- The document summarizes a clinical trial that compared cisplatin chemotherapy plus radiotherapy (standard treatment) to cetuximab (EGFR inhibitor) plus radiotherapy for low-risk HPV-positive oropharyngeal cancer.
- The trial found that using cetuximab instead of cisplatin resulted in no reduction in toxicity but significantly worse tumor control outcomes, including lower 2-year overall survival and higher recurrence rates.
- The results suggest that cisplatin remains the standard of care for concurrent chemotherapy with radiotherapy for HPV-positive oropharyngeal cancer and that treatment de-escalation strategies removing systemic chemotherapy need caution.
2. RADIOTHERAPY PLUS CISPLATIN OR
CETUXIMAB IN LOW-RISK HUMAN
PAPILLOMAVIRUS-POSITIVE
OROPHARYNGEAL CANCER (DE-ESCALATE
HPV):
DETERMINATION OF EPIDERMAL GROWTH FACTOR RECEPTOR-INHIBITOR (CETUXIMAB)
VERSUS STANDARD CHEMOTHERAPY (CISPLATIN) EARLY AND LATE TOXICITY EVENTS IN
HUMAN PAPILLOMAVIRUS-POSITIVE OROPHARYNGEAL SQUAMOUS CELL CARCINOMA
3. AUTHORS
• Hisham Mehanna, Max Robinson, Andrew Hartley, Anthony
Kong, Bernadette Foran, Tessa Fulton-Lieuw, Matthew Dalby,
Pankaj Mistry, Mehmet Sen, Lorcan O’Toole, Hoda Al Booz,
Karen Dyker, Rafael Moleron, Stephen Whitaker, Sinead
Brennan, Audrey Cook, Matthew Griffin, Eleanor Aynsley,
Martin Rolles, Emma De Winton, Andrew Chan, Devraj
Srinivasan, Ioanna Nixon, Joanne Grumett, C René Leemans,
Jan Buter, Julia Henderson, Kevin Harrington, Christopher
McConkey, Alastair Gray, Janet Dunn,
4. JOURNAL – THE LANCET
• VOLUME 393, ISSUE 10166, P51-60, JANUARY 05, 2019
• Open Access Published:November 15, 2019
• Journal Impact Factor of 59·102
• Ranked second out of 160 journals in the Medicine, General &
Internal subject category
5. INTRODUCTION
• Incidence of oropharyngeal squamous cell carcinoma is
increasing rapidly in high-income countries
• This increase has been attributed to a rise in human
papillomavirus (HPV) infection.
• HPV-positive oropharyngeal squamous cell carcinoma is
considered to be a distinct disease entity from HPV-negative
head and neck cancer.
• The disease affects younger adults and treatment can be
successful.
7. CONCURRENT CHEMORADIATION
• Cisplatin Sensitizer is the standard of care for advanced
oropharyngeal squamous cell carcinoma
• Concurrent cisplatin therapy is associated with substantial
increases in acute, sometimes life-threatening, toxicity,
compared with radiotherapy alone.
• The treatment also increases long term sequelae, including
xerostomia and dysphagia.
8. • Global consensus about the need for treatment de-
escalation (reduction of toxicity while preserving anti-
tumour efficacy) for HPV positive patients
• One such strategy seeks to substitute cetuximab for cisplatin
as the radiosensitiser
9. • Radiotherapy can induce epidermal growth factor receptor (EGFR)
expression in head and neck cancers, resulting in acquired
resistance.
• Cetuximab, a targeted EGFR inhibitor, might help overcome this
resistance and might also induce antibody-dependent cell-mediated
cytotoxicity.
• Conversely, an inverse association between HPV positivity and EGFR
status has been reported.
• Therefore, EGFR inhibition might not be as effective as chemo-
therapy in HPV-positive oropharyngeal squamous cell carcinoma.
11. STUDY DESIGN
• Open-label
• Randomised controlled
• Phase 3 trial
• 32 head and neck treatment centres in Ireland, the
Netherlands, and the UK
12. PATIENTS
• Aged at least 18 years
• Histologically confirmed diagnosis of advanced oropharyngeal squamous
cell carcinoma
• T3N0–T4N0 and T1N1–T4N3 AJCC/ UICC] tumour,
node, and metastasis [TNM] 7th Edition
• Tumour sample had to be positive on p16 immunohistochemistry
• Non-smoker or have a lifetime self-reported smoking history of less than 10
pack-years.
• Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1
• Adequate renal, haematological, and hepatic function for cisplatin-based
curative chemoradiotherapy.
13. RANDOMISATION AND MASKING
• Patients were randomly assigned in a 1:1 ratio to receive
cisplatin-based chemoradiotherapy or cetuximab
bioradiotherapy
14. PROCEDURES
• 3 doses of IV cisplatin 100 mg/m² on days
1, 22, and 43 of radiotherapy or
• IV cetuximab 400 mg/m²
loading dose 1 week before followed by
seven weekly infusions of 250 mg/m²
during radiotherapy.
• Patients were assessed for treatment
response 12 weeks after radiotherapy
completion by clinical examination and by
CT, MRI, or PET-CT scan.
• Follow-up consisted of clinical
examination, monthly in the first year and
every 2 months in the second year, for at
least 24 months after treatment completion.
• Nov 12, 2012, and Oct 1, 2016
15. OUTCOMES
• Primary outcome was overall (acute and late) severe toxicity
(grades 3–5)
• Secondary outcomes were overall survival, time to recurrence,
quality of life, swallowing
16. STATISTICAL ANALYSIS
• Mean numbers per patient of toxicity events (shortterm [acute]
toxicity and adverse long-term [late] effects, based on the
TAME method of reporting toxicities6) were compared by t
tests.
• Proportions of patients affected by one or more toxicity event
were compared by Pearson’s χ² test.
• Overall survival and time to recurrence were measured from the
date of randomisation and compared by the log-rank test
17. • Mean age - 57 years.
• 80% of patients - men
• 65% had T1–T2 disease (TNM 7)
• 76% had N2–N3 disease (TNM 7)
• 46% were either current or past smokers, with a median
lifetime smoking history of 8 pack-years.
• Of the 324 (97%) patients tested for HPV-DNA on in-situ
hybridisation, 304 (94%) were positive, 20 were negative, and ten
were unknown.
18. • All patients received a dose of 65 Gy or more, and
• 332 (99%) received intensity-modulated radiation therapy
• Radiotherapy interruptions or modifications occurred in
12 (9%) patients receiving cisplatin and 14 (7%) receiving
cetuximab.
19. CISPLATIN GROUP
• 62 (38%) patients received all three cycles of cisplatin, 83 (51%)
received two cycles, and 16 (10%) received one cycle
• Median total cisplatin dose received was 200 mg/m² (IQR 200–
300) and 26 (16%) received less than 200 mg/m² in total.
• The main reasons for discontinuation or reduction in cisplatin
dose were myelosuppression, oral or gastrointestinal toxicity,
or nausea and vomiting.
20. CETUXIMAB GROUP
• 130 (79%) patients received all eight cycles of cetuximab; 23
(14%) received seven cycles, mainly omitting the final dose
(appendix).
• The median total cetuximab dose received was 2150 mg/m²
(IQR 2133–2150).
• The main reasons for discontinuation were skin rash, patient
decision, and oral or gastro- intestinal toxicity.
24. 2-YEAR OVERALL SURVIVAL
• Significant difference in 2-year overall survival was observed
between cisplatin and cetuximab (97·5% vs 89·4%, & in the
2-year recurrence rate (6·0% vs 16·1%) in favour of cisplatin.
• Giving cetuximab instead of cisplatin was estimated to
lead to one extra death at 2 years for every 12 patients treated
26. 2-YEAR OVERALL SURVIVAL SUB GROUP
ANALYSIS
• Significant difference in 2-year overall survival was observed:
98·4% for the cisplatin group and 93·2% for the cetuximab in
Stage I or II, and 93.3% and 67.1% in Stage III
27. LOCOREGIONAL RECURRENCE AND
DISTANT METS
• Significantly fewer recurrences were observed with cisplatin
than with cetuximab both locoregional recurrence and distant
metastases
29. • In the setting of low-risk oropharyngeal squamous cell
carcinoma, the use of cetuximab bioradiotherapy instead of
cisplatin-based chemoradiotherapy resulted in no overall
benefit in terms of toxicity but showed significant detriment in
tumour control.
• Good survival outcomes of HPV-positive low-risk
oropharyngeal squamous cell carcinoma are in part a function
of the type of treatment received, and not merely a reflection of
favourable intrinsic tumour biology
30. DEMERITS MERITS
• Cetuximab showed reduced
survival rates
• Used p16 & HPV DNA in-
situ hybridisation to assess HPV
status
• HPVE6/E7 RNA evaluation by PCR -
gold standard for testing HPV
status.
• Study reinforced the use of
cisplatin as the standard of care for
HPV positive oropharyngeal
carcinoma
• Better survival outcomes and
reduced toxicity with cisplatin in
contrast to cetuximab was proved.
• caution with de-escalation
strategies, especially those that
remove systemic chemotherapy al
together,
31. CONCLUSION
• No reduction in toxicity with cetuximab
• Confirmed a
statistically and clinically significant detriment in tumour
control and survival endpoints with cetuximab therapy
33. OPTIMA:
• a phase II dose and volume de-escalation trial for human papillomavirus-
positive oropharyngeal cancer.
• Patients with HPV+ oropharyngeal squamous cell carcinoma were assigned
to dose and volume de-escalated radiotherapy (RT) or chemoradiotherapy
(CRT) based on response to induction chemotherapy in an effort to limit
treatment-related toxicity while preserving efficacy.
• Induction chemotherapy with response and risk-stratified dose and volume
de-escalated RT/CRT for HPV+ OPSCC is associated with favorable
oncologic outcomes and reduced acute and chronic toxicity.
34. E1308
• Phase II Trial of Induction Chemotherapy Followed by Reduced-Dose
Radiation and Weekly Cetuximab in Patients With HPV-Associated
Resectable Squamous Cell Carcinoma of the Oropharynx— ECOG-
ACRIN Cancer Research Group
• primary end point was 2-year progression-free survival.
• used induction chemotherapy as a biomarker of responsiveness, and
demonstrated radiation dose could be reduced in a subset of patients with
HPV-positive OPSCC showing tumor sensitivity to chemotherapy, while
maintaining previously described tumor control and survival rates.
35. COMPARISON
• Association of Human Papillomavirus and p16 Status With
Outcomes in the IMCL-9815 Phase III Registration Trial for
Patients With Locoregionally Advanced Oropharyngeal
Squamous Cell Carcinoma of the Head and Neck Treated With
Radiotherapy With or Without Cetuximab. Rosenthal DI1, Harari
PM1, Giralt J1, Bell D1, Raben D1, Liu J1, Schulten J1, Ang KK1,
Bonner JA2.
• Addition of cetuximab to RT improved clinical outcomes
regardless of p16 or HPV status versus RT alone
open-label trial, or open trial, is a type of clinical trial in which information is not withheld from trial participants. In particular, both the researchers and participants know which treatment is being administered.
Netherlands, UK, Ireland
open-label trial, or open trial, is a type of clinical trial in which information is not withheld from trial participants. In particular, both the researchers and participants know which treatment is being administered.
randomized controlled trial is a type of scientific (often medical) experiment that aims to reduce certain sources of bias when testing the effectiveness of new treatments; this is accomplished by randomly allocating
Phase 3 trials are conducted to confirm and expand on safety and effectiveness results from Phase 1 and 2 trials
TAME consolidates traditional adverse-event data into three risk domains: short-term (acute) Toxicity (T), Adverse long-term (late) effects (A), and Mortality risk (M) generated by a treatment programme (E=End results); and assigns treatments to risk classes for each risk domain
did not differ significantly between groups
three cycles of carboplatin/nab-paclitaxel
Low-risk patients with ≥50% response received 50 Gray (Gy) RT (RT50) while low-risk patients with 30%-50% response or high-risk patients with ≥50% response received 45 Gy CRT
