Transoral Robotic Surgery for Oropharyngeal Carcinoma and HPV Viral Load

1
Transoral Robotic Surgery for Oropharyngeal
Carcinoma and HPV Viral Load

• Marc A. Cohen, MDResearch Presentation
• Faculty Advisors Dr. Weinstein and Dr. OMalley

2
Goals of Study

• Determine margins of resection, oncologic
  outcomes, and functional outcomes following
  primary Transoral Robotic Surgery (TORS) for
  oropharyngeal squamous cell carcinoma (OPSCC)
• Determine prevalence of HPV positivity in OPSCC
  in patients that undergo TORS
• Determine prevalence of cervical nodal metastases
  in OPSCC associated with HPV
• Assess patient outcomes in reference to HPV status

3
IntroductionHead and Neck Cancer

• There are 500,000 new cases of squamous cell
  carcinoma of the head and neck per year.1-3
• Overall, 5 year survival is less than 501
• More than 7,000 in US die from oral cavity /
  oropharyngeal cancer per year4
• Oncologic outcomes with oropharyngeal squamous
  cell carcinoma (OPSCC) are reported along a
  widely divergent range.
• Currently, most studies with significant power
  are investigating various chemoradiation
  protocols in OPSCC.

4
Divergent Outcomes with OPSCC IFrench cohort of
stage III and IV OPSCC treated with xrt vs
concomitant chemo/xrt (n226)
5 Denis, F. et al. J Clin Oncol 2269-76 2004
5
Divergent Outcomes with OPSCC IIECOG E2399
phase II chemoradiation trial in resectable AJCC
III and IV OPSCC (n69)
6 Cmelak et al. J Clin Oncol 253971-3977 2007
6
Divergent Outcomes with OPSCC IIIBrazilian
cohort of all stage OPSCC treated with
chemoradiation (n361)
7 Pedruzzi et al. Arch Otolaryngol Head Neck
Surg 20081341196-1204.
7
HPV association with HNSCC

• In past 10 years, there has been evidence
  supporting an association between high risk human
  papillomavirus (HPV) serotypes and HNSCC.8-12
• High risk serotypes (16,18,33) are conserved and
  associated with HNSCC as well as cervical and
  other carcinomas of the anogenital tract.9

8
HPV associated HNSCC

• HPV associated HNSCC comprise a distinct clinical
  entity and pathogenesis
• More basaloid features9
• Less p53 mutations13,14
• Younger patients without conventional risk
  factors8-10
• Lifetime number of sexual partners15
• Better prognosis?

9
Prevalence of HPV

• Data using all molecular techniques yields an
  association of approximately 9-26 in all cases
  of HNSCC with oropharyngeal squamous cell
  carcinoma being associated with 45-709,16-19
• Most common serotypes are HPV 16 (84-94), 18
  (0-3), 33 (1-27)3,16,19-22

10
Prognosis with HPV status

• There has long been debate about whether HPV
  positive lesions are associated with better
  patient prognosis.23-29
• Recent studies have equated HPV positivity with
  decreased recurrence rates, longer disease free
  survival, and overall survival.23-26
• Lack of field cancerization, intact apoptotic
  mechanisms, better immune response to viral
  specific antigens, reduced 2nd primary tumors23,30

11
ECOG chemoradiation outcomes in OP SCC with HPV
status
30 Fakhry et al. J. Natl Cancer Inst. 2008
100261-269.
12
Prognosis with HPV positive OP SCC treated with
CRT

• Worden et al., showed that, induction
  chemotherapy followed by chemoradiation is an
  effective treatment for SCC OP, especially in
  those that are HPV positive. The authors suggest
  CRT should be used in SCC OP that are HPV
  positive with alternative treatments reserved
  for those that do not respond to induction
  chemotherapy.31

13
Worden et al
31 Worden et al. J Clin Oncol 263138-3146 2008
14
Surgical resection of OP lesions and HPV
association
32 Licitra et al. J Clin Oncol 245630-5636 2006
15
Surgical resection of OP lesions and HPV viral
load
33 Cohen et al. Acta Otolaryngol 2008128583-9.
16
Hypotheses

• TORS will be oncologically sound as the primary
  therapy in treatment of select oropharyngeal
  cancers
• The prevalence of HPV positivity in OP lesions
  will be 60-70.
• There will be no difference in cervical
  metastases in HPV positive and HPV negative
  lesions.
• Patients with both HPV positive and negative
  lesions will have favorable prognosis when
  treated with TORS.

17
Research Design

• This clinical study was a retrospective analysis
  of a previously completed prospective trial
  evaluating outcomes of TORS for oropharyngeal
  squamous cell carcinoma.

18
Patient Inclusion

• At least 18 years old
• Presented with therapeutic approaches for a new
  squamous cell carcinoma of the oropharynx
  evaluated on prior endoscopy and with
  pre-operative computed tomography (CT) and/or
  magnetic resonance (MR)
• Lesions that were anatomically amenable to
  transoral robotic surgery
• Signed a written informed consent.

19
Tumor related contraindications

• Unresectability of the tumor or involved lymph
  nodes
• Invasion of the mandible
• Bilateral posterior pharyngeal wall involvement
  (greater than 50)
• Carotid artery involvement
• Tumor fixation to the prevertebral fascia.

20
Additional intervention

• Staged cervical lymphadenectomy was offered to
  all patients.
• Adjuvant therapy with radiation and/or
  chemotherapy as indicated

21
Clinical Patient Data

• Under IRB approved protocol, patient charts were
  evaluated with respect to gender, age, stage,
  margins of OP resection, incidence of pN in the
  neck, post operative radiation, swallowing
  function, and status of disease at follow up.
  This was done in a blinded fashion, prior to
  obtaining HPV data.
• Statistical analysis was performed using SPSS
  16.0. Nonparametric statistics were performed
  using Pearsons Chi Square and Fishers Exact
  Test (2-sided). Kaplan-Meier analysis was
  performed for survival with differences assessed
  by the Log-Rank method.

22
Obtaining HPV data

• In an arrangement with SensiGen, LLC, (Ann Arbor,
  Michigan) a biotechnology company focused on
  molecular diagnosis, we sent paraffin slides of
  oropharyngeal squamous cell carcinoma specimens
  for testing using real-time PCR technology. This
  company has performed HPV assays for other
  institutions.
• Identification of the presence of any of the
  following HPV genotypes 16, 18, 31, 33, 35, 39,
  45, 51, 52, 56, 58, 59, 66, 68, 73 (for the
  16-plex version) in attomoles.
• Measurement of the level of betaglobin DNA
  present, in attomoles.

23
Results Patient Information

• The first 78 patients with oropharyngeal squamous
  cell carcinoma assessed
• 58 patients with minimum 18 months follow up
• 31 patients with HPV evaluation (no minimum
  follow up)
• Mean follow up 21 months (2-41)
• HPV assessed in 31 patients
• 71 HPV positive, 95 of these HPV-16

24
Patient Characteristics
18 month follow (n58) HPV- (n9) HPV (n22)
Mean Age 57.4 55.4 58.6
Females 4 (7) 0 1 (5)
Follow up 25 (18-41) 23 (3-36) 21 (2-39)
Site (tonsil, BOT) 27(47), 26(45) 4(44), 3(33) 9(41), 12(55)
N in at-risk necks 44/56 (79) 6/8 (75) 17/23 (74)
ECS 20/53 (38) 3/8 (38) 7/22 (32)
AJCC (I-IV) 7(12), 4(7), 23(40), 24(41) 2(22), 0, 2(22), 5(55) 1(5), 0, 12(55), 9(41)
25
Oncologic Characteristics following TORS
18 month cohort (n58) HPV- (n9) HPV (n22)
Final margins (close/positive) 5(9), 0(0) 1(11), 0(0) 0 (0), 0 (0)
Local Recurrence 1 (2) 0 1 (5)
Neck Recurrence 1 (2) 1 (11) 0 (0)
Distant Metastases 4 (7) 0 (0) 1 (5)
Overall survival at 1 and 2-year 55/58 (95), 33/41 (81) 7/7 (100), 5/6 (83) 21/22 (95), 11/14 (79)
Disease specific survival 1 and 2-yr 55/56 (98), 33/36 (92) 7/7 (100), 5/5 (100) 21/21 (100), 11/12 (92)
26
58 patients with 18 months follow up overall
survival
27
Comparison of overall survival
Worden, F. P. et al. J Clin Oncol 263138-3146
2008
28
58 patients with 18 month follow up
disease-specific survival
29
Comparison of disease-specific survival
31 Worden et al. J Clin Oncol 263138-3146 2008
30
Overall survival with respect to post operative
adjuvant regimen
P0.585 (log rank)
31
Overall survival with respect to HPV status
P0.87 (log rank)

32
Comparison of outcomes related to HPV status
30 Fakhry et al. J. Natl Cancer Inst. 2008
100261-269.
31 Worden et al. J Clin Oncol 263138-3146 2008
33
Swallowing function

• There is a wide range of cited percentage of
  people after chemoradiation requiring gastrostomy
  tube. This is cited from 3 to approximately
  50.5,34,35
• Ang et al cited the long term need for
  gastrostomy tubes in 30 of those with OPSCC
  treated with chemoradiation.34
• Shiley et al cited the need for gastrostomy tube
  in 48 of those with OPSCC treated with
  chemoradiation.35
• In our cohort 91 (50/55) of at risk patients had
  the gastrostomy tube removed.

34
Conclusions

• TORS appears to be oncologically sound, with
  adequate margins of resection as well as
  satisfactory preliminary overall and disease
  specific survival.
• 1 and 2 year oncologic data is equal to or
  superior to the most recent chemoradiation data.
• On preliminary assessment, negative HPV status
  does not appear to be a negative prognostic
  factor as seen in prior publications.
• Swallowing function without gastrostomy tube is
  preserved in more than 90 of patients.

35
Future directions

• With the cohort created, we can follow out for
  long term survival data.
• We are awaiting quantitative data, with which we
  can further analyze patient outcomes.
• We can compare outcome data for patients
  undergoing surgical resection with those
  undergoing primary chemo/xrt.
• We can compare function of the those undergoing
  surgical resection with those undergoing
  chemo/xrt.

36
References

• 1. Parkin DM, Pisani P, Ferlay J. Global cancer
  statistics. CA Cancer J Clin 1999 4933-64.
• 2. Parkin DM, Bray F, Ferlay J, Pisaniet P.
  Estimating the world cancer burden Globocan
  2000. Int J Cancer 200194153-6.
• 3. Herrero R, Castellsague X, Pawlita M, et al.
  Human papillomavirus and oral cancer the
  International Agency for Research on Cancer
  multicenter study. J Natl Cancer Inst
  2003951772-83.
• 4. Carvalho AL, Nishimito IN, Califano JA,
  Kowalski LP. Trends in incidence and prognosis
  for head and neck cancer in the united states a
  site-specific analysis of the SEER database. Int
  J Cancer 2005114806-16.
• 5. Denis F, Garaud P, Bardet E, et al. Final
  results of the 94-01 French Head and Neck
  Oncology and Radiotherapy Group randomized tiral
  comparing radiotherapy alone with concomitant
  radiochemotherapy in advanced-stage oropharynx
  carcinoma. J Clin Oncol 20042269-76.
• 6. Cmelak AJ, Sigui L, Goldwasser MA, et al.
  Phase II trial of chemoradiation for organ
  preservation in resectable stage III or IV
  squamous cell carcinomas of the larynx or
  oropharynx results of Eastern Cooperative
  Oncology Group Study E2399. J Clin Oncol
  2007253971-7.
• 7. Pedruzzi PA, Kowalski LP, Nishimito IN, et al.
  Analysis of prognostic factors in patients with
  oropharyngeal squamous cell carcinoma treated
  with radiotherapy alone or in combination with
  systemic chemotherapy. Arch Otolaryngol Head Neck
  Surg 20081341196-204.
• 8. Koch WM, Lango M, Sewell D, et al. Head and
  neck cancer in nonsmokers a distinct clinical
  and molecular entity. Laryngoscope
  19991091544-51.
• 9. Gillison ML, Koch WM, Capone RB, et al.
  Evidence for a causal association between human
  papillomavirus and a subset of head and neck
  cancers. J Natl Cancer Inst 200092709-20.
• 10. van Houten VM, Snijders PJ, van den Brekel
  MW, et al. Biological evidence that human
  papillomaviruses are etiologically involved in a
  subgroup of head and neck squamous cell
  carcinomas. Int J Cancer 200193232-5.
• 11. El-Mofty SK, Lu DW. Prevalence of human
  papillomavirus type 16 DNA in squamous cell
  carcinoma of the palatine tonsil, and not the
  oral cavity, in young patients a distinct
  clinicopathologic and molecular disease entity.
  Am J Surg Pathol 2003271463-70.
• 12. Franceschi S, Munoz N, Snijders PJ. How
  strong and how wide is the link between HPV and
  oropharyngeal cancer? Lancet 2000356871-2.
• 13. Blons H, Laurent-Puig P. TP53 and head and
  neck neoplasms. Hum Mutat 2003 21252-7.
• 14. Westra WH, Taube JM, Poeta ML, et al. Inverse
  relationship between human papillomavirus-16
  infection and disruptive p53 gene mutations in
  squamous cell carcinoma of the head and neck.
  Clin Cancer Res 200814366-9.
• 15. Furniss CS, McClean MD, Smith JF, et al.
  Human papillomavirus 16 and head and neck
  squamous cell carcinoma. Int J Cancer
  20071202386-92.
• 16. Gillison ML, Koch WM, Shah KV. Human
  papillomavirus in head and neck squamous cell
  carcinoma are some head and neck cancers a
  sexually transmitted disease? Curr Opin Oncol
  199911191-9.
• 17. Gillison ML, Shah KV. Human
  papillomavirus-associated head and neck squamous
  cell carcinoma mounting evidence for an
  etiologic role for human papillomavirus in a
  subset of head and neck cancers. Curr Opin Oncol
  200113183-8.
• 18. Mork J, Lie AK, Glattre E, et al. Human
  papillomavirus infection as a risk factor for
  squamous-cell carcinoma of the head and neck. N
  Engl J Med 20013441125-31.

37
References II
References

• 19. Klussmann JP, Weissenborn SJ, Wieland U, et
  al. Prevalence, distribution, and viral load of
  human papillomavirus 16 DNA in tonsillar
  carcinomas. Cancer 2001 922875-84.
• 20. Koskinen WJ, Chen RW, Leivo I, et al.
  Prevalence and physical status of human
  papillomavirus in squamous cell carcinomas of the
  head and neck. Int J Cancer 2003107401-6.
• 21. Syrjanen S. HPV infections and tonsillar
  carcinoma. J Clin Pathol 2004 57449-55.
• 22. Smith EM, Ritchie JM, Summersgill KF, et al.
  Age, sexual behavior and human papillomavirus
  infection in oral cavity and oropharyngeal
  cancers. Int J Cancer 2004108766-72.
• 23. Gillison ML, Koch WM, Capone RB, et al.
  Evidence for a causal association between human
  papillomavirus and a subset of head and neck
  cancer. J Natl Cancer Inst 200092709-720
• 24. Schwartz SR, Yueh B, McDougall JK, et al.
  Human papillomavirus infection and survival in
  oral squamous cell cancer a population-based
  study. Otolaryngol Head Neck Surg 20011251-9.
• 25. Weinberger PM, Yu Z, Haffty BG, et al.
  Molecular classification identifies a subset of
  human papillomaviruses--associated oropharyngeal
  cancers with favorable prognosis. J Clin Oncol
  200624736-47.
• 26. Ragin CC, Taioli E. Survival of squamous cell
  carcinoma of the head and neck in relation to
  human papilomavirus infection review and
  meta-analysis. Int J Cancer 20071211813-20.
• 27. Gillison ML. Human papillomavirus-associated
  head and neck cancer is a distinct epidemiologic,
  clinical, and molecular entity. Semin Oncol
  200431744
• 28. Clayman GL, Stewart MG, Weber RS, et al.
  Human papillomavirus in laryngeal and
  hypopharyngeal carcinomas. Relationship to
  survival. Arch Otololaryngol Head Neck Surg
  1994120743-748.
• 29. Snijders PJ, Scholes AG, Hart CA, et al.
  Prevalence of mucosotropic human papillomaviruses
  in squamous-cell carcinoma of the head and neck.
  Int J Cancer 199666464-9.
• 30. Fakhry C, Westra WH, Li S, et al. Improved
  survival of patients with human
  papillomavirus-positive head and neck squamous
  cell carcinoma in a prospective clinical trial. J
  Natl Cancer Inst 2008100261-9.
• 31. Worden FP, Kumar B, Lee SJ, et al.
  Chemoselection as a strategy for organ
  preservation in advanced oropharynx cancer
  response and survival positively associated with
  HPV16 copy number. J Clin Onol 2008263138-46.
• 32. Licitra L, Perrone F, Bossi P, et al.
  High-risk human papillomavirus affects prognosis
  affects prognosis in patients with surgically
  treated oropharyngeal squamous cell carcinoma. J
  Clin Oncol 2006245630-36.
• 33. Cohen MA, Basha SR, Reichenbach DK, et al.
  Increased viral load correlates with improved
  survival in HPV-16-associated tonsil carcinoma
  patients. Acta Otolaryngol 2008128583-9.
• 34. Ang KK, Harris H, Garden AS, et al.
  Concomitant boost radiation plus concurrent
  cisplatin for advanced head and neck carcinomas
  radiation therapy oncology group phase II trial
  99-14. J Clin Oncol 2005233008-15.
• 35. Shiley SG, Hargunani CA, Skoner JM, et al.
  Swallowing function after chemoradiation for
  advanced stage oropharyngeal cancer. Otolaryngol
  Head Neck SUrg 2006134

38
Thank you

• Dr. Weinstein
• Dr. OMalley
• TORS research team
• Department of Otorhinolaryngology Head and Neck
  Surgery