Current Clinical Trials for Oropharyngeal SCC in the HPV Era

Transcription

1 Current Clinical Trials for Oropharyngeal SCC in the HPV Era Dr Caroline Connell Adelaide Radiotherapy Centre Page 1 3 May, 2016

2 Overview Advent of HPV associated Oropharyngeal SCC aetiology/risk factors prognosis treatment de-escalation in p16 +ve patients Current SA trials: *TROG Orator Other trials Conclusions Page 2 3 May, 2016

3 Oropharyngeal SCC Oropharyngeal Cancer, Herrington, May, 2016

4 Oropharyngeal SCC Epidemiology and Risk Factors: historically ETOH and smoking associated increasing incidence despite reduced smoking Page 4 3 May, 2016

5 Smoking Prevalence Among US Adults Oropharyngeal Cancer, Herrington, May, 2016

6 Head and Neck Cancer Incidence Rates Chaturvedi etal JCO May, 2016

7 HPV-associated OP SCC Now recognised that rise in OP SCC due to Human Papilloma Virus: 50-90% OP SCC associated with HPV risk factors include distinct sexual behaviours NOT smoking or ETOH Page 7 3 May, 2016

8 Human Papilloma Virus Small DNA virus Humans only known host Infection common Infects epithelial cells of skin and mucosa Benign warts, pre-cancer, cancer high risk and low risk types HPV 16 is the predominant subtype present in OP SCC p16: TSP over expressed in HPV +ve cells Good surrogate marker of HPV infection Cooper et al Head and Neck Path May, 2016

9 Chaturvedi etal. JCO May, 2016

10 HPV associated Oropharyngeal SCC Distinct Features: site: palatine tonsil/bot histology: non keratinizing/poorly diff morphology basaloid strong reactivity to p16 immunostain radiology: cystic metastases early T, advanced N stage risk factors: sexual behaviour ECOG: better comorbities: fewer risk of 2 nd Ca: less age: younger (<60) sex: men>women prognosis: improved Page 10 3 May, 2016

11 % surviving TROG 02.02, Overall Survival p P16+ (107) P16- (79) HR = 0.35; P = year OS:.92% & 74% Haz ard ratio 95% CI Years TROG Start up meeting, Rischin Dec

12 TROG 0202: Site of First Failure 25 p16+ p16-20 percentage of patients Locoregional Distant Death (no failure) TROG Start up meeting, Rischin 12 Dec 2015

13 Stratification of Risk according to HPV status and smoking history: RTOG 0129 TROG Start up meeting, Rischin Dec Ang et al. NEJM 2010

14 HPV related OP SCC Proposed TNM Staging System O Sullivan et al Lancet Oncology May, 2016

15 Proposed Staging Groups O Sullivan et al Lancet Oncology May, 2016

16 Why improved outcomes? Unknown? Reduced field cancerisation Improved immune surveillance to viral specific tumour antigens Intact apoptosis mechanism on exposure to radiation HPV OPSCC known to have: less p53 mutations, Rb abnormaities, EGFR expression More favourable patients younger, better ECOG?more sensitive to chemort Page 16 3 May, 2016

17 Greater reduction in QOL (FACT) in p16 + oropharyngeal cancer - TROG TROG Start up meeting, Rischin Dec 2015

18 Rationale for De-escalation Trials Currently treatment approaches associated with considerable acute and late toxicity It is likely that low risk HPV positive OP SCC can be treated with less intensive approaches Page 18 3 May, 2016

19 TROG 12.01: HPV Oropharynx A randomised trial of weekly cetuximab and radiation versus weekly cisplatin and radiation in good prognosis locoregionally advanced HPV-associated oropharyngeal squamous cell carcinoma Sponsor: TROG Central site: Peter MacCallum Cancer Institute Study Chair: Danny Rischin Co-chair: June Corry Page 19 3 May, 2016

20 Treatment arms - background Peter Mac experience with weekly cisplatin Urban et al Head and Neck, 2015 patients 31 patients, low risk (RTOG+ T4/N3 excluded) Median FU 30m Median age 56 ( 41 69), Male 74%, St. 4 90% 100% CR, No failures, no deaths 70 Gy 100%, > 5/7 cisplatin doses 84% Enteral feeding 70%, median 51 days (range 6 219) Gr 3 mucositis- 71%, Febrile neutropenia 19% TROG Start up meeting, Rischin Dec

21 Treatment arms background Cetuximab: monoclonal antibody targeting EGFR extensively studied as alternative to chemo for H and N SCC. Bonner et al. improved LRC and OS cf RT alone in HNSCC most benefit in HPV phenotype no report of increased toxicity ASCO 2014, Rosenthal et al. (in press) benefit for Cetuximab greater for p16+ve Page 21 3 May, 2016

22 Trial Objectives and Endpoints Primary objective: To compare patient-reported symptom severity between weekly cisplatin and RT versus weekly cetuximab and RT from baseline to week 20 (13 weeks post completion of radiotherapy). Primary Endpoint Patient-reported: The primary endpoint is the area under the curve of symptom severity as measured by MDASI-HN Symptom Severity Score (average of MDASI-HN items 1-22) from baseline to week 20 (13 weeks postcompletion RT) TROG Start up meeting, Rischin Dec 2015

23 TROG Start up meeting, Rischin Dec 2015

24 MD Anderson Symptom Inventory Head and Neck (MDASI-HN) Developed to overcome deficiencies in existing measures: relevant symptoms/effect on ADL s Assess 22 symptoms: Scale H and N cancer specific (RT acute toxicity) 13 core (cancer and chemo related) Internal consistency reliability Correlates closely with objective scores (FACT-HN) Page 24 3 May, 2016

25 Secondary Endpoints patientreported Modified MDASI-HN Symptom Score (average of items 1,2,3,4,8, 12,14,15,16,18,19,20,21 + hearing and tinnitus items ) MDASI-HN Symptom Interference Score (average of items 23-28) MDASI-HN Symptom clusters e.g., mucositis: items 1,2,8,9,10,14,15,20,21 and common severe items: items 1,2,4,8 and 9) TROG Start up meeting, Rischin Dec 2015

26 (secondary endpoints patient reported) FACT- HN Questionnaire Page 26 3 May, 2016

27 (secondary endpoints- patient reported) FACT-HN Page 27 3 May, 2016

28 (secondary endpoints) PSS - HN Page 28 3 May, 2016

29 Secondary Endpoints Toxicity Grading (CTCAE v4.0) reported as worst toxicity and as overall acute toxicity burden (T-score) Unacceptable locoregional treatment outcome Rate of enteral feeding at 12 months from end of treatment Functional swallowing outcome (video fluoroscopy) Hearing impairment (audiometry) Hearing-related HRQOL (HHIA-S) Depression and anxiety as assessed by HADS Overall survival Failure-free survival Time to locoregional failure FDG-PET-CT complete response rate at week 20 (13 weeks post-completion RT) Patterns of disease failure (local, nodal, distant, and combinations) Cost of health resource utilisation Quality adjusted life years (QALYs) (using the EQ-5D-5L) Work status and time to return to work. TROG Start up meeting, Rischin Dec 2015

30 Sample Size and Trial Duration In order to detect a difference in AUC of MDASI-HN total score, corresponding to an effect size of 0.50, between the two arms with a power of 90% using a two-sided test with alpha = 0.05, a total of 170 fully evaluable patients would need to be analyzed. To allow for missing HRQOL data and uncertainties associated with specification of the MID it is planned to accrue an additional 15% of patients to give a target sample size of 200 patients Accrual duration: 34 months Follow-up for the trial cease when the last patient accrued has a minimum 2yrs follow-up from end of treatment (ie: after attending the 24 months followup visit). Total trial duration is 60 months (=5 years). TROG Start up meeting, Rischin Dec

31 Inclusion Criteria Aged 18 years or older. Has provided written informed consent for participating in this trial Histologically confirmed squamous cell carcinoma of the oropharynx with p16 positive status confirmed locally by immunohistochemistry Stage III (excluding T1-2N1) or stage IV (excluding T4, N3 and distant metastasis) if smoking history of 10 pack years. If > 10 pack years nodal disease must be N0-N2a. If an excisional biopsy performed, patient remain eligible provided there is clinically measurable disease prior to commencing RT. The residual disease should still meet the stage criteria required for the trial. No prior treatment for oropharyngeal cancer. Adequate haematological, renal and hepatic function. ECOGperformance status score of 0-1 Participants capable of childbearing are using adequate contraception and intend to continue use of contraception for at least 6 months following completion of treatment. Negative pregnancy test within 72hrs prior to randomisation of women who are of childbearing potential Suitable for follow-up for at least 24 months as per trial protocol. Sufficient proficiency in English, cognitive capacity and willingness to complete questionnaires.

32 Exclusion Criteria History of unknown primary of the head and neck T4, N3 or distant metastases Smoking history > 10 pack years with N2b or c nodal status Women who are pregnant or lactating Previous radiotherapy to the area to be treated (excluding superficial radiotherapy for a cutaneous malignancy) Previous cisplatin or carboplatin chemotherapy Prior EGFR targeted therapy of any kind Primary surgery to the affected area (excisional biopsy allowed) Peripheral neuropathy grade 2 (CTCAE v4.0) History of interstitial lung disease or evidence of interstitial lung disease on pre-registration CT. History of myocardial infarction within 12mnths prior to study entry, uncontrolled congestive heart failure, unstable angina, active cardiomyopathy, unstable arrhythmia, uncontrolled psychotic disorders, active serious infections, active peptic ulcer disease, immunosuppression due to post-organ transplantation or use of immunosuppressants for autoimmune disorders. Patient known to be HIV positive Other cancer that was diagnosed: - more than 5 years prior to current diagnosis with (i) subsequent evidence of disease recurrence or (ii) clinical expectation of recurrence is greater than 10% OR - within 5 years of the current diagnosis, with the exception of successfully treated basal cell or squamous cell skin carcinoma, in situ melanoma, or carcinoma in situ of the cervix. TROG Start up meeting, Rischin Dec 2015

33 Study Design ELIGIBILITY (includes) p16 positive Stage III-IV OPSCC T1-2, N2 or T3, N0-2 Smoking > 10 pack years N2b-c excluded STRATIFICATION (minimisation) T (1,2,3) N (0,1,2) Treating Institution Neck irradiation (unilateral, bilateral) R A N D O M I S A T I O N ARM 1: RT CISPLATIN RT 70Gy in 7 weeks Cisplatin 40mg/m2 weekly 1:1 ARM 2: RT CETUXIMAB RT 70Gy in 7 weeks Cetuximab 400mg/m2 loading dose then 250mg/m2 weekly x 7 TROG Start up meeting, Rischin 33 Dec 2015

34 Radiotherapy 1. Patients in: Both arms will receive conventionally fractionated radiotherapy : 70Gy in 35 fractions, 5 days a week for 7 weeks. Arm 1 will commence RT at the same time in conjunction with cisplatin in Week 1. Arm 2 will commence RT in the week of the second dose of cetuximab (cetuximab loading dose given one week prior, ie: week -1) 2. All patients will have a planning CT. For treatment, only fixed gantry IMRT and Tomotherapy techniques are permissible. 3. Radiotherapy delays and reschedule: Patients who miss a radiotherapy treatment should preferably have that treatment made up as outlined in the protocol. TROG Start up meeting, Rischin Dec 2015

35 TROG Start up meeting, Rischin Dec 2015

36 Chemotherapy Patients in arm 1 will receive 40mg/m 2 of cisplatin weekly along with RT. Patients in arm 2 will receive 400mg/m 2 loading dose of cetuximab and then weekly dose of 250mg/m2 along with RT. CISPLATIN administration - Cisplatin is part of standard of care treatment. Drug not supplied. - Doses will not be recalculated unless there is a > 10% change in weight vs baseline or the previous weight that caused a dosage change. Cetuximab administration - Cetuximab is a chimeric antibody and can produce allergic response in some patients. A physician experienced in the use of antineoplastic agents must be present during administration. - Patients should be observed in an area with resuscitation equipment during infusion and for at least 1hr afterwards - Premedication is recommended at first and all subsequent infusions, as outlined in the protocol. TROG Start up meeting, Rischin Dec 2015

37 Schedule of Treatments and Investigations TROG Start up meeting, Rischin Dec 2015

38 Tissue and Plasma Samples p16 immunohistochemistry for protocol eligibility will be done locally > Gr 2 intensity in > 70% cells Tissue sample collection mandatory for central p16 and HPV analyses Consent will be requested for samples to be available for translational research TROG Start up meeting, Rischin Dec

39 Post Treatment Neck Surgery Neck Dissection Unless there is evidence of progressive disease, no neck surgery may be performed before the post-treatment assessment in Week 20 (13 wks following RT completion). At week 20 FDG-PET or FDG-PET CT assessment: - complete clinical and complete metabolic response, then patient WILL NOT have neck dissection. - If nodal mass ceases regressing or begins to grow or shows metabolic activity, MUST proceed to neck dissection. - Residual metabolically inactive mass - observe with 3 monthly PET-FDGup to 9 months post. If 1-2 cm, stable and metabolically inactive can continue to observe. Salvage Neck Dissection May be undertaken for recurrent disease at any time TROG Start up meeting, Rischin Dec 2015

40 Study Specific Investigations Swallowing Video Fluoroscopy Prerego Pretreatment Wk 7 Wk 20 6 mths 12 mths 24 mths 36 mths Audiometry FDG-PET or FDG PET-CT CT or MRI of head and neck (with contrast) Fibre-optic* nasoendoscopy # ## *In addition to the above time points, fibre-optic nasoendoscopy is also done at months 9, 15, 18, 21, 28, 32, 42, 48, 54 and 60. # must be within 6wks of registration. ## done either wk 7 or 8 in patients with base of tongue primaries to more fully assess mucositis. TROG Start up meeting, Rischin Dec 2015

41 Current Status of TROG (Dec 2015) Total no of pts = 81 (Arm 1 = 41, Arm 2 = 40) Sites NHMRC funded from for $1,097, Per patient payment: Total = AUD 2250 per patient 1 patient so far enrolled in SA via FMC Initiated Austin Health - Austin Hospital 30/06/2015 Liverpool Hospital 8/12/2014 Calvary Mater Newcastle Hospital 10/06/2014 Princess Alexandra Hospital 2/12/2013 Peter MacCallum Cancer Centre - East Melbourne 3/06/2013 Royal Brisbane and Women's Hospital 12/02/2014 Auckland City Hospital 18/11/2013 TROG Start up meeting, Rischin Dec 2015

42 Orator Trial A Phase II Randomised Trial For Early-Stage Squamous Cell Carcinoma of the Oropharynx: Radiotherapy vs Trans-Oral Robotic Surgery (ORATOR) Sponsor: Lawson Health Research Institute Principle Investigators: Dr David Palma Dr Anthony Nichols Page 42 3 May, 2016

43 Orator Activation Meeting, David Palma Transoral Robotic Surgery vs. Radiotherapy

44 Orator Activation Meeting, David Palma

45 Orator Background Oropharyngeal SCC historically managed with open surgery +/- chemo/rt: good tumour control BUT poor speech/swallowing/cosmesis and organ preservation approaches with RT +/- chemo surgery reserved for salvage No RCT Meta-analysis of observational studies (Parsons et al, Cancer 2002): equivalent survival major complications worse with primary surgery. Orator Protocol, Palma et al. March May, 2016

46 Orator Background Concurrent cisplatin based chemo + RT toxic in acute and late settings: chemo increases PEG dependence from 1 13% Renewed interest in less invasive surgical techniques laser *TORS (Trans Oral Robotic Surgery) improved visualisation and access preservation neuromuscular structures encouraging functional/qol outcomes Orator Protocol, Palma et al. March May, 2016

47 Orator - Objectives To compare QOL after primary RT (+/-chemo) vs TORS (+/- adjuvant chemo/rt) in patients with ES SCC oropharynx, to compare toxicity profiles, and conduct a non-definitive comparison of survival between the two modalities. Orator Protocol, Palma et al. March May, 2016

48 Endpoints Primary Endpoint Quality of life 1-year post-treatment MD Anderson Dysphagia Inventory (MDADI) Secondary endpoints: Overall Survival Progression-free survival Quality of life at other time points MDADI, EORTC QLQ-C30, H&N35, VHI-10 Toxicity NCI-CTC version 4 Swallowing function, measured by: Feeding tube rate at 1-year MDADI CTC-AE Dysphagia scores Required Sample Size: 68 Patients Orator Activation Meeting, Palma et al.

49 Orator Activation Meeting, Palma et al. Timeline

50 Inclusion Criteria Age 18 or older, informed consent, ECOG 0-2 Histologically confirmed squamous cell carcinoma Primary tumor site in the oropharynx (includes tonsil, soft palate, base of tongue, walls of oropharynx) Tumor stage: T1 or T2, with likely negative resection margins at surgery Nodal stage: N0, N1 ( 3 cm), or N2 (up to 2 nodes between 1-3 cm, on either side of the neck), without extranodal extension on pre-randomization imaging. Assessed at head and neck MDT (by radiation oncologist and surgeon) and presented at multidisciplinary tumor board prior to randomization. Orator Activation Meeting, Palma et al.

51 Exclusion Criteria Prior history of head and neck cancer within 5 years Prior head and neck radiation at any time Serious medical comorbidities/ treatment contraindications Metastatic disease Inability to attend full course of radiotherapy or follow-up visits Neck disease with unknown primary site Prior invasive malignant disease unless disease-free for at least 5 years or more, with the exception of non-melanoma skin cancer Unable or unwilling to complete QoL questionnaires Poor transoral access Retropharyngeal carotid artery Orator Activation Meeting, Palma et al.

52 Radiotherapy Target Volume Gross Tumor and Nodes Radical-intent dose* (Arm 1) 70 Gy in 35 fractions over 7 weeks Adjuvant dose (Arm 2) N/A Region of Positive Margins or Extra-nodal extension N/A 64 Gy in 30 fractions over 6 weeks High-risk nodal areas (and operative bed in Arm 2) 63 Gy in 35 fractions over 7 weeks 60 Gy in 30 fractions over 6 weeks Low-risk nodal areas 56 Gy in 35 fractions over 7 weeks 54 Gy in 30 fractions over 6 weeks Orator Activation Meeting, Palma et al.

53 Concurrent Chemotherapy in Arm 1 Stage T1N0 or T2N0 T1-2N1-2 Treatment Radiotherapy Alone Radiotherapy with Systemic Therapy Chemotherapy will consist of cisplatin 100 mg/m 2 delivered every 3 weeks, in 3- week cycles. For patients who are deemed unfit for high dose cisplatin, the dose and/or schedule can be modified, or cetuximab or weekly carboplatin AUC 1.5 can be used, at the discretion of the medical oncologist. Orator Activation Meeting, Palma et al.

54 Adjuvant Therapy in Arm 2 Radiotherapy can be omitted if there are no adverse pathological features (i.e. none of the following: extranodal extension, positive margins, pt3 or pt4 disease, nodal disease, or lymphovascular invasion). Adjuvant radiotherapy alone is recommended for the following risk factors: Any node positive Lymphovascular invasion pt3 or pt4 tumor Close resection margins (<2 mm) For patients with perineural invasion (PNI) alone and no other indications for radiotherapy, radiotherapy will be omitted. Adjuvant chemotherapy concurrent with radiotherapy is required for patients with positive margins or extra-capsular extension. Also, for patients with 3 or more pathologically positive nodes, adjuvant chemotherapy is indicated. Orator Activation Meeting, Palma et al.

55 Test Schema YEAR 1 Before Entry Month 3* Month 4 Month 6 Month 9 Month 12 History and Physical X X X X X Baseline staging X investigations (see section 5.0) QOL scoring X X X Toxicity Scoring X X X X X Follow-up CT head and X neck to assess for residual nodes post-rt (Arm 1) Follow-up CT head, X neck and chest (Both Arms) Follow-up chest x-ray X Audiogram X X BUN, Creatinine, and CBC/Differential during treatment and at 12 months X Orator Activation Meeting, Palma et al.

56 Test Schema Orator Activation Meeting, Palma et al.

57 Biomarker Studies HPV testing of tumor P16 status (marker of HPV status) is required for stratification at the time of randomization. This is done routinely by our pathologists The biomarker study will determine HPV status by real-time PCR, not for the purposes of randomization, but to confirm the accuracy of P16 results and also for subtyping of HPV strain. For patients randomized to radiotherapy, pre-treatment formalin fixed paraffin embedded primary site biopsy specimens will be retrieved. For patients randomized to TORS, a portion of the operative specimen will be taken at the time of surgery and frozen at -80 degrees Celsius. DNA will be extracted from the specimens for HPV testing by real-time polymerase chain reaction (PCR). Mutational and copy number variation analysis DNA will be extracted either from formalin fixed specimens or preferably fresh tumor for patients undergoing TORS as well as 10mL of venous blood drawn prior to the initiation of treatment. Specimens yielding DNA of adequate quantity and quality (>5μg, OD between 1.8 and 2.0) will be subjected to high-throughput sequencing and gene copy number. Orator Activation Meeting, Palma et al.

58 Orator - Current Status Started recruiting June 2012 Estimated completion date June 2021 (collection of data for primary outcome) Sites: RAH (only Oz site) Canada: London Ottawa Toronto Montreal Vancouver (not yet recruiting) Page 58 3 May, 2016

59 Randomised trials HPV positive Eligible RT Arm 1 Arm 2 Endpoint RTOG 1016 All AF High dose cis x 2 De- ESCALaTE TROG Low risk + exclude T4&/or N3 Quarterback Low risk CF High dose cis x 3 < 20 pack y TPF responders Cetux OS Cetux Gr 3-5 acute and late toxicity CF Weekly cis Cetux AUC MDASI-HN Symptom Severity Score CF 70 Gy + carbo 56 Gy carbo + cetux Adept Resected N+ ECE CF 60Gy RT RT + cis ECOG3311 Resected TORS Low risk + exclude T4, N2c-3 CF 60Gy RT (high risk postop chemort) 50 Gy RT 2 yr PFS TROG Start up meeting, Rischin Dec 2015 NRGHN002 Low risk, exclude T4, N2c-3 60 Gy CF+ weekly cis 60 Gy AF 59

60 Conclusion Increasing incidence of p16 related OPSCC Distinct entity Improved prognosis cf p16 ve disease BUT significant morbidity with current treatment approaches Enrollment in randomised clinical trials of treatment deescalation essential to optimally treat these patients in the future while minimising morbidity and optimising long term QOL Page 60 3 May, 2016

61 TROG If you have patients suitable and interested in participating in the TROG study, please contact: Dr Caroline Connell Adelaide Radiotherapy Centre, Flinders Private Hospital Page 61 3 May, 2016

62 Acknowledgements Up to date Head and Neck Cancers in Australia AIHW, 2014 Danny Rischin TROG Start-up meeting David Palma Orator Start-up meeting. Page 62 3 May, 2016