2. Introduction
• More than 50% 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 Chemo RT 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 with RT 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 trial showed 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 chemotherapy in
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 Induction Chemotherapy
• 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 kinase receptor 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….
• EGFR levels 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
10.
11.
12.
13. Immunotherapy and other investigational
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
15. Types of chemotherapeutic agents
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:
– Have structural 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
– Bind to 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 of the 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 is commonly 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
– Doxorubicin most 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
• Same total 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
28. Chemoradiation after Surgery for 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 combinations of 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 who had 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 the RTOG 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-free survival: 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 reduce toxicities
• 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
