Background: In contrast to pharyngo-laryngeal cancer, definitive radiation-chemotherapy of advanced oral cavity cancer (OCC) results in inferior disease control rates. Surgery in combination with radiation +/- concomitant chemotherapy is therefore the treatment of choice for squamous cell OCC stages >/=pT1-2pN0-1. Modern intensity modulated radiation techniques (IMRT) allow more conformal dose distribution to the tumor area with consecutively less dose to surrounding normal tissues. Aim was to give a recent overview about outcome data in OCC treated in the modern IMRT era (i.e. time period since ~2000) including presentation of the own single institution results.

Methods: our OCC IMRT cohort was evaluated with respect to disease control and radioosteonecrosis (RON) as most serious late term effect following radiation. .

Results: 202 OCC patients treated between 10/2002-10/2013 with a follow up of mean 30months (3-124) were assessed. 5-year overall and distant metastasis free survival, local and nodal control rates for postoperatively (n=147 (73%), 60-66Gy tumor dose) vs definitively (n=55 (27%), 70Gy) irradiated patients was 70 vs 36% (p<0.0001) and 84%vs84% (p=0.2), 70% vs 40% (p<0.0001) and 83% vs 70% (p=0.006), respectively. The incidence of RONgrade 1-2 was 3% (:12/147 (9%) in postoperative, 1/55 (2%) in definitive IMRT); 1grade 3 RON was observed after post IMRT dental implants. In all grade 1-2 RON, restitutio ad integrum was achieved after conservative treatment or limited surgery (debridment/ decortication/sequestrectomy).

Conclusion: Disease control and survival following combined postoperative MRT are significantly higher than after definitive IMRT(-chemotherapy). The RON incidence revealed being higher in the operated subgroup.

•    Oral cavity cancer
•    Radiation and oral cavity cancer
•    IMRT and oral cavity cancer
•    Radio necrosis and oral cavity cancer

Studer G, Bredell M, Huber G, Studer S, Glanzmann C (2014) Outcome in Irradiated Oral Cavity Carcinoma: An Update. JSM Dent 2(3): 1036.

OCC: Oral Cavity Cancer; RON: Radio-Osteonecrosis

Oral Cavity Cancer (OCC) is an aggressive disease with high risk for loco-regional treatment failure in intermediate and advanced stage disease. While interstitial brachytherapy achieves excellent results in early stage T1, 2 tumors of the mobile tongue or floor of the mouth, definitive radiationchemotherapy (i.e. IMRT without surgery but as potential salvage treatment) of advanced OCC results in inferior disease control rates compared to results following postoperative radiation- in contrast to pharyngo-laryngeal cancer. Surgery in combination with radiation +/- concomitant chemotherapy (i.e. postoperative IMRT) is therefore the treatment of choice for most advanced squamous cell oral cavity cancer (OCC) stages >pT1-2p N0- 1. Modern modulated radiation therapy techniques (MRT) allow more conformal dose distribution to the tumor area with consecutively less dose to surrounding normal tissues. This was shown to translate into substantially reduced rates of severe (grade 3) radio-osteonecrosis (RON) as compared to former three-dimensional non-modulated radiation techniques [1,2]. Aim of this work was to give a recent overview about outcome data in OCC treated in the modern IMRT era (i.e. time period since ~2000).

The own single center OCC cohort was retrospectively evaluated with respect to disease control and treatment late term tolerance following IMRT (including intensity modulated radiation therapy (IMRT) as well as volumetric modulated arc therapy (VMAT)). In 73% of our patients, MRT was combined with concomitant cisplatin chemotherapy or with the monoclonal EGFR antibody cetuximab. Reasons not to combine with systemic therapy were age, comorbidity, early stage disease, or patient refusal. The percentage of patients treated with no systemic therapy was comparable in the postoperative versus definitive IMRT subgroups (76 % and 72%, NS). Mean age was 62.3 years (range 21-93), male : female ratio was 2:1 in the postopIMRT, 1.5:1 in the definitive IMRT subgroup. T1/2/3/4 and recurrence stage distribution was the following: 12%, 34%, 11%, 31% and 12%; the corresponding percentage for N0/1/2/3 and nodal recurrences were 33%, 16%, 45%, 1% and 5%, respectively.

The data collection was prospectively performed since 2002 (when IMRT was clinically implemented in the own department). In order to minimize avoidable oral damage due to radiation, all patients underwent prophylactic and/or therapeutic dental care procedures prior to, during and after IMRT, respectively, according to our in-house routine dental care program. This less invasive ‘risk adapted’ dental care procedure was reactively adjusted to the IMRT-related option of improved normal tissue sparing [3].

RON rates were assessed using the grading system according to Glanzmann and Graetz [4], Table 1.

Parts of the presented data on our OCC cohort have been presented in former publications [1,3,5].

Published IMRT literature in English language with focus on OCC available in PubMed was considered for comparison purposes.

Statistical calculations (survival analysis, Kaplan-Meier curves) were performed using StatView® Version 4.5. P-values <0.05 were considered as statistically significant.

Disease control

202 OCC patients treated at the Department of Radiation Oncology University Hospital Zurich between 10/2002 and 10/2013 with a follow up of mean 30 months (3-124) were assessed.

At the time of analysis (December 2013), 72% of the postoperative MRT patients (n=147, 73% of the entire OCC cohort) were alive with no evidence of disease when last time seen; 7% were alive with disease, 3% had died from other reasons, and 17% had died from disease, respectively.

The corresponding rates for the definitively irradiated subgroup (n=55, 27%) were 29%, 10%, 10%, and 51%.

5-year overall and distant metastasis free survival, local and nodal control rates for postoperatively (n=147, 60-66Gy tumor dose) vs definitively (n=55, 70Gy tumor dose) irradiated patients was 70% vs 36% (p<0.0001) and 84% vs 84% (p=0.2), 70% vs 40% (p<0.0001) and 83% vs 70% (p=0.006), respectively.

In sum, treatment regimens of OCC including surgery in order to eliminate macroscopic disease significantly increases loco-regional disease control as well as overall survival in OCC patients. No difference was found in the probability for distant metastases. These results are in concordance with several other reports on OCC cohorts treated by MRT (+/- systemic therapy) with and without surgery, Table 2 [6-17], i.e. postoperative radiation translates into higher loco-regional disease control as well as higher overall survival rates, while surgery seems not to have any impact on the distant metastasis rate. The comparison definitively and postoperatively irradiated cohorts as well as between the listed reports is somewhat limited by the fact of retrospectively analyzed series with different TN stages or stage grouping (l-lV), and a substantially larger number of postoperative IMRT patients (which is due to the known poor outcome of OCC patients undergoing definitive radiation). The impact of additional systemic therapy to postoperative radiation in advanced stages head neck cancer has been proven back in 2004 by two independent prospective randomized trials (RTOG 9501 and EORTC 22931 [18,19]: level l evidence). The impact of additional radiation on the outcome of operated high risk OCC patients is not quantified based on prospective trials, however many cohort reports confirm satisfying disease control in advanced disease stages treated with postoperative irradiation [20]. While MRT not seems to obviously change disease control in OCC as compared to previous radiation techniques, the substantially improved late term profile following MRT is proven [1,2,21] and nowadays MRT considered the standard technique for head neck cancer radiation.

RON

The incidence of RON grade 1-2 (Table 1) in the own cohort was 7%: 12/147 (9%) after postoperative, 1/55 (2%) after definitive IMRT; 1 grade 3 RON after postMRT dental implant was observed. In all RON grade 1-2 restitutio ad integrum was achieved after limited surgery (debridment/decortication/ sequestrectomy). In 4 of the 14 cases, RON occurred following manipulations in the high dose area (boost): n=3 following postMRT implants, n=1 following tooth extraction in the boost area immediately prior to MRI start, n=1 following soft tissue plastic reconstruction postIMRT that was complicated by osteomyelitis (counted as ‘RON’ in this analysis). In sum, 4/14 RON developed following invasive manipulation in the high dose area (>60-72Gy), i.e. 10 cases remaining as ‘real’ RON grade 1 - 2-3 events (5%). Interestingly, the higher incidence of RON was observed in postoperative MRT (13/147): in the postoperative setting lower radiation doses are needed and therefore lower RON rates expected. This finding may indicate the impact of surgical manipulations on soft or bony tissues on the RON risk, likely viaim paired local trophic conditions.

Another relevant late term effect is grade 3-4 xerostomia. Due to improved salivary gland sparing achieved by IMR and by consequent dental care, the incidence of severe xerostomia grade 3-4 and its oral complications could be reduced as well. In the own entire MRT cohort this was below 1% (affected were patients with nasopharyngeal carcinoma, [21]).

Disease control and survival of OCC patientsis significantly higher following combined postoperative IMRT (-chemotherapy) than after definitive IMRT (-chemotherapy). The higher RON rate in the operated subgroup may indicate surgery being a relevant co-risk factor for RON.

1. Studer G, Studer SP, Zwahlen RA, Huguenin P, Grätz KW, Lütolf UM, et al. Osteoradionecrosis of the mandible: minimized risk profile following intensity-modulated radiation therapy (IMRT). Strahlenther Onkol. 2006; 182: 283-288.

2. Ben-David MA, Diamante M, Radawski JD, Vineberg KA, Stroup C, Murdoch-Kinch CA, et al. Lack of osteoradionecrosis of the mandible after intensity-modulated radiotherapy for head and neck cancer: likely contributions of both dental care and improved dose distributions. Int J Radiat Oncol Biol Phys. 2007; 68: 396-402

3. Studer G, Glanzmann C, Studer SP, Grätz KW, Bredell M, Locher M, et al. Risk-adapted dental care prior to intensity-modulated radiotherapy (IMRT). Schweiz Monatsschr Zahnmed. 2011; 121: 216-229.

4. Glanzmann C, Grätz KW. Radionecrosis of the mandibula: a retrospective analysis of the incidence and risk factors. Radiother Oncol. 1995; 36: 94-100.

5. Studer G, Brown M, Bredell M, Graetz KW, Huber G, Linsenmeier C, et al. Follow up after IMRT in oral cavity cancer: update. Radiat Oncol. 2012; 7: 84.

6. Eisbruch A, Marsh LH, Dawson LA, Bradford CR, Teknos TN, Chepeha DB, et al. Recurrences near base of skull after IMRT for head-and-neck cancer: implications for target delineation in high neck and for parotid gland sparing. Int J Radiat Oncol Biol Phys. 2004; 59: 28-42. 

7. Yao M, Chang K, Funk GF, Lu H, Tan H, Wacha J, et al. The failure patterns of oral cavity squamous cell carcinoma after intensitymodulated radiotherapy-the university of iowa experience. Int J Radiat Oncol Biol Phys. 2007; 67: 1332-1341.

8. Studer G, Zwahlen RA, Graetz KW, Davis BJ, Glanzmann C. IMRT in oral cavity cancer. Radiat Oncol. 2007; 2: 16.

9. Gomez DR, Zhung JE, Gomez J, Chan K, Wu AJ, Wolden SL, et al. Intensity-modulated radiotherapy in postoperative treatment of oral cavity cancers. Int J Radiat Oncol Biol Phys. 2009; 73: 1096-1103.

10. Chen WC, Hwang TZ, Wang WH, Lu CH, Chen CC, Chen CM, et al. Comparison between conventional and intensity-modulated postoperative radiotherapy for stage III and IV oral cavity cancer in terms of treatment results and toxicity. Oral Oncol. 2009; 45: 505-510.

11. Collan J, Lundberg M, Vaalavirta L, Bäck L, Kajanti M, Mäkitie A, et al. Patterns of relapse following surgery and postoperative intensity modulated radiotherapy for oral and oropharyngeal cancer. Acta Oncol. 2011; 50: 1119-1125.

12. Sher DJ, Thotakura V, Balboni TA, Norris CM Jr, Haddad RI, Posner MR, et al. Treatment of oral cavity squamous cell carcinoma with adjuvant or definitive intensity-modulated radiation therapy. Int J Radiat Oncol Biol Phys. 2011; 81: e215-222.

13. Daly ME, Le QT, Kozak MM, Maxim PG, Murphy JD, Hsu A, et al. Intensity-modulated radiotherapy for oral cavity squamous cell carcinoma: patterns of failure and predictors of local control. Int J Radiat Oncol Biol Phys. 2011; 80: 1412-1422.

14. Geretschläger A, Bojaxhiu B, Crowe S, Arnold A, Manser P, Hallermann W, et al. Outcome and patterns of failure after postoperative intensity modulated radiotherapy for locally advanced or high-risk oral cavity squamous cell carcinoma. Radiat Oncol. 2012; 7: 175.

15. Zhang H, Dziegielewski PT, Biron VL, Szudek J, Al-Qahatani KH, O’Connell DA, et al. Survival outcomes of patients with advanced oral cavity squamous cell carcinoma treated with multimodal therapy: a multi-institutional analysis. J Otolaryngol Head Neck Surg. 2013; 42: 30.

16. Chan AK, Huang SH, Le LW, Yu E, Dawson LA, Kim JJ, et al. Postoperative intensity-modulated radiotherapy following surgery for oral cavity squamous cell carcinoma: patterns of failure. Oral Oncol. 2013; 49: 255-260.

17. George JR, Yom SS, Wang SJ. Improved outcomes for oral cavity carcinoma adjuvant radiotherapy at an academic center: matchedpair analysis. Laryngoscope. 2013; .

18. Laryngoscope. 2013.

19. Cooper JS, Pajak TF, Forastiere AA, Jacobs J, Campbell BH, Saxman SB, et al. Postoperative concurrent radiotherapy and chemotherapy for high-risk squamous-cell carcinoma of the head and neck. N Engl J Med. 2004; 350: 1937-1944.

20. Bernier J, Domenge C, Ozsahin M, Matuszewska K, Lefèbvre JL, Greiner RH, et al. Postoperative irradiation with or without concomitant chemotherapy for locally advanced head and neck cancer. N Engl J Med. 2004; 350: 1945-1952.

21. Studer G, Furrer K, Davis BJ, Stoeckli SS, Zwahlen RA, Luetolf UM, et al. Postoperative IMRT in head and neck cancer. Radiat Oncol. 2006; 1: 40.

22. Studer G, Linsenmeier C, Riesterer O, Najafi Y, Brown M, Yousefi B, et al. Late term tolerance in head neck cancer patients irradiated in the IMRT era. Radiat Oncol. 2013; 8: 259.