# Radiation Oncology/Toxicity/Parotid

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Parotid Gland Radiation Toxicity

## Normal Tissue Tolerance

* Mean MTD dose: 25 Gy; expect recovery to pre-treatment within 1-2 years, but can continue to improve even at 5 years
* Emami tables: TD5/5 32 Gy; TD50/5 46 Gy
* Michigan
** 2007 PMID 17141973 -- "The impact of dose on parotid salivary recovery in head and neck cancer patients treated with radiation therapy." (Li Y, Int J Radiat Oncol Biol Phys. 2007 Mar 1;67(3):660-9. Epub 2006 Dec 4.)
*** Prospective. 142 patients treated with 3D-conformal or IMRT. 266 parotid glands flow rates (stimulated and unstimulated) measured prior, and at 1, 3, 6, 12, 18, and 24 months
*** Outcome: high dose results in less saliva. Largest reduction at 1-3 month after RT, followed by gradual recovery
*** Stimulated flow: mean dose <24 Gy - recovery to pretreatment at 12 months vs. mean dose >30 Gy does not recover to normal
*** Unstimulated flow: mean dose 25 Gy - recover to 86% pretreatment vs. mean dose >40 Gy recovery to 30% pretreatment
** 1999 (1994-1997) PMID 10524409 -- "Dose, volume, and function relationships in parotid salivary glands following conformal and intensity-modulated irradiation of head and neck cancer." (Eisbruch A, Int J Radiat Oncol Biol Phys. 1999 Oct 1;45(3):577-87.)
*** Prospective. 88 patients treated with 3D-conformal or IMRT. 152 parotid stimulated and unstimulated flow rates measured prior and at 1, 3, 6, 12 months after completion. NTCP endpoint defined as flow rate <=25% at 12 months
*** Mean MTD: 24 Gy for unstimulated and 26 Gy for stimulated, returned to 76% and 114% of pre-treatment respectively.
*** Higher mean dose: little saliva with no recovery over time
*** Partial volume thresholds: 67% to 15 Gy, 45% to 30 Gy, 24% to 45 Gy (correlated highly to mean dose)
*** NTCP parameters: TD50 = 28.4 Gy, n=1, m=0.18
* Washington University, 2005 PMID 15990009 -- "Dose-volume modeling of salivary function in patients with head-and-neck cancer receiving radiotherapy." (Blanco AI, Int J Radiat Oncol Biol Phys. 2005 Jul 15;62(4):1055-69.)
** Prospective. 65 patients, treated with IMRT (45) or 3D conformal (20). Salivary flow measured prior, and at 6, 12 months. Xerostomia defined as <25% pretreatment flow
** Final model: mean dose 25.8 Gy reduces single gland flow to 25%. Function lost ~5%/1 Gy of mean dose
* Utrecht (Netherlands)
** 2005 PMID 15964708 -- "A comparison of mean parotid gland dose with measures of parotid gland function after radiotherapy for head-and-neck cancer: Implications for future trials." (Roesink JM, Int J Radiat Oncol Biol Phys. 2005)
*** Conclusion: "Stimulated flow measurements using Lashley cups, with a complication defined as flow </=25% of the preradiotherapy output, correlated best with the mean parotid gland dose."
** 2005 PMID 15936542 -- "Long-term parotid gland function after radiotherapy." (Braam PM, Int J Radiat Oncol Biol Phys. 2005)
*** Conclusion: "Salivary output can still recover many years after RT. At 5 years after RT, we found an increase in the salivary flow rate of approximately 32% compared with at 12 months after RT."

## Acute Parotitis (Sialadenitis)

* Rapid destruction of acinar cells by apoptosis; cell membrane damage as early as 2 hours after RT
* Increase in serum amylase produced by acinar cells even after 0.5 Gy (and typically after first or second treatment); appears to be dose-dependent. Peak (up to 50x) 1-2 days after RT. Return to normal in 5-6 days. Frequently associated parotid gland swelling, dry mouth, and loss of taste
* Salivary (parotid) serum amylase is a very rapid and sensitive bio-indicator of radiation exposure; no change in pancreatic serum amylase
* Treatment is with aspirin or NSAIDs; symptoms typically resolve within 48 hours

### After TBI

* Florence, 2001 (Italy) PMID 11776255 -- "Proposal for biochemical dosimeter for prolonged space flights." (Becciolini A, Phys Med. 2001;17 Suppl 1:185-6.)
** Evaluated different doses per fraction and fractionation schedules. Direct correlation between absorbed dose, and serum amylase (synthesized by acinar cells) and tissue polypeptide antigen (synthesized by ductal cells)
** Elevation after I-131 also correlates to dose
* MD Anderson, 1992 PMID 1620884 -- "Post-irradiation hyperamylasemia as a biological dosimeter." (Dubray B, Radiother Oncol. 1992 May;24(1):21-6.)
** Prospective. 31 patients with TBI, 40 patients with H&N RT, and 22 patients with pancreatic RT
** Outcome: significant increase in serum amylase at doses >0.5 Gy; sigmoid function of dose and maximum amylasemia
** Conclusion: Post-RT hyperamylasemia is good for triage of accidentally irradiated patients
* Karolinska, 1991 (Sweden) PMID 1716901 -- "Isoamylase levels in bone marrow transplant patients are affected by total body irradiation and not by graft-versus-host disease." (Brattstrom C, Transpl Int. 1991 Jun;4(2):96-8.)
** Pre-TBI: Mean serum amylase 3.2 (50% salivary, 50% pancreatic).
** Post-TBI: Mean serum amylase 100.3 (90% salivary, 10% pancreatic). All patients clinical symptoms of parotitis, none pancreatitis
** Time course: Peak within 24 hours, normalized in 5 days, then subnormal for 3 weeks
** Dose: 7.5 Gy at 26cGy/min peak 32 vs. 10 Gy at 4 cGy/min peak 76 (SS). 6 month amylase higher after 7.5 Gy regimen
* Lange, 1990 (Germany) PMID 1700482 -- "Increased serum amylase in patients after radiotherapy as a probable bioindicator for radiation exposure." (Hofmann R, Strahlenther Onkol. 1990 Oct;166(10):688-95.)
** Prospective. 41 patients with TBI or H&N RT.
** Dose-dependent amylase increase up to 80x; pancreatic proteins contribute minimally
** Conclusion: Serum amylase bioindicator for radiation exposure
* Royal Marsden, 1986 (UK) PMID 2420486 -- "Salivary amylase and pancreatic enzymes in serum after total body irradiation." (Junglee D, Clin Chem. 1986 Apr;32(4):609-10.)
** Prospective. 6 patients given TBI (high dose cyclophosphamide followed by ~10 Gy RT). Measured pancreatic enzymes (trypsin, amylase, lipase) and salivary amylase
** Parotitis: Salivary amylase increased by up to 50x, peaking first day after RT. Associated with clinical parotitis. Resolved by 48 hours. Xerostomia and altered taste persisted for up to 6 months
** Pancreatitis: Pancreatic enzymes increased to much smaller degree, and inconsistently. No associated clinical pancreatitis
** Conclusion: Parotitis consistent after TBI
* Guildford, 1982 (UK) PMID 6178460 -- "Changes in serum amylase and its isoenzymes after whole body irradiation." (Barrett A, Br Med J (Clin Res Ed). 1982 Jul 17;285(6336):170-1.)
** Prospective. 12 patients. Amylase levels evaluated
** Total serum amylase: rapid rise within 12 hours of RT; maximum at 36 hours, normalize by 6 days. Majority from salivary damage, with much smaller pancreatic component. Clinically associated with swelling of the parotid gland, dry mouth, and loss of taste
* 1981 PMID 6164661 -- "Early membrane injury in lethally irradiated salivary gland cells." (El-Mofty SK, Int J Radiat Biol Relat Stud Phys Chem Med. 1981 Jan;39(1):55-62.)
** Rat experiments. 2-20 Gy to neck. Light and electron microscopy.
** Parotid glands: acinar cell necrosis 12-24 hours after RT. >2x increase in serum amylase prior to cell necrosis. As early as 2 hours, signs of cell membrane injury
** Submandibular and sublingual glands were resistant
* 1973 PMID 4699791 -- "Radiation-induced change in serum and urinary amylase levels in man." (Chen IW, Radiat Res. 1973 Apr;54(1):141-51.)
** In the field, 1-3 Gy to people can produce 12x increase in serum amylase activity

### After Whole Brain RT

* 1980 PMID 6155101 -- "Acute parotitis and hyperamylasemia following whole-brain radiation therapy." (Cairncross JG, Ann Neurol. 1980 Apr;7(4):385-7.)
** Parotitis observed in 4 patients. Previously unreported
** Acute symptoms included fever, dry mouth, pain, swelling, and tenderness. Hyperamylasemia. Among 10 patients receiving WBRT, 8 had serum amylase elevations without symptoms

### After mantle field

* Fox Chase, 1995 (1967-1993) No PMID Abstract -- "Acute parotitis during mantle irradiation: Incidence, onset, duration, and treatment" (Fein D, Radiation Oncology Investigations, Volume 2, Issue 6 , Pages 291 - 294, 1995)
** Retrospective. 126 patients treated with mantle for HL, up to external acoustic meatus.
** Clinical parotitis: 5%; palpable swelling in 3% all during first week. Treated with aspirin, and symptoms resolved within 48 hours. If no treatment, can persist for 5 days

### After I-131 Administration

* Royal Marsden, 2007 PMID 17305259 -- "Salivary gland toxicity after radioiodine therapy for thyroid cancer." (Hyer S, Clin Oncol (R Coll Radiol). 2007 Feb;19(1):83-6.)
** Prospective. 76 patients treated with I-131 for thyroid CA.
** Symptoms: 26% toxicity - 15% within 48 hours (sialadenitis), 11% after 3 months (xerostomia); 5 patients in database with chronic salivary gland swelling (up to 23 years)
** Conclusion: Salivary gland compromise frequent
* UCLA, 1984 PMID 6737074 -- "Sialadenitis following I-131 therapy for thyroid carcinoma: concise communication." (Allweiss P, J Nucl Med. 1984 Jul;25(7):755-8.)
** Retrospective. 87 patients receiving I-131 for thyroid Ca
** Outcome: 11% developed acute and/or chronic sialadenitis of the parotid (5 patients) or submandibular (4 patients) or both
** Conclusion: This complication occurs more often than has been appreciated

## Xerostomia

* to be edited ...
* Please see Supportive Care for management