Does Dose Volume Histogram of Parotid Glands Correlate with Xerostomia Radiation Therapy Oncology Group Scores in Locoregionally Advanced Head and Neck Cancer Patients Treated with Intensity-Modulated Radiation Therapy?

Introduction

Xerostomia is one of the most common complications of radiotherapy (RT) in patients with head and neck cancer. Xerostomia can be assessed both objectively by cannulation of ducts and subjectively with questionnaire. Subjective xerostomia does not reach a steady state even more than 5 years after RT and thus continues to influence a patient’s quality of life (QOL).^{1,2,3,4,5,6,7,8} Various studies have shown that patient-reported end points are more indicative of its true effect.^{9,10,11,12,13}

It is a well-established fact that dosimetric and volumetric sparing of the parotid glands improves subjective xerostomia. In this regard, a parotid gland mean dose of ≤26 Gy should be the planning goal if functional recovery of the parotid gland is desired.¹⁴ However, we would have to introspect if this was truly achievable even in patients with locoregionally advanced head and neck cancer.

This study was conducted at a tertiary cancer center in India with a primary objective to correlate dose volume histogram (DVH) of the parotid glands with xerostomia Radiation Therapy Oncology Group (RTOG) scores in locoregionally advanced head and neck cancer patients treated with intensity-modulated radiation therapy (IMRT). The secondary objectives were to compare various subjective xerostomia scores obtained postradiation with preradiation values and to study the time trends of xerostomia.

Subjects and Methods

Results

In this study, the oral cavity was the commonest subsite followed by oropharynx and hypopharynx. All patients had squamous cell carcinomas except one with sinonasal lymphoepithelioma. Around 51% patients in the whole group presented with T1/T2 lesion, and 20.9% patients each presented with T3/T4 lesions and nodal mass with unknown primary. Most of them had locally advanced disease, with stage III and IV seen in 81.4% cases. The dose to 95% PTV ranged from 55 to 69.9 Gy, with the mean dose being 61.5 Gy. The pattern of lymph nodes showed N3 disease in 2.3% patient, N2 in 46.5%, and N1 in 27.9% patients. The most common lymph nodes were upper deep cervical group (Table 3). The mean doses to I/L and C/L nodal CTV 95 in the definitive radiation group were 60.8 and 58.5 Gy, respectively (Fig. 1). The mean doses to I/L and C/L nodal CTV 95 in the postoperative group were 57.5 and 55 Gy, respectively (Fig. 1).

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Fig. 1 Doses delivered to various target volumes during radiotherapy. CL, contralateral; CTV, clinical target volume; GTV, gross tumor volume; IL, ipsilateral; PTV, planning target volume.

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The mean doses achieved by I/L and C/L parotid gland were 36.5 Gy (range: 9.0–62.9 Gy) and 28.3 Gy (range: 6.7–39.6 Gy), respectively (Fig. 2). The average volume of the parotid gland above the threshold value (35 Gy for the I/L parotid gland and 25 Gy for the C/L parotid gland) as determined from DVH was 21.1 mL in the I/L parotid gland and 23.5 mL in the C/L parotid gland (Figs. 2).

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Fig. 2 Doses received by contoured volumes of I/L (A) and C/L (B) parotid glands. C/L, contralateral; I/L, ipsilateral.

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No statistically significant direct correlation between mean dose and grades of xerostomia was noted postradiation at 1 month (p = 0.500 for I/L and 0.450 for C/L), 3 months (p = 0.455 for I/L 0.509 for C/L), 6 months (p = 0.762 for I/L and 0.461 for C/L), 9 months (p = 0.674 for I/L and 0.713 for C/L), and 12 months (p = 0.225 for I/L and 0.423 for C/L). No direct statistical correlation was seen between the grades of xerostomia and the volume of the parotid glands at 3 months (p = 0.343 for I/L and 0.862 for C/L), 6 months (p = 0.271 for I/L and 0.892 for C/L), 9 months (p = 0.438 for I/L and 0.773 for C/L), and 12 months (p = 0.503 for I/L and 0.523 for C/L) (Table 4). The percentage of patients with xerostomia grade 2 or more at various months of follow-up is shown in Table 5.

Recovery in the grades of xerostomia was assessed at 3-month interval after completion of RT. A statistically significant improvement was seen between grades of xerostomia at 3 and 6 months (p = 0.00), 3 and 9 months (p = 0.020), 6 and 9 months (p = 0.009), 6 and 12 months (p = 0.05), and 9 and 12 months (p = 0.00). The time trends of grade 3 xerostomia revealed a static phase from 6 to 9 months, whereas a decrease was seen between 3 to 6 months and 9 to 12 months, with the slope of this downfall more than that at 3 months (Fig. 3). Thus, significant recovery was noticed at 9 months.

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Fig. 3 Time trends in xerostomia: X-axis shows the time (in months) Y-axis shows the number of patients.

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Concurrent chemotherapy was delivered to 74.4% patients in the form of cisplatin and cetuximab. Eleven patients received RT alone. Minor deviation in the treatment protocol was seen in two patients who received neoadjuvant chemotherapy before chemoradiation.

All patients except one were able to complete their treatment as defined in the protocol. In the whole group, one patient was lost to follow-up after completing 25 fractions of treatment, and one patient refused for participation in the study after 3 months; overall, five patients were lost to follow-up. The median follow-up of the study was 15 months.

Discussion

In this study, more than 80% of patients had a locoregionally advanced disease. The two radiobiological concepts of IMRT using accelerated fractionation with simultaneous integrated boost and conformal avoidance were utilized.¹⁸ As the prescription dose was the dose covering 95% PTV, majority of patients received adequate radiation with whole group mean equal to 61.5 Gy.

The salivary gland questionnaire with which we evaluated patients showed a decrease in the number of patients with grade 2 or worse xerostomia over a 12-month follow-up period (Table 5). Overall comfort was poorest at 1 month postradiation. Most of the patients felt thirsty and had to carry water along with them. There was difficulty in speaking and disabled sleep in most of the patients but improved in few cases only. The patients in the whole group complained of decreased amount of saliva, though the number in the definitive radiation group increased between 6 and 9 months and decreased at 12 months. Similar results were seen with the change in taste, suggesting that taste depends on the saliva. These replies were in contrast with Amosson’s study in which questions related to overall comfort, eating, and abnormal taste correlated significantly, and questions related to thirst, difficulty with sleep or speech, and the need to carry water daily did not correlate statistically with the dosimetric parameters of the parotid glands.¹⁶

The mean dose to the parotid glands is the most important parameter to assess for saliva production.¹⁶ The mean parotid thresholds of 24 and 26 Gy for unstimulated and stimulated flow rates, respectively, showed substantial preservation of the flow rates following RT and continued to improve over time for up to 12 months duration.¹⁹ The threshold doses known to cause xerostomia ranges from 26 to 39 Gy, as reported by Chao and Eisbruch et al.^1,2 Nearly every oncologist desires to achieve a mean dose of ≤26 Gy to the parotid gland, as shown in a review of prospective phase 1 and 2 trials on parotid sparing RT.²⁰ When we looked at these trials individually, Chao et al achieved an average parotid doses of 30.02 ± 9.93 Gy (17.15–70.27) in the definitive setting and 28.37 ± 13.17 Gy (1.95–53.79) in the postoperative setting.⁷ Eisbruch et al achieved I/L parotid mean dose of 55.2 Gy (standard deviation [SD]: 7.8) in the bilateral RT group and 48.2 Gy (SD: 14.5) in the unilateral RT group, and C/L parotid mean dose of 21.9 Gy (SD: 5.2) in the bilateral RT group and 4.1 Gy (SD: 2.8) in the unilateral RT group.²¹ Maes et al achieved a mean dose of 49 Gy (SD: 12) to the I/L parotid gland and 21 Gy (SD: 5) to the C/L parotid gland.⁹ Parliament et al achieved the averages of mean dose to each parotid gland as 29.6 Gy (right; 95% confidence interval [CI]: 23.9–35.2) and 28.7 Gy (left; 95% CI: 23.2–34.2).10 The average combined mean dose to parotid tissue was 30 Gy (95% CI: 26.9–33.1).¹⁰ Blanco et al achieved mean doses of 31.7 ± 18.3 and 34.1 ± 19.2 Gy to left and right parotid gland at 6 months after radiation therapy.²² Scrimger et al could achieve a mean dose of 18.4 Gy to the spared portion of the parotid glands, whereas the mean dose to parotid tissue was 27.1 Gy.¹¹ When we reviewed the Indian data, the average doses to I/L and C/L glands were 44.1 Gy (SD: 12.5; 95% CI: 41.3–46.8 Gy) and 31.5 Gy (SD: 6.5; 95% CI: 30.2–32.9 Gy), respectively.²³ Nutting et al were able to achieve a dose of 47.6 Gy to the I/L parotid gland and 25.4 Gy to the C/L parotid gland.²⁴

In this study, we chose to apply same practical dose constraints as used by Amosson, that is, 35 Gy to the I/L parotid gland and 25 Gy to the C/L parotid gland.¹⁶ We were able to achieve mean doses of 36.8 Gy and 28.3 Gy to the I/L and C/L parotid glands, respectively. These values compared well with other authors, suggesting that even with large tumors, it was possible to achieve the prescribed dose constraints.²⁴ However, there was no direct correlation between the mean dose received by both I/L and C/L parotid glands and the grades of xerostomia at 1, 3, 6, 9, and 12 months postradiation. This stood contrary to Amosson’s study but matched well with Nishimura et al.^16,25 When we looked into the reasons why these data showed clinical insignificance, we realized that xerostomia starts even when few grays of radiation are delivered. The parotids could not be spared from higher doses due to lymph nodal positivity in the upper deep cervical region (most of them being N2 or N2c) or tumors lying in adjacent region (naso-oropharynx). Majority of patients selected by various other scientists were of N0 or N1 stage.¹⁶ The other reason for insignificance was that a small number of patients receiving higher doses were selected for the study. An effort to keep the dose to at least the C/L parotid gland to ≤26 Gy was even difficult. Both parotid glands received a mean dose of >26 Gy. The salivary function in each gland appeared to be lost exponentially at a rate of approximately 5% per 1 Gy of mean dose.²² We did not compromise local control in preference to achieving mean dose to parotids. The addition of chemotherapy in more than 75% cases in this study also seems contributory to xerostomia.

The absolute volume of the parotid glands likely reflects reserve saliva output and predicts xerostomia in parotid-sparing IMRT. The absolute volume of the I/L and C/L parotid glands in this study was between 3.2 and 45.9 mL (mean = 21.1 mL) and 3.7 and 54.7 mL (mean = 23.5 mL), respectively. Since this was a randomized nonbiased study, and the patient with smallest volume of parotid was most compliant, she was included. The study did not show a direct statistical correlation between grades and initial volume of the parotid glands. This contrasted with the findings of Nishimura et al who showed a significant correlation between the initial volume of the parotid glands and the grades of xerostomia.²⁵ Parotid gland in his study was recontoured in the boost phase of treatment, whereas we did it only once before starting external beam RT.²⁵ During the course of IMRT, the volume of the parotid glands decreases significantly.²⁶ The parotid glands decrease in volume (0.6% per day of initial volume) and shift medially.²⁶ We maintained a good nutritional status of the patient so that shrinkage of parotid could be avoided. Wherever required, Freka’s nasogastric or percutaneous endoscopic gastrostomy tube insertion was performed. During the study, we realized that parotids need to be recontoured in the fifth week of treatment. We are further evaluating changes in volume and xerostomia scores by adaptive RT in our institution.

The partial volume thresholds as given by Eisbruch et al were 67, 45, and 24% gland volume receiving more than 15, 30, and 45 Gy, respectively.¹⁹ We calculated doses received by partial volumes of the parotid glands. The I/L parotid 1/3, 1/2, and 2/3 volume received a mean dose of 42.4 Gy (range: 22–68 Gy), 36.8 Gy (range: 14.5–64.9 Gy), and 30.4 Gy (range: 10.0–60.5 Gy), respectively. The C/L parotid 1/3, 1/2, and 2/3 volume received a mean dose of 33.7 Gy (range: 8.0–48.7 Gy), 28.8 Gy (range: 6–41 Gy), and 23.3 Gy (range: 4.5–37 Gy), respectively. Even the partial volume thresholds were statistically insignificant. The full (3/3) volume of the I/L and C/L parotid glands received a median dose of 19.5 Gy (range: 2.6–46.3 Gy) and 15.2 Gy (range: 1.9–36.4 Gy), respectively. Thus, it is difficult in locally advanced tumors to volumetrically spare the parotid gland especially if the disease or lymph node is lying ipsilaterally. It is said that more than 50% of the parotid glands have to be outside the radiation field to prevent severe dryness; irradiation of submandibular and sublingual glands had only a minor effect.²⁷ However, we included patients in whom parotids were lying in radiation portals.

The parotid salivary function continues to improve between 6 and 12 months after radiation, as shown by Blanco et al.²² A phase 3 multicenter randomized controlled trial (PARSPORT) compared patients treated with IMRT with those treated with conventional radiation. At 12 and 24 months, grade 2 or worse xerostomia was significantly lower in the IMRT group; there was significant recovery in saliva secretion and clinically significant improvements in dry-mouth-specific and global QOL scores.²⁴ Similarly, in our study, recovery in grade 2 or worse xerostomia score was significantly evident around 9 months postradiation, suggesting that maximum recovery occurred within this time period (Table 5).

Conclusion

There is no direct statistically significant correlation between the DVH of the parotid glands and the grades of xerostomia, although statistically evident recovery in grades was seen at 9 months. The study assumed significance when a small number of locoregionally advanced cases of head and neck cancer were selected for the study. The results might appear contrary to the well-established beliefs; in a parallel organ such as parotid, the severity and grades of xerostomia are inversely proportional to the amount of parotid spared by radiation.

We also felt that the change in dosimetric parameters for parotid gland might not be sufficiently accurate when only preradiation CT scan was used for planning.²⁸ As GTV decreased significantly during fractionated RT, serial imaging and sequential IMRT boost planning might be necessary. Sequential IMRT boost might adequately spare the parotid gland, thereby reducing the mean dose, but it was an expensive and time-consuming strategy.²⁹

Based on our observations, we acknowledged the following few facts:

• Xerostomia gets aggravated because of a complex interplay of subjective, objective, and psychosocial factors.

• Subjective questionnaires assessed xerostomia better.

• IMRT in head and neck can be exploited to decrease parotid dose but not at the cost of good local control.

• Adaptive RT offers some practical solution.

The study had its limitation in the form of delay in publication. The data were variously assessed for its importance. This was conducted at a time when IMRT was gaining strong foothold in an established tertiary care center.