Advanced head and neck cancers are difficult to manage despite the large treatment arsenal currently available. The multidisciplinary effort to increase disease-free survival and diminish normal tissue toxicity was rewarded with better locoregional control and sometimes fewer side effects. Nevertheless, locoregional recurrence is still one of the main reasons for treatment failure. Today, the standard of care in head and neck cancer management is represented by altered fractionation radiotherapy combined with platinum-based chemotherapy. Targeted therapies as well as chronotherapy were trialled with more or less success. The aim of the current work is to review the available techniques, which could contribute towards a higher therapeutic ratio in the treatment of advanced head and neck cancer patients.
The major goal of cancer treatment is to improve the clinical outcome by increasing the therapeutic ratio (TR). Most commonly, the therapeutic ratio is quantitatively defined as the ratio between tumour control probability (TCP) and normal tissue complication probability (NTCP). In order to maximise the therapeutic ratio, tumour control needs to increase while normal tissue complications need to decrease. As with any other malignancy, the objective in the treatment of advanced head and neck cancer is to improve TR through both components: TCP and NTCP.
After decades of treatment optimisation via novel irradiation techniques, new cytotoxins and several adjuvant agents to improve tumour response to therapy, advanced unresectable head, and neck cancers are still a clinical challenge. Although the locoregional control showed improvement along the implementation of new treatment techniques, the death rate does not seem to decline for this malignancy [
Several randomised clinical trials showed a significant improvement in locoregional tumour control and disease-free survival when radiation was combined with cisplatin, as compared to radiation as a single agent [
Cisplatin is a platinum compound with complex properties when it comes to radiation-drug interaction. Through inhibition of DNA repair and cell cycle arrest cisplatin demonstrates radiosensitizing properties [
Irrespective of the exact mechanism that leads to radiosensitization cisplatin is a powerful drug, and since its clinical implementation it remains a fundamental cytotoxic agent for the management of head and neck cancer.
Tumour hypoxia and accelerated proliferation of tumour cells during therapy (both radiotherapy and chemotherapy) remain some of the biggest challenges concerning the treatment of advanced head and neck cancer. The unpredictability of acute hypoxia in tumours often leads to treatment failure, and so does the rapid proliferation of tumour cells after the initiation of therapy. Cellular recruitment from the quiescent phase, accelerated accelerated stem cell division, abortive division, and loss of asynchronous stem cell division are thought to be the main mechanisms responsible for accelerated regrowth in squamous cell carcinomas of the head and neck [
Although altered fractionation increased locoregional control, there were trials that showed no treatment gain because of normal tissue complications. For instance, in the EORTC 22851 randomised trial [
While being one of the most potent chemotherapeutic agents, cisplatin is highly toxic to various organs. Nephrotoxicity and ototoxicity are some of the most commonly reported side effects during cisplatin-based chemotherapy. Other side effects, such as hematologic and central nervous system-related toxicities, are often dose-limiting factors or reason for treatment interruption. The rate of treatment completion is frequently reported to be below 100% due to adverse events. New radiotherapy delivery techniques might be a possible solution in reducing side effects due to better tumour conformity, as shown by studies comparing helical tomotherapy to conventional IMRT [
The risk of developing a second primary cancer after head and neck cancer treatment was shown to be strongly linked to the original risk factors, which initiated the first primary cancer, that is, smoking and alcohol consumption as well as the oncogenic human papillomavirus [
However, there is evidence that chemotherapy, particularly cisplatin, can induce carcinogenesis in patients treated with this agent for their primary malignancy. While proven to be toxic to normal tissue since the beginning of its clinical use, cisplatin was not shown to be carcinogenic until later. A large clinical study undertaken by Travis et al. showed an increased risk of leukaemia in patients previously treated with cisplatin [
Risk of leukaemia as a function of the cumulative dose of platinum agents (based on Travis 1999 data [
The most commonly used methods to optimise the therapeutic ratio are reviewed below. While some of these techniques are widely accepted among the medical community (altered fractionation, cisplatin-based radiochemotherapy, and image-guided radiotherapy) others either are less successful in their clinical implementation or await more conclusive results (bioreductive drugs, normal tissue radioprotectors, and chronotherapy).
There is an extensive number of trials on head and neck cancer comparing the clinical effect of combined chemoradiotherapy versus radiotherapy alone. In order to collate and examine the results, a metaanalysis of the role of chemotherapy in head and neck cancer (MACH-NC) was published based on 93 randomised trials (conducted between 1965 and 2000) [
The advances in knowledge concerning head and neck radiobiology over the last few decades lead to clinical implementation of various altered fractionation schedules with and without chemotherapy. Altered fractionation radiotherapy combined with cisplatin-based chemotherapy became a common practice within the management of advanced head and neck cancer patients [
Cisplatin-based chemoradiotherapy regimens employing IMRT techniques.
Clinical study | Patient no. | Radiotherapy | Chemotherapy | Clinical outcome |
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42 | IMRT total dose of 70 Gy | Cisplatin (50 mg/m2 on days 1, 2, 22, 23, 43, and 44) and bevacizumab (15 mg/kg on days 1, 22, and 43) |
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224 | Median total dose of 74.4 Gy, 1.2 Gy twice daily 5 days per week | Two cycles of cisplatin (20 mg/m2 for 5 consecutive days during weeks 1 and 5) |
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30 | IMRT median dose of 70 Gy | Cetuximab: initial dose of 400 mg/m2 7–10 days before concurrent IMRT weekly cisplatin (30 mg/m2/week) and cetuximab (250 mg/m2/week) |
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39 | IMRT to high-risk planning target volume 70 Gy of 1.25 Gy twice daily fractions. Intermediate and low-risk PTVs of 60 Gy and 50 Gy, at 1.07 and 0.89 Gy/fraction | Cisplatin 33 mg/m2 weekly |
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43 | IMRT with simultaneous integrated boost (67.5, 60, and 54 Gy in 30 daily fractions of 2.25, 2, and 1.8 Gy) | Cisplatin 40 mg/m2 weekly or 100 mg/m2 every 3 weeks during radiotherapy + weekly cetuximab (3 patients only) |
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22 | IMRT of 69-70 Gy at 2.12–2.3 per fraction delivered to the PTV (including nodes) | Cisplatin 40 mg/m2 weekly for six cycles |
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31 | Median dose of 70 Gy at 2.12 Gy/fraction to the PTVGTV; 59.4 Gy at 1.8 Gy/fraction to the PTV of high-risk subclinical disease | Cisplatin 2 to 3 cycles 100 mg/m2 intravenously within 2 days every 3 weeks |
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The studies presented in Table
The addition of bevacizumab [
Although locoregional control is significantly improved with the conversion of conventional therapy into IMRT, long-term survival remains at low rates, mainly due to tumour recurrence.
The mixed results achieved with altered fractionation combined with chemotherapy suggest that there is need for a careful selection of patients who would benefit from such therapy. The RTOG 0129 phase III randomised trial showed that combining cisplatin with altered fractionation (accelerated concomitant boost) does not give superior clinical results to standard fractionation combined with cisplatin [
One of the main challenges with injectable cisplatin is normal tissue toxicity. Therefore, the idea of oral administration of cisplatin was worth testing in order to investigate its level of tolerability. Tao et al. have designed a dose-escalation trial where oral cisplatin (CP Ethypharm) was administered in combination with radiotherapy to 18 head and neck cancer patients [
A new platinum compound is on the horizon, namely, mitaplatin, which is a fusion between cisplatin and the orphan drug dichloroacetate previously developed to treat lactic acidosis [
Image-guidance represents today an important tool for increasing the therapeutic gain by better targeting the tumour, especially during fractionated radiotherapy when tumour shrinkage is expected over time and by better sparing of the surrounding normal tissue. Image-guided radiotherapy can be optimally achieved by employing cone beam CT during the course of radiotherapy then adapting the treatment plan according to the new tumour parameters [
Another imaging method, which assists in improving tumour control in head and neck cancer patients, is PET/CT. The functional properties supplied by PET together with the anatomical tumour delineation offered by CT provide a powerful tool in tumour classification and prediction of treatment outcome as well as selective targeting of hypoxic regions within the tumour. Beside 18F-FDG, which is still considered the standard radiotracer for PET imaging, there are hypoxia-specific radiotracers (F-MISO, F-FAZA) as well as proliferation-specific radiotracers (F-FLT) successfully used in clinical settings [
A clinical study conducted by Rothschild et al. [
An innovative radiation therapy trial is currently accruing patients for analysing the predictive value of biological markers and 89Zr-cetuximab uptake in head and neck cancer treated with cisplatin versus cetuximab and standard radiotherapy versus redistributed radiotherapy. The focus of the ARTFORCE trial is on individualised treatment, using functional imaging for the assessment of dose escalation to the FDG-PET positive region and adaptive replanning accounting for anatomical changes during treatment [
The epidermal growth factor receptor (EGFR) plays a vital role in head and neck cancer development, growth, and metastatic spread and angiogenesis, owing to promotion of epidermal cell growth and regulation of cell proliferation. It was clinically proven that overexpression of EGFR leads to increased tumour proliferation and other growth-promoting behaviour. Of all head and neck squamous cell carcinomas a value as high as 90% exhibits overexpression of epidermal growth factor receptor [
A clinical trial conducted by Bonner et al. [
The combined effect of cetuximab and cisplatin-based chemoradiotherapy was studied in a phase II trial for patients with advanced head and neck cancer [
Another anti-EGFR monoclonal antibody investigated as an agent for targeted therapies in head and neck cancer is panitumumab. As shown by preclinical studies, panitumumab has higher affinity for EGFR than other monoclonal antibodies developed to target EGFR [
Angiogenesis inhibitors target those signalling molecules which stimulate the endothelial cells to migrate, divide, and form new blood capillaries. One such signalling molecule is the vascular endothelial growth factor (VEGF). Antiangiogenic drugs bind to VEGF before they could connect with the receptors of the endothelial cell to initiate the angiogenic process.
An angiogenic inhibitor that recognises and binds to VEGF is bevacizumab, a monoclonal antibody which was the first agent of its kind to slow tumor growth in glioblastoma, nonsmall cell lung cancer, and metastatic colorectal cancer patients [
An interesting study undertaken by Wang et al. [
The same research group showed that bevacizumab has antitumour effect beyond antiangiogenesis, potentiating the cytotoxicity of cisplatin on squamous cell carcinomas [
The rate and degree of normal tissue toxicity in head and neck cancer patients treated with radiation have justified the clinical need for a normal tissue radioprotector for reduction of side effects.
Amifostine is a commonly used normal tissue radioprotector, which has been trialled in combination with both radiotherapy and chemoradiotherapy. Amifostine was also proven to be an effective cytoprotector against the side effects caused by cisplatin [
The future use of amifostine remains uncertain owing to conflicting results regarding normal tissue toxicities. While some of amifostine’s properties such as selectivity (i.e., lack of tumour protection) and safety were confirmed by several studies, the reduction in normal tissue toxicity was not always demonstrated [
It is a known and accepted fact that biological functions in humans are organised around a circadian (day/night) clock. Circadian rhythms are controlled by the suprachiasmatic nucleus of the hypothalamus, also known as the “master pacemaker”. Consequently, several biological processes are dictated by this clock including sleep, hormone secretion, and cell proliferation. Experimental findings suggest the existence of crosstalk between clock gene molecules and those molecules, which are responsible for cellular progression through the cell cycle [
Chronotherapy refers to treatment that is timed around this biological clock, which was shown to differ between normal and cancer cells [
One of the most common side effects during and after chemoradiotherapy of head and neck cancers are those involving the oral mucosa. The goal of chronotherapy is to take into account the biological clock of various tissues in trying to schedule treatment in the most opportune time for the tumour and the least harmful time for the normal cells. Therefore, investigating the peak times of oral mucosa cells could dictate the timing of treatment to diminish side effects. Bjarnason et al. have investigated the circadian variation of human oral epithelium through the expression of cell-cycle proteins [
The circadian rhythm of normal oral mucosa cells (data from Bjarnason et al. [
Cycle phase | Early G1 | Late G1 | S | G2 | M |
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Peak time | 6 am | 11 am | 3 pm | 4 pm | 9 pm |
Phase marker | p27 | p53 | cyclin E | cyclin A | cyclin B |
Experimental studies support the evidence whereby the DNA synthesis rhythm in normal cells is in phase opposition with that of tumour cells, observation that is valid for the mitotic phase as well [
There are clinical studies supporting the evidence whereby treatment timing according to cellular circadian rhythm can improve treatment outcome in head and neck cancer patients. Bjarnason et al. [
It was shown that circadian dosing time could also influence drug-related toxicities [
The results achieved with chronotherapeutics in leukaemia patients, ovarian cancer patients, and metastatic colorectal cancer patients are even more pronounced. For instance, a twofold increase in survival and disease free rate after 5 years was reported in a chronotherapy trial involving children with acute lymphoblastic leukaemia when chemotherapy (antimetabolites) was administered in the evening (80% survival) versus morning treatment (40% survival) [
To obtain conclusive results with head and neck cancer chronotherapy, there is need for further studies involving a multidisciplinary approach and an open-minded attitude towards less orthodox treatment methods that showed promising results in the past.
Advanced head and neck cancers are difficult to manage despite the large treatment arsenal currently available. The multidisciplinary effort to increase disease-free survival and diminish normal tissue toxicity is rewarded with better locoregional control and sometimes fewer side effects. Nevertheless, locoregional recurrence is still one of the main reasons for treatment failure.
In order to increase therapeutic ratio, there are methods to improve tumour control as well as normal tissue sparing. Some of the techniques to achieve these goals are listed below.
Techniques to increase TCP: optimum fractionation schedules; optimum timing between radiotherapy and cisplatin administration based on cisplatin’s pharmacokinetics and pharmacodynamics as well as the interaction between cisplatin and radiation; knowledge of pretreatment radiobiological tumour parameters such as oxygenation status and cellular proliferative capacity; image-guidance during radiotherapy; EGFR inhibitors such as cetuximab; angiogenic inhibitors; chronotherapy involving knowledge of tumour circadian rhythm.
Techniques to decrease NTCP: optimum timing between radiotherapy and cisplatin administration; more conformal radiotherapy (IMRT); image-guidance during treatment; normal tissue radioprotectors such as amifostine; chronotherapy involving knowledge of normal tissue circadian rhythms, especially of the oral mucosa and bone marrow to diminish side effects of both radiotherapy and chemotherapy.
The latest treatment techniques combined with adjuvant and/or targeted therapies succeeded in increasing locoregional control in advanced head and neck cancer patients. The downside, however, is the increased rate of side effects. Furthermore, overall survival in this patient group has not seen any considerable improvement over the last decades. While there are promising results with targeted therapies involving monoclonal antibodies as well as with chronotherapy, the optimal treatment for advanced head and neck cancer patients is yet to be established.
This work was supported by a grant of the Ministry of National Education, CNCS-UEFISCDI, Project no. PN-II-ID-PCE-2012-4-0067.