Critical Clinical Updates

Transcription

1 Critical Clinical Updates ASTRO Spring Refresher Course JW Marriott Hotel Ramesh Rengan MD PhD Department of Radiation Oncology Friday March 22, 2013

2 Learning Objectives At the conclusion of this activity, the learner will be able to do the following: 1. Identify recently reported toxicities associated with novel radiation regimens. 2. Identify recently reported toxicities associated with novel combined modality regimens. 2

3 1. A 65-year old man presents with a left upper lobe ttf-1 positive adenocarcinoma. A bronchoscopy is performed confirming lymph node involvement at 4L and 7. Staging studies confirm no evidence of distant metastatic disease. The patient is presented in a multidisciplinary tumor board and the consensus is for definitive concurrent chemoradiotherapy. The medical oncologist plans to employ a regimen of carboplatin/ taxol/bevacizumab extrapolating from the results of ECOG 4599 showing a survival benefit with this regimen in advanced disease. Which of the following is true regarding thoracic radiotherapy in this setting? a) Concurrent involved field thoracic radiotherapy to a dose of 60Gy should be employed. b) Concurrent involved field thoracic radiotherapy to a dose of 74Gy should be employed. c) Sequential thoracic radiotherapy to a dose of 60Gy should be employed. d) Thoracic radiotherapy is contraindicated with this regimen and therefore patient should receive chemotherapy alone e) Thoracic radiotherapy is contraindicated with this regimen and therefore the medical oncologist should be asked to employ an alternate regimen 3

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5 Critical Clinical Updates: Rationale ASTRO Spring Refresher Attendees Previously was resident trainees and clinicians preparing for board examination Transitioned to radiation oncologists in clinical practice interest in staying up-to-date (82% rad oncs in practice vs 14% trainees -40% in 2006) Session designed to disseminate recently identified clinical outcome and toxicity information relevant to daily clinical practice Anticipate that this information would not be results of large phase III clinical trial Example: Report by Allen et al. on fatal pneumonitis in 6/13 patients with hemithoracic IMRT s/p EPP for mesothelioma (2006) 5

6 Objectives To provide radiation oncologists with clinically useful outcome/toxicity data that has been recently reported (within the past 5 years) We anticipate that these data will apply to scenarios that are routinely encountered in a radiation oncology clinical practice setting 6

7 Clinical Vignette 57 yom with stage IV patient diagnosed 3 years ago Doing well on systemic chemotherapy +/- targeted agent has an isolated progressive disease referred for palliative rt to isolated disease Can you treat with SBRT? Impact of location If the patient is receiving targeted therapy can we treat safely with SBRT or standard fractionation RT to a palliative or higher dose (goal of control)? 7

8 Rationale for this referral: Changing face of stage IV disease 8

9 Survival in Advanced NSCLC 25 Survival in Advanced NSCLC 20 Median Survival ECOG 1594 (platin; all histo) 2002 ECOG 4599 (non-scc; bev) 2006 JMEN (non-scc; pem maint) 2008 IPASS (EGFR Mut +)

10 Patterns of failure in Advanced NSCLC Percentage (%) All SBRT Local Only Local + Distant Distant Only Pattern of Failure 10

11 Patterns of failure in Advanced NSCLC 11

12 The value of local control in stage IV disease 25 patients with oligometastatic stage IV NSCLC Received high-dose thoracic radiotherapy Rengan, in submission Matched cohort comparison to patients who received chemotherapy alone 12

13 SBRT in Stage IV Disease Convenient Minimal acute toxicity Able to deliver without significant disruption of chemotherapy timing Increasing importance with advent of maintenance chemotherapy 13

14 SBRT and Stage IV disease Limitations of outcome data with SBRT Largest volume of SBRT is from the stage I inoperable lung setting Unclear that the morbidities of the medically inoperable stage I patient (advanced COPD, etc) is applicable to a good PS stage IV patient (32 yo never smoker with pulmonary nodules) Clinical trial infrastructure designed to capture/report acute toxicities Late toxicities are far more difficult to capture 14

15 Grade 3-5 Toxicity: Location p =

16 Medically Inoperable Early Stage: Hypofractionated Stereotactic Radiation 16

17 SBRT: Central Lesion Toxicity 17

18 Medically Inoperable Early Stage: Hypofractionated Stereotactic Radiation Correspondence Central-Airway Necrosis after Stereotactic Body-Radiation Therapy N Engl J Med 2012; 366:

19 SBRT to Spine: PMH experience Al-Omair; J Neurosurg March 2013 L3 L4 L3 L4 12 Gy X 2 20Gy x 1 Case 1: Stage IIIA NSCLC s/p chemort surgery adjuvant chemort Isolated progression at L2 at 2 years 20Gy x 1 then tarceva 6 months post-sbrt scan- shown above 24 months post-sbrt symptomatic and MR evidence of VCF progression- biopsy shows necrosis with scatter fragments of adenoca Observed. Continues to be NED 4 months post-kyphoplasty/biopsy Case 2: Metastatic neuroendocrine tumor with spine mets s/p DDDP/VP-16 x 6. Isolated progression at L3/4 12Gy x 2 3- years post SBRT symptomatic and MR evidence of VCF progression- biopsy shows fibrosis Observed. No progression 6-months post-kyphoplasty/biopsy 19

20 Hypofractionated Radiotherapy Generally safe, effective, and convenient Long-term monitoring of patients is important especially when delivering SBRT to High-risk locations Near vital organs Near large vessels Oligometastatic setting Patients will go on to receive systemic therapies Try to obtain tissue to confirm abnormal radiographic findings 20

21 TARGETED THERAPY AND RT 21

22 Survival in Advanced NSCLC 25 Survival in Advanced NSCLC 20 Median Survival ECOG 1594 (platin; all histo) 2002 ECOG 4599 (non-scc; bev) 2006 JMEN (non-scc; pem maint) 2008 IPASS (EGFR Mut +) 2009 Shaw (Alk+)

23 Targeted Therapies Novel, targeted therapies leading to improved survival in advanced NSCLC Bevacizumab (with chemo, 1 st line): ECOG MS 12.3 mos vs mos, HR=0.80; p=0.013 HR=0.80; p=0.013 Cetuximab (with chemo, 1 st line): Flex 2 MS 11.3 vs mos, HR 0.871, p= Erlotinib (single agent, 2 nd and 3 rd line): BR21 3 MS 6.7 vs. 4.7 mos, HR 0.73, HR<0.001 Crizotinib (single agent, 2 nd or 3 rd line): 87% Disease control rate; 57% with PR or better 1: Sandler et al NEJM 355: , : Pirker et al ASCO Abstract 3, : Shepherd et al NEJM 353: , : Bang et al PASCO

24 The promise of targeted agents Pre-Treatment Crizotinib x 12 weeks Targeted therapies offer the promise of selective systemic therapy Can result in dramatic responses in patients harboring the target mutation or receptor New questions arise Effect of targeted agents on normal tissue? Rarely, if ever, curative- value of local control in these patients? Limited long-term data in combination with RT 24

25 Targeted agents and RT: What information do we have? 25

26 Anti-angiogenic agents Vascular endothelial growth factor (VEGF) is the predominant mediator of angiogenesis throughout the development of many tumor types VEGF is the only angiogenic factor known to be present throughout the tumor life cycle 1 As the tumor develops, it may activate secondary angiogenic pathways 1 VEGF continues to be overexpressed and remains one of the critical mediators of angiogenesis 2-5 Overexpression contributes to tumor growth and metastases VEGF VEGF bfgf TGFβ-1 VEGF bfgf TGFβ-1 PIGF VEGF bfgf TGFβ-1 PIGF PD-ECGF Expression of angiogenic factors throughout the tumor life cycle 1 VEGF bfgf TGFβ-1 PIGF PD-ECGF Pleiotrophin 1. Folkman J. In: DeVita VT Jr, et al, eds. Cancer: Principles & Practice of Oncology. Vol 2. 7th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2005: Bergers G et al. Nat Rev Cancer. 2003;3: Jain RK et al. Nat Clin Pract Oncol. 2006;3: Bergers G et al. Nat Cell Biol. 2000;2: Inoue M et al. Cancer Cell. 2002;1:

27 VEGF: Targeted Approaches Bevacizumab Anti-receptor blocking antibodies None FDA approved DC101 (mouse) Tyrosine kinase inhibitors Sunitinib Antiligand blocking antibodies Adapted from Noonberg and Benz. Drugs. 2000;59:

28 Avastin (bevacizumab) Recombinant humanized monoclonal IgG1 antibody Recognizes all isoforms of VEGF- A and blocks VEGF function Half-life is approximately 20 days (range, 11 to 50 days) Avastin (bevacizumab) prescribing information. South San Francisco, Calif: Genentech;

29 Targeted Therapies Novel, targeted therapies leading to improved survival in advanced NSCLC Bevacizumab (with chemo, 1 st line): ECOG MS 12.3 mos vs mos, HR=0.80; p=0.013 HR=0.80; p=0.013 Cetuximab (with chemo, 1 st line): Flex 2 MS 11.3 vs mos, HR 0.871, p= Erlotinib (single agent, 2 nd and 3 rd line): BR21 3 MS 6.7 vs. 4.7 mos, HR 0.73, HR<0.001 Crizotinib (single agent, 2 nd or 3 rd line): 87% Disease control rate; 57% with PR or better 1: Sandler et al NEJM 355: , : Pirker et al ASCO Abstract 3, : Shepherd et al NEJM 353: , : Bang et al PASCO

30 Bevacizumab and thoracic RT Multiple reports of TE fistula with bevacizumab and mediastinal RT Goodgame et al JTO 2008 (bevacizumab 2 months after chemort) Gore et al JTO 2009 (bevacizumab 21 months after chemort) Socinski et al JCO 2012 (carbo/tax/bev concurrent with chemort) Severe esophageal toxicity Grade 3 fistulas observed 30

31 Targeted Therapies in metastatic RCC Sunitinib- small molecule, multi-targeted inhibitor of receptor tyrosine kinase Approved for RCC and imatinib-resistant GIST by FDA Anti-angiogenic and anti-proliferative effects 31

32 Targeted Therapies in metastatic RCC Ann Pharmacotherapy 2010 Patient received 300 x 10 to bulky subcarinal adenopathy Sunitinib started one week after RT Dramatic reduction of tumor perforation identified monitored Cicatrix formation 12 months later death 32

33 SBRT and Sunitinib Surg Today 2012 Patient received 36Gy x 1 to a dominant left lower lobe mass Subsequently received sunitinib 33

34 Targeted therapies and RT: Conclusions Mediastinal/thoracic RT and anti-angiogenic agents such as avastin should be avoided No clear safe dose Palliative, standard, and hypofractionation have all been reported to result in fistulae Importance of continued follow-up of definitive patients even after patient develops DM Discuss with medical oncologist if an anti-angiogenic agent is to be used after thoracic RT Long-term impact of anti-angiogenic agents on normal tissue remains to be determined 34

35 Future topics Emerging data on re-irradiation When is it safe? What are predictors for toxicity? Particle beam radiotherapy Who benefits? Emerging toxicity data 35

36 1. A 65-year old man presents with a left upper lobe ttf-1 positive adenocarcinoma. A bronchoscopy is performed confirming lymph node involvement at 4L and 7. Staging studies confirm no evidence of distant metastatic disease. The patient is presented in a multidisciplinary tumor board and the consensus is for definitive concurrent chemoradiotherapy. The medical oncologist plans to employ a regimen of carboplatin/ taxol/bevacizumab extrapolating from the results of ECOG 4599 showing a survival benefit with this regimen in advanced disease. Which of the following is true regarding thoracic radiotherapy in this setting? a) Concurrent involved field thoracic radiotherapy to a dose of 60Gy should be employed. b) Concurrent involved field thoracic radiotherapy to a dose of 74Gy should be employed. c) Sequential thoracic radiotherapy to a dose of 60Gy should be employed. d) Thoracic radiotherapy is contraindicated with this regimen and therefore patient should receive chemotherapy alone e) Thoracic radiotherapy is contraindicated with this regimen and therefore the medical oncologist should be asked to employ an alternate regimen 36

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