Oral Cavity Cancer Combined modality therapy

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1 Oral Cavity Cancer Combined modality therapy Dr. Christos CHRISTOPOULOS Radiation Oncologist Head and Neck Cancers Centre Hospitalier Universitaire (C.H.U.) de Limoges, France

2 Disclosure slide I have no conflicts of interest to disclose

3 Overview

4 Introduction Overview

5 Introduction Overview RT techniques

6 Overview Introduction RT techniques Patient selection

7 Overview Introduction RT techniques Patient selection Risk factors

8 Overview Introduction RT techniques Patient selection Risk factors Time factor

9 Overview Introduction RT techniques Patient selection Risk factors Time factor Technical aspects

10 Overview Introduction RT techniques Patient selection Risk factors Time factor Technical aspects Immunotherapy

11 Overview Introduction RT techniques Patient selection Risk factors Time factor Technical aspects Immunotherapy Conclusion

12 Introduction Overview

14 Oral cavity cancer is a surgical disease but RT plays a capital role in the treatment of OCSCC either exclusively or as adjuvant after surgery. RT may be administered using two techniques: external beam radiotherapy (EBRT) and brachytherapy (BT). patients with unresectable or advanced disease will receive RT plus CHT or targeted therapy with monoclonal antibodies against epidermal growth factor receptor (EGFR) in order to enhance the cytotoxic effect of radiation.

17 Introduction Overview RT techniques

18 The role of RT is crucial in the treatment management Tecnological improvements for better precision IMAT / VMAT TOMOTHERAPY STEREOTACTIC RT IGRT IMRT 3D 2D New methods for better immaging

19 Radiotherapy techniques External Beam Radiation Therapy (EBRT)

20 Radiotherapy techniques External Beam Radiation Therapy (EBRT) Brachytherapy (BT).

21 EBRT CT simulation + multi-modal imaging (PET scan, MRI) IMRT technique

22 Can create radiation beams of different strengths Can shape RT beams more precisely: different doses of RT to different parts of treatment area so that dose to normal tissues is kept as low as possible Types: IMRT with static fields Dynamic IMRT Rotational IMRT (VMAT or Tomotherapy) GOLDEN STANDARD is the IMRT 2D -RT 3D -RT IMRT

23 IMRT Conclusion: IMRT compared with traditional 2D-EBRT has been shown to improve toxicity and survival in patients with head neck cancer.

iridium needles (192Ir) Τhis technique has been

24 Brachytherapy Traditionally BT implant has been performed with low dose rate (LDR) by inserting iridium needles (192Ir) Τhis technique has been gradually displaced by the so-called high dose rate (HDR) BT

$Brachytherapy The equivalent fractionation and total dosing between LDR and HDR is unknown.$

25 Brachytherapy The equivalent fractionation and total dosing between LDR and HDR is unknown. Neither the Groupe Européen de Curiethérapie-European Society for Radiotherapy and Oncology (GEC-ESTRO) nor the American Brachytherapy Society (ABS) came to publish a consensus, although they recommended not to exceed a dose of 6 Gy per fraction. In the comparative meta-analysis of Liu et al., the mean dose administered was Gy in LDR group and Gy in the HDR.

when the risk of involvement is significant due to the

26 EBRT + BT The main indication for combining EBRT and BT is the need to irradiate the cervical lymph node chains when the risk of involvement is significant due to the primary site, tumor thickness greater than 4 cm and stage ct2-t3.

27 Stages I-II best results were obtained when BT is part of the treatment, either exclusively or as tumor overdose after EBRT.

28 Stages I-II

29 Stages I-II Evidence is based entirely on retrospective series.

30 Stages III-IV RT alone Modification of EBRT fractionation allows to intensify radiation dose by means of two way: (a) increase in the total dose with hyperfractionation; and (b) shorten the duration of using accelerated fractionation radiotherapy.

31 Stages III-IV RT alone Hyperfractinated EBRT alone CF EBRT alone Accelerated EBRT alone Conclusion: statistically significant benefit in terms of overall survival (OS) HR = 0.92 in favor of MF-EBRT as well as an improvement in locoregional control (LRC) HR = Hyperfractionated EBRT was also significantly better in terms of OS than accelerated EBRT, with an absolute benefit of 8% at 5 years.

$Stages III-IV RT alone Hyperfractinated EBRT alone CF EBRT alone Accelerated EBRT alone Conclusion: MF-EBRT, reduces overall mortality, HR = 0.$

32 Stages III-IV RT alone Hyperfractinated EBRT alone CF EBRT alone Accelerated EBRT alone Conclusion: MF-EBRT, reduces overall mortality, HR = 0.86, and increased LRC HR = Trials included as "purely hyperfractionated" also showed a significant gain in OS compared with the accelerated fractionation HR = 0.78.

33 Stages III-IV RT + CHT CF EBRT CF EBRT + CHT Conclusion: Overall improvement in OS was demonstrated when CHT is added to RT. Maximum benefit was found when CHT is administered concurrently with EBRT: 5-year OS 8% improvement. The benefit of CRT is applicable to all locations of the head and neck.

34 Stages III-IV MF-RT vs. RT + CHT Accelerated EBRT alone CF EBRT + CHT Accelerated EBRT + CHT Conclusion: No statistically significant difference was found between the treatment groups at 3-year OS: 32.2% vs. 37.6% vs. 34.1%, nor distant metastasis (DM). However, both LRF (49.9% vs. 41.7% vs. 45.4%) and PFS (32.2% vs. 37.6% vs. 34.1%) were significantly lower in the accelerated EBRT arm. Mucosal acute toxicity and the need for feeding tube were significantly higher in patients treated with MF-EBRT.

35 Stages III-IV MF-RT vs. RT + CHT MF - EBRT alone MF - EBRT + CHT Conclusion: No statistically significant difference was found in 8-year OS (48% in both arms) LRF (37% vs. 39%) PFS (42% vs. 41%) or DM (15% vs. 13 %). No statistically significant differences in toxicity were found either. In conclusion, no advantage in combining MF-EBRT and CMT have been proved so far.

Stages III-IV Targeted therapies Conclusion: The inhibition of EGFR by monoclonal antibodies (cetuximab) associated with EBRT in patients with nonoperated AHNC showed an increase 5-year OS

36 Stages III-IV Targeted therapies Conclusion: The inhibition of EGFR by monoclonal antibodies (cetuximab) associated with EBRT in patients with nonoperated AHNC showed an increase 5-year OS (46% vs. 36%) and LRC (47% vs. 34%) compared with EBRT alone. Notably in this trial did not include patients with OCSCC therefore clinical benefit in this group of patients is presently unknown.

37 Stages III-IV Standard of care Nowadays, the standard of treatment for non-operable AHNC, including OCSCC, is EBRT plus CHT despite the fact that its benefit in OS and LRC probability equals of the hyperfractionated-ebrt. The reasons that have led to this situation are basically two: (1) logistics, due to the consumption of resources and the drawbacks associated with treating patients twice a day, for 7-8 weeks; and (2) the development of high conformation techniques as IMRT, which allow to exploit the different sensitivity to radiation of the tumor and healthy tissues using a single fraction per day with a shorter overall time of treatment, usually 5-6 weeks.

38 Post-op RT Conclusion: Post-op RT for the high-risk neck can reduce the rate of recurrence within a dissected neck, delayed metastasis within an undissected neck, cancer-related death, and death from any cause.

39 Post-op RT Conclusion: adjuvant RT resulted in an approximately 10% absolute increase in 5-year cancer-specific survival and overall survival for patients with lymph node-positive HNSCC compared with surgery alone. Despite combined surgery and adjuvant RT, outcomes in this high-risk population remain suboptimal, emphasizing the need for continued investigation of innovative treatment approaches.

40 Post-op RT Conclusion: In a large population-based analysis, adjuvant RT significantly improves overall survival for patients with node-positive HNSCC. All nodal stages, including N1, appear to benefit from the addition of RT to definitive surgery.

41 Overview Introduction RT techniques Patient selection

42 Overview Introduction RT techniques Patient selection Risk factors

43 Risk factors for LRF Extracapsular extension (ECE) in cervical lymph node metastases Involvement of surgical resection margins (ISRM)

44 Risk factors for LRF Extracapsular extension (ECE) in cervical lymph node metastases Involvement of surgical resection margins (ISRM)

46 Consensus Major criteria: ECE or ISRM; Minor criteria: inadequate surgical margins (< 5 mm), 2 lymph nodes metastases (N2b-N3), stage pt3-t4 even with negative margins, in primary oral cavity metastases in levels IV and V, presence of PNI or LVI.

47 Consensus Major criteria: ECE or ISRM; Minor criteria: inadequate surgical margins (< 5 mm), 2 lymph nodes metastases (N2b-N3), stage pt3-t4 even with negative margins, in primary oral cavity metastases in levels IV and V, presence of PNI or LVI.

48 Consensus Major criteria: ECC or ISRM; Minor criteria: inadequate surgical margins (< 5 mm), 2 lymph nodes metastases (N2b-N3), stage pt3-t4 even with negative margins, in primary oral cavity metastases in levels IV and V, presence of PNI or LVI.

49 RT + CHT Two large randomized trials evaluating RT with or without cisplatin chemotherapy in high-risk resected head and neck squamous cell cancers. EORTC RTOG High risk features: >2 + nodes, +ECE, + margins (EORTC also included perineural spread and vascular tumor embolism) NEJM 2004; 350: NEJM 2004: 350:

50 RT + CHT Radiation dose: 60 Gy RTOG; 66 Gy EORTC Cisplatin 100 mg/m2 days 1, 22, 43 both 334 EORTC RTOG patients (793 total) 26-27% oral cavity primaries In combined analysis, only patients with +ECE and/or + margins benefited from addition of cisplatin Head Neck 2005; 27:

51 Risk factors for LRF RT RT - CHT

52 RTOG 0234 RT + CHT

RTOG 0234 60 Gy + CETUXIMAB + CDDP 30 mg/m² 2-y OS: 69% Toxicity Grade 3-4: 28% Mucositis: 56% Stage III - IV N= 238

53 RTOG Gy + CETUXIMAB + CDDP 30 mg/m² 2-y OS: 69% Toxicity Grade 3-4: 28% Mucositis: 56% Stage III - IV N= 238 pts Median f-up: 4.4 yrsschnc 60 Gy + CETUXIMAB + TAXOL 15 mg/m² 2-y OS: 79% mo Toxicity Grade 3-4: 19% Mucositis 54%

54 Overview Introduction RT techniques Patient selection Risk factors Time factor

55 Time factor in Post-op RT

56 Time factor in Post-op RT Evidence exists suggesting that the risk of LRC is higher in patients with AHNC when receiving PORT more than 6 weeks after surgery (OR: 2.89.) Further work confirmed elevated RR 1.28 on LRC and decrease in OS (RR: 1.16) per month of delay. The waiting list to start radiotherapy has negative effect on the prognosis according to a Dutch national study.

57 Time factor in Post-op RT

58 Time factor in Post-op RT The accelerated repopulation during radiotherapy is a cause of treatment failure, that can be increased by the undue prolongation of radiation therapy. Loss in LRC of 1-1.2% per extra-day or 12-14% per extra-week. Prolongation of radiotherapy negatively interferes LRC and OS even in case of CRT. The overall treatment time (OTT) from the day of surgery to the end of PORT showed prognostic significance for the LRC and OS in a randomized trial when the entire duration of treatment was greater than 13 weeks.

59 Overview Introduction RT techniques Patient selection Risk factors Time factor Technical aspects

60 Technical aspects of Post-op RT Particular challenge from the point of view of the radiation oncologist. Anatomy distortion due to tumor resection, Presence of reconstruction flaps, prosthetic material and the position of scars may influence routes of dissemination Close collaboration between the radiation oncologist and head and neck surgeon Engagement with radiologist and pathologist will be necessary in most cases. There is currently no international consensus on standard volumes for PORT irradiation in AHNC, but there are some guidelines published.

61 Guidelines for contouring

62 RTOG 0234 Radiotherapy radiation dose established 60 Gy as postop RT dose MD Anderson performed prospective randomized trial evaluating RT dose for 240 patients with resected stage III/IV cancers of oral cavity, oropharynx, hypopharynx, larynx Daily fraction of 1.80 Gy Dose ranged from 52.2 Gy to 68.4 Gy IJROBP 1993; 26:3-11

63 RTOG 0234 Radiotherapy radiation dose Patients receiving < 54 Gy had significantly higher failure rate. No dose response beyond 57.6 Gy except for patients with extracapsular nodal spread. +ECE needed at least 63 Gy Clusters of two or more of the following also predicted increased risk of failure and need for 63 Gy: oral cavity primary, positive/close margins, nerve invasion, > 2 positive nodes, largest node >3 cm, treatment delay > 6weeks, Zubrod performance status > 2 Moderate to severe complications seen in 7.1%; more if RT dose > 63 Gy Dose escalation above 63 Gy does not appear to improve the therapeutic ratio. Locally Recurrent Disease Re-irradiation

64 Overview Introduction RT techniques Patient selection Risk factors Time factor Technical aspects Immunotherapy

66 Blocking PD1/PDL1 to restore anti-tumourt-cell responses in SCCHN-High response rates in second line treatment (compared to chemotherapy and cetuximab) Approval by FDA (Pembrolizumab and Nivolumab) Favorable safety profile Effective both in HPV+ and More activity if PD-L1 high.

Étude randomisée de phase II évaluant l'efficacité et la tolérance du Pembrolizumab ou du Cétuximab combiné à la radiothérapie chez des patients ayant un carcinome

68 Étude randomisée de phase II évaluant l'efficacité et la tolérance du Pembrolizumab ou du Cétuximab combiné à la radiothérapie chez des patients ayant un carcinome épidermoïde de la tête et du cou localement avancé Locally advanced HNSCC non suitable for RT-CHT R A N D O M IS A TI O N PEMBROLIZUMAB 200 mg x 3 + RT CETUXIMAB + RT

randomized studies ongoing in R/M and LA SCCHN Numerous questions on

69 New PD-1/PD-L1 immunotherapy: a real benefit in SCCHN How to integrate them in stead of or in addition to +/- adjuvant to the existing SOC Numerous randomized studies ongoing in R/M and LA SCCHN Numerous questions on mechanisms / sequencing / timing / which type of combination / which tumors do benefit?? etc

70 Overview Introduction RT techniques Patient selection Risk factors Time factor Technical aspects Immunotherapy Conclusion

71 Take home messages OCSCC is a surgical disease Brachytherapy plays an important role EBRT in case of advanced stages, or in case of presence of risk factors IMRT: standard of care for H & N cases treated in France Altered fractionation schemes preferred if RT only Altered fractionation schemes could be dangerous without using IMRT Concurrent CHEMO-RT, is the standard of care for Advanced OCSCC Postoperative (chemo)radiation is recommended in the presence of advanced disease or adverse histological features. The role of modern techniques is of extreme priority, in order to diminish serious side effects Loss in LRC of 1-1.2% per extra-day or 12-14% per extra-week. Prolongation of radiotherapy negatively interferes LRC and OS even in case of CRT. New emerging challenges with Immunotherapy More research is needed to identify criteria leading to optimal patient outcomes (QoL, functional outcomes)

72 Take home messages OCSCC is a surgical disease Brachytherapy plays an important role EBRT in case of advanced stages, or in case of presence of risk factors IMRT: standard of care for H & N cases treated in France Altered fractionation schemes preferred if RT only Altered fractionation schemes could be dangerous without using IMRT Concurrent CHEMO-RT, is the standard of care for Advanced OCSCC Postoperative (chemo)radiation is recommended in the presence of advanced disease or adverse histological features. The role of modern techniques is of extreme priority, in order to diminish serious side effects Loss in LRC of 1-1.2% per extra-day or 12-14% per extra-week. Prolongation of radiotherapy negatively interferes LRC and OS even in case of CRT. New emerging challenges with Immunotherapy More research is needed to identify criteria leading to optimal patient outcomes (QoL, functional outcomes)

73 Take home messages OCSCC is a surgical disease Brachytherapy plays an important role EBRT in case of advanced stages, or in case of presence of risk factors IMRT: standard of care for H & N cases treated in France Altered fractionation schemes preferred if RT only Altered fractionation schemes could be dangerous without using IMRT Concurrent CHEMO-RT, is the standard of care for Advanced OCSCC Postoperative (chemo)radiation is recommended in the presence of advanced disease or adverse histological features. The role of modern techniques is of extreme priority, in order to diminish serious side effects Loss in LRC of 1-1.2% per extra-day or 12-14% per extra-week. Prolongation of radiotherapy negatively interferes LRC and OS even in case of CRT. New emerging challenges with Immunotherapy More research is needed to identify criteria leading to optimal patient outcomes (QoL, functional outcomes)

74 Take home messages OCSCC is a surgical disease Brachytherapy plays an important role EBRT in case of advanced stages, or in case of presence of risk factors IMRT: standard of care for H & N cases treated in France Altered fractionation schemes preferred if RT only Altered fractionation schemes could be dangerous without using IMRT Concurrent CHEMO-RT, is the standard of care for Advanced OCSCC Postoperative (chemo)radiation is recommended in the presence of advanced disease or adverse histological features. The role of modern techniques is of extreme priority, in order to diminish serious side effects Loss in LRC of 1-1.2% per extra-day or 12-14% per extra-week. Prolongation of radiotherapy negatively interferes LRC and OS even in case of CRT. New emerging challenges with Immunotherapy More research is needed to identify criteria leading to optimal patient outcomes (QoL, functional outcomes)

75 Take home messages OCSCC is a surgical disease Brachytherapy plays an important role EBRT in case of advanced stages, or in case of presence of risk factors IMRT: standard of care for H & N cases treated in France Altered fractionation schemes preferred if RT only Altered fractionation schemes could be dangerous without using IMRT Concurrent CHEMO-RT, is the standard of care for Advanced OCSCC Postoperative (chemo)radiation is recommended in the presence of advanced disease or adverse histological features. The role of modern techniques is of extreme priority, in order to diminish serious side effects Loss in LRC of 1-1.2% per extra-day or 12-14% per extra-week. Prolongation of radiotherapy negatively interferes LRC and OS even in case of CRT. New emerging challenges with Immunotherapy More research is needed to identify criteria leading to optimal patient outcomes (QoL, functional outcomes)

76 Take home messages OCSCC is a surgical disease Brachytherapy plays an important role EBRT in case of advanced stages, or in case of presence of risk factors IMRT: standard of care for H & N cases treated in France Altered fractionation schemes preferred if RT only Altered fractionation schemes could be dangerous without using IMRT Concurrent CHEMO-RT, is the standard of care for Advanced OCSCC Postoperative (chemo)radiation is recommended in the presence of advanced disease or adverse histological features. The role of modern techniques is of extreme priority, in order to diminish serious side effects Loss in LRC of 1-1.2% per extra-day or 12-14% per extra-week. Prolongation of radiotherapy negatively interferes LRC and OS even in case of CRT. New emerging challenges with Immunotherapy More research is needed to identify criteria leading to optimal patient outcomes (QoL, functional outcomes)

77 Take home messages OCSCC is a surgical disease Brachytherapy plays an important role EBRT in case of advanced stages, or in case of presence of risk factors IMRT: standard of care for H & N cases treated in France Altered fractionation schemes preferred if RT only Altered fractionation schemes could be dangerous without using IMRT Concurrent CHEMO-RT, is the standard of care for Advanced OCSCC Postoperative (chemo)radiation is recommended in the presence of advanced disease or adverse histological features. The role of modern techniques is of extreme priority, in order to diminish serious side effects Loss in LRC of 1-1.2% per extra-day or 12-14% per extra-week. Prolongation of radiotherapy negatively interferes LRC and OS even in case of CRT. New emerging challenges with Immunotherapy More research is needed to identify criteria leading to optimal patient outcomes (QoL, functional outcomes)

78 Take home messages OCSCC is a surgical disease Brachytherapy plays an important role EBRT in case of advanced stages, or in case of presence of risk factors IMRT: standard of care for H & N cases treated in France Altered fractionation schemes preferred if RT only Altered fractionation schemes could be dangerous without using IMRT Concurrent CHEMO-RT, is the standard of care for Advanced OCSCC Postoperative (chemo)radiation is recommended in the presence of advanced disease or adverse histological features. The role of modern techniques is of extreme priority, in order to diminish serious side effects Loss in LRC of 1-1.2% per extra-day or 12-14% per extra-week. Prolongation of radiotherapy negatively interferes LRC and OS even in case of CRT. New emerging challenges with Immunotherapy More research is needed to identify criteria leading to optimal patient outcomes (QoL, functional outcomes)

79 Take home messages OCSCC is a surgical disease Brachytherapy plays an important role EBRT in case of advanced stages, or in case of presence of risk factors IMRT: standard of care for H & N cases treated in France Altered fractionation schemes preferred if RT only Altered fractionation schemes could be dangerous without using IMRT Concurrent CHEMO-RT, is the standard of care for Advanced OCSCC Postoperative (chemo)radiation is recommended in the presence of advanced disease or adverse histological features. The role of modern techniques is of extreme priority, in order to diminish serious side effects Loss in LRC of 1-1.2% per extra-day or 12-14% per extra-week. Prolongation of radiotherapy negatively interferes LRC and OS even in case of CRT. New emerging challenges with Immunotherapy More research is needed to identify criteria leading to optimal patient outcomes (QoL, functional outcomes)

80 Take home messages OCSCC is a surgical disease Brachytherapy plays an important role EBRT in case of advanced stages, or in case of presence of risk factors IMRT: standard of care for H & N cases treated in France Altered fractionation schemes preferred if RT only Altered fractionation schemes could be dangerous without using IMRT Concurrent CHEMO-RT, is the standard of care for Advanced OCSCC Postoperative (chemo)radiation is recommended in the presence of advanced disease or adverse histological features. The role of modern techniques is of extreme priority, in order to diminish serious side effects Loss in LRC of 1-1.2% per extra-day or 12-14% per extra-week. Prolongation of radiotherapy negatively interferes LRC and OS even in case of CRT. New emerging challenges with Immunotherapy More research is needed to identify criteria leading to optimal patient outcomes (QoL, functional outcomes)

81 Take home messages OCSCC is a surgical disease Brachytherapy plays an important role EBRT in case of advanced stages, or in case of presence of risk factors IMRT: standard of care for H & N cases treated in France Altered fractionation schemes preferred if RT only Altered fractionation schemes could be dangerous without using IMRT Concurrent CHEMO-RT, is the standard of care for Advanced OCSCC Postoperative (chemo)radiation is recommended in the presence of advanced disease or adverse histological features. The role of modern techniques is of extreme priority, in order to diminish serious side effects Loss in LRC of 1-1.2% per extra-day or 12-14% per extra-week. Prolongation of radiotherapy negatively interferes LRC and OS even in case of CRT. New emerging challenges with Immunotherapy More research is needed to identify criteria leading to optimal patient outcomes (QoL, functional outcomes)

82 . Take home messages What is more important and ethical is to objectively inform our patients of the various options, and provide them with reasonable expectation of outcomes, as it relates to each treatment approach K. Thomas Robbins Arch Otolaryngol Head Neck Surg Sep;131(7):819

83 . Take home messages

Oral cavity cancer Post-operative treatment

Oral cavity cancer Post-operative treatment Dr. Christos CHRISTOPOULOS Radiation Oncologist Centre Hospitalier Universitaire (C.H.U.) de Limoges, France Important issues RT -techniques Patient selection