Head and Neck Cancer and Proton Therapy

Reviewer: Eric Shinohara MD, MSCI
Abramson Cancer Center of the University of Pennsylvania
Last Modified: May 26, 2008

Presenter: William Mendenhall, MD
Presenter's Affiliation: University of Florida
Type of Session: Reporting

There are several potential advantages to proton treatment compared with IMRT in the treatment of patients with head and neck cancers. The major advantage is likely to be a decrease in the late side effects associated with radiation therapy. Head and neck cancers are already taken to a high dose and Dr. Mendenhall believes that escalation beyond what is already being used has the potential to increase late toxicities. Hence, he believes that using protons to improve our ability to get adequate dose into areas which are typically difficult to treat (ie base of skull) may be where the greatest benefit is seen. 

He notes that potential disadvantages for proton use in the head and neck include the proton’s range dependence on the daily changes in air cavity density which must be accounted for, increase skin reaction, and the potential to be too conformal. It is possible that we may have more marginal misses with the greater conformality afforded by proton therapy and it is very difficult to salvage such patients. 
The specific head and neck sites that Dr. Mendenhall believes are most likely to benefit from proton therapy include: the nasopharynx, minor salivary glands, nasal cavity and paranasal sinuses. In the oropharynx he believes that the greatest benefit will be decreased xerostomia due to greater sparing of the contralateral parotid.  He believes that a proton boost can decrease the mean contralateral parotid dose to less than 26 Gy which should decrease xerostomia. Additionally, in tumors of the oropharynx it may be possible to decrease dose to the brainstem and spinal cord substantially. The head and neck sites which he believes are unlikely to benefit from proton therapy include: the orocavity, larynx, hypopharynx, and thyroid.

Dr. Mendenhall then asked where are the data that support the above theories? There have been numerous dosimetric studies which have demonstrated better conformality with protons, but what are the true long term outcomes and side effects? He reports that there is only limited long term data available for head and neck proton therapy and that these studies are limited by a number of factors including small patient numbers and variable sites included in the studies. Proton data was then presented by disease site with comparisons with patients treated with photons:

University of Florida:  From 1964-2005 109 patients were accrued. Of these patients, 56 patients were treated with definitive (photon) radiation therapy. 96 patients (88%) were treated using altered fractionation. The median follow up was 9.4 years. 5 Year data is shown below: 

T1-T3 tumors
T4 tumors
Local Control
Overall Survival

In the definitive treatment group 16% of patients had severe complications (the majority involved loss of vision).
Massachusetts General Hospital: 91 patients were accrued and treated to a median dose of 73.6 CGE with a similar proportion of patients treated with altered fractionation as the University of Florida study (~88%). Median follow up was 45 months. 5 year outcomes are as follows: Local control was 82%, disease free survival 52%, and overall survival was 58%. There were 4 patients who had changes on brain MRI. One patient developed soft tissue necrosis and another developed bone necrosis. 
Chiba University14 patients were accrued. 5 year outcomes: Local control was 84%, progression free survival 71% and overall survival 91%. There was one patient with bone necrosis.
When the proton results are compared with the prior Florida photon data it appears that local control rates were similar or better while the late complication rates were lower for the proton based therapy.
Adenoid Cyst Carcinoma:
Photon data from the University of Florida demonstrated that the local control rate at 5 years is approximately 77%. Data from Harvard demonstrated that the local control rate at 5 years is 93%. There were only 23 patients treated with protons at the Harvard facility, but the majority had biopsy alone (48%) or subtotal resection (39%).
Loma Linda: From 1991-2002 29 patients were accrued and overall local control at 5 years was 88% with 3/29 patients having late grade 3 toxicity. All patients were treated with accelerated fractionation. 

Number of Patients
% T4 patients
% Stage IV
5 year Local Control
Late Toxicity
Loma Linda
University of Florida (tonsil)
University of Florida (base of tongue)

The Loma Linda Data was compared with photon data from the University if Florida and there appeared to be less late toxicity with greater local control.

Author's Conclusions

1)      There are still only limited long term data regarding the use of protons in head and neck cancer. The greatest benefit associated with protons is likely to be reduced late toxicity. Late toxicities, such as swallowing difficulties, can occur years after treatment.  Therefore studies with long term follow up are needed to truly assess the benefits and toxicity of protons.
2)      It is unlikely that there will be better local control in oropharyngeal tumors as they are already high with IMRT. However, there is the potential for decreased toxicity, specifically xerostomia. The greatest benefit regarding dose escalation is likely to be seen with tumors which involve the base of skull.
3)      The greater conformality associated with proton therapy does increase the risk of marginal miss and target delineation is critical.

Clinical/Scientific Implications

Definitive radiation treatment of head and neck cancers has significant morbidity, particularly when combined with concurrent chemotherapy. The decreased exit dose associated with protons appears to be of benefit in escalating tumor dose in base of skull tumors. The decrease in exit also has the potential to decrease both long and short term side effects. It is a possibility that dose escalation may prove useful in some patients. Increasingly, the role of HPV infection in head and neck cancer and the cancer’s response to radiation are being recognized. It is possible that dose escalation may be of benefit in patients with head and neck cancers which are not associated with HPV. There are a number of issues with proton therapy that need to be resolved. As Dr. Mendenhall states the changes in density in air pockets, such as the sinus, will have a critical role in shaping the distal edge of the beam. Dealing with dental artifacts and how to best compensate for this to allow proper calculation of proton range will also be critical. However, there is great potential for improving side effects in head and neck cancers with protons and studies are ongoing.