During collection of saliva, patients were seated and asked to minimize orofacial movements and not to attempt to influence salivary flow (such as by sucking or swallowing). Just before the collection, the patients were instructed to allow saliva to accumulate in the floor of the mouth for 60 s without swallowing. The patients were instructed to then spit the accumulated saliva into a pre-weighted 50 ml vial. The patients were asked to repeat this procedure four more times for a total collection time of 5 min. Subjects were instructed not to swallow the saliva during the entire collection procedure.

Stimulated whole saliva

After the collection of unstimulated saliva, patients had fresh lemon juice applied with cotton-tipped applicators to the lateral tongue bilaterally five times over a 2-min period (0, 30, 60, 90 and 120 s). The mouth was then to be emptied of the retained lemon juice solution. Saliva was then collected for 5 min in the same manner as for unstimulated saliva.

Statistical analysis

Patient, disease and treatment variables were summarized as means and standard deviations or as proportions or percentages. Statistical significance of differences in proportions was tested using the χ² test while differences in means were tested using the t-test.

Results

Between July 2003 and July 2005, 36 patients with SCC of the oral cavity, oropharynx, larynx and hypopharynx, belonging to stages III and IV (AJCC 1997), with no evidence of disease at 12 months following RT, and with a minimum of baseline and 12-month saliva flow rate values, were included for this analysis. Patient and disease characteristics are detailed in [Table - 1]. The median age was 52 years (range, 30-77 years); 33 (92%) were male; the primary site of disease was the oral cavity, oropharynx, larynx or the hypopharynx and 30 (83%) subjects were admitted to regular tobacco usage. The treatment interventions and field sizes are detailed in [Table - 2]. All but one patient received concurrent weekly cisplatin. The 3-field technique using lateral opposed face and neck fields and a low-anterior neck field was used in 28 (78%) of patients. The mean area of field size was 128 cm2. A 70% decrease in unstimulated and stimulated salivary flow rate at 3 months (P = 0.000, both for unstimulated and stimulated) was observed and these rates decreased further till 6 months (P = 0.015 and 0.000 for unstimulated and stimulated, respectively) after which a partial recovery in flow rates was seen by 12 months stimulated salivary flow rates before treatment and up to 12 months after completion of RT are shown in [Table - 3] and [Figure - 1] and [Figure - 2].

These patients have a median follow-up of 29 months and, at the last follow-up, 21 (58%) were free of disease, eight (22%) had recurred and seven (20%) had succumbed to illness.

Discussion

The patient subset was chosen out of a phase II trial that tested a moderately accelerated course of concurrent CTRT and inclusion was based on patients who had measurements at least at base line and by 12 months and with no evidence of any locoregional or systemic recurrence. This trial design was based on our earlier experience and the reported evidence in the literature. ^{[8],[9],[10],[11],[12]} A sharp decline in unstimulated and stimulated saliva output was observed at 3 and 6 months following RT. This was followed by minimal recovery at 1 year. This study aimed to provide baseline (CTRT) data for comparison with the changes in salivary flow rate following introduction and implementation of a parotid-sparing intensity-modulated RT (IMRT) technique, currently being used in the department. The observations therefore do not segregate the impact of chemotherapy from radiotherapy.

We chose to estimate saliva produced by both parotids together, including any insignificant contribution from the submandibular glands (as they would have received near-radical doses in conventional RT techniques). Different saliva estimation protocols have been practiced in the literature. We chose to stimulate saliva production with fresh lemon juice, which is readily available. Others have used 2% citric acid solution. ^[13] Chao et al., for instance, estimated whole saliva (stimulated and unstimulated) at 6 months following treatment in the patient whose submandibular glands had received dose >50Gy. ^[14] Eisbruch et al., on the other hand, estimated saliva (stimulated and unstimulated) from individual parotids for a longer period of time during follow-up, i.e. up to 2 years. ^[13]

Many three-dimensional (3-D) conformal/IMRT studies in SCC of H and N have documented a dose-volume effect relationship of individual salivary glands with RT. Garden et al. have shown that doses of 35-45Gy to at least 90% of parotid glands reduced the salivary output to 10% of the baseline value by 6 weeks, but recovery up to 30% of the basal flow rate occurred during the first year. ^[15] Eisbruch et al. reported the experience of the University of Michigan in a group of patients in whom the parotid of one side was spared. They observed a significant recovery over time with parotid-sparing IMRT. A mean threshold dose for both unstimulated and stimulated parotid saliva flow rate to reduce the saliva to <25% of the pre-treatment level was 24 and 26Gy, respectively. Portions of the glands receiving a lower mean dose showed time-related recovery, whereas most glands receiving a higher dose produced no measurable output and did not recover over time. ^[13] Chao et al. also observed an exponential relationship between saliva output reduction and mean parotid dose. They found that the stimulated saliva flow rate at 6 months following treatment reduced exponentially, for each gland independently, at a rate of 4%/Gy of the mean parotid gland dose. ^[16] In the current study, we observed a dramatic fall in the saliva flow rate (unstimulated and stimulated saliva from both the parotid glands) to one-forth of its baseline value at 3 months. This is comparable to other studies such as that by Eisbruch et al., who reported a 0-50% reduction in the unstimulated and 50-68% in the stimulated saliva output at 3 months following completion of treatment in two consecutive studies. ^[6] Unlike Chao et al. who observed the saliva flow changes up to 6 months only, Eisbruch et al. reported the flow rates up to 24 months post-radiotherapy, in which saliva flow rate started to improve after 6 months of therapy. ^[6]

The salivary output recovery at 12 months was by 29% with stimulated saliva flow as compared with 33% with unstimulated saliva. This temporal pattern has been observed in most studies (including the present) and was found to be independent of the technique used, i.e. conformal or conventional technique. ^{[16],[17],[18]}

The magnitude of dryness is a function of volume of the parotid glands irradiated. ^[15] Conventional fields usually encompass larger volumes of normal structures as compared with conformal RT, and leave the patient with a greater proportion of dryness, as also reported in our earlier trial (i.e., 78%). ^[8] The conventional field sizes depend on the location of the tumor and its patterns of spread, i.e. the cranial field edge is placed higher in superiorly located tumors (or its CTV) and therefore a greater amount of parotid gland gets irradiated. In the present study, we observed that there was considerable variation in the field sizes due to different primary locations. Studies have also shown that there is considerable variability in size and position of the parotid gland among patients. ^[19] We did not attempt a subset analysis as the resulting sample size would be small. Since 3-D treatment planning was not done, it was not possible to comment on the size and location of the parotid gland with respect to the treatment portal in the present cohort of patients.

Although multivariate analysis have shown that radiation dose to the parotid gland is the sole predictive factor for xerostomia, ^[14] yet shielding blocks for the oral cavity were used along with the large-field conventional RT to spare minor salivary glands. Although minor salivary glands produce <10% of the total saliva volume, they contribute >70% of the total mucin. It is therefore presumed that their sparing may lead to a better perception of oral wetness by the patient. ^[20] In the present subset chosen, blocks at the anterosuperior borders of the lateral fields were placed in only five of the 31 patients who had tumors placed posteriorly or inferiorly.

The relevant endpoint is also the patients′ perception of dryness, and one of the short comings of the present data is a lack of information on quality of life issues. Although the literature is replete with reports and experiences of different centers showing encouraging results in terms of effective parotid sparing (at least of the contralateral gland) with IMRT, ^[21] in resource-constrained environments such as in India, conventional RT is being practiced and continues to take centerstage in the radiotherapeutic armamentarium of the locally advanced H and N cancer burden. In this context, it is relevant to quantify parotid function with conventional RT, especially with concomitant CT + RT, as this is now offered in appropriately selected patients. CT when used along with RT has shown significantly more damage to salivary glands than with RT alone. ^[22] Similarly, accelerated RT also demonstrates a greater degree of dryness as compared with conventional RT. ^[23] Further, the issue of dryness is also linked to extensive tobacco chewing habit, submucous fibrosis, poor oral hygiene and poor baseline nutritional and hydration reserves. ^[23] It is in this context that we believe that the impact of both concurrent CT and accelerated RT on salivary flow changes must be documented as a starting point with which to compare parotid-sparing IMRT using similar CT + RT schedules.

Acknowledgment

This work was a part of a project funded by the Uttar Pradesh Council of Science and Technology (UPCST), Lucknow.

References

Copyright 2010 - Journal of Cancer Research and Therapeutics

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