Chemoradiation for

Head and Neck Cancers

Dr. Krishna Koirala

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

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

• 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

• RTOG trial showed superior rate

of larynx preservation with

concurrent therapy than

induction chemotherapy

followed by RT

• Paved the way for concurrent

chemo RT

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

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

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

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

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

• Other agents under 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

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

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

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)

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

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

….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

• 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

• 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

• 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

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

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

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

• Accelerated fractionation

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)

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

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

• 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

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

• 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

• 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

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