Article
Radiotherapy
X-rays were the first form of photon radiation to be used to treat cancer. The higher the energy of the x-ray beam, the deeper x-rays penetrate the target. Radiotherapy (RT) is an extremely effective treatment for oral cancer, both as a primary modality and as an adjuvant following surgery. A range of types is available (Table 1).
| Type | Definition | Sub-types |
|---|---|---|
| External beam | Machines focus radiation (eg x-rays) on a cancer. |
Linear accelerators produce x-rays of increasingly greater energy. |
| Internal radiotherapy | Radioactive implants placed directly into tumour, resulting in less radiation exposure to other body parts. | Brachytherapy, interstitial irradiation |
| Particle beam radiation therapy | Fast-moving subatomic particles used to treat localized cancers. Sophisticated equipment is needed to produce and accelerate the particles for this. Some particles (neutrons, pions, and heavy ions) deposit more energy (high linear energy transfer or high LET) than do x-rays or gamma rays, thus causing more damage to cells they hit. |
A planning session is needed before RT. This includes CT scan and measurements of the area to be treated, as well as skin markings to help treatment positioning. A mask immobilizes the patient's head so that radiation will only be delivered to designated areas. The total radiation dose prescribed by the oncologist is given in small amounts (fractions) usually every day for 10 to 15 minutes, 5 days in a row with a 2 day break each weekend. Most of this time is spent ensuring that blocking devices, which restrict the radiation to the appropriate area, are properly located, and patient and machine properly positioned. The daily dose must be enough to destroy cancer cells while sparing normal tissues of excessive radiation: typically 2Gy is delivered daily to a 64–70Gy total dose.
Radiation toxicities
Conventional RT causes significant acute (during and up to 3 months post-radiation), and late, toxicities when used at doses required to treat (‘sterilize’) the loco-regional disease effectively (radical doses). These acute toxicities – mainly mucositis, dysphagia, xerostomia, dermatitis and pain – significantly impair QoL, as do late RT-induced toxicities, especially hyposalivation (up to 90% incidence) and grade 3 (severe) dysphagia (up to 30%). Late toxicity is permanent and also may include jaw osteoradionecrosis, sensori-neural hearing loss, skin fibrosis and laryngeal cartilage necrosis.
Intensity modulated radiotherapy (IMRT), however, delivers radical radiation doses to the target but spares most normal tissue, reducing toxicities.
Intensity modulated radiotherapy (IMRT)
3-D treatment planning and conformal therapy in IMRT irradiates irregularly-shaped volumes and can produce concavities in treatment volumes, thus permitting greater sparing of normal structures including:
Escalation of radiation dose with IMRT may also improve outcomes in patients with oral cancer. IMRT can be optimized further using advances in the imaging techniques, ie image-guided radiotherapy (IGRT).
Image guided radiotherapy (IGRT)
IGRT uses adaptive radiotherapy based on regular scanning and planning to reduce dosimetric uncertainties associated with the volume changes in tumours and organs at risk. Radiation dose escalation could improve the outcomes in advanced cancers. Selective dose escalation, based on the biological activity of tumours determined by positron emission tomography (PET), might improve outcomes without increasing toxicities. [(18)-F] fluoro-2-deoxy-D-glucose PET highlights proliferating areas of a tumour, and can guide dose escalation using IMRT. Hypoxic regions of tumours are radioresistant but radioresistance might be overcome by increasing the dose. PET scanning using two tracers, namely fluorine-18-labeled fluoromisonidazole (F-MISO) and copper (II)-diacetyl-bis(N(4)-methylthiosemicarbazone) (Cu-ATSM), highlight these hypoxic areas where the radiation dose can be escalated without additional acute toxicity. The PET images could be fused with the planning CT scans for biological dose optimization but follow-up data for outcomes and toxicity are needed before this approach can be introduced into standard clinical practice.
Volumated intensity modulated arc therapy (VMAT)
In contrast to standard IMRT, which uses fixed gantry beams, VMAT delivers IMRT-like distributions in a single rotation of the gantry, varying the gantry speed and dose rate during delivery. This has been implemented in RapidArc (RA) which potentially offers shorter planning and treatment time, lesser monitor units for treatment delivery, better dose homogeneity and normal tissue sparing.
Particle therapy
Charged particles like protons deposit little energy until they reach the end of their range (depending on their energy) at which point most of the energy is deposited in a small area, the Bragg peak. The advantages are of low radiation dose to normal tissue with tissue sparing, and better dose homogeneity.
Intensity modulated proton therapy (IMPT) permits 3-D dose distributions and, although there are no randomized trials comparing it with IMRT, reported tumour control rates comparable to historical controls using IMRT alone may be possible. However, proton therapy is restricted by the limited availability of machines and so the current role lies in the treatment of tumours close to the skull base or spinal cord, and in children, where it provides maximum benefit in terms of normal tissue sparing.
Chemotherapy
Systemic cytotoxic chemotherapy (CTX) is increasingly incorporated into treatment plans for oral cancer but adverse effects (toxicities) limit this. Systemic CTX, as part of primary treatment, can be administered with radiotherapy (CRT), either:
There is increasing evidence supporting the benefits of CTX in all these settings, but at the cost of higher treatment-related toxicities. Therefore, if the cancer is advanced (advanced stage III or stage IV), radiation treatment schedules sometimes include CTX, most commonly using cisplatin and Cetuximab. Occasionally, other drugs may include fluorouracil (5-FU), carboplatin, and paclitaxel.
Concomitant chemoradiotherapy (CRT)
Concomitant chemotherapy when single agent cisplatin is the cytotoxic agent is more effective than induction or adjuvant therapy, improving loco-regional control rates, and organ conservation.
Patients treated surgically who prove to have extra-capsular spread in the involved cervical lymph nodes and/or positive surgical margins, obtain the maximum benefit from post-operative CRT.
Unfortunately, CRT causes increased acute toxicity: indeed, only 70–80% of patients tolerate 3 cycles. Therefore most centres use a less toxic schedule with either 2 cisplatin cycles, weekly low dose cisplatin or single agent carboplatin. Combinations of paclitaxel and carboplatin weekly, 5-fluorouracil (5-FU) and carboplatin and 5-FU and mitomycin-C are other choices.
High-dose intra-arterial cisplatin and CRT (RADPLAT) may minimize drug toxicity by using simultaneous intravenous infusion of the neutralizing agent sodium thiosulphate, with a 2-year overall survival of stage IV cancer of ~65%.
CRT has thus emerged as the ‘standard of care’ for organ preservation.
Induction chemotherapy
The rationale for the use of induction CTX is that drug delivery is likely to be better in untreated well-vascularized cancers, disease may be down-staged before definitive treatment and micro-metastases may be targeted. Disadvantages might include added toxicity without improved survival, and a delay of definitive RT leading to greater resistance of surviving cancer cells. Induction CTX may reduce distant metastases, increase organ preservation and improve survival rates. Combinations (PF) of cisplatin and 5-fluorouracil every 3 weeks is the most common regimen and yields a 5% improvement in 5-year survival. Trials adding taxanes to the standard sequential approach suggest that treatment with multiple drug regimens may be increasingly used in future.
Induction CTX used in the post-operative setting shows comparable toxicity but improved outcomes compared to patients receiving post-operative CRT alone.
Newer targeted therapies
Epidermal growth factor (EGFR) oncogene over-expression produces adverse outcomes in head and neck cancer. EGFR inhibitors affect signal transduction pathways, thereby inhibiting cell proliferation.
Radiotherapy and targeted agents
A monoclonal antibody against EGFR (cetuximab), combined with RT showed significantly improved disease-free survival, loco-regional control rates and overall survival versus RT alone, with comparable toxicities except for higher incidences of acneiform rashes, mucosal toxicity and infusion reactions.
Chemotherapy and targeted agents
The addition of cetuximab to induction CTX gave a response in the primary site, 17% partial and 83% complete and was well tolerated with a rash in 50% of patients but no additional toxicity.
Cisplatin plus cetuximab showed improved overall survival in metastatic head and neck cancer patients. Panitumamab, carboplatin and paclitaxel with IMRT as primary treatment in patients with advanced carcinoma produced grade 3 mucositis and dysphagia in more than 94%. Cetuximab with paclitaxel and carboplatin for induction treatment followed by cisplatin-based CRT was a tolerable regimen with response rates that were comparable to historical controls, and cetuximab plus TPF for induction treatment was safe and tolerable with 100% response rates.
Combining CTX with tyrosine kinase inhibitors makes scientific sense as both agents are active in head and cancer and have different mechanisms of action. Gefitinib, in combination with CTX (docetaxel and carboplatin) as induction, produced mucositis and myelosuppression in many patients.
Chemo-radiation plus targeted agents
Several trials have incorporated EGFR inhibitors with CTX and RT but more evidence of efficacy is required. Agents used include:
Anti-angiogenic approaches with anti-VEGF (vascular endothelial growth factor) antibodies also show some promise when combined with CRT.