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What’s new in Nasopharynal Carcinoma

Research into Nasopharynal Carcinoma (NPC) has been dormant for a decade and a half. That is until recently, when quite a few trials have taken place. In a CME Talk, Dr Ivan Tham presented some insights into new developments in the diagnosis and treatment of NPC. His talk touched on the disease’s global burden, new imaging techniques, current treatments and their known toxicities, local radiotherapy treatment for metastatic disease and a view into future treatment possibilities in light of the recent developments. Dr Lim Hong Liang continues the discussion with insights into new research on systemic treatments.

A disproportionately high number of NPC cases in Asia

According to the World Health Organization, Asian countries account for 85% of all cases. Half of the global incidences come East Asia (mostly China) and Southeast Asia, and, despite Southeast Asia being a fairly small region, it accounts for a quarter of the total global incidence. Indonesia has the largest burden of the disease in the region and Singapore, while small, sees around 600 cases annually.

Symptoms to look out for

GPs should be alert to the following symptoms and refer their patients on for a possible NPC diagnosis:

• Chinese male with a nasal mass

• Enlarged lymph nodes

• Blocked nose

• Cough with blood-stained sputum

• Blocked ears, tinnitus and hearing loss

The most commonly involved nodes

Nodes in NPC commonly involve the supraclavicular area. The majority of patients, up to 70%, present with them in the retropharyngeal region or the upper cervical level 2 lymph node region. The submandibular region is involved in less than 3% of patients with newly diagnosed NPC and the supraclavicular forsa is listed as at 3% but the real numbers could be higher, depending on how the borders of the region are defined. But in summary, supraclavicular nodes are more common than submandibular nodes.

With new imaging modalities coming into play such as PET-CT, Dr Tham reports that for T classification, MRI is still better demarcated, probably because of the superior soft tissue contrast as well as the better ability with MRI to see intracranial disease. But PET-CT is more accurate for nodal and metastasis staging. The new hybrid machine PET/MRI combines both technologies in a single scan for superior imaging.

Treating NPC with radiation therapy

A plan of where to focus the radiotherapy is first decided. Currently all patients are treated with linear accelerators, which basically shoot high energy x-rays. All linear accelerators feature an onboard CT Imaging unit to facilitate image-guided treatment that can be accurate to within less than one millimetre.

Typically, the patient undergoes 61⁄2 weeks of treatment, usually 33 sessions of 25 minutes each. The majority of patients will also receive some kind of chemotherapy. Typically, 10% of patients would be at stage 4B, which is metastatic disease, another 10% will be at stage 1 and can be treated with radiotherapy alone, and the remaining cases are typically stage 2, 3 and 4. These will receive concurrent chemotherapy plus or minus possibly induction chemotherapy or adjuvant chemotherapy.

Outcomes with current IMRT treatment therapy

Looking at the local extent of disease, 90% of patients at stage 1, 2 and 3 tend to have their condition in control locally. But at stage 4, large infiltrative tumors invade the brain or involve the cranial nerves and there is a high local failure rate so the aim here would be to intensify local treatment. Patients in all 4 non-metastatic stages have a reasonable chance of cure, but where rates are much poorer than the local control rates, distant metastasis is the dominant failure mode. Intensive systemic treatment is recommended, tailored for the highest risk patients.

How does IMRT treatment compare

Once 3D radiotherapy was introduced, rates improved. However, it took IMRT in combination with chemotherapy to show an improved survival compared to older techniques.

Managing toxicity

Most patients will have some form of toxicity such as Dermatitis, Mucositis, Dysphagia and Xerostomia. These are moderate and severe grade 3 or 4 toxicities and a significant minority of patients will get significant moderate to severe side effects. The need for a feeding tube is usually temporary and occurs in about 5% of patients and most patients will lose an average of 4 kilogrammes or 5-7% of their total body weight. The aim is to control high doses of radiation to reduce toxicities and target radiation to reduce side effects such as hearing loss to a low level. IMRT has improved the late toxicity profile, especially for high doses of radiation away from the tumour.

Managing recurrence

When recurrence occurs, this indicates resistance to radiotherapy, so surgery is the preferred option where possible. For patients that are inoperable, reradiation can be proposed but patients must be made aware of the high risks. Young patients and those who tolerated the first course of treatment fairly well and have a small disease tend to do better.

Local therapy can also give good results in some cases where high-dose radiation can be applied to metastatic disease and improve overall survival and reduce mortality. This benefit is seen mainly in younger patients and undifferentiated carcinoma. Improvement of overall survival is seen when local RT is added to treatment in metastatic disease. Another option is the prevention of self-seeding into the distant sites.

Future trends

Linear accelerators now all have onboard CT scanners, but new machines also feature an integrated MRI, which allows excellent soft tissue contrast to be seen just before treatment and motion management to be better visualized with very rapid MRI. This detects small changes and moving tumours very quickly. Another therapy offering possibilities is proton beam therapy. There is already some evidence that reducing the oral cavity radiation dose with proton therapy can reduce the acute toxicity and reduce feeding tube use. There are controversies with this treatment, however, related to its cost effectiveness. Artificial intelligence will also have a role to play in the future. Looking at how to spare the brain stem while giving maximum radiation to the tumour, particle therapy, protons or flash radiation may be an answer.

Role of systemic treatment in non-metastatic (Stage I to IVA) NPC

Primary treatment in non-metastatic NPC is radiation. Radiation alone results in long-term cure in the majority of stage I NPC. As the stage increases, the cure rate drops due to higher recurrence rate. With better local control with modern radiotherapy, the main sites of recurrence post radiation are in the distant sites – bone, lung and liver metastases.

To improve long-term survival rates, chemotherapy is added to radiation in the treatment of non-metastatic NPC. The main benefit of chemotherapy is the reduction of distant recurrence. To a lesser extent, chemotherapy when given concurrently with radiation, sensitizes the tumour to the effect of radiation resulting in better local control.

Chemotherapy is given concurrently during the approximately 7 weeks of radiation treatment. Cisplatin alone is the agent of choice. Cisplatin can be given in two accepted ways concurrent with radiation – a lower dose on a weekly basis, or a higher dose once every 3 weeks.

In some centres, 3 further cycles of combination chemotherapy (cisplatin and 5 fluorouracil) are given after the completion of chemo-radiation (adjuvant chemotherapy). However, the benefit of adjuvant chemotherapy has not been proven conclusively, and a significant proportion of patients are unable to tolerate further chemotherapy due to unresolved toxicities from upfront chemo-radiation.

In the last couple of years, induction chemotherapy (chemotherapy given before concurrent chemo-radiation) has become more commonly accepted for higher risk stage III and IVA patients, due to the positive results of recently conducted randomised trials. Induction chemotherapy are better tolerated as patients are treatment naïve. The most commonly accepted induction regimen is 3 cycles of the 2- drug combination – cisplatin and gemcitabine.

To further improve the outcome of high risk non-metastatic NPC, trials are ongoing to optimise the incorporation of anti-PD1/PD-L1 immunotherapy into the overall treatment strategy. Another area of ongoing research is the role of plasma EBV DNA to risk stratify patients for more or less intensive treatment.

Role of systemic treatment in Stage IVB / metastatic NPC

About 10% of newly diagnosed NPC present with stage 4B disease with distant metastases. Approximately one third of locally advanced NPC recurs after chemo-radiation. These patients are considered to have incurable disease. Aims of treatment in these patients include control of their disease for prolongation of survival and prevention of complications, and palliation of tumour-related symptoms.

The combination of platinum and 5 fluorouracil (5 FU) used to be the standard treatment. The use of 5 FU was considered cumbersome by many patents as the drug is infused continuously over 96 hours via a central venous line every 3 weeks.

This changed in 2016 when a randomized study showed the combination of cisplatin/gemcitabine was superior to platinum/5FU. The response rate increased from 42% to 64%, and the median survival increased from 21 months to 30 months. This study established cisplatin and gemcitabine as the standard first-line combination.

Anti-PD-1 / PD-L1 immunotherapy has been approved in the treatment of many cancers, including squamous cell head and neck cancers. These immunotherapy agents have shown promising activity in NPC in early trials. Phase II and Phase III trials are actively ongoing to establish the role of immunotherapy in patients with metastatic NPC.