WEBINAR ON ADVANCES IN HEAD AND NECK CANCERS

1. NEWER ADVANCES IN
MANAGEMENT OF RECURRENT
HNC
DR. PANKAJ AGARWAL
4/9/2022
DR,PANKAJ AGARWAL CONSULTANT RO KIRAN
MULTISPECIALITY HOSPITAL

2. INTRODUCTION
• HNC SIXTH MC CANCER WORLDWIDE
• 57.5% of global head and neck cancers occur in Asia
• India :30% of all cancers.
• 60 to 80% of patients present with advanced disease as compared to
40% in developed countries.
International Journal of Head and Neck Surgery, January-April 2013;4(1):29-35
4/9/2022
DR,PANKAJ AGARWAL CONSULTANT RO KIRAN
MULTISPECIALITY HOSPITAL

3. Recurrent/metastatic disease
• LRF in locoregionally advanced SCCHN who have been treated with upfront surgery or upfront
chemoradiation remains around 40-50%.
• Distant failure rates in LA SCCHNC 20-30%
• Difficult to treat with poor prognosis
• Median survival of 12 months
• SALVAGE SURGERY
• RE RADIATION
• SYSTEMIC THERAPY
4/9/2022
DR,PANKAJ AGARWAL CONSULTANT RO KIRAN
MULTISPECIALITY HOSPITAL

4. • one of the largest cohort studies describing prognostic features related to salvage surgery
after primary radiotherapy or chemoradiation for HNSCC
• N=189
• Prognosis per tumor subsite, corrected for disease stage
• Differences in prognosis after salvage surgery for local, regional, and locoregional
recurrences
Otolaryngology–Head and Neck Surgery Foundation 2018;DOI: 10.1177/0194599818818443
4/9/2022
DR,PANKAJ AGARWAL CONSULTANT RO KIRAN
MULTISPECIALITY HOSPITAL

5. Otolaryngology–Head and Neck Surgery Foundation 2018;DOI: 10.1177/0194599818818443
4/9/2022
DR,PANKAJ AGARWAL CONSULTANT RO KIRAN
MULTISPECIALITY HOSPITAL

6. Otolaryngology–Head and Neck Surgery Foundation 2018;DOI: 10.1177/0194599818818443
DFS AT 5 YEARS
Residual Ds 26%
Recurrent Ds 37%
DFS AT 5 YEARS
Larynx Ds 38%
Pharynx Ds 26%
DFS AT 5 YEARS
Early stage 62%
Advanced rec 22%
DFS AT 5 YEARS
Local Ds. 43%
Regional Ds 27%
Locoregional 13%
4/9/2022
DR,PANKAJ AGARWAL CONSULTANT RO KIRAN
MULTISPECIALITY HOSPITAL

7. • High pT stage and ASA score are independent predictors for worse DFS
• 5-year OS: 33%; Median OS: 18 months
• Post op RE Radiation was used in only few subset with positive margins (1/3rd of R1 patients).
• Larynx carcinoma was associated with more favorable local and locoregional control than
pharyngeal carcinoma. BUT NO OS benefit
• In oropharyngeal carcinoma impact of HPV was evaluated : HPV in recurrent setting does not
necessarily have any prognostic effect*
Otolaryngology–Head and Neck Surgery Foundation 2018;DOI: 10.1177/0194599818818443
4/9/2022
DR,PANKAJ AGARWAL CONSULTANT RO KIRAN
MULTISPECIALITY HOSPITAL

8. Recurrent/metastatic disease
• LRF in locoregionally advanced SCCHN who have been treated with upfront surgery or upfront
chemoradiation remains around 40-50%.
• Distant failure rates in LA SCCHNC 20-30%
• Difficult to treat with poor prognosis
• Median survival of 12 months
• SALVAGE SURGERY
• RE RADIATION
• SYSTEMIC THERAPY
4/9/2022
DR,PANKAJ AGARWAL CONSULTANT RO KIRAN
MULTISPECIALITY HOSPITAL

9. • Patients with R & SP squamous carcinoma originating in a previously-irradiated
field (≥40Gy) who underwent re-irradiation with IMRT (≥40 Gy re-IMRT) were
included.
• Factors for OS were entered into a recursive partitioning analysis (RPA).
• Only patients treated with conventionally or hyper fractionated regimens of 1-3
Gy per fraction were included. SBRT (>5Gy per fraction was NOT included)
• Salvage surgery to the primary or neck prior to re-irradiation were included
To identify prognostic subgroups for which the risk-benefit ratio of modern re-irradiation appears favorable
Int J Radiat Oncol Biol Phys. 2018; 100(3):586–594, doi:
4/9/2022
DR,PANKAJ AGARWAL CONSULTANT RO KIRAN
MULTISPECIALITY HOSPITAL

10. Concurrent chemo : 75%
Salvage surgery : 45% (P+N 50%;P alone 25%; N alone 25%)
Int J Radiat Oncol Biol Phys. 2018; 100(3):586–594, doi:
4/9/2022
DR,PANKAJ AGARWAL CONSULTANT RO KIRAN
MULTISPECIALITY HOSPITAL

11. The 2-year and 5-year OS: 50% and 30%
The 2-year and 5-year LRC: 60% and 50%
Median survival time was 25.1 months.
Median survival for those who received definitive reirradiation was 27.7 months and 22.8 months
for those who received adjuvant reirradiation (nonsignificant).
4/9/2022
DR,PANKAJ AGARWAL CONSULTANT RO KIRAN
MULTISPECIALITY HOSPITAL

12. • Predictors of grade 3 toxicity on multivariate analysis:
• CTV1 retreatment volume 50 cc (HR 3.11,PZ.003); (volume 25
cc did not experience any grade 3 toxicity)
4/9/2022
DR,PANKAJ AGARWAL CONSULTANT RO KIRAN
MULTISPECIALITY HOSPITAL

13. • Salvage surgery + RERT in 90% oral cavity (OC) and 80% neck
recurrences
• RE RT alone in oropharyngeal (OP) and Retropharyngeal (RP)
recurrences
• Irrespective of the local modality 2-year LRC: 52% OC/OP vs 73% non-
OC/OP; P=.001)
• The large discrepancy in those receiving surgery for OC (90%) compared
with OP (25%) patients, with both groups doing equally poorly, supports an
independent and unfavorable prognostic value of mucosal recurrences in
those with SCC tumors.
• LRC rates after neck retreatment Salvage surgery + RERT: LRC @2-year
83%
• RERT ALONE: retropharynx, nasopharynx, and skull base: LRC @2-year
73%
Int J Radiat Oncol Biol Phys.2016; 95(4): 1117–1131, doi:
10.1016/j.ijrobp.2016.03.015
4/9/2022
DR,PANKAJ AGARWAL CONSULTANT RO KIRAN
MULTISPECIALITY HOSPITAL

14. • DEFINITIVE Re Radiation (Excluded RPA class I) of unresected r SCCHN previously-
irradiated to ≥40 Gy
• 414 patients : IMRT-217,SBRT-197
• no significant differences in the BED10Gy between the IMRT and SBRT groups.
• Elective neck in 30% in IMRT group
• Unadjusted overall 2-year OS was 35.4% for IMRT and 16.3% for SBRT (p<0.01)
• Analysis by IPTW model of neutralizing baseline characteristics: no statistically
significant differences in OS between IMRT and SBRT (HR 0.877) was seen.
• Analysis by RPA class showed similar OS between IMRT and SBRT for class III
patients
• In all class II patients, IMRT was associated with improved OS (p<0.001)
• Subset analysis demonstrated comparable OS when >35 Gy was delivered with SBRT
DOI: 10.1016/j.ijrobp.2017.04.017
DEFINITIVE
RERT
:IMRT
VS
SBRT
4/9/2022
DR,PANKAJ AGARWAL CONSULTANT RO KIRAN
MULTISPECIALITY HOSPITAL

15. • RPA III: similar OS b/w IMRT
and SBRT
• RPA II: IMRT had improved OS
(p<0.001)
• Subset analysis: comparable
OS when >35 Gy was
delivered with SBRT to small
tumor volumes.
DEFINITIVE
RERT
:IMRT
VS
SBRT
4/9/2022
DR,PANKAJ AGARWAL CONSULTANT RO KIRAN
MULTISPECIALITY HOSPITAL

16. • RPA III: similar OS b/w IMRT
and SBRT
• RPA II: IMRT had improved OS
(p<0.001)
• Subset analysis: comparable
OS when >35 Gy was
delivered with SBRT to small*
tumor volumes.
* <= 25 cc OR rT 0-2
DEFINITIVE
RERT
:IMRT
VS
SBRT
4/9/2022
DR,PANKAJ AGARWAL CONSULTANT RO KIRAN
MULTISPECIALITY HOSPITAL

17. • RPA III: similar OS b/w IMRT
and SBRT
• RPA II: IMRT had improved OS
(p<0.001)
• Subset analysis: comparable
OS when >35 Gy was
delivered with SBRT to small*
tumor volumes.
* <= 25 cc OR rT 0-2
DEFINITIVE
RERT
:IMRT
VS
SBRT
4/9/2022
DR,PANKAJ AGARWAL CONSULTANT RO KIRAN
MULTISPECIALITY HOSPITAL

18. • The 2-year cumulative incidence of
grade ≥3 late toxicity ( not pre-existing
and occurring beyond 90 days )
controlling for the competing risk of
recurrence or death was 12.4% with
IMRT & 11.6% with SBRT
• 2-year cumulative incidence of
competing risks (progression or death):
73.1% with IMRT 79.2% with SBRT
• Less than 1 in 5 patients is alive and
disease free without having experienced
late effects at 2 years after re-irradiation.
• Carotid blowout: 2 in IMRT and 2 in
SBRT: overall crude rate of 1.0%.
DEFINITIVE
RERT
:IMRT
VS
SBRT
4/9/2022
DR,PANKAJ AGARWAL CONSULTANT RO KIRAN
MULTISPECIALITY HOSPITAL

19. • LIMITATIONS:
• Retrospective date
• IMRT GTV was not computed
• OUTCOMES:
• largest comparative report of modern re-irradiation
• Re-irradiation with both SBRT and IMRT appear relatively safe with favorable toxicity
compared to historic studies
• RPA classification retained an independent association with OS, providing prognostic
classification for these patients
• Survival for class III patients is poor and SBRT, systemic therapy alone, and
supportive care are all reasonable strategies
DEFINITIVE
RERT
:IMRT
VS
SBRT
4/9/2022
DR,PANKAJ AGARWAL CONSULTANT RO KIRAN
MULTISPECIALITY HOSPITAL

20. METASTATIC DIRECTED THERAPY
4/9/2022
DR,PANKAJ AGARWAL CONSULTANT RO KIRAN
MULTISPECIALITY HOSPITAL

21. METASTATIC DIRECTED THERAPY
To evaluate the outcomes of metastatic HNC disease burden with an
emphasis on metastasis-directed therapy in patients with limited metastatic
disease burden
5-year OS: 35% for single metastasis
5-year OS: 4%% for multiple metastases
4/9/2022
DR,PANKAJ AGARWAL CONSULTANT RO KIRAN
MULTISPECIALITY HOSPITAL

22. Recurrent/metastatic disease
• LRF in locoregionally advanced SCCHN who have been treated with upfront surgery or upfront
chemoradiation remains around 40-50%.
• Distant failure rates in LA SCCHNC 20-30%
• Difficult to treat with poor prognosis
• Median survival of 12 months
• SALVAGE SURGERY
• RE RADIATION
• SYSTEMIC THERAPY
4/9/2022
DR,PANKAJ AGARWAL CONSULTANT RO KIRAN
MULTISPECIALITY HOSPITAL

23. ROLE OF IMMUNOTHERAPY
• CheckMate 141: Platinum refractory disease: HR for death: 0.7
This trial resulted in the approval of nivolumab in the R/M
second-line HNSCC setting.
• KEYNOTE-048 : For CPS score 20 or more: HR for death 0.6
• Based on PDL-1 combined positive score (CPS)(score of 20 or
more) either pembrolizumab alone or with chemotherapy
represents the first choice for these patients
• nivolumab showed a 13% ORR and pembrolizumab a 17% ORR
when considered in the total population and a 23% ORR in the
population with PDL-1 CPS 20
4/9/2022
DR,PANKAJ AGARWAL CONSULTANT RO KIRAN
MULTISPECIALITY HOSPITAL

24. ROLE OF IMMUNOTHERAPY: WITH RT
• ABSCOPAL EFFECT
• Distant lesions responding to locoregional treatment
• By inducing “immunogenic cell death” (ICD), with release of tumor-associated antigens (TAAs)
• The outcome is the activation of the innate and adaptive immune systems.
4/9/2022
DR,PANKAJ AGARWAL CONSULTANT RO KIRAN
MULTISPECIALITY HOSPITAL

25. ROLE OF IMMUNOTHERAPY: WITH RT
ABSCOPAL EFFECT
4/9/2022
DR,PANKAJ AGARWAL CONSULTANT RO KIRAN
MULTISPECIALITY HOSPITAL

26. ROLE OF IMMUNOTHERAPY: WITH RT
• Pre-clinical models suggest high dose per fraction to maximize the abscopal effect
• RT schedule best suited abscopal effect synergism: SBRT > other hypofractionated
Regimens
4/9/2022
DR,PANKAJ AGARWAL CONSULTANT RO KIRAN
MULTISPECIALITY HOSPITAL

27. ROLE OF IMMUNOTHERAPY: WITH RT
• Immunotherapy is being integrated in several NEOADJUVANT
combinations with radiation or chemotherapy prior to surgery
• Aim to de-intensify the treatment impact by adding
immunotherapy
• Immunotherapy with SBRT: KEYSTROKE
4/9/2022
DR,PANKAJ AGARWAL CONSULTANT RO KIRAN
MULTISPECIALITY HOSPITAL

28. Ongoing since 2018 : RTOG 3507 KEYSTROKE PEMBRO WITH SBRT
4/9/2022
DR,PANKAJ AGARWAL CONSULTANT RO KIRAN
MULTISPECIALITY HOSPITAL

29. ROLE OF IMMUNOTHERAPY
• Immunotherapy is being integrated in several NEOADJUVANT
combinations with radiation or chemotherapy prior to surgery
• Aim to de-intensify the treatment impact by adding
immunotherapy
• Immunotherapy with SBRT: KEYSTROKE
• Immunotherapy with CRT: JAVELIN 100
4/9/2022
DR,PANKAJ AGARWAL CONSULTANT RO KIRAN
MULTISPECIALITY HOSPITAL

30. 4/9/2022
DR,PANKAJ AGARWAL CONSULTANT RO KIRAN
MULTISPECIALITY HOSPITAL

31. AVELUMAB + CRT VS or PLACEBO + CRT f/b avelumab or placebo
maintenance therapy for up to 1 year
NO statistically significant improvement in PFS with avelumab +
CRT vs placebo + CRT
4/9/2022
DR,PANKAJ AGARWAL CONSULTANT RO KIRAN
MULTISPECIALITY HOSPITAL

32. TAKE HOME ALGORITHM
4/9/2022
DR,PANKAJ AGARWAL CONSULTANT RO KIRAN
MULTISPECIALITY HOSPITAL

33. CONCLUSIONS
• With LRC of 40-50% and DM rate of 20-30% about half of the patients with LASCCHN have a
recurrent/metastatic disease in common clinical practice
• Salvage surgery results in 33% 5 Year OS rates in operable cases
• RPA classification identifies three distinct subgroups which can guide patient selection for therapy
• Re-irradiation with both SBRT (<25cc/>35Gy) and IMRT (CTV<50cc) appear relatively safe with favorable
toxicity compared to historic studies
• Data combining immunotherapy and radiation in recurrent/metastatic SCCHN have been unsatisfactory
regarding abscopal effect
• Needs multidisciplinary approach: integrating multiple therapeutic modalities based on patient /tumor
characteristics
4/9/2022
DR,PANKAJ AGARWAL CONSULTANT RO KIRAN
MULTISPECIALITY HOSPITAL

34. 4/9/2022
DR,PANKAJ AGARWAL CONSULTANT RO KIRAN
MULTISPECIALITY HOSPITAL