Radiation Oncology/Head & Neck/Salivary gland

Tumors of the Salivary Glands Epidemiology Median age for salivary gland malignancy is 55-65. Median age for benign salivary gland tumor is 10 yrs younger. Salivary gland malignancies represent 3-6% of head and neck cancers. Tumor distribution (Perez 5th edition): Parotid gland 70% Submandibular gland 8% Minor salivary glands 22% Histology 75% of parotid masses are benign Low grade tumors of the parotid: acinic cell, low grade mucoepidermoid High grade tumors of the parotid: high grade mucoepidermoid, adenoid cystic, adenoCA, squamous cell Most common histology of malignant parotid gland tumor is mucoepidermoid (30%). Predominant histology of a malignant submandibular gland tumor is adenoid cystic. Histologic classification is often difficult, with significant interobserver variability and reclassification rate Anatomy Salivary Glands: Parotid - superficial to and behind ramus of the mandible. LN drainage to parotid nodes, and then to superficial LNs along SCM muscle and to deep cervical chain Submandibular - in triangle between digastric muscle bellies and lower border of the mandible. LN drainage to both submandibular LNs and directly to anterior subdigastic LNs Sublingual - medial to mandible, lateral to genioglossus muscle of the tongue, superior to mylohyoid muscle, inferior to mucous membrane of the floor of the mouth. LN drainage to submandibular LNs or to deep internal jugular chain Minor Salivary Glands - widely distributed throughout the upper aerodigestive tract (see below) Parotid Gland Anatomical borders of parotid gland Superior - zygomatic arch Inferior - upper border of posterior belly of digastric Anterior - 2nd maxillary molar Posterior - tip of mastoid Lobes of parotid gland: Parotid gland divided into superficial and deep lobes. Lobes of parotid separated by relation to facial nerve (no fascial plane separating them). Nodal drainage of Salivary Glands: Parotid: Periparotid and intraparotid nodes Level I, Level II, Level III Submandibular Level I, Level II, Level III Contouring / Anatomy See Radiation Oncology/Head & Neck/Anatomy (e.g. COSTAR trial) Staging AJCC 7th Edition (2009) Tumor T1 - 2cm or less w/o extraparenchymal extension T2 - >2cm but not greater than 4cm; and w/o extraparenchymal extension T3 - >4cm or with extraparenchymal extension T4a - invades skin, mandible, ear canal or facial nerve T4b - invades skull base, pterygoid plates or encases carotid Nodes (same as for most H&N sites) Overall stage I - T1 N0 II - T2 N0 III - T3 N0-1, or T1-3 N1 (i.e. T3 or N1) IVA - T4a N0-2, or T1-4a N2 (i.e. T4a or N2) IVB - T4b N0-3, or T1-4b N3 (i.e. T4b or N3) IVC - M1 Older staging systems AJCC 6th Edition (2002) No changes compared to 7th edition Treatment Treatment of choice for malignancy of salivary glands is surgical resection. Superficial parotidectomy if possible for parotid malignancy Total parotidectomy indicated if tumor invades into or adjacent to deep lobe. Total parotidectomy still attempts to spare CNVII. Facial nerve should be sacrificed if invasion of CNVII or facial palsy Indications for adjuvant RT typically includes positive margins, invasion outside of salivary gland, positive nodes, high grade histology Treatment volume: No need for contralateral neck treatment even with positive ipsilateral neck nodes (see Harrison, 1990). Treat parotid bed only for low grade cancers with indications for local irradiation but no lymph node involvement. Treat parotid bed and ipsilateral neck for high grade cancers, recurrent cancers, or LN metastases. Radiation dose: Tumor bed - 60 Gy at 2 Gy/fx or 63 Gy at 1.8 Gy/fx. Positive margins - 66-70 Gy. Neck (undissected) - 50-54 Gy. Neck (dissected) - 60-63 Gy Neutrons are superior to photon RT based on a randomized RTOG-MRC trial; local control was dramatically better but so was the rate of severe late effects. Neutron therapy is not routinely available, and not actively pursued Adjuvant Radiation Dutch Head and Neck Oncology Cooperative Group (NWHHT), 2005 15629600 -- Terhaard CHJ et al. "The role of radiotherapy in the treatment of malignant salivary gland tumors," Int J Radiat Oncol Biol Phys. 2005 Jan 1;61(1):103-11. Largest series published for malignant salivary gland tumors. 498 pts w/ malignant primary salivary gland carcinoma. Of pts treated w/ surgery, 78% received adjuvant xrt (median dose 62 Gy) Factors in which adjuvant radiation significantly improved local control included T3-T4, close margin, incomplete resection, bony invasion, and PNI. Local control for surgery alone if T1-2 and clear margins was 95% at 5 yrs, and 90% at 10 yrs 5yr local control if definitive xrt was 50% if 66-70 Gy delivered. Memorial Sloan Kettering 2166187, 1990 -- "Postoperative radiation therapy for major salivary gland malignancies." Harrison L et al. J Surg Oncol. 1990 Sep;45(1):52-5. 2306346, 1990 (1966-82) — "Malignant tumors of major salivary gland origin. A matched-pair analysis of the role of combined surgery and postoperative radiotherapy." Armstrong JG et al. Arch Otolaryngol Head Neck Surg. 1990 Mar;116(3):290-3. Matched pair analysis of patients with combined surgery + post-op RT and pts treated with surgery alone (1939-65). 5-year survival for Stage I-II 81.9% (S+RT) vs 95.8% (S), and for Stage III-IV 51.3% vs 16.8%. For LN+ 48.9% vs 18.7%. Conclusion: post-op RT improves survival for Stage III-IV and LN+. Johns Hopkins, 1990 (1975-87) 2115032 -- North CA et al. "Carcinoma of the major salivary glands treated by surgery or surgery plus postoperative radiotherapy," Int J Radiat Oncol Biol Phys 1990 Jun;18(6):1319-26. 87 pts w/ carcinoma of major salivary gland (70 parotid) tx'd w/ either surgery or surg + post-op RT (median 60 Gy). Factors associated w/ poor outcome included facial nerve paresis, undifferentiated histology, male sex, skin invasion, and no RT. Patients w/ local recurrence had major advantage if RT was given as part of salvage. Elective Nodal Irradiation UCSF; 2007 (1960-2004) 17234357 -- "Patterns of nodal relapse after surgery and postoperative radiation therapy for carcinomas of the major and minor salivary glands: what is the role of elective neck irradiation?" (Chen AM, Int J Radiat Oncol Biol Phys. 2007 Mar 15;67(4):988-94.) Retrospective. 251 patients, N0 salivary gland malignancy (adenoid cystic 33%, mucoepidermoid 24%, adenoCA 23%), gross total resection (R0 44%, R1 56%), no LND + RT. Median primary RT dose 63 Gy. 52% had elective neck irradiation (ipsilateral neck 69%, bilateral 31%) 10-year outcome: Nodal failures in T1 7%, T2 5%, T3 12%, T4 16%. ENI reduced 10-yr nodal relapse from 26% to 0%, especially in squamous cell (67%), undifferentiated CA (50%), adenoCA (34%). No nodal failures in adenoid cystic CA (0/84) or acinic cell (0/21), regardless of ENI. Conclusion: ENI effectively prevents nodal relapses Memorial Sloan Kettering, 1992 - 1730113, (1939-82) Armstrong JG et al. "The indications for elective treatment of the neck in cancer of the major salivary glands." Cancer. 1992 Feb 1;69(3):615-9. 474 pts. Clinically LN+ in 14%. Pathologically positive (occult) LN mets in 12% of those with clinically negative neck. Size and grade were predictive of LN mets. Size: 20% (>4 cm) vs 4%; Grade: 49% (High grade) vs 7% (int or low grade). Definitive Radiation Therapy UCSF, 2006 (1960-2004) 16965870 -- Chen AM et al. "Long-term outcome of patients treated by radiation therapy alone for salivary gland carcinomas." Int J Radiat Oncol Biol Phys. 2006 Nov 15;66(4):1044-50. 45 pts w/ newly dx'd salivary gland carcinoma tx'd w/ definitive xrt to median dose of 66 Gy. 5 yr estimated local control was 70%, 10 yr 57% T3-4 disease and <66 Gy were predictors for local recurrence. Gainesville, 2005 (1964-2003) 15880750 -- Mendenhall WM et al. "Radiotherapy alone or combined with surgery for salivary gland carcinoma." Cancer. 2005 Jun 15;103(12):2544-50. Retrospective review of pts at U of FL tx'd w/ curative intent w/ RT alone (64) vs surg (160). T stage and use of surgery were predictors of local control. RT cured approximately 20% of advanced stage tumors if used alone. Neutron Therapy RTOG-MRC Neutron Trial -- neutrons vs. photons/electrons Randomized. Stopped early due to neutron advantage. 32 patients, inoperable or recurrent major or minor salivary gland tumors. Arm 1) Neutrons (17-22 nGy) vs. Arm 2) photon/electrons (55 Gy/4 weeks or 70 Gy/7.5 weeks) 2-years; 1988 2846479 -- "Neutron vs photon irradiation of inoperable salivary gland tumors: results of an RTOG-MRC Cooperative Randomized Study." (Griffin TW, Int J Radiat Oncol Biol Phys. 1988 Nov;15(5):1085-90.) Minimum F/U 2 years Outcome: 2-year LRC neutrons 67% vs. photons/electrons 17% (SS); 2-year OS 62% vs. 25% (NS) Conclusion: Neutrons superior for local control, but no impact on survival Final; 1993 8407397 -- "Neutron versus photon irradiation for unresectable salivary gland tumors: final report of an RTOG-MRC randomized clinical trial." (Laramore G, Int J Radiat Oncol Biol Phys. 1993 Sep 30;27(2):235-40) Outcome: 10-year LRC neutrons 56% vs. photons/electrons 17% (SS); OS 25% vs. 15% (NS). Median OS 3 years vs. 1.2 years Toxicity: Severe toxicity worse in neutron arm, but no difference in "life-threatening" complications Conclusion: Fast neutron RT appears to be the treatment of choice for patients with inoperable/recurrent salivary gland tumors Comment: Remains as only randomized trial for malignant salivary gland tumors University of Washington, 2003 12975266 -- Douglas JG et al. "Treatment of salivary gland neoplasms with fast neutron radiotherapy." Arch Otolaryngol Head Neck Surg 2003 Sep;129(9):944-8. 279 pts tx'd w/ curative intent using fast neutron therapy (263 had evidence of gross residual dz). Multivariate analysis showed improved CSS for pts w/ stage I-II dz, lack of skull base invasion, minor salivary site. Minor Salivary Glands Widely distributed throughout the upper aerodigestive tract: tumors present in 38% palate, 12% cheek/lips, 12% antrum, 10% tongue, 10% nasal cavity, multiple other sites <10% Imaging depends on location, but should involve evaluation of bone involvement Definitive diagnosis should be via excisional biopsy Histology: 40% adenoid cystic, 16% mucoepidermoid, 16% adenoCA, 28% others Prognosis: worst for adenoid cystic General management (based on Perez 5th edition) Depending on site, attempt surgical resection (though not simple excision, as significant residual disease can be left behind) Radiation may be used as adjuvant or primary, with techniques similar to squamous cell cancers in the same location, except: Adenoid cystic involving a named branch of cranial nerve, in which case nerve path to skull base should be treated. For focal perineural invasion, treatment to skull base should be based on anatomic location For paranasal sinuses or palate, base of skull should be treated due to proximity Fields may not need to electively include LNs, except if located in tongue, floor of mouth, pharynx, or larnyx and neck was not dissected. However, UCSF data on elective nodal irradiation (ENI) above suggest no benefit for adenoid cystic or acinic cell RT dose Negative margins: 60/30 Microscopically positive margins: 66/33 Grossly residual disease or primary treatment: 70/35 Netherlands Cancer Institute; 2000 (Belgium)(1973-1994) 11002213 -- "Stage as major long term outcome predictor in minor salivary gland carcinoma." (Vander Poorten VL, Cancer. 2000 Sep 15;89(6):1195-204.) Retrospective. 55 patients with minor salivary gland cancer. Median F/U for alive patients 11.1 years Outcome: 5-year DSS 76%, 10-year DSS 74% Prognostic factors: younger age, lower AJCC stage, LN+, vascular invasion, nasopharynx/paranasal sinus location Conclusion: comparable outcome to major salivary gland patients Adenoid Cystic Carcinoma Overview First described in 1853, named adenoid cystic in 1953 Slow-growing epithelial tumor of salivary glands, thought to arise from intercalated mucous-secreting ducts. Can arise anywhere within the upper respiratory tract Predominance in 5th-6th decade, and in females Estimated 5-10% of all salivary tumors, but common in minor salivary glands (30-40%). Parotid gland is the single most common site, and accounts for ~25%. Minor salivary glands account for ~60% in total; most common site is palate Histologically shows 3 patterns: glandular, tubular, and solid (worse prognosis) Characterized by persistent local recurrences, perineural spread, and distant metastases; lymphatic spread less common Distant metastases may happen late, commonly affect lungs, are are frequently slow-growing and surgically resectable Most important prognostic factor is Stage; more favorable outcome of major parotid glands compared with minor is probably earlier diagnosis Overall, 5-year OS is exceptionally good but 10- and 20-year OS is exceptionally poor Most are treated surgically Role of adjuvant RT is controversial; some institutions use for all patients while others use for those with unfavorable features. It is probably reasonable to offer adjuvant radiation for most patients, especially with positive surgical margins or perineural invasion. RT dose should be >60 Gy Perineural invasion of small unnamed nerves may not be correlated with worse control if treated with adjuvant RT; named branches of cranial nerves should probably be treated to skull base In patients with skull base extension (and likely R2 resection or unresectable), dose intensification with proton therapy or carbon ion boost appears superior to IMRT alone Photon Therapy MSKCC; 2007 (1990-2004) 18029108 -- "Outcomes and Prognostic Variables in Adenoid Cystic Carcinoma of the Head and Neck: A Recent Experience." (Gomez DR, Int J Radiat Oncol Biol Phys. 2007 Oct 27 [Epub ahead of print]) Retrospective. 59 patients (oral cavity 28%, paranasal sinuses 22%, parotid 14%, submandibular 14%) treated with RT. Stage T1-T4. Base of skull treated in 90%. Median F/U of survivors 5.9 years Outcome: 5-year LC 91%, DM-free 81%, OS 87%; 10-year LC 81%, DM-free 49%, OS 65% Worse predictors: T4, gross/clinical nerve involvement, LN+ Conclusion: RT combined with surgery offers excellent local control Heidelberg; 2006 16756669 -- "Inverse planned stereotactic intensity modulated radiotherapy (IMRT) in the treatment of incompletely and completely resected adenoid cystic carcinomas of the head and neck: initial clinical results and toxicity of treatment." (Munter MW, Radiat Oncol. 2006 Jun 6;1:17.) Retrospective. 25 patients, huge adenoid cystic tumors. Surgery R0 (16%), R1 (4%), R2 (80%). Treated with IMRT, most using integrated boost. Median F/U 1.9 months Outcome: 3-year OS 72%. LF 12%, RF (adjacent LN) 12% Toxicity: Grade 3+ if small number of patients Conclusion: IMRT provides good control and low side effects UCSF; 2006 (1960-2004) 16904520 -- "Adenoid cystic carcinoma of the head and neck treated by surgery with or without postoperative radiation therapy: prognostic features of recurrence." (Chen AM, Int J Radiat Oncol Biol Phys. 2006 Sep 1;66(1):152-9.) Retrospective. 140 patients treated with definitive surgery. T1 26%, T2 28%, T3 20%, T4 26%. SM+ 56%. Post-op RT 64%, median dose 64 Gy (54-71 Gy). Base of skull treated routine for all patients with PNI. Elective neck in 54%. Median F/U 5.5 years Outcome: LC 5-year 88%, 10-year 77%; 10-year OS 64%. Sites of failure: all LR were localize to original site except for 2 base of skull recurrences in patients treated with surgery alone. No cervical LN failures. DM sites were lung 71%, bone 14%, liver 9%, brain 6% Poor prognosis: T4, PNI, major nerve involvement, lack of post-op RT. Post-op RT beneficial in essentially all subgroups except possibly if SM-. If received post-op RT, dose <60 Gy, T4, and major nerve involvement poor prognosis Conclusion: Combined modality therapy with RT >60 Gy should be standard of care University of Florida; 2004 (1966-2001) 14762884 -- "Radiotherapy alone or combined with surgery for adenoid cystic carcinoma of the head and neck." (Mendenhall WM, Head Neck. 2004 Feb;26(2):154-62.) Retrospective. 101 patients, treated with RT alone or surgery + RT. Median F/U 6.6 years Outcome: LC 5-years RT 56% vs surgery + RT 94%, 10-years 43% vs. 91% (SS). OS 5-years 57% vs. 77%, 10-years 42% vs. 55%. Predictors for survival T-stage, clinical nerve invasion. DM 10-years 27% Conclusion: Optimal treatment for ACC is surgery + adjuvant RT Hanover; 2004 (Germany)(1981-2000) 14690656 -- "Adenoid cystic carcinoma of the head and neck--a 20 years experience." (Kokemueller H, Int J Oral Maxillofac Surg. 2004 Jan;33(1):25-31.) Retrospective. 74 patients. Complete resection 45/74. Post-op RT 14 patients. Outcome: LC 5-years 64%, 10-years 56%, 15-years 52%; mean local control time 11.1 years; DM control 72%, 62%, 59%; mean distant control time 14.4 years; OS 71%, 54%, 37%; mean OS 4.7 years Poor prognosis: large size, PNI, SM+ Conclusion: Insight into behavior of ACC UCLA; 2004 (1963-1997) 15577803 -- "Adenoid cystic carcinoma of the submandibular gland: a 35-year review." (Cohen AN, Otolaryngol Head Neck Surg. 2004 Dec;131(6):994-1000.) Retrospective. 22 patients, ACC of submandibular gland. Surgery in 21/22. Post-op RT if advanced size, PNI, SM+, or LN+. Median F/U 5.6 years Outcome: DFS 3-years 66%, 5-years 57%, 10-years 41%; OS 76%, 70%, 37% Poor prognosis: large tumor, SM+, PNI, local recurrence Conclusion: High DFS rates; early Dx, wide surgery and post-op RT associated with favorable prognosis MD Anderson; 1995 (1962-1991) 7790247 -- "The influence of positive margins and nerve invasion in adenoid cystic carcinoma of the head and neck treated with surgery and radiation." (Garden AS, Int J Radiat Oncol Biol Phys. 1995 Jun 15;32(3):619-26.) Retrospective. 198 patients, ACC treated with surgery, then post-op RT. Parotid 15%, submandibular/sublingual 21%, minor salivary 62%, lacrimal 2%. Resection R1 42%, close 28%. PNI 69%, major nerve PNI 28%. Median RT 60 Gy to tumor bed. Median F/U 7.8 years Outcome: LR 5-years 95%, 10-years 86%, 15-years 79%. LR by margin: positive 18%, close 9%, negative 5% (SS). By PNI, PNI major nerve 18% vs. PNI minor nerve 9% (SS). Trend to better control with higher dose. DM primary mode of recurrence (37%) Conclusion: Excellent local control using combined surgery + postop RT. PNI only adverse with major nerve involvement. Recommend 60 Gy to tumor bed, 66 Gy if SM+ Proton Therapy Please also see the general H&N proton therapy page Harvard 2008 (1991-2002) 17902164 -- "Extent of surgery in the management of locally advanced sinonasal malignancies." (Resto VA, Head Neck. 2008 Feb;30(2):222-9.) Retrospective. 102 patients, locally advanced, treated with proton therapy with or without surgery (R0 20%, R1 49%, R2/biopsy 31%). Squamous cell 32%, neuroendocrine 29%, adenoid cystic 20%, sarcoma 13%, adenocarcinoma 6%. Median RT dose if R0 resection 67.6 Gy, if R1/R2 resection 75.6 Gy usually given BID. Median proton contribution 57%. Concurrent chemo 33% (typically for neuroendocrine). Median F/U 3.6 years, alive 5.1 years Outcome: 5-year LC R0 95% vs R1 82% vs R2 87% (NS, no difference by histology); 5-year DFMS 95% vs. 69% vs 52% (no difference by histology). 5-year OS 90% vs 49% vs 39% (worst for squamous cell). Regional failure rate 12% Conclusion: High dose proton RT excellent local control regardless of extent of surgery. However, DFS and DMFS depended on extent of surgery. Can consider observation for regional neck 2006 (1991-2002) 17116822 -- "Proton beam radiation therapy for skull base adenoid cystic carcinoma." (Pommier P, Arch Otolaryngol Head Neck Surg. 2006 Nov;132(11):1242-9.) Retrospective. 23 patients, adenoid cystic with skull base extension. Sinonasal 75%, nasopharynx 22%. Surgery 52%. All patients definitive combined photon and proton RT (photons typically to elective LNs, proton contribution 31-72%). Median dose 76 Gy BID or 73 Gy QD. Median F/U 5.2 years Outcome: 5-year LC 93%, DMFS 62%, DFS 56%, OS 77%. Prognostic factors vision change initially and sphenoid sinus/clivus involvement Conclusion: Encouraging local control Carbon Ion Heidelberg IMRT vs carbon; 2005 (1995-2003) 15937907 -- "Therapy strategies for locally advanced adenoid cystic carcinomas using modern radiation therapy techniques." (Schulz-Ertner D, Cancer. 2005 Jul 15;104(2):338-44.) Retrospective. 63 patients with ACC, 2 groups depending on carbon ion beam availability. Group A (n=29): combined photons/carbon boost. Group B (n=34): photons only, delivered as stereotactic or IMRT. Carbon ion allowed higher median GTV dose (72 GyE vs. 66 GyE). Median F/U Group A 1.3 years vs Group B 2 years Outcome: LRC 2-years photons/carbon 77% vs. IMRT 72%, 4-years 77% vs. 25% (p=0.08). 4-year DFS 53% vs. 23%, 4-year OS 76% vs. 78% Toxicity: Severe late toxicity <5% for both groups Conclusion: Combination of IMRT and carbon ion seemed advantageous over IMRT alone Overall; 2004 (1997-2002) 14751537 -- "Results of carbon ion radiotherapy in 152 patients." (Schulz-Ertner D, Int J Radiat Oncol Biol Phys. 2004 Feb 1;58(2):631-40.) Retrospective. 152 patients treated with carbon ion RT, 21 unfavorable adenoid cystic with infiltration of skull base and R2 resection enrolled (18 primary, 8 recurrent). Photons to 54 Gy (but 8/21 received lower dose due to neighboring organ tolerances) followed by carbon ion boost 18 GyE. 14/21 patients planned with IMRT. Median F/U 14 months Adenoid cystic outcome: LRF 4/21 (19%); 3-year LRC 62%, OS 75% Toxicity: acute Grade 3 in 9% (1 abscess, 1 mucositis) Conclusion: Carbon ion therapy is safe and offers high local control Feasibility; 2003 (1998-2002) 12738314 -- "Feasibility and toxicity of combined photon and carbon ion radiotherapy for locally advanced adenoid cystic carcinomas." (Schulz-Ertner D, Int J Radiat Oncol Biol Phys. 2003 Jun 1;56(2):391-8.) Phase I/II. 16 patients, ACC with R2 resection. Combined photon/carbon boost RT to 72 GyE. Photons were stereotactic RT/IMRT. Median F/U 1 year Outcome: 1-year LC 65%, 3-year LC 65%; OS 100% and 83% Toxicity: No Grade 3+ acute toxicity Conclusion: Combined photon/carbon ion therapy is feasible and effective