To the best of our knowledge, this is the first long-term and mature (at 10-years) report of clinical outcomes of any RCT comparing IMRT with older techniques in the indexed medical literature. To date, seven RCTs involving 1155 patients have directly compared IMRT with 2D-RT (3 trials) or 3D-CRT (4 trials) in HNSCC (8-14). Four such trials included patients with non-nasopharyngeal HNSCC (oropharyneal, laryngo-pharyngeal, and oral cavity primaries), while the other three were limited to nasopharyngeal cancers. Five of them were rather small comprising fewer than 100 patients (in both arms), with only one trial having a large sample size (>600 patients). The primary objective in 5 index RCTs was salivary gland toxicity (xerostomia), with only 1 trial each using LRC and OS as primary endpoints respectively for sample size calculation. All of them reported early salivary gland toxicity, but only three RCTs reported xerostomia at 3-years (11,13,14) with >5-year xerostomia outcomes being reported in only a single trial (13). The mean absolute difference in the proportion of patients with moderate to severe xerostomia at 1-year between 3D-CRT and IMRT was around 23% but varied widely across different studies ranging from 14% (24% vs 10%) in one Indian study (13) to 47% (66% to 19%) in the French study (14) in favour of IMRT. Pooling of data from all seven RCTs for quantitative synthesis in a meta-analysis (7) demonstrated that the use of IMRT was associated with a significant reduction in relative risk (RR) of acute ≥grade 2 xerostomia (RR=0.64, 95%CI=0.49-0.84; p=0.001) compared to 2D-RT/3D-CRT. Furthermore, significantly reduced risk of grade 2 or worse xerostomia with IMRT was seen at all time-points (6-months, 1-year, 2-years, and 3-years post-treatment). The use of IMRT was also associated with a relative reduction in the risk of loco-regional recurrence with a hazard ratio (HR) of 0.76 (95%CI: 0.57-1.01; p=0.06) and relative reduction in risk of death (HR=0.70, 95%CI=0.57-0.88; p=0.002) compared to 2D-RT/3D-CRT, albeit with low statistical power due to inadequate patient numbers. However, this benefit of IMRT for LRC and OS was restricted to nasopharyngeal cancer, largely driven by the large Chinese study (12), with no significant difference in efficacy between the two techniques in patients with cancers of the oropharynx and laryngo-pharynx. QOL outcomes could not be pooled in the meta-analysis due to inadequate and incomplete reporting of data.
One of the most common and debilitating toxicity of head-neck irradiation is xerostomia (subjective sensation of a dry mouth) caused by salivary gland hypofunction (decrease in salivary flow or output) leading to persistent dryness of mouth, sticky saliva, oral discomfort, and difficulty in speech and swallowing with consistent negative impact upon health-related QOL (3,5). It is widely believed that salivary function does recover over time (6,7,16) with demonstrable improvement in subjective symptoms of xerostomia (dryness of mouth and excessive thirst) largely due to compensatory increase in acinar cell production although these new acinar cells are thought to have a different morphology than the unirradiated ones (17). In the current report, we have demonstrated that the clinically meaningful benefit of parotid-sparing IMRT over 3D-CRT in reducing moderate to severe xerostomia is sustained over time even at 8-10-years after treatment. Grade 3 late xerostomia, which can be severely debilitating was not seen in any patient treated with IMRT, but, was documented in 4 patients (3 dead and 1 alive without disease) in the 3D-CRT arm. The sustained long-term benefit with IMRT may be attributable in part to the dose-volume histogram patterns in salivary gland sub-volumes (18) including lesser doses of irradiation to parotid stem cells (compared to conventional techniques) with potential to influence salivary injury and recovery leading to better post-treatment regenerative capacity and gradual progressive recovery of salivary function. In keeping with the prevailing guidelines and recommendations at that time (19), we had mandated a mean dose of ≤26Gy as the dose-volume constraint for the contralateral parotid gland. This is much higher than the current Quantifying Normal Tissue Effects in the Clinic (QUANTEC) guidelines (20) that recommend keeping the mean dose for single parotid gland to below 20Gy during optimization to reduce the risk of moderate to severe xerostomia.
Apart from xerostomia, we also demonstrated significant reduction in the risk of moderate to severe subcutaneous fibrosis with IMRT compared to 3D-CRT that was also largely sustained over time. Although, dose-constraints were not applied separately, reduction in doses to subcutaneous tissue with IMRT may have led to better long-term restoration of vascularity in the dermal and subdermal layers. Mean doses to the thyroid gland were similar in both arms (dose-volume constraints not applied separately) with no significant difference in the incidence of biochemical hypothyroidism between the two techniques. The incidence of other late toxicities was too small for any meaningful statistical comparison. Three cases of cerebrovascular accidents (all in 3D-CRT arm) may have been induced by high doses of RT to bilateral carotid arteries with resultant stenosis and compromised vascular supply to the brain (21). Non-cancer related deaths were somewhat higher in the 3D-CRT arm including stroke and aspiration pneumonia, although the exact cause of death was not known in four patients. As head and neck cancer survivorship improves, consensus guidelines and newer dose-volume constraints for various other OARs such as dysphagia-aspiration related structures (DARS) and carotid arteries would need to be tested in prospective studies to reduce some of the late morbidities and resultant non-cancer related deaths (22,23). The incidence of second new primaries was quite similar in both the arms of our study raising doubts over the hypothesis that IMRT is associated with an increased incidence of second malignant neoplasms due to larger volumes of low-dose spillage and resultant higher integral doses (24).
Some previous studies (25,26) of IMRT have shown marginal recurrence rates of 5-15% in the vicinity of the spared parotid gland raising valid concerns regarding the safety of such an approach. Reassuringly, the long-term rates of disease-related outcomes (LRC and OS) were quite similar in both arms of our study suggesting that parotid-sparing was not at the expense of disease control. We followed standard target volume delineation and contouring guidelines with stringent quality control in treatment planning and delivery to ensure the safety of IMRT. However, our study was not adequately powered to demonstrate equivalence or non-inferiority of IMRT over 3D-CRT in terms of disease-related outcomes (LRC or OS), which would need over a thousand patients to be randomized.
Caveats and limitations: Despite the strength of a prospective RCT with long-term and mature follow-up, certain caveats and limitations remain. Given the difference in RT techniques, we could not blind patients or physicians to treatment arm leaving room for ascertainment and reporting bias. The use of different dose and dose fractionation in the two arms, though deemed radiobiologically equivalent, could also be a potential source of bias. The number of patients included and randomized on our study was quite small (N=60), with even much lesser numbers on long-term follow-up (between 5-10 years), impairing statistical power, precision, and validity of the late toxicity analyses. We tried to spare only the contralateral parotid gland without attempting submandibular gland sparing (27), which is the greatest contributor to whole saliva during rest and is a better moistener for oral tissues. Underestimation of xerostomia cannot be entirely ruled out as we used physician-rated xerostomia as the primary endpoint and not patient-reported outcomes. A xerostomia-specific questionnaire was not used in our study which would have been more useful rather than a general QOL instrument. We did not test our patients with p16 immunohistochemistry to identify HPV-associated oropharyngeal cancer which is now established as a distinct clinical entity with prognostic implications and a separate new staging system (28). Apart from increasing availability of particle beam therapy with its unique depth-dose characteristics (29), the last decade has also witnessed further technological improvements in photon-based treatment planning, delivery, and verification (30) with the introduction of volumetric modulated arc therapy/rotational IMRT, robust optimization, in-room image-guidance, and adaptive RT, none of which was used in our study.