Dose, volume, and function relationships in parotid salivary glands following conformal and intensity-modulated irradiation of head and neck cancer

Eisburch. IJROBP 1999;45:577

 To determine the relationships between the three-dimensional dose distributions in parotid glands and their saliva production, and to find the doses and irradiated volumes that permit preservation of the salivary flow following irradiation (RT).

Saliva flow rates data were available for 152 parotid glands. Glands receiving a mean dose below or equal to a threshold (24 Gy for the unstimulated and 26 Gy for the stimulated saliva) showed substantial preservation of the flow rates following RT and continued to improve over time (to median 76% and 114% of pre-RT for the unstimulated and stimulated flow rates, respectively, at 12 months). In contrast, most glands receiving a mean dose higher than the threshold produced little saliva with no recovery over time. The output was not found to decrease as mean dose increased, as long as the threshold dose was not reached. Similarly, partial volume thresholds were found: 67%, 45%, and 24% gland volumes receiving more than 15 Gy, 30 Gy, and 45 Gy, respectively. The partial volume thresholds correlated highly with the mean dose and did not add significantly to a model predicting the saliva flow rate from the mean dose and the time since RT. The NTCP model parameters were found to be TD₅₀ (the tolerance dose for 50% complications rate for whole organ irradiated uniformly) = 28.4 Gy, n (volume dependence parameter) = 1, and m (the slope of the dose/response relationship) = 0.18. Clinical factors including age, gender, pre-RT surgery, chemotherapy, and certain medical conditions were not found to be significantly associated with the salivary flow rates. Medications (diuretics, antidepressants, and narcotics) were found to adversely affect the unstimulated but not the stimulated flow rates.

Conclusions: Dose/volume/function relationships in the parotid glands are characterized by dose and volume thresholds, steep dose/response relationships when the thresholds are reached, and a maximal volume dependence parameter in the NTCP model. A parotid gland mean dose of ≤26 Gy should be a planning goal if substantial sparing of the gland function is desired.

Changes in salivary gland function after radiotherapy of head and neck tumors measured by quantitative pertechnetate scintigraphy: Comparison of intensity-modulated radiotherapy and conventional radiation therapy with and without Amifostine

Munter. IJROBP 2007;67:651

Aim of the inverse dose optimization process was the protection the parotid glands. At least one parotid gland should receive a median dose of <26 Gy. Sparing of both parotid glands was intended for all patients. Protection of the submandibular glands was not intended.

Recently, different approaches have been established to protect the salivary glands and to prevent xerostomia and related side effects after radiotherapy.  Amifostine is widely used as a radioprotector to reduce xerostomia and mucositis in the treatment of head-and-neck cancer. The Phase III trial of Brizel  supported the capability of Amifostine for radioprotection in head-and-neck cancer and a reduction of the incidence of acute xerostomia Grade 2 or higher was shown to be reduced from 78% to 51%. Late effect xerostomia Grade 2 or higher was reduced from 57% to 34%. In this study, the outcome for both endpoints was highly significant. A recent update of this study presented a follow-up of 2 years and showed that the incidence of Grade 2 or higher xerostomia is still significantly reduced using Amifostine compared with the control group without Amifostine. The authors furthermore stated that Amifostine did not compromise locoregional control rates, progression-free survival, or overall survival.

Buentzel et al. presented a randomized, placebo-controlled, Phase III study comparing radiochemotherapy with and without Amifostine for head-and-neck tumors. In this trial, Amifostine could not reduce acute or late xerostomia. Xerostomia Grade 2 or higher late xerostomia was 37% with and 24% without Amifostine respectively. These results are comparable to the functional data after QSGS presented in our study. However it should be mentioned that, in contrast to the study by Buentzel et al., the majority of the patients in our study received radiotherapy and not radiochemotherapy.

For high radiation doses we could find only a significant difference compared with that in the conventional treatment group for the maximum uptake in the Amifostine group for the parotid and submandibular glands together. Patients treated with reduced total doses of <40.6 Gy plus Amifostine had a significantly better functional outcome for ΔF and ΔU as compared with those in the conventional treatment group.

Higher doses of Amifostine might be necessary to reduce toxicity in patients receiving therapy for primary and postoperative disease. Experimental studies confirmed that the cytoprotective effect of Amifostine is dose dependent. Several studies with increased i.v. doses of Amifostine showed a significant effect. In our study, the recommended standard dose of 200 mg/m2 Amifostine was i.v. administered, and an increased dose might have improved the functional outcome of the salivary glands. Another important aspect is the daily timing of Amifostine administration with respect to the start of radiotherapy. A time frame of <30 min between administration and radiotherapy is currently recommended.

For the endpoint “reduction of the relative excretion rate of more than 50% (ΔF≤50%)” the D50-value of 44.3 Gy for the parotid glands in the Amifostine group was significantly increased as compared with the IMRT and conventional treatment group. This clearly demonstrates that the protective potential of Amifostine for the salivary glands. In our study, however, no significant functional sparing was found for high radiation doses plus Amifostine, indicating that administration of Amifostine is effective only if the radiation doses are not too large.

The D50-value for the parotid glands in the IMRT group was 35.0 Gy. Kuhnt  presented a comparable D50-value of 36,9 Gy for the parotid glands using stimulated saliva flow measurement. A recent study presented a somewhat higher D50-value for the parotid gland of 43 Gy. This value, however, was measured by salivary gland scintigrapy at 1 year rather than 3 months.

The significantly increased D50-value of the Amifostine group and the results of the patient group receiving Amifostine and radiation doses of <40.6 Gy supports the conclusion that the scavenging of radiation-induced free radicals by Amifostine can protect the parotid glands below a certain dose threshold. For higher doses, however, the dose–response curve increases and the parotid glands are not spared anymore. Rades  reported a large number of serious adverse effects necessitating discontinuation of Amifostine treatment and a delay in the radiotherapy course. If Amifostine is administered in a daily routine, these adverse effects as well as the high treatment costs should also be considered.

The patients receiving IMRT for salivary gland protection had a significant better functional outcome in almost all tested parameters in comparison to the conventional and the Amifostine-high group. Besides this, a significant better functional outcome for ΔF and ΔU was found, especially for the parotid gland in the IMRT-low group (mean dose <26 Gy) as compared with the IMRT-high group (mean dose ≥26 Gy). Therefore, the preservation of the salivary gland function as measured by QSGS may be better achieved by using modern irradiation techniques such as IMRT than by using the radio-protector Amifostine.

In the last few years, several studies have been published that demonstrated the capability of IMRT in improving the dose distributions for head-and-neck cancer. In particular the potential of IMRT to protect the parotid glands has been shown. Attempts to preserve the function of the salivary glands should not cause an increased locoregional failure rate. This can be achieved by the high dose gradient between the planning target volume and the parotid glands. Up to now, increased local failure rates resulting from protection of the parotid gland were not reported. In most cases at least one or both parotid glands were protected to prevent xerostomia in the different published studies. In a recent study by Saarilathi , the contralateral submandibular gland was protected additional to the ipsi- or contralateral parotid glands. Within a median follow-up of 31 months no locoregional failure was found in the study of Saarilathi et al.

To spare the salivary glands, the dose should be reduced as much possible without compromising the target coverage. In a recent study by Eisbruch) a threshold of 26 Gy for the mean dose to the parotid glands was proposed. In our study, this threshold was used as planning goal. The mean dose averaged over the protected parotid glands was 20.1 Gy in this study. Mean doses of <20 Gy are currently recommended by some investigators, for the parotid glands to receive the best functional outcome. However it should be considered that such an excellent protection might cause inadequate treatment of the directly adjacent target volume, which may result in recurrent disease.