1. Evidence Based Management Gingivo-Buccal Cancer Dr. A D’ Cruz Tata Memorial Hospital

2. Oral Cancer – Global Incidence 10th most common cancer 389,000 new cases annually (2000) 2/3 rd in developing countries 200,000 deaths annually Stable or increased in last four decades Sharp increase in incidence in Germany, Denmark, Scotland, Central & Eastern Europe Same increase in Japan, Australia, New Zealand & USA ( non-whites)

3. Oral Cancers Oral cancer common cancer in India – Observations reported since late 19 th century

4. Cancer of the oral cavity Site Distribution TONGUE & FOM GINGIVOBUCCAL COMPLEX [ BUCCAL MUCOSA + RMT + LOWER GUM]

5. Biological Distinctions in Oral Cancer GINGIVO – BUCCAL Ca TONGUE Ca STAGE AT PRESENTATION PROPENSITY TO NECK METASTASES NO – 52% N+ – 48% NO – 29% N+ – 71% FIRST NODAL STATION LEVEL I LEVEL II / III PATTERN OF FAILURE PREDOMINANTLY AT THE PRIMARY SITE PREDOMINANTLY IN THE NECK

6. GINGIVOBUCCAL CANCER – THE INDIAN ORAL CANCER 2275 PTS. (1997-99)

7. Gingivo-Buccal Cancers Areca nut is the fourth most common psychoactive substance in the world (after caffeine, alcohol and nicotine), the use extending to several hundred million people. Tobacco chewers (with cancer)105 AGE AND SEX MATCHED Tobacco chewers (no cancer ) 71RELATIVE RISK = 12.5% GHOSH S. Eur J Surg Oncol, 1996

8. Pre-malignant conditions n = 2275 (97-99) LEUKOPLAKIA - 8.5% (194) SMF -10.8%(245)

9. Gupta PC et al. National Medical Journal of India; 11(3): 113-116, 1998. Prevalence of tobacco use among oral submucous fibrosis (OSF) cases Oral Cancers Submucous fibrosis

10. Hazare VK et al. National Medical Journal of India. 11(6): 299, 1998. Relative risk of oral submucous fibrosis by the daily frequency of areca nut use - a case control study from Government Dental College, Nagpur Oral Cancers Submucous fibrosis

11. Chemoprevention

13. Chemoprevention- Limitations Costly Side effects Long duration Lesion return on – stoppage Exact agents not known (curcumin) Encourage patient to stop habits Oral / Dental Hygiene Good Diet

14. TREATMENT Early Stage I & IILate Stage III & IV Single modality treatment SX RT Operable III & IVa In Operable Combined modality treatment Sx + PORT / CT RT Radical RT IV c Low GC / Symptomatic Rx IV b CT RTPall CT Gingivo - buccal cancer

15. Gingivo – buccal cancers Goals of treatment MAXIMIZING CURE RATES MAXIMIZING CURE RATES PRESERVING FUNCTION PRESERVING FUNCTION COSMESIS COSMESIS COST EFFECTIVE COST EFFECTIVE EXPEDITING CARE EXPEDITING CARE

16. Gingivobuccal Cancers Factors Affecting Treatment TUMOR FACTORS TUMOR FACTORS T size, Location to bone, Type of lesion, Nodal disease T size, Location to bone, Type of lesion, Nodal disease PATIENT FACTORS PATIENT FACTORS Performance status, Persistence of habits, Preference Performance status, Persistence of habits, Preference PHYSICIAN FACTORS PHYSICIAN FACTORS Availability of MULTIDISCIPLINARY TEAM & EXPERTISE Availability of MULTIDISCIPLINARY TEAM & EXPERTISE

17. GINGIVO – BUCCAL CANCERS EARLY T1/T2 CANCERS Cancer of the Oral Cavity – Jatin P. Shah & M J Zelefsky SX = RT

18. Radiotherapy Carcinoma Buccal Mucosa 185 cases 2 years DFS- 48% RT 46% SX Early Stage Chaudhary, Seminars in Surgical Oncology 1989

19. GINGIVO – BUCCAL CANCERS EARLY T1/T2 CANCERS - RT BOTH EXTERNAL & INTERSTITIAL NEEDED BOTH EXTERNAL & INTERSTITIAL NEEDED PROLONGED TREATMENT PROLONGED TREATMENT SIDE EFFECTS SIDE EFFECTS Xerostomia, Dental caries, ORN. Xerostomia, Dental caries, ORN. CAN BE ONLY GIVEN ONCE CAN BE ONLY GIVEN ONCE Not suited for alveolar lesions Not suited for alveolar lesions “ Radiotherapy is chosen when surgery not possible / functional or cosmetic problems are anticipated”

20. SIMPLE SIMPLE EXPEDIOUS EXPEDIOUS NO SIGNIFICANT FUNCTIONAL & COSMETIC DEFECTS NO SIGNIFICANT FUNCTIONAL & COSMETIC DEFECTS REPEATED PROCEDURE POSSIBLE REPEATED PROCEDURE POSSIBLE COST EFFECTIVE COST EFFECTIVE CHOICE OF TREATMENT CHOICE OF TREATMENT GINGIVO – BUCCAL CANCERS EARLY T1/T2 CANCERS - Surgery

21. GB Cancers – T1/T2 cancers Surgery ( margins) WIDE; ADEQUATE MARGINS > 5mm WIDE; ADEQUATE MARGINS > 5mm DEPTH – BUCCINATOR MUSCLE DEPTH – BUCCINATOR MUSCLE Sieczka et al ( Roswell Park, Am J Otolaryngol 2001) Sieczka et al ( Roswell Park, Am J Otolaryngol 2001) - 40% local failure T1 – T2 Post-op ADJUVANT NECESSARY Post-op ADJUVANT NECESSARY

22. Gingivo – Buccal Cancers (T1 / T2) Gingivo – Buccal Cancers (T1 / T2) M D Anderson Experience Jan 1974 – Dec1998 250 Pts ; 119 untreated T1 25 - 78% (5 Yr Survival) T2 45 - 66% (5 Yr Survival) Worse than other head & neck cancers stage matched Bad Prognostic factors – muscle, Stenson duct involvement, ECS Diaz, Head & Neck ; April 2003

23. GBS Cancers – The TMH Experience (1997-99) Early Stage(I/II) n207pts Median follow up2.2 yrs DFS 2yrs65.7% 5yrs50.33% Local Rec. rate21% Salvage rate 37%

24. GINGIVO – BUCCAL CANCERS EARLY T1/T2 CANCERS – SURG. v/s RT IS A RANDOMIZED TRIAL FEASIBLE? IS A RANDOMIZED TRIAL FEASIBLE? NO – IT WOULD BE, NO – IT WOULD BE, UNETHICAL UNETHICAL DIFFICULT OT ACCRUE PATIENTS DIFFICULT OT ACCRUE PATIENTS

25. Early GBS Cancers (T1/T2) Management of the Neck Low propensity to cervical metastasis [ <10% ] Low propensity to cervical metastasis [ <10% ] 7.2% Clinically N0 have occult metastasis 7.2% Clinically N0 have occult metastasis (Nair, Cancer 1988) CAN WAIT & WATCH UNLESS CAN WAIT & WATCH UNLESS Poor follow up Poor follow up Cheek flap for surgical access Cheek flap for surgical access

26. Marginal Mandibulectomy for GBS Cancers: TMH Experience Pradhan SA et al Indian J Cancer 1987 Control rate: 79% Pradhan SA et al Indian J Cancer 1987 Control rate: 79% Pathak KA et al EJSO 2004 Pathak KA et al EJSO 2004 1994-2001 n=83 1994-2001 n=83 2-year local control: 79% 2-year local control: 79%

27. Marginal Mandibulectomy Contraindications Locoregional control influenced by soft tissue margins (p<0.01)* - 127pts / 94 marginal mandibulectomies O’Brien C.J., Int J Oral Maxillofac Surg 2003

28. GB Cancers – Locally advanced T3, T4 SURGERY FOLLOWED BY PORT RADIOTHERAPY WITH SALVAGE SURGERY  NO RANDOMIZED CONTROL TRIALS

29. Radiotherapy Carcinoma Buccal Mucosa 185 cases 2 years DFS- 5% RT 33% SX Chaudhary, Seminars in Surgical Oncology 1989 Late Stage

30. Gingivo – Buccal Sulcus Tumors Radiotherapy 234 patients ( Nair et al Cancer 1988) Stage I – 85%, Stage II – 63%, Stage III – 41%, Stage IV -15% Radium implant (28) = Small Volume ext. RT (62% Vs 64%) Dismal Survival with RT in advanced stage poor surgical salvage Compared three groups : S alone / S – PORT / RT (no survival) Chhetri D.K., Otolaryngol Head Neck Surg 2000

31. Adjuvant RT ( RTOG 73.03 ) 1973-1979 ( N=277) Pre-opPOST OP RT LR CONTROL48% 65% [p=0.04] SURVIVAL33% 38% [ p=O.1,better trend] COMPLICATIONSSAME ORAL CAVITY (43)PREOP RT PORT SUBSET OAS 30%36% ANALYSISLRC 43%52%

32. Radiotherapy in head and neck Cancers Radiotherapy in head and neck Cancers RTOG 73-03 277 PATIENTS - FOLLOW UP 9-15 yrs PRE OP RTPOST OP RT [ 50.0 GY ] [ 60.0 GY ] LOCO REGIONAL CONTROL BETTER(p = 0.04) NO DIFFERENCE IN ABSOLUTE SURVIVAL (p = 0.15) COMPLICATIONS SAME(p - NS)

33. Surgery + PORT (1988 – 1994) Surgery + PORT (1988 – 1994) n-57 – ( Sx + RT) RT 45 – 68.4 (61.2 Gy) Poor prognostic factors – (Univariate) - Positive Surgical Margin - Tumor invasion of cheek Poor prognostic factors – (Multivariate) - Tumor invasion of skin (p=0.0014) Fu-min Fang et al Head & Neck 1997

34. GBS Cancers – The TMH Experience Prognostic factors -Late Stage ( III / IVa) Univariate Analysis Gradep=0.002 Cut marginsp=0.04 Node positivityp=0.000 Perinodal extensionp=0.008 Thickness > 4mmp=0.004 Multivariate Analysis Node positivityp=0.001, HR=2.81, CI (1.5 – 5.2) Thickness >4mmp=0.002, HR=1.8, CI (1.2 – 2.8) n 624 DFS 2yrs 38.5% 5yrs 13%

35. Surgery v/s Surgery + PORT (1989 – 1993) N=176 patients115(S)61(S+R) LR control 11%48% III/IV (p=0.001) 71%75%I/II (p=NS) 71%75%I/II (p=NS) PROGNOSTIC FACTORS Margins Margins Thickness Thickness Bone invasion Bone invasion Grade Grade Nodal involvement Nodal involvement RT BETTER IF BEFORE 30 DAYS - Dixit S, Vyas RK, Ann Surg Oncol. 1998 - Dixit S, Vyas RK, Ann Surg Oncol. 1998

36. GB Sulcus Cancers – POST OP RT RCT GB CANCERS (T3; T4, N0 – N2b) SURGERY (60) SURGERY + RT (80) 58 – 65 GY 30 MONTHS FOLLOW UP DISEASE FREE SURVIVAL 38% v/s 68%( p < 0.005) Mishra et al (1996 – European Journal of Surgical Oncology)

37. RCT – Role of RT Peters et al (1993)RISK GROUPS RCT N = 240 LOW RISKHIGH RISK DOSE A DOSE B DOSE C DOSE A DOSE B DOSE C 52 – 54 Gy/ 6wks 63Gy/ 7wks/35# 68.4Gy/7.5wks/35# Interim Analysis Higher Recc 57.6Gy/ 6.5wks CONCLUSIONS: a. A minimum of 57.6 Gy with boost of 63 Gy to sites of high risk and ECS, is essential b. Treatment should be started as soon as possible c. Dose escalation above 63 Gy does not appear to improve therapeutic ratio

38. POST OP RT RCT – 213 patients Low risk n = 31 NO ADJUVANT RT Intermediate risk n = 31 57.6 Gy/ 6.5 weeks High risk n = 151 n = 76 63 Gy / 6.5 weeks n = 75 63 Gy / 7weeks RISK FACTORS: Oral cavity primary Margins close / positive Perineural invasion  2 positive lymph nodes Largest node > 3 cms Performance status  2 [WHO] Delay > 6 weeks (Ang et al, 2001)

39. Low risk / Intermediate risk had similar control & survival They did better than high risk They did better than high risk High risk had a trend towards better control when RT was given over 5 weeks High risk had a trend towards better control when RT was given over 5 weeks Ang et al, 2001 Results

40. POST OP CHEMORADS EORTC – NEJM 2004 Curative post surgery 167 RT [66 Gy / 6.5 weeks] 167 CT / RT [100mg Cispat/m2 T3;T4;Node +ve &T1/T2 adverse factors Median follow up 60 months I.Progression free survival47% v/s 36%(p = 0.04) II.Overall survival53% v/s 40%(p = 0.02) III.Locoregional recurrences18% v/s 31%(p = 0.007) IV.Toxicity [GR  3]41% v/s 21%(p = 0.001)

41. POST OP CHEMORADS RTOG (9501) – NEJM 2004 Curative surgery 231 RT [60 – 66 Gy ] 228 RT + Cisplat [100mg/m2, Day 1,22,43]  2 nodes; ECS; +ve margins Median follow up 60 months I.Locoregional control82% v/s 72%(p = 0.01) II.Disease free survivalbetter(p = 0.04) III.Overall survivalsimilar(p = 0.19) IV.Acute toxicity [GR  3]77% v/s 34%(p < 0.001)

42. Gingivo – Buccal Cancers (T3 / T4) Prospective Randomised Control Trial 135 patients ; Stage III / IV (65) Inj. MTX 50mg / m2 (day 3,10,17) (70) Observation DFS 61% Vs 37% (p=0.01) Local Recurrence less in first 6 months (p=0.002) Rao et al Am J Surg. 1994

43. G B Cancers - T 3 / 4 Management of nodes 1980 – 1989 - 527 patients Extent of neckSD SOHD RND Dissection (Level I ) (Level I – III) (Level I – V ) N0 N+ N0 N+ N0 N+ Nodes 95 71 141 42 67 111 Regional 11(12%) 24(34%) 7(5%) 8(19%) 2(3%) 20(18%) Recurrence Pradhan S.A., D’Cruz A.K. – Eur Arch Otorhinolaryngol (1995) 252 – 143 - 145

44. Recurrent Oral Tumors 38 patients who recurred after curative treatment Salvage better if :- i) Initial tumor stage I / II Vs III / IV ( p < 0.001) ii) Recurring after 6 months ( p < 0.005) iii) Surgery for salvage Vs RT / CT ( p < 0.001) iv) Stage of recurrence (N S) Overall Salvage rate 21% Overall salvage rate whether 15% (Wheeler, 1990) Schwatz, Head & Neck, Jan 2000

45. Management of Advanced Unresectable Head and Neck cancers Altered fractionation radiation Altered fractionation radiation Induction chemotherapy Induction chemotherapy Alternating chemo-radiotherapy Alternating chemo-radiotherapy Concurrent CT RT Concurrent CT RT

46. Altered Fractionation Radiation RTOG 9303 N=1113 patients N=1113 patients Four arms Four arms Standard fractionation Standard fractionation Hyperfractionation Hyperfractionation Accelerated hyperfractionation with Split Accelerated hyperfractionation with Split Accelerated fractionation with Concomitant boost Accelerated fractionation with Concomitant boost Results Results Better locoregional control with Hyperfractionation (p=0.045) & Accelerated fractionation with Concomitant boost (p=0.050) Better locoregional control with Hyperfractionation (p=0.045) & Accelerated fractionation with Concomitant boost (p=0.050) All three Altered fractionation group had increased acute toxicity and comparable late toxic effects All three Altered fractionation group had increased acute toxicity and comparable late toxic effects Fu et al,Int J Radiat Oncol Biol Phys 2000

47. GB cancers stage- IV B/C No conclusive evidence confirming the role of chemotherapy in palliation as compared to best supportive care

48. Foscan study in advanced disease Objectives Objectives improvement in quality of life improvement in quality of life objective tumour response (complete and partial) objective tumour response (complete and partial) toxicity, tolerability and safety toxicity, tolerability and safety one-year survival one-year survival

49. PDT Advanced Cancers 147 patients assessed to date [ 109 M, 38 F] 50% Caucasians, 50% Asians Clinical benefit 24% objective response 24% objective response 53% overall palliative benefit 53% overall palliative benefit

50. Overall study results Overall palliative benefit 53% (64 patients) 43 patients were optimally treated 61% showed overall palliative benefit Palliation ( 122 patients.)

51. VERRUCOUS CARCINOMA 5% of all SCC 5% of all SCC LOCALLY AGGRESSIVE LOCALLY AGGRESSIVE DE-DIFFERENTIATION WITH RT (Medina’ 84) DE-DIFFERENTIATION WITH RT (Medina’ 84) Recent studies DO NOT CONFIRM above Recent studies DO NOT CONFIRM above (Tharp, Laryngoscope 1998; McCafferey 1998) Better results with SURGERY compared to RT Better results with SURGERY compared to RT

53. Chemoradiation in Advanced Head & Neck cancers Induction Chemotherapy Induction Chemotherapy Initial response rates 50 – 90% with Cisplatin-5FU based schedules Initial response rates 50 – 90% with Cisplatin-5FU based schedules However, multiple RCT’s – Failure to demonstrate a survival advantage with either Single / Multiagent Chemotherapy However, multiple RCT’s – Failure to demonstrate a survival advantage with either Single / Multiagent Chemotherapy

54. Chemoradiation in Advanced Head & Neck cancers Alternating Chemoradiation Alternating Chemoradiation 2 RCT’s 2 RCT’s Complete response rates, Progression free survival and OAS – significantly better for Alternation chemoradiation arm as compared to Radiation Complete response rates, Progression free survival and OAS – significantly better for Alternation chemoradiation arm as compared to Radiation - Merlano, Cancer 1991; Merlano J Natl Cancer Inst 1996 Concurrent Chemoradiation Concurrent Chemoradiation MACH-NC: 63 RCT’s, 10,000 patients MACH-NC: 63 RCT’s, 10,000 patients 5 yr OAS benefit = 8% (p<0.0001) 5 yr OAS benefit = 8% (p<0.0001) -Pignon et al, Lancet 2000

55. TMH RETROSPIVE REVIEW 3YRS [ 1997 – 1999] Chart review of 2275 patients Chart review of 2275 patients DFS DFS Median followup Median followup No of patients with surgery +/- RT No of patients with surgery +/- RT Stages at presentation Stages at presentation Reccurrence rates Reccurrence rates

56. Adjuvant Chemotherapy for stage III / IV Head & Neck Contracts Program Randomise Surgery Induction CT Maintenance Radiation 71 / 152 (Standard) Induction CT Surgery RT 60 /140 (Induction) Induction CT Surgery RT CT (Maintenance) 67 /151 1978 -1982 ; 462 patients (Median Follow-up 61 months) OS & DFS similar (p=0.86 & p= 0.16) DM less in maintenance group ( p=0.025 & p= 0.021) Time to 1 st relapse increased ( p= 0.032 & p= 0.022) Cancer 1980

59. GBS Cancers – The TMH Experience (1997-99) Late Stage(III/IVa) n624 Median follow up1.91 yrs DFS 2yrs38.5% 5yrs13% OAS 2yrs85% 5yrs78% Overall recc rate37% Salvage rate 19%