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