Principles of Chemotherapy and Chemoprevention

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Principles of Chemotherapy and Chemoprevention

Head and Neck Surgery
Author Credentials 

Jonathan Riess, MD, MS
Assistant Professor
Internal Medicine-Hematology/Oncology
UC Davis Comprehensive Cancer Center
Sacramento, CA

Module Summary

Rapid advances are being made in the treatment of advanced head and neck squamous cell cancers (SCCHN). Chemoradiation with cisplatin as the most established regimen is the standard of care for post-surgical patients with positive margins or extracapsular extension of tumor in lymph node. For definitive, non-surgical treatment, the addition of chemotherapy or the EGFR-monoclonal antibody cetuximab to radiotherapy has been shown to improve survival compared to radiation alone with high-dose cisplatin being the most established regimen. In nasopharynx cancer cisplatin and concurrent radiotherapy followed by cisplatin/5FU has been the standard treatment regimen, though in the metastatic setting of nasopharynx cancer platinum/gemcitabine has shown to be superior to platinum/5FU in terms of progression-free survival. The addition of cetuximab to platinum-based chemotherapy improves overall survival in first-line metastatic treatment of SCCHN. After first line therapy for metastatic disease, the immune checkpoint inhibitor (PD-1 antibody) nivolumab is approved based on an overall survival benefit compared to single agent docetaxel chemotherapy.

Module Learning Objectives 
  1. Explain where the application of chemotherapy has been shown to provide a survival advantage and/or an alternative to conventional therapeutic approaches for patients with advanced squamous cell carcinomas of the head and neck (SCCHN).
  2. List the principles of neoadjuvant or induction therapy, sequential and concurrent chemoradiotherapy.
  3. Describe the principles of organ preservation. 
  4. Recognize the subsequent risk of developing additional UADT cancers following successful treatment of an initial tumor.
  5. Discuss the yearly and cumulative risk of second UADT cancers in patients with SCCHN.
  6. Explain the role and sequencing of chemotherapy with radiation and surgery.
  7. Review the role of immunotherapy in advanced SCCHN.

Pathogenesis

Learning Objectives 

Understand the role that tobacco, viruses, alcohol, and other carcinogenic substances play in initiation and promotion of SCCHN.

References 
  1. Schnool RA, Lerman C. Smoking behavior and smoking cessation among head and neck cancer patients. In: Ensley JF, Gutkind S, Jacobs JR, et al., editors. Head and neck cancer: emerging perspectives. San Diego. Academic Press; 2002. p. 185-200.
  2. Kucuk O, Prasad A. Nutrients, phytochemicals and squamous cell carcinoma of the head and neck. In: Ensley JF, Gutkind S, Jacobs JR, et al., editors. Head and neck cancer: emerging perspectives. San Diego. Academic Press; 2002. p. 201-12.
  3. Chung, CH. and Gillison, ML. Human Papillomavirus in Head and Neck Cancer: Its Role in Pathogenesis and Clinical Implications. Clin Cancer Res. 2009 Nov 15;15(22):6758-62.
  4. Nitobetek G. Epstein-Barr virus infection in the pathogenesis of nasopharyngeal carcinoma. Mol Pathol. 2000 Oct; 53(5):248–254.

Basic Science

Learning Objectives 

Understand the role that translational research can play in understanding the pathophysiology of SCCHN, the identification of natural history and treatment outcome groups, and the development of therapeutic strategies and regimens.

References 
  1. Chan, KC et al. Analysis of Plasma Epstein–Barr Virus DNA to Screen for Nasopharyngeal Cancer. N Engl J Med. 2017;377:513-522.
  2. Postow, MA et al. Immune Checkpoint Blockade in Cancer Therapy. J Clin Oncol. 2015 Jun 10;33(17):1974-82. doi: 10.1200/JCO.2014.59.4358. Epub 2015 Jan 20.

Genetics

Learning Objectives 

Understand the major genetic changes that develop in SCCHN.

References 
  1. The Cancer Genome Atlas Network. Comprehensive genomic characterization of head and neck squamous cell carcinomas. Nature. 517:576-82. 

Medical Therapies

Learning Objectives 
  1. Understand the origin and composition of currently employed single agent and combination chemotherapy for neoadjuvant/induction therapy as well as chemoradiotherapy concurrent regimens.
  2. Understand where these regimens have been shown to provide a survival advantage or offer an alternative to initial surgery-based approaches to treatment of patients with advanced SCCHN.
  3. Understand the role of EGFR-monoclonal antibodies in treating SCCHN.
  4. Understand the role of immune checkpoint inhibitors (PD-1 antibodies) in the treatment of advanced SCCHN.
References 
  1. Ma J, Liu Y, Yang X, Zhang CP, Zhang ZY, Zhong LP. Induction chemotherapy in patients with resectable head and neck squamous cell carcinoma: a meta-analysis. World J Surg Oncol. 2013;11:67.
  2. Pignon JP, Bourhis J, Domenge C, Designe L. Chemotherapy added to locoregional treatment for head and neck squamous-cell carcinoma: three meta-analyses of updated individual data. MACH-NC Collaborative Group. Meta-Analysis of Chemotherapy on Head and Neck Cancer. Lancet. 2000;355(9208):949–55.
  3. Pignon JP, Maitre A, Maillard E, Bourhis J. 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.
  4. Bernier J, Cooper JS, Pajak TF, van Glabbeke M, Bourhis J, Forastiere A, et al. Defining risk levels in locally advanced head and neck cancers: a comparative analysis of concurrent postoperative radiation plus chemotherapy trials of the EORTC (#22931) and RTOG (# 9501). Head Neck. 2005;27(10):843–50.
  5. Forastiere AA, Zhang Q, Weber RS, Maor MH, Goepfert H, Pajak TF, et al. Long-term results of RTOG 91–11: a comparison of three nonsurgical treatment strategies to preserve the larynx in patients with locally advanced larynx cancer. J Clin Oncol. 2013;31(7):845–52.
  6. Forastiere AA, Goepfert H, Maor M, Pajak TF, Weber R, Morrison W, et al. Concurrent chemotherapy and radiotherapy for organ preservation in advanced laryngeal cancer. N Engl J Med. 2003;349(22):2091–8.
  7. Bonner JA, Harari PM, Giralt J, Cohen RB, Jones CU, Sur RK, et al. Radiotherapy plus cetuximab for locoregionally advanced head and neck cancer: 5-year survival data from a phase 3 randomised trial, and relation between cetuximab-induced rash and survival.[Erratum appears in Lancet Oncol. 2010 Jan;11(1):14]. Lancet Oncol. 2010;11(1):21–8.
  8. Cooper JS, Pajak TF, Forastiere AA, Jacobs J, Campbell BH, Saxman SB, et al. Postoperative concurrent radiotherapy and chemotherapy for high-risk squamous-cell carcinoma of the head and neck. N Engl J Med. 2004;350(19):1937–44.
  9. Bernier J, Domenge C, Ozsahin M, Matuszewska K, Lefebvre JL, Greiner RH, et al. Postoperative irradiation with or without concomitant chemotherapy for locally advanced head and neck cancer. N Engl J Med. 2004;350(19):1945–52.
  10. Posner MR, Hershock DM, Blajman CR, Mickiewicz E, Winquist E, Gorbounova V, et al. Cisplatin and fluorouracil alone or with docetaxel in head and neck cancer. N Engl J Med. 2007;357(17):1705–15. 51.
  11. Vermorken JB, Remenar E, van Herpen C, Gorlia T, Mesia R, Degardin M, et al. Cisplatin, fluorouracil, and docetaxel in unresectable head and neck cancer. N Engl J Med. 2007;357(17):1695–704.
  12. Al-Sarraf M, LeBlanc M, Giri PG, et al: Chemoradiotherapy versus radiotherapy in patients with advanced nasopharyngeal cancer: Phase III randomized Intergroup study 0099. J Clin Oncol 16:1310-1317, 1998.
  13. Vermorken, JB et al. Platinum-Based Chemotherapy plus Cetuximab in Head and Neck Cancer. N Engl J Med 2008; 359:1116-1127.
  14. Zhang, L et al. Gemcitabine plus cisplatin versus fluorouracil plus cisplatin in recurrent or metastatic nasopharyngeal carcinoma: a multicentre, randomised, open-label, phase 3 trial. Lancet. 2016 Oct 15;388(10054):1883-1892.
  15. Ferris, N et al. Nivolumab for Recurrent Squamous-Cell Carcinoma of the Head and Neck. N Engl J Med 2016; 375:1856-1867.
  16. Colevas, AD. Chemotherapy options for patients with metastatic or recurrent squamous cell carcinoma of the head and neck. J Clin Oncol. 2006 Jun 10;24(17):2644-52.

Case Studies

  1. 55 year-old man with a 45 pack-year tobacco history has a 2 cm primary oral cavity cancer resected with 6 mm invasion. Margins are negative. 2 lymph nodes in ipsilateral level I, max 1.8 cm are positive for cancer. 1 lymph node has extracapsular extension. Otherwise he has no significant medical co-morbidities and recovers well from surgery.
    1. It is important to discuss the improved outcomes including overall survival of adding concurrent chemotherapy to adjuvant radiotherapy for resected SCCHN with positive margins and/or extracapsular extension.
  2. A 40 year-old Asian man presents with nasal congestion and L ear fullness. Endoscopy reveals a nasopharyngeal mass with biopsy showing a non-keratinizing  squamous cell carcinoma. In situ hybridization is positive for Epstein Barr Virus.
    1. Know the proper workup and imaging for nasopharygeal tumors.
    2. Know the current grading and staging for nasopharyngeal tumors.
    3. Know the current standard of care treatment for tumors of the nasopharynx.
  3. A 60 year-old woman with 50 pack-year smoking history presents with hoarseness. Endoscopy with right supraglottic mass involving false cord, piriform sinus, right arytenoid fixed, right true vocal cord not seen and left true vocal cord with normal mobility. Biopsy shows moderately differentiated squamous cell carcinoma.
    1. Know the proper workup and imaging to assess the patients cancer including imaging.
    2. It is important to discuss with patient conventional approaches to treatment and non-surgical larynx preservation approaches if warranted.
    3. It is critical treatment be rendered by a multidisciplinary team, including medical oncologists, radiation therapists, otolaryngologists and other ancillary personnel knowledgeable and experienced in treating head and neck cancer.
    4. Recommendations regarding smoking cessation should be made.
References 
  1. Cooper JS, Pajak TF, Forastiere AA, Jacobs J, Campbell BH, Saxman SB, et al. Postoperative concurrent radiotherapy and chemotherapy for high-risk squamous-cell carcinoma of the head and neck. N Engl J Med. 2004;350(19):1937–44.
  2. Bernier J, Domenge C, Ozsahin M, Matuszewska K, Lefebvre JL, Greiner RH, et al. Postoperative irradiation with or without concomitant chemotherapy for locally advanced head and neck cancer. N Engl J Med. 2004;350(19):1945–52.
  3. Pignon JP, Bourhis J, Domenge C, Designe L. Chemotherapy added to locoregional treatment for head and neck squamous-cell carcinoma: three meta-analyses of updated individual data. MACH-NC Collaborative Group. Meta-Analysis of Chemotherapy on Head and Neck Cancer. Lancet. 2000;355(9208):949–55.
  4. Pignon JP, Maitre A, Maillard E, Bourhis J. 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.
  5. Bernier J, Cooper JS, Pajak TF, van Glabbeke M, Bourhis J, Forastiere A, et al. Defining risk levels in locally advanced head and neck cancers: a comparative analysis of concurrent postoperative radiation plus chemotherapy trials of the EORTC (#22931) and RTOG (# 9501). Head Neck. 2005;27(10):843–50.
  6. Forastiere AA, Zhang Q, Weber RS, Maor MH, Goepfert H, Pajak TF, et al. Long-term results of RTOG 91–11: a comparison of three nonsurgical treatment strategies to preserve the larynx in patients with locally advanced larynx cancer. J Clin Oncol. 2013;31(7):845–52.
  7. Forastiere AA, Goepfert H, Maor M, Pajak TF, Weber R, Morrison W, et al. Concurrent chemotherapy and radiotherapy for organ preservation in advanced laryngeal cancer. N Engl J Med. 2003;349(22):2091–8.
  8. Al-Sarraf M, LeBlanc M, Giri PG, et al: Chemoradiotherapy versus radiotherapy in patients with advanced nasopharyngeal cancer: Phase III randomized Intergroup study 0099. J Clin Oncol. 1998;16:1310-1317.

Review

Review Questions 
  • In what populations (organ sites) of SCCHN should organ preservation be appropriate with the addition of systemic chemotherapy?
  • What are the current modalities and potential side effect of systemic treatment for SCCHN?
  • What systemic SCCHN treatments improve survival in the metastatic (as a single modality) and locally advanced setting (as combined modality)?