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Chemoradiation for head and neck cancers
- 1. Chemoradiation for Head and NeckCancers Dr. Krishna Koirala
- 2. Introduction • More than50% of patients who die from HNC have locoregional disease as the only site of failure • 90% of patients with distant failure also have persistent locoregional disease • Therefore, the efficacy of any curative approach is measured by its ability to achieve locoregional control
- 3. Evolution of ChemoRT in Locally Advanced Head and Neck Malignancies • 1950s: advent of megavoltage units in radiotherapy paved the way for a more aggressive role of external radiotherapy in deeply seated tumors • 1960s: combination or radiation and surgery pioneered by Evers and Fletcher Fletcher GH, Evers W. Radiotherapeutic management of surgical recurrences and postoperative residuals in tumors of the head and neck. Radiology 1970;95:185–188
- 4. • DFS withRT alone in locally advanced disease : 30% - 40% • Chemotherapy introduced in the form of neoadjuvant /concurrent or sequential modality in addition to RT • Veterans Administration Cooperative Group Trial: – Induction cisplatin and 5-FU followed by standard fractionation vs laryngectomy and post op RT in advanced laryngeal cancer – Larynx preservation possible without compromising on overall survival
- 5. • RTOG trialshowed superior rate of larynx preservation with concurrent therapy than induction chemotherapy followed by RT • Paved the way for concurrent chemo RT
- 6. Induction/ Neo-adjuvant chemotherapyin HNSCC • Rationale – Treating the systemic burden of the disease, therefore preventing/reducing distant metastasis – Reducing the burden of the disease to facilitate loco-regional treatment
- 7. Regimens of InductionChemotherapy • TPF (Docetaxel+ cisplatinum + 5-FU) has been proved to be superior in terms of both PFS & OS as compared to PF (cisplatinum + 5-FU) both when given before RT or CRT • However, the use of Induction chemotherapy still remains a CATEGORY 3 recommendation for HNSCC
- 8. EGFR • Tyrosine kinasereceptor of the Erb -B family (expressed in a variety of solid tumors, including HNSCC • Plays an important role not only in tumor cells, but also in the tumor stroma, which provides a permissive and supportive environment for tumor growth • Over expression of EGFR and its ligand TGF-α are prevalent in HNSCC
- 9. EGFR contd…. • EGFRlevels are increased in advanced-stage tumors and in poorly differentiated tumors • There is up-regulation of EGFR even in the normal epithelium adjacent to tumor (supports the field cancerization hypothesis) • High EGFR expression has been correlated with tumor size, metastasis, angiogenesis and survival
- 13. Immunotherapy and otherinvestigational agents • Cetuximab – Bonner et al in a landmark trial demonstrated the efficacy of Cetuximab ( an anti EGFR monoclonal antibody ) in terms of LRC and OS when given concurrently with RT (NEJM 2006 Feb 9;354(6): 567-78) – However, its role in CRT is yet to be fully defined – Can be given in patients where concurrent Chemo-RT is not advisable
- 14. • Other agentsunder investigation – Selective EGFR receptor monoclonal antibody - hR3 (nimotuzumab) – Anti-angiogenesis VEGF receptor monoclonal antibody - Bevacizumab – Hypoxic cell sensitizers – Mitomycin – C , Tirapazamine – COX 2 inhibitors – Celecoxib , Rofecoxib – Tyrosine Kinase inhibitors – Geftinib ,Erlotinib
- 15. Types of chemotherapeuticagents 1. Alkylating Agents: – Interact with DNA – Cause substitution, cross-linking or strand-breaking reactions – Inhibition of /inaccurate DNA replication with resultant mutation or cell death – E.g. cisplatin, carboplatin
- 16. 2. Antimetabolites: – Havestructural or functional similarity to naturally occurring metabolites involved in nucleic acid synthesis – Inhibit critical enzymes involved in nucleic acid synthesis or become incorporated into the nucleic acid and produce incorrect codes – Results in an inhibition of DNA synthesis and ultimate cell death. – E.g.methotrexate,5-FU
- 17. 3. Antitumor Antibiotics: •Antimicrobial compounds produced by Streptomyces species in culture • Affect the structure and function of nucleic acids by intercalation between DNA base pairs (Doxorubicin), DNA strand fragmentation (Bleomycin), or cross- linking of DNA (Mitomycin)
- 18. 4. Alkaloids – Bindto free tubulin dimmers and disrupt the balance between microtubule polymerization and depolymerization, resulting in the destruction of the mitotic spindle, and arrest of cells in metaphase. Eg.vincristine, vinblastine 5. Taxanes – Disrupt equilibrium between free tubulin and microtubules causing stabilization of ordinary cytoplasmic microtubules and the formation of abnormal bundles of microtubules – Eg. Paclitaxel, Docetaxel
- 19. Antimetabolites • Earliest ofthe agents to be used effectively against SCCHN • Cytotoxicity depends on dose and duration of exposure (prolonged time of exposure enhances antitumor activity) • Methotrexate was the first agent used for palliation – Replaced with combination chemotherapy – Remains an alternative due to its relatively low toxicity
- 20. ….continued • 5-Fluorouracil iscommonly used as a combination agent but has some anti-tumor effects as a single agent as well • Hydroxyurea is mainly used in conjunction with chemoradiation as a radiation sensitizer • Side effects – Mucositis, myelosuppression, nausea, vomiting, diarrhea
- 21. • Platinum Derivatives –use began with the introduction of cisplatin, the most potent agents for use in SCCHN – Cisplatin has been reported as having a single agent response rate of 27-30%, nearly double that of the antimetabolites – Carboplatin has a lower response rate as a single agent, but also has lower toxicity – Side effects • Myelosuppression, complete alopecia, ototoxicity, peripheral neuropathies, renal failure and severe emesis
- 22. • Anthracyclines – Doxorubicinmost commonly used agent – Toxicities : extravasation necrosis, myelo suppression, alopecia, CHF, pericarditis and arrhythmias • Plant Alkaloids – Vincristine, Vinblastine ,Vinorelbine – Toxicities : peripheral neuropathy, nausea, extravasation necrosis and myelosuppression – Vinorelbine shows the greatest activity against SCCHN among the alkaloids
- 23. • Taxanes :Paclitaxel and Docetaxel – Newest group of agents with very encouraging activity against SCCHN – Toxicities: myelosuppression ,nonreversible neurotoxicity • Cisplatin and 5-FU combination: success rates up to 90% • Combination higher toxicity with subsequent treatment interruptions • Hence, single agent cisplatinum @ 100 mg/ m 2 on days 1, 22, 43 ) is presently the standard of care
- 24. Altered fractionation schemes •Conventional radiotherapy involves daily treatments, Monday to Friday, over three to seven weeks e.g. 66Gy in 33 fractions (200 cGy per fraction ) over 6 and a half weeks • Hyperfractionation : low dose per fraction given in the same overall time as routine treatment by giving treatment twice per day and achieving a higher dose in an attempt to increase local tumor control with equal late morbidity
- 25. Rationale for Hyperfractionation •A low dose per fraction could give reduced morbidity in the late-reacting normal tissues : spinal cord, bone, subcutaneous tissue and lungs • EORTC trial in oropharyngeal cancer – 1.15 Gy given twice per day to a total dose of 80.5 Gy vs 2 Gy per fraction to 70 Gy in the same overall time – Hyperfractionated group showed an increase in local tumor control: 56% versus 38% at five years with equal morbidity
- 26. Accelerated Fractionation • Sametotal dose delivered in half the time duration by the expedient of delivering two or more fractions per day • Rationale – To reduce the tumor repopulation in rapidly proliferating tumors
- 27.
- 28. Chemoradiation after Surgeryfor High-Risk Head and Neck Cancer Patients • Patients with locally advanced (stages III/IV) operable head and neck squamous cell carcinoma (HNSCC) are at high risk of treatment failure starting from Local regrowth lymphatic spread systemic dissemination: – Local-regional recurrence rate : 30% – Rate of distant metastasis : 25% – 5-year survival rates : 40% (Laramore GE, Scott CB, al-Sarraf M et al. Adjuvant chemotherapy for resectable squamous cell carcinomas of the head and neck: report on Intergroup Study 0034. Int J Radiat Oncol Biol Phys 1992;23:705–713)
- 29. Peters et al(risk assessment in HNSCC - 1990s) • Designed to clarify which patients needed postoperative radiotherapy • 3 main principles 1. Presence in the surgical specimen of two or more lymph nodes that contained cancer 2. Extracapsular extension (ECE) of tumor beyond the capsule of a node
- 30. 3. Increasing combinationsof two or more risk factors namely – oral cavity primary – close or positive mucosal margins – nerve invasion – largest node >3 centimeters in diameter – treatment delay >6 weeks – Karnowsky’s performance status >2 were associated with a progressively higher risk of local failure
- 31. • Patients whohad no adverse surgical-pathologic features were shown not to need postoperative radiotherapy • Intergroup #0034 and RTOG #85-03 trials: – Microscopically involved surgical margins of resection was also shown independently linked to a higher risk of local failure
- 32. EORTC and theRTOG cooperative groups Two large-scale randomized trials measuring treatment outcome for adjuvant chemoRT after potentially curative surgery in patients with high-risk operable, locally advanced tumors
- 33. • EORTC study –Concomitant cisplatin and radiotherapy versus radiotherapy alone in high-risk head and neck – Following surgery patients were randomly assigned to either radiotherapy alone (66 Gy in 33 fractions over 6.5 weeks) or chemoradiation, using the same radiation therapy schedule combined with three courses of cisplatin 100 mg/m2 on days 1, 22, and 43
- 34. • Median progression-freesurvival: 23 months in the RT and 55 months in the chemoRT group • Significant difference in Overall Survival on chemoRT arm • Acute reactions markedly increased with chemoradiation, especially in the mucosa and skin (34% vs77% grade III reactions) • Intravenous rehydration, gastric feeding tubes during treatment, and narcotics for severe pain must be implemented in a high percentage of the patients undergoing chemoradiation
- 35. Methods to reducetoxicities • Use of radioprotectors – Amifostine, a thiol compound, neutralizes free radicals produced by RT and chemo agents, reducing the incidence and severity of mucositis and fibrosis • Use of conformal radiotherapy – Increased concentrations of growth factors during the healing period might account for acceleration of tumor cell repopulation during a long postoperative latency period