Cleveland, OH Corresponding author: John H. Suh, MD, Cleveland Clinic, Department of Radiation Oncology, T28, 9500 Euclid Ave, Cleveland, OH 44195; suhj@ccf.org

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76 The current standard of care for most patients with IIIA-N2 NSCLC patients is concurrent chemoradiotherapy [37]. However, long-term outcomes with this treatment are poor, due to a high rate of distant metastases and of local recurrence. In an individual patient meta-analysis, Aupérin et al. reported local tumor progression in 36% of patients with locally advanced NSCLC treated with concurrent chemoradiation [22]. The true incidence of LR when more thoroughly assessed, is even higher [38]. Importantly, this meta-analysis demonstrated that about two-thirds of the magnitude of improvement in local control was translated in improved overall survival a viable alternative could be sequential chemotherapy, surgery and postoperative radiotherapy (PORT), the latter tailored according to risk groups for local recurrence. This strategy would allow optimization of the systemic treatment, which may be hampered when delivered concomitantly with radiotherapy, and avoids possible increased complications with preoperative radiotherapy.

77 Because of the recruitment of patients in the studies of the PORT meta-analysis went from 1966 to 1995, they included also patients treated with cobalt machines without CT-based planning. The excess of toxicity (mostly cardiac and pulmonary) and non-cancer related deaths observed in the post-operative radiotherapy arm of the trials included in the meta-analysis can probably be explained by excessive volumes of radiation, old radiation techniques, too large doses and fraction sizes [11] and [12]. Trials with contemporary radiotherapy techniques demonstrated that there was no increase of death from intercurrent disease [13], [14], [15], [16], [17] and [18]. With individualized, isotoxic, accelerated radiotherapy (INDAR) biological doses of over 80 Gy can be delivered, but with toxicity levels that are comparable to 65 Gy [51]. Another trial using linear accelerators only, demonstrated a decrease in LR in patients with stage III N2 NSCLC receiving PORT compared to surgery alone [55]. A subgroup analysis of the ANITA trial suggests that PORT may indeed improve long-term survival [56].

78 Highlights of ASCO 2015 ( educational Concepts Group) Faculty Editors Gregory Otterson, MD Professor, Internal Medicine Co-Director, Thoracic Oncology Program Program Director, Hematology & Medical Oncology Fellowship Program The Ohio State University Medical Center Columbus, Ohio Heather Wakelee, MD Associate Professor Department of Medicine, Division of Oncology Co-Director, Thoracic Oncology Clinical Research Group Stanford University Stanford, California Summary The 2015 ASCO Annual Meeting provided an excellent venue for the dissemination of important clinical trial information on the treatment of NSCLC that may impact clinical practice positively.

79 Highlights ASCO 2015 Early-Stage NSCLC PROCLAIM Trial Concurrent Chemotherapy With Concurrent Thoracic Radiotherapy (TRT) Followed by Consolidation Chemotherapy, presenhted by Senan et al. The standard of care for inoperable stage III NSCLC is concurrent chemoradiotherapy 1,2 ; In locoregionally advanced NSCLC, the combination of pemetrexed+cisplatin and concurrent TRT showed favorable results in PFS and an acceptable safety profile, although it did not demonstrate superiority to etoposide + cisplatin in OS.

80 Emphasis will be on reviewing the latest advances from ASCO 2015 and WCLC 2015 in immunotherapy as well as next generation agents in the management of EGFR-mutant and Alk-positive lung cancer. Attendees will work with experts in the field to review all of the recent advances in a highly interactive case-based discussion format, supported by didactic lectures.

81 Highlights ASCO 2015 Whole Brain Radiation Therapy Plus Radiosurgery in Brain Metastases The trial was designed for patients with 1-3 brain metastases (< 3 cm) to determine if cognitive progression 3 months post-srs is less with SRS alone than with SRS + WBRT. The trial stratified patients by age, extra-cranial disease status, number of brain metastases, and institution, then randomized to SRS or SRS + WBRT. Assessments at baseline and over time included MRI scan, Functional Assessment of Cancer Therapy-Brain (FACT-Br), and a cognitive battery of tests that assesses multiple cognitive domains. This multicenter trial enrolled 213 patients (2 ineligible and 3 canceled prior to receiving treatment) between 2002 and 2013, with a median follow-up of 7.2 months. The median age was 60 and approximately 70% of patients had a lung primary.

82 Highlights ASCO 2015 Whole Brain Radiation Therapy Plus Radiosurgery in Brain Metastases (2) Results: Cognitive progression at 3 months was more frequent after SRS + WBRT vs SRS alone (91.7% vs 63.5%, respectively; P = ). This outcome persisted at 6 months for treatment with SRS + WBRT vs SRS alone (97.9% vs 77.8%, respectively; P = 0.032). More specifically, there was more cognitive deterioration in the SRS + WBRT arm, which reached statistical significance at 3 months for immediate recall (P = 0.004), memory (P = 0.002), and verbal fluency (P = 0.02). WBRT did significantly improve intracranial control at 3 months, at 6 months, and beyond (Figure 3). However, despite the improvement in intracranial control, there was no difference between treatment arms in median OS (SRS 10.4 months vs SRS + WBRT 7.4 months; HR = 1.02). This may be explained by the fact that patients randomized to SRS alone underwent salvage therapy. Patient reported quality of life (QoL) for all measures were higher in the SRS arm, including overall QoL. Conclusions: The overall results of this study indicate that, for patients with newly diagnosed brain metastases who are amenable to SRS, initial treatment with SRS alone and close monitoring to better preserve cognitive function and QoL are recommended compared to the use of WBRT.

83 2015 by American Society of Clinical Oncology Next-Generation Sequencing of Pulmonary Sarcomatoid Carcinoma Reveals High Frequency of Actionable MET Gene Mutations Xuewen Liu, et al Marked advances have been made in the development of targeted agents for the treatment of molecularly defined subsets of NSCLC, with dramatic efficacy of epidermal growth factor receptor (EGFR) and ALK tyrosine kinase inhibitors in EGFR- and ALK-mutated lung adenocarcinomas. 28 the preferential amplification of the mutated allele, along with the rapid and dramatic response, certainly argues for the utility of MET inhibition in this setting.

84 Thank you for taking the questionnaire. You are helping to determine the current practice patterns for patients with ES-SCLC. Please, contact us if you have any questions, suggestions or concerns with this survey. Have a nice day!

85 Possible methods to improve brain toxicity Memantine Hydrochloride and Whole-Brain Radiotherapy With or Without Hippocampal Avoidance in Reducing Neurocognitive Decline in Patients With Brain Metastases This study is currently recruiting participants. (see Contacts and Locations) Verified August 2015 by NRG Oncology National Cancer Institute (NCI) Radiation Therapy Oncology Group Donepezil for Irradiated Brain Tumor Survivors: A Phase III Randomized Placebo-Controlled Clinical Trial:JCO JCO ; published online onapril 20, 2015; Donepezil Helps Some Patients Treated With Brain Irradiation Veronica Hackethal, MD April 30, by American Society of Clinical Oncology Hippocampal-Avoidance Whole-Brain Radiation Therapy: A New Standard for Patients With Brain Metastases? : John H. Suh, MD, Cleveland Clinic, All these studies are in phase II-III. Are we ready to use them?

86 Summary The 2015 ASCO Annual Meeting provided an excellent venue for the dissemination of important clinical trial information on the treatment of NSCLC that may impact clinical practice positively. 1/ In locoregionally advanced NSCLC, the combination of pemetrexed+cisplatin and concurrent TRT showed favorable results in PFS and an acceptable safety profile, although it did not demonstrate superiority to etoposide + cisplatin in OS. 2/ combination of WBRT plus SRS in patients with newly diagnosed brain metastases concluded that initial treatment with SRS alone and close monitoring are recommended to minimize cognitive changes. 3/Some of the most promising and exciting data came in the area of immunotherapy with encouraging results for treatment with nivolumab, atezolizumab, and pembrolizumab.

87 NSCLC non resectable The superiority of concurrent chemoradiotherapy compared with sequential chemotherapy followed by RT is illustrated by the results of two large, multicenter, randomized phase III trials [61-64]: Published 1n 2011 JNCI: In the Radiation Therapy Oncology Group (RTOG) trial 9410, 610 patients with unresected stage III disease were randomly assigned to sequential cisplatin plus vinblastine for two cycles followed by conventional RT (60 Gy in 30 fractions) or to two cycles of the same chemotherapy administered concurrently with conventional RT [62]. A third study arm evaluated concurrent cisplatin plus etoposide with twice daily RT to a total dose of 69.6 Gy. With over 95 percent of patients followed until death, concurrent chemoradiotherapy with conventional RT fractionation was superior to sequential chemoradiotherapy (median survival 17.0 versus 14.6 months, hazard ratio for death 0.81, 95% CI ). The difference between the conventional fractionation chemoradiotherapy and twice daily regimen was not statistically significant (median survival 17.0 versus 15.6 months). Acute grade 3 or higher nonhematologic toxicity was more frequent with the concurrent regimens, but late toxicity rates were similar. Published JCO, 1999: In a Japanese study, 320 patients with unresectable stage III NSCLC were randomly assigned to either concurrent chemotherapy (two cycles of cisplatin, mitomycin, and vindesine) plus split-course thoracic RT (two courses of 28 Gy in 2 Gy daily fractions, separated by ten days) or to two cycles of the same chemotherapy regimen followed by a single course of RT (56 Gy in 28 fractions) [63,64]. Despite the use of a split-course RT schedule, concurrent therapy was associated with a significantly better response rate (84 versus 66 percent), median survival (17 versus 13 months), and two- and five-year survival rates (35 versus 27 percent and 16 versus 9 percent, respectively).

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