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Integración de cetuximab en cáncer de cabeza y cuello
Mauricio Lema Medina MD
Clínica de Oncología Astorga, Clínica SOMA, Medellín21.03.2017
Topics
Locally-advanced (non metastatic) HNCaConcomittant chemoradiationInduction chemotherapyCetuximab + RTInduction chemotherapy and cetuximabCetuximab or Cisplatin + RTWhen to avoid cisplatinUnresolved 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
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
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
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
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
RT
Cisplatin + 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
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
Induction chemotherapy
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
Induction chemotherapy after 2000 (2)
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.
GORTEC 2001-01
Docetaxel + Cisplatin + FU
RT +/- Chemo
Cisplatin + FUImproved LR control
No improvement in PFS/OS
R
Ideal “next” clinical trial
LA HNCa
Cisplatin + RT
Chemotherapy RT
R
Induction chemotherapy after 2000 (3)
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, 2014
Docetaxel + Cisplatin + FU
Cisplatin + RT
None
DeCIDE
Docetaxel + Cisplatin + FU
RT + Chemo
NoneN2c 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
Cetux + RT
RT
Cisplatin + RT
RT
Induction chemotherapy in the cetuximab era
Induction chemotherapy in the cetuximab era
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.
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
Ideal “next” clinical trial
LA HNCa
Cisplatin + RT
Cetuximab + RT
R
Ideal “next” clinical trial
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 retrospective1808 patients
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.
Selection BIAS
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.
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.
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.
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.
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 HNCaLema’s take
01Poor performance status
(ECOG 2/3)02
Renal dysfunction (CCR <60 mL/min)
03Age > 70
04Hearing loss / Peripheral
neuropathy (Grade 2, or more)05
Marrow/Hepatic/Respiratory dysfunction (Grade 2, or more)
06Cardiovascular disease (Hypertension,
Diabetes, Unstable cardiac disease)
07Previous use of cisplatin (ie, during induction) /
other nephrotoxic agents
08Unintended weight loss
(20%, or more)09
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%
9%
5%
8%
3%
Locally-advanced HNCa
Contraindications to cisplatin
Poor PSRenal dysfunctionAge > 70HypertensionDiabetes mellitusOrgan damage (Nerves / ear / Marrow / Liver / Lung / Cardiovascular)Previous use of cisplatinWeight lossLack of social support (poor insurance)
ChemoRT with Cetuximab ChemoRT with Cisplatin
YesNo
Unresolved issues
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
cCRHPV+ or p16+, OPSCC
LA HNCa
Yes
No
Endpoint: 2-yr PFS
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.
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)
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.
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.
Outcomes in cCR group
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.
Outcomes in favorable cohort
Favorable cohort (post-hoc)Non-T4Non-N2cSmoker ≤ 10 ppycCR 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.
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
Back-up slides
Carbo/FU + RT
RT
RT
Cisplatin + RT
Carbo/FU + RT
RT
Cetux + RT
RT
Carbo/FU + RT
RT
Cetux + RT
RT
Cisplatin + RT