Combined chemotherapy and intensity-modulated radiotherapy for the treatment of head and neck cancers

Radiotherapy (RT) is an extremely effective treatment for head and neck cancer, both as a primary modality and as an adjuvant treatment following surgery. RT causes significant acute (during and up to 3 months postradiation) and late toxicity when used at doses required to sterilize the locoregional disease (radical doses). The acute toxicities include mucositis, dysphagia, xerostomia, dermatitis and pain. Radiation-induced mucositis of the upper aerodigestive tract results in significant morbidity and altered quality of life (QoL) during RT [1]. The late radiation-induced toxicity includes xerostomia (60–90% incidence) [2], grade 3 dysphagia (15–30%) [2–3], osteoradionecrosis (ORN) of the mandible (5–15%) [4], sensori-neural hearing loss (40–60%) [5], skin fibrosis and laryngeal cartilage necrosis. The late radiation toxicity is permanent and results in reduced QoL for the patient; xerostomia and dysphagia in particular [6].

Benefits of intensity-modulated RT

Intensity-modulated radiotherapy (IMRT) is an advanced approach to 3D treatment planning and conformal therapy. It optimizes the delivery of irradiation to irregularly shaped volumes and has the ability to produce concavities in radiation treatment volumes. It allows for greater sparing of normal structures, such as salivary glands, upper aerodigestive tract mucosa, optic nerves, cochlea, pharyngeal constrictors, brain stem and spinal cord [7–9]. Salivary gland sparing using IMRT in various head and neck subsites has been demonstrated in three randomized Phase III trials. The multicenter study (PARSPORT) that compared parotid-sparing IMRT with standard RT in patients with oropharyngeal and hypopharyngeal cancer demonstrated a significant reduction (40 vs 74%) in the rate of grade 2 xerostomia (LENT-SOMA) in the IMRT arm at 1 year post-RT [2]. Two Phase III randomized controlled trials, investigating parotid-gland sparing using IMRT for patients with nasopharyngeal cancer demonstrated similar results [10,11]. This also translates into improved QoL for the patients. IMRT also enables sparing of the pharyngeal constrictor muscles, which are important for a normal swallow and, therefore, has the potential to reduce acute and late radiation-induced dysphagia. By virtue of its ability to spare the cochlea, IMRT has the potential to reduce the incidence of radiation-induced hearing loss. The significant increase in the burden of toxicity resulting from RT can be reduced using IMRT.

Escalation of the radiation dose may improve outcomes in this group of patients by taking advantage of the steep dose–response relationships for squamous cell carcinomas (SCCs). The initial results from a Phase I dose-escalation study using IMRT with concomitant cisplatin in patients with stage III and IV SCC of the larynx/hypopharynx demonstrated that dose escalation was safe and tolerable. [12]. The 2-year locoregional control was higher for escalated-dose patients. There was no other significant late toxicity of note. Although the patient numbers are small and the follow-up short, the results are encouraging and justify further investigation [13].

Role of chemotherapy

The outcomes with radiation alone for advanced (stage III and IV) head and neck cancer are disappointing. In recent years systemic chemotherapy has increasingly been incorporated into the treatment plan. As part of the primary treatment, systemic chemotherapy can be administered before (induction or neoadjuvant chemotherapy) or during (concomitant chemotherapy) RT (CRT). Using CRT has been demonstrated to improve survival and rates of organ preservation [14–15]. Cisplatin is considered the gold standard for concomitant treatment in head and neck cancers [16]. Studies of induction have demonstrated that chemotherapy can reduce the rate of distant metastases and improve survival [17,18]. Induction treatment with combined cisplatin and 5-fluorouracil (5-FU) (the PF regimen) yields a 5% improvement in 5-year survival [16,18]. Recently, reported Phase III studies have demonstrated that the addition of a third drug docetaxel to cisplatin and 5-FU (as part of the so-called TPF regimen) results in superior progression-free and overall survival rates compared with PF [19–20]. CRT is now the standard of care as an organ-sparing approach in the treatment of stage III and IV SCCs of the larynx and the hypopharynx [15,21–22].

Addition of concomitant chemotherapy results in the increased incidence and exacerbation of acute radiation toxicity [3,23]. In a meta-analysis of chemotherapy trials the relative risk of acute mucositis was nearly three-times that of treatment with radiation alone [24]. The late radiation-induced toxicity includes xerostomia (60–90% incidence) [2], grade 3 dysphagia (15–30%) [2–3], ORN of the mandible (5–15%) [4], sensori-neural hearing loss (40–60%) [5], skin fibrosis and laryngeal cartilage necrosis. The addition of chemotherapy to radical RT also results in a significant increase in risk of radiation-induced late toxicity [25,26]. Hey et al. compared the normal tissue complication probability parameter, D50 (dose at which 50% complication probability is expected) for the parotid salivary glands for patients having RT alone and CRT. The D50 was higher for patients receiving RT alone (39.6 vs 32.6) [27]. Studies using CRT or altered radiation fractionation strategies have reported rates of 12–50% significant late dysphagia (i.e., feeding tube dependency at 1 year), which significantly affects patient’s QoL [28–33]. The threshold dose for cochlear damage from radiation alone is 40 Gy [5]. This threshold is lowered to 10 Gy with the addition of concomitant cisplatin [34]. Treatment intensification using induction chemotherapy in addition to concomitant chemotherapy places additional burden on patients in terms of normal tissue toxicity, especially when adding agents, such as docetaxel.

Newer targeted agents

EGF receptor (EGFR) overexpression has been shown to result in adverse outcomes in head and neck cancer [35]. A randomized trial of cetuximab, a monoclonal antibody against EGFR has demonstrated a survival benefit compared with RT alone [36]. Lapatinib, a small-molecule inhibitor of tyrosine kinases associated with EGFR and human EGFR type 2 (HER2) has demonstrated activity in head and neck cancer and is undergoing Phase III trials in combination with CRT [37]. The antitumor effect of the EGFR inhibitors is due to the effect on the signal transduction pathways, which leads to inhibition of cell proliferation. It has been postulated that these agents also have an indirect effect on the inhibition of DNA repair, which might explain their efficacy in combination with radiation. However, the EGFR inhibitors could also inhibit the radiation-induced DNA repair in normal tissue, causing increased acute toxicity and radiation-induced carcinogenesis.

Combining chemotherapy with tyrosine kinase inhibitors makes scientific sense as both agents are active in head and neck cancer and have different mechanisms of action. Proof of principle was obtained in a Phase III study of first line cisplatin plus cetuximab, which demonstrated improved overall survival in metastatic head and neck cancer patients [38]. Wirth et al. investigated the feasibility of combining panitumumab, carboplatin and two dose levels of paclitaxel with radiation delivered using IMRT as primary treatment in patients with advanced head and neck cancer [39]. The incidence of grade 3 mucositis and dysphagia was greater than 94%. In addition, 34% of patients had a treatment break owing to toxicity, in spite of optimal tissue sparing using IMRT.

Future directions & conclusions

The volumes that receive a radical (potentially curative) radiation dose even when using IMRT, is quite large. Treating smaller volumes is limited by the resolution of imaging modalities (computed tomography and MRI) used for IMRT planning. Newer imaging modalities, such as PET, provide information on the biological activity of tumors. The PET images could be used for biological dose optimization during IMRT planning. This would enable a more focused radical dose delivery, further reducing normal tissue toxicity, during concomitant treatment with highly dose-intense chemotherapeutic regimens. Strategies to improve the efficacy of radiation, by targeting repair mechanisms in the tumor, after radiation damage (DNA repair), are currently being explored in preclinical and early Phase I studies [40]. These agents are likely to affect the DNA repair in normal tissues, placing further importance on minimizing the radiation dose to normal tissues using IMRT.

Intensity-modulated radiotherapy allows for radiation dose escalation and/or treatment with more dose-intense concomitant chemotherapeutic regimens, with reduction in the normal tissue toxicity, and therefore improving the therapeutic index in patients with advanced head and neck cancers.

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.