Integración de cetuximab en cáncer de cabeza y cuello

Integración de cetuximab en cáncer de
cabeza y cuello
Mauricio Lema Medina MD
Clínica de Oncología Astorga, Clínica SOMA, Medellín
21.03.2017

Topics
Locally-advanced (non metastatic) HNCa
Concomittant chemoradiation
Induction chemotherapy
Cetuximab + RT
Induction chemotherapy and cetuximab
Cetuximab or Cisplatin + RT
When to avoid cisplatin
Unresolved issues
Cetuximab in chemo-naive metastatic HNCa

Meta-analysis of chemotherapy in head and neck cancer
(MACH-NC): An update on 93 randomised trials and
17,346 patients
Pignon J-P, le Maître A, Maillard E, Bourhis J, MACH-NC Collaborative Group JS, Das N. Meta-analysis of chemotherapy in head and neck cancer (MACH-NC):
an update on 93 randomised trials and 17,346 patients. Radiother Oncol. 2009;92(1):4-14. doi:10.1016/j.radonc.2009.04.014

An Intergroup Phase III Comparison of Standard Radiation Therapy and Two
Schedules of Concurrent Chemoradiotherapy in Patients With Unresectable
Squamous Cell Head and Neck Cancer
Adelstein DJ, Li Y, Adams GL, et al. An intergroup phase III comparison of standard radiation therapy and two schedules of concurrent chemoradiotherapy in
patients with unresectable squamous cell head and neck cancer. J Clin Oncol. 2003;21(1):92-98. doi:10.1200/JCO.2003.01.008.
RT
Chemo (Cisplatin-
based) + RT

Final Results of the 94–01 French Head and Neck Oncology and
Radiotherapy Group Randomized Trial Comparing Radiotherapy Alone With
Concomitant Radiochemotherapy in Advanced-Stage Oropharynx Carcinoma
Denis F, Garaud P, Bardet E, et al. Final results of the 94-01 French Head and Neck Oncology and Radiotherapy Group randomized trial comparing
radiotherapy alone with concomitant radiochemotherapy in advanced-stage oropharynx carcinoma. J Clin Oncol. 2004;22(1):69-76.
doi:10.1200/JCO.2004.08.021.

Carbo/FU + RT
RT
RT
Cisplatin + RT

Concomitant chemoradiotherapy versus acceleration of radiotherapy with
or without concomitant chemotherapy in locally advanced head and neck
carcinoma (GORTEC 99-02): an open-label phase 3 randomised trial.
Bourhis, J., Sire, C., Graff, P., Grégoire, V., Maingon, P., Calais, G., … Aupérin, A. (2012). Concomitant chemoradiotherapy versus acceleration of radiotherapy
with or without concomitant chemotherapy in locally advanced head and neck carcinoma (GORTEC 99-02): an open-label phase 3 randomised trial. The
Lancet Oncology, 13(2), 145–153. https://doi.org/10.1016/S1470-2045(11)70346-1

A meta-analysis comparing cisplatin-based to carboplatin-
based chemotherapy in moderate to advanced squamous cell
carcinoma of head and neck (SCCHN).
Guan J, Li Q, Zhang Y, et al. A meta-analysis comparing cisplatin-based to carboplatin-based chemotherapy in moderate to advanced squamous cell
carcinoma of head and neck (SCCHN). Oncotarget. 2016;7(6):7110-7119. doi:10.18632/oncotarget.6858.
12 studies, 1165 patients

Standard-of-care, year 2000
MACH-NC Cisplatin + RT
Pignon J-P, le Maître A, Maillard E, Bourhis J, MACH-NC Collaborative Group JS, Das N. Meta-analysis of chemotherapy in head and neck cancer (MACH-NC):
an update on 93 randomised trials and 17,346 patients. Radiother Oncol. 2009;92(1):4-14. doi:10.1016/j.radonc.2009.04.014

Ideal “next” clinical trial
LA HNCa
Cisplatin + RT
Chemotherapy RT
R

Induction chemotherapy after 2000 (1)
Chapman CH, Parvathaneni U, Yom SS. Revisiting induction chemotherapy before radiotherapy for head and neck cancer, part I:
carcinoma of non-nasopharyngeal sites. Futur Oncol. 2017;13(6):469-475. doi:10.2217/fon-2016-0502.
Hitt, 2005
Paclitaxel +
Cisplatin + FU
Cisplatin +RT
Cisplatin + FU
TAX323, 2007
Docetaxel +
Cisplatin + FU
RT
Cisplatin + FU
TAX324, 2007
Docetaxel +
Cisplatin + FU
Cisplatin + RT
Cisplatin + FU
12% did
not go to
ChemoRT
21% did
not go to
ChemoRT
R
R
R

GORTEC 2001-01
Docetaxel +
Cisplatin + FU
RT +/- Chemo
Cisplatin + FU
Improved LR control
No improvement in PFS/OS
R

Hitt, 2014
Docetaxel +
Cisplatin + FU
Cisplatin + RT
None
DeCIDE
Docetaxel +
Cisplatin + FU
RT + Chemo
None
N2c disease
30% did
not go to
ChemoRT
PARADIGM
Docetaxel +
Cisplatin + FU
RT + Carbo
None Cisplatin + RT
R
R
R

Why induction chemotherapy failed?
Toxicity may impact compliance
with RT

Cetuximab + RT in locally-
advanced HNCa

Radiotherapy plus Cetuximab for Squamous-Cell
Carcinoma of the Head and Neck
Bonner JA, Harari PM, Giralt J, et al. Radiotherapy plus Cetuximab for Squamous-Cell Carcinoma of the Head and Neck. N Engl J
Med. 2006;354(6):567-578. doi:10.1056/NEJMoa053422.
Bonner, 2006
Cetuximab + RT
RT
R
Stage III or IV, nonmetastatic, measurable squamous-cell carcinoma of the
oropharynx, hypopharynx, or larynx.

Radiotherapy plus Cetuximab for Squamous-Cell
Carcinoma of the Head and Neck
Bonner JA, Harari PM, Giralt J, et al. Radiotherapy plus Cetuximab for Squamous-Cell Carcinoma of the Head and Neck. N Engl J
Med. 2006;354(6):567-578. doi:10.1056/NEJMoa053422.

Cetux + RT
RT
Cisplatin + RT
RT

Induction chemotherapy in the
cetuximab era

Induction chemotherapy in the cetuximab era
TREMPLIN TPF
Cisplatin + RT
Cetuximab + RTLaryngeal carcinoma
Spanish, 2007-01 TPF
Cisplatin + RT
Cetuximab + RTOther sites
GORTEC, 2007-01
TPF Cetuximab + RT
Chemo (Carbo
+ FU) + RT
N2b-N2c disease
R
R
R

Cetuximab or Cisplatin for
Locally-advanced HNCa

LA HNCa
Cisplatin + RT
Cetuximab + RT
R

LA HNCa
Cisplatin + RT
Cetuximab + RT
R
At least, not a large, well conducted Phase III trial…

Concomitant platinum-based chemotherapy or cetuximab with
radiotherapy for locally advancedhead and neck cancer: a systematic review
and meta-analysis of published studies.
Petrelli F, Coinu A, Riboldi V, et al. Concomitant platinum-based chemotherapy or cetuximab with radiotherapy for locally advanced head and neck cancer:
A systematic review and meta-analysis of published studies. Oral Oncol. 2014;50(11):1041-1048. doi:10.1016/j.oraloncology.2014.08.005.
15 studies
12 retrospective
1808 patients

Selection BIAS

Conclusion
Cisplatin based chemo-RT remains the
standard-of-care for locally-advanced
HNCa.

When should we AVOID cisplatin
in locally-advanced HNCa?

Clinical recommendations for defining platinum unsuitable head and neck
cancer patient populations on chemoradiotherapy: A literature review
Ahn M-J, D’Cruz A, Vermorken JB, et al. Clinical recommendations for defining platinum unsuitable head and neck cancer patient populations on
chemoradiotherapy: A literature review. Oral Oncol. 2016;53:10-16. doi:10.1016/j.oraloncology.2015.11.019.

9 reasons not to use Cisplatin in locally-advanced HNCa
Lema’s take
Poor performance status
(ECOG 2/3)
Renal dysfunction (CCR
<60 mL/min)
Age > 70
Hearing loss / Peripheral
neuropathy (Grade 2, or more)
Marrow/Hepatic/Respiratory
dysfunction (Grade 2, or
more)
Cardiovascular disease (Hypertension,
Diabetes, Unstable cardiac disease)
Previous use of cisplatin
(ie, during induction) /
other nephrotoxic agents
Unintended weight loss
(20%, or more)
No social support / no
support at home
Ahn M-J, D’Cruz A, Vermorken JB, et al. Clinical recommendations for defining platinum unsuitable head and neck cancer patient populations on
chemoradiotherapy: A literature review. Oral Oncol. 2016;53:10-16. doi:10.1016/j.oraloncology.2015.11.019.

About 30% older than 70
https://seer.cancer.gov/statfacts/html/oralcav.html

High Prevalence of Stage 3 Chronic Kidney Disease in Older Adults Despite
Normal Serum Creatinine
Overall, 36.1% of older adults in the US have stage 3 or
greater CKD as defined by eGFR values.
Among older adults with stage 3 CKD, 80.6% had
creatinine values ≤1.5 mg/dl, and 38.6% had creatinine
values ≤1.2 mg/dl.
Optimal cutoff values for serum creatinine in the
diagnosis of stage 3 CKD in older adults were ≥1.3 mg/dl
for men and ≥1.0 mg/dl for women, regardless of the
presence or absence of hypertension, diabetes, or
congestive heart failure.
Duru OK, Vargas RB, Kermah D, Nissenson AR, Norris KC. High prevalence of stage 3 chronic kidney disease in older adults despite normal serum creatinine.
J Gen Intern Med. 2009;24(1):86-92. doi:10.1007/s11606-008-0850-3.

The impact of comorbidity on outcome in 12 623 Danish head and neck
cancer patients: a population based study from the DAHANCA database.
Bøje CR, Dalton SO, Grønborg TK, et al. The impact of comorbidity on outcome in 12 623 Danish Head and Neck Cancer Patients: A population based study
from the DAHANCA database. Acta Oncol (Madr). 2013;52(2):285-293. doi:10.3109/0284186X.2012.742964.

The impact of comorbidity on outcome in 12 623 Danish head and neck
cancer patients: a population based study from the DAHANCA database.
Bøje CR, Dalton SO, Grønborg TK, et al. The impact of comorbidity on outcome in 12 623 Danish Head and Neck Cancer Patients: A population based study
from the DAHANCA database. Acta Oncol (Madr). 2013;52(2):285-293. doi:10.3109/0284186X.2012.742964.
6%
5%
8%

Locally-advanced HNCa
Contraindications to
cisplatin
Poor PS
Renal dysfunction
Age > 70
Hypertension
Diabetes mellitus
Organ damage (Nerves / ear / Marrow / Liver / Lung / Cardiovascular)
Previous use of cisplatin
Weight loss
Lack of social support (poor insurance)
ChemoRT with Cetuximab ChemoRT with Cisplatin
Yes
No

Human Papillomavirus (HPV): A Criterion for
Therapeutic Decision in Squamous Cell
Carcinoma of the Head and Neck?
“When deciding how to treat patients with squamous cell carcinoma
of the head and neck (SCCHN), several factors have to be taken into
account: disease factors, patient factors, treatment factors, and the
wish of the patient. This symposium article is summarizing the
information on HPV (p16) in the context of decision making in SCCHN
patients with locoregionally advanced disease and those with
recurrent/metastatic disease. The literature data suggest that
HPV(p16) has prognostic significance, both in locoregionally advanced
disease (in particular, in oropharynx cancer) and in
recurrent/metastatic disease, while there are only limited data on its
predictive significance. Results of HPV (p16) testing should not
change management outside clinical trials.”
Vermorken, J. B. (2017). Human Papillomavirus (HPV): A Criterion for Therapeutic Decision in Squamous Cell Carcinoma of the Head
and Neck? In Recent results in cancer research. Fortschritte der Krebsforschung. Progres dans les recherches sur le cancer (Vol. 206,
pp. 137–147). https://doi.org/10.1007/978-3-319-43580-0_10

Cetuximab may be used to limit
RT dose in HPV+ tumors
Phase II, use with caution!

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.
Marur S, Li S, Cmelak AJ, et al. 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. J Clin Oncol. 2017;35(5):490-497. doi:10.1200/JCO.2016.68.3300.
Paclitaxel +
Cisplatin +
Cetuximab
IMRT 54 Gy +
Cetuximab
RT 69.3 Gy +
Cetuximab
cCR
HPV+ or p16+, OPSCC
LA HNCa
Yes
No
Endpoint: 2-yr PFS

At 12 months, significantly fewer patients
treated with a radiation dose ≤ 54 Gy had
difficulty swallowing solids (40% v 89%; P = .011)
or had impaired nutrition (10% v 44%; P = .025)

Outcomes in cCR group

Outcomes in favorable cohort
Favorable cohort (post-hoc)
Non-T4
Non-N2c
Smoker ≤ 10 ppy
cCR on induction

Cetuximab in metastatic HNCa
EXTREME

Platinum-Based Chemotherapy plus
Cetuximab in Head and Neck Cancer
Vermorken, J. B., Mesia, R., Rivera, F., Remenar, E., Kawecki, A., Rottey, S., … Hitt, R. (2008). Platinum-Based Chemotherapy plus
Cetuximab in Head and Neck Cancer. New England Journal of Medicine, 359(11), 1116–1127.
https://doi.org/10.1056/NEJMoa0802656
.
EXTREME, 2008
Platinum + FU
Platinum + FU +
Cetuximab
R
Untreated recurrent or metastatic squamous-cell carcinoma of the head and neck.
KPS >70

Platinum-Based Chemotherapy plus
Cetuximab in Head and Neck Cancer
Vermorken, J. B., Mesia, R., Rivera, F., Remenar, E., Kawecki, A., Rottey, S., … Hitt, R. (2008). Platinum-Based Chemotherapy plus
Cetuximab in Head and Neck Cancer. New England Journal of Medicine, 359(11), 1116–1127.
https://doi.org/10.1056/NEJMoa0802656
.

Vermorken, J. B., et al. New England Journal of Medicine, 359(11), 1116–1127.

Cetuximab in Head and neck
cancer
Radiation + Cetuximab is an aceptable
option for CISplatinum inelegible locally
advanced HNCa
Cisplatin inelegibility is excedingly common
in HNCa
Cetuximab + Platinum + FU is of proven
benefit in patients with relapsed /
metastatic HNCa, as 1st-line therapy

Carbo/FU + RT
RT
Cetux + RT
RT

Carbo/FU + RT
RT
Cetux + RT
RT
Cisplatin + RT

Integración de cetuximab en cáncer de cabeza y cuello

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