Management of carcinoma hypopharynx

Pre-treatment evaluation
Staging
Treatment overview



Evidence based treatment
NCCN guidelines

1. Management of carcinoma hypopharynx By- Dr. Isha Jaiswal Moderator- Dr. Shantanu Sapru Date: 10 th December 2014

2. Topics to be covered: Pre-treatment evaluation Staging Treatment overview Evidence based treatment NCCN guidelines Surgery Radiotherapy Chemotherapy Biological therapy

3. Evaluation of patients with suspected hypopharyngeal cancer Clinical Exanimation of head & neck Fiber optic laryngopharyngoscopy & biopsy of primary tumor Contrast enhanced CT scan face and neck Contrast enhanced MRI face & neck Chest X Ray Blood investigations Optional investigations CECT chest PET Scan Barium swallow

4. Fiber-optic direct laryngoscopy used routinely to complement the laryngeal mirror examination. assessment of extent of primary tumor & mobility of vocal cords. critical in assessing the superficial spread of neoplasm superior to any imaging modality in detecting mucosal spread can be attached to a photographic device biopsy of the tumor is done for histopathological confirmation.

5. Typical findings of hypopharyngeal cancer on endoscopy: Ulceroproliferative/infiltrative growth. mucosal ulceration . pooling of the saliva in the pyriform fossa . oedema of the arytenoids . fixation of the cricoarytenoid joint, or true vocal cords or both.

6. CECT Scan Face & Neck Timing : should be done before biopsy of to avoid post biopsy oedema. Advantages : aids in staging by detection of: Limitations invasion into larynx. extra laryngeal/extra pharyngeal spread. paraglottic space spread. spread to retropharyngeal space. c linically occult metastatic lymphadenopathy. Failure to detect small superficial tumours & early laryngeal cartilage involvement. Underestimating ulcerative and infiltrative lesions overestimating tumor extent due to inflammation/ oedema & distortion of adjacent normal structures

7. MRI Face & Neck Compared to CECT shows better soft tissue contrast & less artifact from dental fillings. An important adjunct study in three situations: Disadvantages : Determining cartilage invasion : shown by increase T2 signal & post contrast enhancement. Determining extent of extralaryngeal / paraglottic space involvement Determining oesophageal involvement shown by increased T2 signal, wall thickening and effaced fat planes motion artefacts. overestimating tumour extent :inflammation/ oedema /distortion

8. In detection of unknown /small primary tumor In evaluating clinically occult nodal involvement In follow up to differentiate between treatment sequelae & tumor recurrence/residual Role Of 18FDG PET-CT

9. Impact Of FDG-PET On Staging &Management of H&N SCC* A multicenter study of 233 H&N SCC patients (including 46 hypopharyngeal cancer) TNM staging and therapeutic decisions were first determined based on conventional workup & then FDG-PET data was used to restage the patients & reanalyse their management. PET and conventional workup revealed discordant TNM staging in 100 patients (43%). PET was deemed significantly more accurate than conventional staging & improved the staging in 20% of patients. Incorporation of PET data ultimately impacted management in 32 patients (13.7%). * Lonneux M, Hamoir M, Reychler H, et al. Positron emission tomography with [18F] fluorodeoxyglucose improves staging and patient management in patients with head and neck squamous cell carcinoma: a multicenter prospective study.  J Clin Oncol  2010;28:1190–1195.

10. CONCLUSIONS: FDG-PET is a reliable imaging procedure in the detection of clinically occult primary tumor/node and recurrent/residual carcinomas localized in the head and neck. it cannot as yet replace other diagnostic procedures in pretreatment planning but does contribute valuable complementary diagnostic information.

11. TNM STAGING- AJCC 7 TH edition (2010)* T1: Tumour limited to one subsite of hypopharynx and ≤ 2 cm in greatest dimension. T2: Tumour invades more than one subsite or adjacent site or measures >2cm but ≤ 4 cm without fixation of hemilarynx. T3: Tumours > 4 cm or with fixation of hemilarynx or extension into esophagus T4a: Tumor invades thyroid/cricoid cartilage, hyoid bone, thyroid gland, central compartment of soft tissue. T4b: Tumor invades prevertebral fascia, encases the carotid artery or involves mediastinal structures. *Edge SB, Byrd DR, Compton CC, et al.  AJCC cancer staging handbook,  7th ed. New York: Springer, 2010 .*

12. TNM STAGING- AJCC 7 TH edition (2010)* N0: No regional LN N1: Single ipsilateral LN ≤ 3cm N2a: Single ipsilateral LN 3-6cm b: Multiple ipsilateral LNs ≤ 6cm c: Bilateral or contralateral LNs ≤ 6cm N3: Any LN more than 6cm M stage: Mx - cannot be assessed, M0- no distant metastasis, M1- distant metastasis

13. Stage grouping Stage Tis N0 M0 Stage I T1 N0 M0 Stage II T2 N0 M0 Stage III T1, T2 T3 T3 N1 N0 N1 M0 M0 M0 Stage IV A T1,T2,T3 T4a N2 N0,N1 ,N2 M0 M0 Stage IV B Any T T4b N3 Any N M0 M0 Stage IV C Any T Any N M1

14. Treatment options Surgery Types Indications Evidence Targeted therapy Types Indications Evidence Chemotherapy Types Indications Evidence Radiotherapy Types Indication Evidence Multi modality treatment

15. General Treatment Recommendations Based On Hypopharynx Tumor Stage* * Perez & Brady's Principles and Practice of RadiationOncology

16. Single Modality: – Surgery or RT Choice depends on – Tumor: site, extension – Patient: preference, comorbidities – Expertise of the multidisciplinary team , available resources Equally effective : however no randomised trials for surgery vs. RT. Each modality can salvage the other if local recurrence. EARLY STAGE (I-II)(T1-T2, N0)

17. ADVANCED STAGE:(III/IV) T1-2 , N1-3 / T3-4, N0-N+ Multi Modality: Radiotherapy with altered fractionation schedules Radiotherapy with chemotherapy R adiotherapy with biological therapy Neoadjuvant chemotherapy f/b surgery Surgery f/b RT/CT-RT Choice depends on Tumor: site, extension Patient: preference, comorbidities Expertise of the multidisciplinary team, available resources

18. RADIATION THERAPY Definitive RT conventional fractionation hyper fractionation accelerated radiotherapy Preop-RT Post-op RT

19. Benefits of RT over surgery Probability of functional morbidity or cosmetic defects is reduced. Risk of a major postoperative complication is avoided Elective neck RT can be included with little added morbidity. Surgical salvage of RT failure is supposed to have better outcome than the RT salvage of a surgical failure. Indications for primary radiotherapy small sized tumor larynx/voice preservation those who refuse surgery

20.   CAUSE-SPECIFIC AND OVERALL SURVIVAL FOR CARCINOMA OF THE PYRIFORM SINUS TREATED WITH RADIATION ALONE 2001 As stage increases 5 years survival with RT alone decreases

21. Radiation treatment intensification 2 . Addition of chemotherapy to RT 1 . Altered fractionation RT 3.Chemotherapy +Altered fractionation RT 4. Addition of biological therapy to RT

22. *2Horiot JC. Controlled clinical trials of hyperfractionated and accelerated radiotherapy in otorhinolaryngologic cancers [in French]. Bull Acad Natl Med  1998;182(6 ) *#Cummings B, O’Sullivan B, Keane T. 5-year results of a 4 week/twice daily radiation schedule: the Toronto Trial.  Radiother Oncol 2000 *2 *3 TRIALS OF HYPERFRACTIONATION

23. 1992 EORTC 22791

24. TRIALS OF PURE ACCELERATED FRACTIONATION *!Jackson et al. A randomised trial of accelerated versus conventional radiotherapy in head and neck cancer. Radiother Oncol   1997 *2Skladowski Ket al. 7-day-continuous accelerated irradiation (CAIR) of head and neck cancer —.   Radiother Oncol   2000;55 *3Overgaard J,. The DAHANCA 6 and 7 trial: a study of 5 versus 6 fractions per week of conventional radiotherapy of ( SCC) of the head and neck.  Radiother Onco   *4Hliniak AZ..   Radiother Oncol  2000;56:S5. *1 *2 *3 *4

25. Aim: to find whether shortening of treatment time by use of six instead of five radiotherapy fractions per week improves the tumour response in squamous-cell carcinoma. Lancet. 2003 randomised trial between January, 1992, and December, 1999, 1485 patients treated with primary radiotherapy alone, 1476 eligible patients were randomly assigned five (n=726) or six (n=750) fractions per week at the same total dose and fraction number (66-68 Gy in 33-34 fractions)

26. TWO SUBPROTOCOLS : DAHANCA 6 , which included all glottic carcinomas , and DAHANCA 7 , included tumours of the supraglottic larynx,pharynx , and oralcavity The only difference in the two subprotocols was that DAHANCA 6 dealt only with the fractionation effect, whereas the DAHANCA 7 also included treatment with the hypoxic radiosensitiser nimorazole . More than 97% of the patients received the planned total dose . Median overall treatment times were 39 days (six-fraction group) and 46 days (five-fraction group ).

27. Primary locoregional tumour control as function of number of fractions per week Overall 5-year locoregional control rates were 70% and 60% for the six-fraction and five-fraction groups, respectively (p=0.0005). primary tumour control (76 vs 64% for six and five fractions, p=0.0001), but was non-significant for neck-node control

28. Disease specific survival Overall survival Disease-specific survival improved (73 vs 66 %) for six and five fractions but not overall survival

29. Early and late radiation-related morbidity Acute morbidity was significantly more frequent with six than with five fractions , but was transient. CONCLUSION Accelerated radiotherapy applied to squamous-cell carcinoma of the head and neck yields better locoregional control than does a conventional schedule with identical dose and fractionation.

30. 2010 IAEA-ACC

31. *1 Dische , et al. A randomised multicentre trial of CHART versus conventional radiotherapy in head and neck cancer .  Radiother Oncol  1997 ; *2 Poulsen , et al. A randomised trial of accelerated and conventional radiotherapy for stage III and IV SCCHN: aTTROG   Radiother Oncol  2001 ; *3   Bourhis , et al. Preliminary results of the GORTEC 96–01 randomized trial, comparing very accelerated radiotherapy versus concomitant radio-chemotherapy for locally inoperable HNSCC.  Int J Radiat Oncol Biol Phys  2001 ; *1 *2 *3

32. 1997

33. 2010

34. . Patients with stage III or IV SCC (n=1076) were randomized to 4 treatment arms: 2000

35. Standard fractionation 70 Gy /35 daily fractions/7 weeks (2) Hyper fractionation 81.6 Gy /68 twice-daily fractions/7 weeks (3) Accelerated fractionation with split 67.2Gy(1.6bid )/42 fractions/6 weeks with a 2-week rest after 38.4 Gy (4) Accelerated fractionation with concomitant boost 72 Gy /42 fractions/6 weeks.(1.8Gy/f with 1.5 Gy /f boost on last 12 fractions)

36. RTO 90-03 Results: at 2years LRC : significant improvement in 2 yr locoregional control for the hyper fractionation and concomitant boost arms . DFS : trend toward improved disease-free survival (p = 0.067 and p = 0.054 respectively for the hyper fractionation and concomitant boost arms OS: difference in overall survival was not significant. TOXICITY : altered fractionation regimens were associated with higher incidence of grade 3 or worse acute mucosal toxicity , but no significant difference in overall toxicity at 2 years following completion of treatment.

37. 2006 GORTEC 9402

38. CHEMOTHERAPY NEOADJUVANT CONCURRENT ADJUVANT

39. 1996 EORTC 24891 EORTC trial 24891 compared PF (cisplatin and 5-FU) induction chemotherapy followed by radiation therapy (RT) versus total laryngectomy , radical neck dissection, and postoperative RT in patients with hypopharyngeal cancer  Role of NACT for larynx preservation NACT-RT Vs Surgery-RT

40. Patient characteristics

41. Survival Disease free survival Metastasis free survival Larynx preservation

42. Treatment failures occurred at approximately the same frequencies in both arms. F ewer failures at distant sites in the induction-chemotherapy arm The median duration of survival was 25 months in the immediate-surgery arm and 44 months in the induction-chemotherapy arm The 3- and 5-year estimates of retaining a functional larynx in patients treated in the induction chemotherapy arm were 42 % and 35 % respectively . CONCLUSION OF EORTC 24891

43. Choice of chemotherapy regimen: 2 drug vs.3 drug regimen

44. 2007: TAX323/EORTC 24971

45. PATIENT CHRACTERISTICS: 29%pts of ca hypopharynx Aim : compare TPF with PF as induction chemotherapy in patients with locoregionally advanced, unresectable disease. P rimary end point : PFS 358 patients underwent randomization, with 177 assigned to the TPF group and 181 to the PF group ARM A (N=177) ARM B(N=181) TOTAL P value

46. CONCLUSION OF TAX 323 At a median follow-up of 32.5 months, the median PFS was 11.0 months in the TPF group and 8.2 months in the PF group . There were more grade 3 or 4 events of leukopenia and neutropenia in the TPF group and more grade 3 or 4 events of thrombocytopenia, nausea , vomiting, stomatitis, and hearing loss in the PF group .

47. 2007: TAX 324

48. 15% patients of ca hypopharynx Aim: compare induction chemotherapy with docetaxel plus cisplatin and fluorouracil (TPF) with cisplatin and fluorouracil (PF), followed by chemoradiotherap y for treatment of SCCH& N

49. Results of TAX 324 more patients survived i n the TPF group than in the PF group e stimates of overall survival at 3 years were 62% in theTPF group and 48% in the PF group, median overall survival was 71 months and 30 months, respectively (P = 0.006). better locoregional control in the TPF group than in the PF group (P = 0.04) i ncidence of distant metastases in the two groups did not differ significantly (P = 0.14 ) Rates of neutropenia and febrile neutropenia were higher in the TPF group ; chemotherapy was more frequently delayed because of hematologic adverse events in the PF group

50. 2009 GORTEC 2000-01

51. CONCURRENT CHEMORADIOTHERAPY

52. An Intergroup Phase III Comparison of Standard Radiation Therapy and Two Schedules of Concurrent Chemoradiotherapy in Patients With Unresectable Squamous Cell Head and Neck Cancer. J Clin David J. Adelstein Oncol 21:92-98. 2003 2003 CTRT VS RT ALONE which one is better in unresectable HNSCC?

53. ARM C CTRT of 2 Gy /d, was split between the first CT course (30 Gy ) & third CT course (30 to 40 Gy ). A total dose of 60 to 70 Gy was given The radiation therapy break was planned to allow for the possibility of surgical resection in those patients rendered resectable after the first two courses of chemotherapy and the first 30 Gy of radiation . Patients who had achieved a complete response after this induction or who remained unresectable proceeded, without surgery, to complete chemoradiotherapy .

54. 2003, 2006,2012 Forastiere et al RT Vs. CTRT Vs. NACT-RT which one is better? J Clin Oncol.  2013 Mar 1;31(7):845-52. doi: 10.1200/JCO.2012.43.6097. Epub 2012 Nov 2 Journal of Clinical Oncology, 2006 ASCO Annual Meeting Proceedings Vol 24, No 18S (June 20 Supplement), 2006: 5517

55. 2012 Radiotherapy Alone Vs . Concurrent CTRT Vs. Sequential NACT-RT J Clin Oncol.  2013 Mar 1;31(7):845-52. doi: 10.1200/JCO.2012.43.6097. Epub 2012 Nov 2

56. Loco regional control Overall survival Larynx preservation 2012 UPDATE

57. No Published Phase 3 Trial Study Have Tested Induction Chemotherapy f/b chemoradiotherapy Vs Upfront Chemoradiotherapy

58. ALTERED FRACTIONATION ± CHEMO-RADIOTHERAPY

59. Lancet Oncol .  2012 Feb;13(2):145-53. doi : 10.1016/S1470-2045(11)70346-1. Epub 2012 Jan 18 2012 aimed to assess the efficacy and safety of a combination of approaches.

60. STAGE III/IV, M0 HNSCC n=840 R A N D O M I Z E D Arm A Conventional chemo radiotherapy

61. RT – 70Gy/6w 1 st 40Gy  2Gy/#/d, 5#/w Next 30Gy (off the spinal cord)  1.5Gy/#/BD CT – 2 cycles of 5days each, 4w apart. Carboplatin 70mg/ sqm /d + 5FU 600mg/ sqm /d RT – 70Gy/35#/7w at 2Gy/#, 5#/w CT – 3 cycles of 4days each, 3w apart. Carboplatin 70mg/ sqm /d + 5FU 600mg/ sqm /d RT – 64.8Gy/3.5w at 1.8Gy/#/BD, 5#/ w Arm A Conventional chemoradiotherapy Arm B Accelerated RT with concomitant CT Arm C Very Accelerated RT . Median follow-up was 5·2 years

62.   Accelerated radiotherapy-chemotherapy offered no PFS benefit compared with conventional chemoradiotherapy or very accelerated radiotherapy conventional chemoradiotherapy improved PFS compared with very accelerated chemoradiotherapy , 34·1% (28·7-39·8) after accelerated radiotherapy-chemotherapy, and 32·2% (27·0-37·9) after very accelerated radiotherapy. More patients in the very accelerated radiotherapy group had RTOG grade 3-4 acute mucosal toxicity (226 [84%] of 268 patients) compared with accelerated radiotherapy-chemotherapy (205 [76%] of 271 patients) or conventional chemoradiotherapy (180 [69%] of 262; p=0·0001 ). ( 60 %) of patients in the conventional chemoradiotherapy group, ( 64%) of patients in the accelerated radiotherapy-chemotherapy group, and ( 70%) of patients in the very accelerated radiotherapy group were intubated with feeding tubes during treatment (p=0·045). Results of GORTEC 9902

63. CONCLUSION OF GORTEC 9902 Chemotherapy has a substantial treatment effect given concomitantly with radiotherapy. 2. Acceleration of radiotherapy cannot compensate for the absence of chemotherapy. 3. Acceleration of radiotherapy is probably not beneficial in concomitant chemo-radiotherapy schedules.

64. 2000 Lancet.  2000 Mar 18;355(9208):949-55 2007 Radiother Oncol .  2007 Oct;85(1):156-70. Epub 2007 May 4. 2009 Radiother Oncol .  2009 Jul;92(1):4-14. doi : 10.1016/j.radonc.2009.04.014. Epub 2009 May 14 2011 Radiother Oncol .  2011 Jul;100(1):33-40. doi : 10.1016/j.radonc.2011.05.036. Epub 2011 Jun 16

65. ABSOLUTE BENEFITS- oral cavity-8.9% oropharynx-8.1% larynx-5.4% hypopharynx-4% 2011 update

66. platinum based regimen more effective. no significant difference efficacy between mono and multi drug platinum regimens

67. LEVEL 1 EVIDENCE OF ADDITION OF CT IN TERMS OF OVER ALL SURVIVAL. ADDITION OF CT-ABSOLUTE BENEFIT IN SURVIVAL-5%IN 5 YRS. INDUCTION/ADJUVANT-2% SUVIVAL BENEFIT CONCURRENT CTRT 8% 5YR SURVIVAL BENEFIT BENEFIT MORE IN CONCURRENT CTRT BENEFIT DECREASES WITH INCREASING AGE. ABSOLUTE BENEFITS-oral cavity 8.9% oropharynx-8.1% larynx-5.4% hypopharynx-4% MACH- NC-CONCLUSIONS

68. MARCH META-ANALYSIS 2006 2010 The Lancet,  Volume 368, Issue 9538 , Pages 843 - 854, 2 September 2006

69. 15 Randomized Trials of Varied Fractionation (1970-1998) PATIENT CHARACTERISTICS 7073 patients Tumours sites: mostly oropharynx and larynx 74% patients had stage III—IV disease hyper fractionated accelerated accelerated with total dose reduction Overall survival was the main endpoint median follow up:6 yr

70. benefit Conventional vs Altered Hyper fractionation vs Accelerated fractionation Locoregional control Loco regional control 6.4 % times higher benefit was higher with hyper fractionated radiotherapy ( OS 8% at 5 years ) than with accelerated radiotherapy ( 2% with accelerated fractionation without total dose reduction and 1·7% with total dose reduction at 5 years, p=0·02) Survival benefit absolute benefit of 3·4% at 5 years with altered fractionated radiotherapy,

71. RESULTS OF MARCH META-ANALYSIS: There was a significant surviva l benefit in altered fractionation.(3.4%at 5 years) There was a benefit on locoregional control in favour of altered fractionation versus conventional radiotherapy (6·4% at 5 years; p<0·0001 The benefit was significantly higher in the youngest patients Interpretation Altered fractionated radiotherapy improves survival in patients with head and neck squamous cell carcinoma. Comparison of the different types of altered radiotherapy suggests that hyperfractionation has the greatest benefit

72. Role of biological therapy Cetuximab with RT Bonner et al- 424 patients Locally advanced SCCHN 15% pt : Ca hypopharynx

73. Bonner et al, 2006 Drawback: in control arm RT alone given (not a standard treatment for stage III and IV HNSCC)

74. LOCOREGIONAL CONTROL OVERALL SURVIVAL

75. Bonner et al 2010 update: 5 years follow up

76. subgroups analysis demonstrated effect of cetuximab was pronounced in patients with oropharyngeal carcinoma , T1-T3 disease, concomitant boost radiation, N1-N3, KPS 90-100 , male patients, EGFR expression ≤ 50%, ≤65 years.

77. Surgical options in operable Ca hypopharynx Voice preservation surgery in early hypopharynx cancer Supraglottic laryngectemy Hemilaryngectomy Partial laryngopharyngectomy Radical Laryngectomy in advanced stages Total laryngectomy Total laryngopharyngectomy

78. Primary Surgery T1 and T2 Tumors: voice conservation surgery I NDICATIONS CONTRAINDICATIONS voice conservation approaches possible refuse radiation vocal fold fixation, cartilage invasion, postcricoid invasion, deep pyriform sinus invasion, extension beyond the larynx T3 / T4 Tumors INDICATIONS d ysfunctional larynx pt. with bulky destructive tumor that severely compromise airway or destroy cartilage, bone, soft tissue undergo immediate laryngopharyngectomy and post op radiation

79. operation indication parts removed contraindication hemilaryngectomy horizontal partial supraglottic laryngectomy(SGL) T1/T2 pyriform sinus tumor voice preservation for early supraglottic extension epiglottis aryepiglottic fold false cords upper 1/3-1/2 of thyroid cartilage ±hyoid bone preserves one or both arytenoids & true vc thyroid,cricoid cartilage invasion arytenoid involvement vocal fold fixation postcricoid invasion deep pyriform sinus invasion extension beyond the larynx fixed neck nodes inadequate pulmonary function extended supraglottic laryngectomy supraglottic lesion with<1cm base of tongue invasion same as SGL with removal of i/l bot upto circumvallete papillae

80. operation indications removes contraindication partial laryngopharyngectomy used for small medial and anterior pyriform sinus lesion false vocal cord epiglottis aryepiglottic fold pyriform sinus, tvc are preserved transglottic extension, cartilage invasion vocal cord paralysis, pyriform apex invasion, postcricoid invasion extralaryngeal spread poor pulmonary reserve total laryngectomy Advanced pyriform sinus lesion cartilage invasion removes hyoid, thyroid, cricoid cartilage, epiglottis strap muscle. Patient left with a permanent tracheostoma and pharynx reconstruction total laryngopharyngectomy for more advanced hypopharyngeal lesion total laryngectomy plus removal of varying amount of pharyngeal wall

81. Advances in surgery In recent years, advancements in organ preservation surgery have included the use of Transoral laser microsurgery Transoral robotic surgery. Advantage Less morbidity avoiding tracheostomy and the use of feeding tubes

82. Transoral Laser Surgery: Inclusion Criteria * Complete endoscopic visualization of the growth Tumor extension to the contralateral VC < 3mm Absence of arytenoid involvement (except vocal process) Subglottic extension < 5mm Supraglottic extension no further than lateral extension of ventricle Mobile vocal folds No cartilage involvement * Motamed M, et. al. Salvage conservation laryngeal surgery after irradiation failure for early laryngeal cancer. Laryngoscope 2006; 116:451-455

83. ADJUVANT RADIOTHERAPY IN OPERATED HNSCC

84. Preoperative RT Vs postoperative RT: RTOG 73-03 Phase III study of preoperative radiation therapy (50.0 Gy ) versus postoperative radiation therapy (60.0 Gy ) for supraglottic larynx and hypopharynx primaries duration of follow-up was 9-15 years, Loco-regional control& absolute survival was estimated & compared 1987

85. N=277 patients. Operable stage T2-T4 / N± oral cavity(14%) Oropharynx(17%) Supraglottic larynx(26%) Hypopharynx(43%) Postoperative stage III or IV SCCHN R A N D O M I Z E Arm 2:Post-op RT 60 Gy . n= 141 Arm 1: Pre-op RT 50 Gy n=136

86. Long-term Follow-up Of RTOG Study 73-03 * ( Tupchong L et al. Int J Radiat Oncol Biol Phys. 1991 Jan;20(1):21-8.) outcome preopRT postopRT LRC 58% 70% LRF within 2 years 59% 58% LRF after 2years 27% 8% Overall survival similar toxicity similar Post op RT is better than preop RT for LRC 1991

87. Indications for post operative radiotherapy Primary: Large primary - T4 or T3 with soft tissue infiltration Close or positive margins of excision Deep infiltrative tumour High grade tumour Lympho -vascular and perineural invasion Lymph nodes: Bulky nodal disease N2 / N3 Extra nodal extension Multiple level involvement

88. POSTOPERATIVE RADIOTHERAPY Is PO CTRT better than PORT alone?

89. RANDOMIZE Cisplatin 100 mg/m 2 d 1, 22, 43 XRT XRT Cooper et al, 2004; Bernier et al, 2004. SURGERY RTOG 95-01 459 patients EORTC 22931 334 patients EORTC (66 Gy over 6 ½ wks ) RTOG (60–66 Gy over 6-6 ½ wks ) Postoperative Chemoradiotherapy

90.   RESULTS OF POSTOP CHEMORADIATION TRIAL

91. EORTC 22931 only Bernier et al N=334 EORTC 22931 and RTOG 9501 RTOG 9501 only Cooper et al.2004 N=459 stage III/IV disease margin+ ≥2positive l.n ECE+ ECE + ECE + margin + margin+ PNI+ embolism

92. NCCN GUIDELINES