“Optimizing Chemoradiation Sequencing in Cervical Cancer”

“Optimizing Chemoradiation Sequencing in Cervical Cancer”

1. Optimizing the combination or sequencing of systemic therapies and radiotherapy in carcinoma cervix Dr Kanhu Charan Patro MD,DNB(Radiation Oncology),MBA,FICRO,FAROI(USA),PDCR,CEPC Clinical Director, HOD-Radiation Oncology ISRo - I nstitute of S tereotactic R adiation o ncology Mahatma Gandhi Cancer Hospital & Research Institute, Visakhapatnam [email protected] /M- [phone]/ www.drkanhupatro.com

2. Dr. Kanhu Charan Patro Clinical Director and HOD (Radiation Oncology) (Brain Tumor Specialist) Mahatma Gandhi Cancer Hospital & RI, Visakhapatnam MBBS (Gold Medalist) MD, DNB (Radiation Oncology) MBA (HA), FICRO, FAROI [USA], CEPC, PDCR Visiting Fellow Manheim Cancer Center, Germany V isiting trainee in Accuray Genolier, Switzerland Visiting Fellow Well Cornell Medical College, New York Ex. Resident (TMH-Mumbai) Visiting trainee (AIIMS-New Delhi) [email protected] / M-9160470564/drkanhupatro.com   SL SUBJECT INFERENCE 1 Area of interest NEURO AND URO-ONCOLOGY, NON - INVASIVE BRACHYTHERAPY 2 Clinical experience 25+ years 3 Cancer patients handled (RADIOTHERAPY) Nearly 10000 4 Brain tumors handled Nearly 900 5 Brachytherapy cases handled Nearly 4000 6 Interstitial brachytherapy cases handled Nearly 600 7 SRS/SBRT cases handled Nearly 200 8 Article publication Nearly 50 9 Slide share presentations Nearly 300 10 E Books/Chapter/Abstract Nearly 120 11 Awards received 12 12 Faculty invite- conferences More than 100 13 Thesis guided 10 14 Academic teacher experience 8 years 15 Fellowships awarded 4

3. THE GLOBAL BURDEN

4. Incidence cervical cancer

5. IN INDIA

6. IN INDIA

7. Those 5 trials 10/31/2025 7 Trial (Year, Journal) Stage/Setting Treatment Arms Main Results Key Takeaway GOG-85 / SWOG-8695 (Whitney et al., JCO, 1999) Stage IIB–IVA RT + Cisplatin/5-FU vs RT + Hydroxyurea 3-yr OS: 65% vs 47%; Local control improved Cisplatin-based CCRT superior to non-cisplatin regimens RTOG-90-01 ( Morris et al., NEJM, 1999) Stage IIB–IVA (para-aortic negative) Extended-field RT vs Pelvic RT + Cisplatin/5-FU 8-yr OS: 67% vs 41% (p<0.001) Established CCRT as standard for locally advanced cases GOG-120 ( Rose et al., NEJM, 1999) Stage IIB–IVA RT + Weekly Cisplatin (40 mg/m²) vs RT + 5-FU/HU or HU alone 3-yr PFS: 67% vs 58% vs 47% Weekly cisplatin most effective and least toxic GOG-123 ( Keys et al., NEJM, 1999) Stage IB2 (>4 cm) RT + Extrafascial Hysterectomy ± Weekly Cisplatin 3-yr PFS: 83% vs 63%; OS 81% vs 71% Added concurrent cisplatin improved outcome before surgery SWOG-8797 / GOG-109 / RTOG-9112 ( Peters et al., JCO, 2000) High-risk postoperative (positive nodes, margins, or parametria) Adjuvant RT vs Adjuvant RT + Cisplatin/5-FU 4-yr PFS: 80% vs 63%; OS: 81% vs 71% CCRT beneficial in postoperative high-risk disease

8. Green Metaanalysis 10/31/2025 8

9. NCI ANNOUNCEMENT 10/31/2025 9

10. The Cisplatin and Carboplatin 10/31/2025 10

11. ICMR guideline

12. NCG guideline

13. EMBRACE Program me EBRT (IMRT/IGRT) MRI-guided adaptive brachytherapy

14. RetroEMBRACE (2005–2011) Design: Retrospective analysis of 731 patients from 12 institutions Objective: Validate MRI-guided adaptive brachytherapy outcomes

15. RetroEMBRACE (2005–2011) Endpoint 3-Year (%) 5-Year (%) Local Control (LC) 91.0 89 Pelvic Control (PC) 87.0 84 Cause-Specific Survival (CSS) 79.0 73 Overall Survival (OS) 74.0 65 LC by Stage IB 98.0 98 LC by Stage IIB 93.0 91 LC by Stage IIIB 79.0 75 PC by Stage IB 96.0 96 PC by Stage IIB 89.0 87 PC by Stage IIIB 73.0 67 5-yr Grade 3-5 Morbidity (Bladder) 5 5-yr Grade 3-5 Morbidity (GI Tract) 7 5-yr Grade 3-5 Morbidity (Vaginal) 5

16. Embrace I (2008) Design: International, multicenter, prospective observational study Population: 1416 patients with cervical cancer treated with MRI-guided adaptive brachytherapy Key Findings: Actuarial overall 5-year local control was 92% Improved outcomes compared with historical controls Safety: acceptable late toxicity rates

17. EMBRACE -I-2021

18. Embrace II (Ongoing, since 2016) Design: International prospective study building on Embrace I Aims Optimize image-guided brachytherapy Integrate modern EBRT (IMRT/IGRT) Reduce morbidity while preserving efficacy Endpoints: Local control, progression-free survival, quality of life, toxicity reduction

19. Dose, Fractionation, Timing EBRT 45–50.4 Gy /25–28 fx with weekly cisplatin Brachy : 4–5 fractions HDR; individualize per HR‑CTV volume and OAR D2cc Finish OTT ≤ 56 days; use workflow pathways to avoid delays

20. IMAGE GUIDED RADIATION THERAPY EQUIPMENT REQUIRED CT-SCAN MRI PET-CT 10/31/2025 20 Mahatma Gandhi Cancer Hospital & Research Institute,Visakhapatnanm

21. Radiation proctits

22. Radiation cystitis

23. Radiation vaginal stenosis

24. Radiation intestinal stricture

25. Radiation Pelvic insufficiency fracture

26. Radiation vascular necrosis

27. LINEAR ACCELERATOR 10/31/2025 6:23:10 AM 28

28. 10/31/2025 6:23:10 AM 29 Conformal Radiotherapy-IMRT

29. IGRT

30. IGRT

31. IGRT & Adaptive EBRT Daily CBCT for set-up and organ filling variations Re‑planning for tumor regression/bladder/rectum changes Consider offline/online adaptation in weeks 3–4 if significant regression

32. Intracavitary brachytherapy 10/31/2025 6:23:10 AM 33

33. 10/31/2025 6:23:10 AM 34 Intracavitary brachytherapy

34. Intracavitary brachytherapy 10/31/2025 6:23:10 AM 35 Uterine Sound Foley’s Bulb Bladder

35. Interstitial brachy 10/31/2025 6:23:11 AM 36

36. Radiation toxicity Bladder related Rectum related Bowel related Bone related Acute Late 10/31/2025 6:23:11 AM 37

37. Imaging to Plan Well Pelvic MRI for primary and parametria PET-CT for nodal staging Use MRI/CT for target delineation per GEC‑ESTRO concepts (GTV, HR‑CTV, IR‑CTV)

38. Role of PET CT When things are suspicious PET CT is auspicious Identifying suspicious nodes Boosting the nodes Reirradiation settings

39. Role of PET CT- RT planning

40. Role of PET CT- ReRT

41. Why Advanced RT Matters High burden in LMICs; many present with locally advanced disease Concurrent chemoradiation with brachytherapy remains standard of care Advanced RT Improves local control Reduces toxicity vs. 2D plans

42. The default and standard sequence 10/31/2025 43 Concurrent chemoradiation with cisplatin + brachytherapy, completed within ~8 weeks.

43. Discussion points 10/31/2025 44 INTERLACE NEOADJ OUTBACK ADJUVANT CALLA DURVALUMAB KEYNOTE PEMBRO. EORTC NEOADJ. Sx

44. Interlace trial 10/31/2025 45

45. Kaplan–Meier PFS analysis

46. Kaplan–Meier OS analysis

47. Distance recurrence

48. Pa nodal recurrence

49. Adverse event analysis

50. Higher hematological toxicity in NACT arm (30% Grade 3–4 vs 13% in CTRT arm) Main toxicities: Neutropenia (19% vs 5%), Anemia (28% vs 17%) Non-hematological toxicities were similar between both groups Toxicity

51. 3 deaths within 30 days of completing treatment, one (respiratory failure) in the induction chemotherapy with chemoradiotherapy group , 2 in the chemoradiotherapy alone group (sepsis and pulmonary embolism); none were considered treatment-related. Death

52. Temporary decline in QoL during induction chemotherapy phase No long-term differences between the two groups after treatment QOL

53. Result table

54. What are the criticisms ?

55. This is a phase 3 study Electronic randomization of 500 patients. It was a Multicentric study involving around 32 nations. ITT analysis Significance level at 0.05 Power is level at 80% Central review of radiation details Strong Points favoring the study

56. FIGO 2008 staging was used to stage the patient prior to allocating the treatment arm. Acute toxicity was higher in the NACT arm Adherence to concurrent chemotherapy during radiotherapy was hindered in the NACT arm, resulting in deviation from the standard of care treatment. The increase in overall treatment time in the NACT arm is a concern. Temporary decline in the QOL is present in the NACT arm. 10 percent lost to follow up Negative Points of the study

57. Is it practice changing ?

58. OUTBACK 10/31/2025 59

59. Outback-result 10/31/2025 60 Negative. Do not add by routine. OUTBACK (phase III): No OS or PFS benefit with adjuvant carboplatin/paclitaxel after definitive CCRT. 5-yr OS 72% with AC vs 71% CCRT alone (HR 0.90; p=0.81)

60. Calla trial- Durvalumab 10/31/2025 61

61. Calla trial- Durvalumab 10/31/2025 62 CALLA ( durvalumab + CCRT): no significant PFS benefit in an all-comers population

62. Keynote A-18 10/31/2025 63

63. Keynote A-18 10/31/2025 64

64. Comparisons 10/31/2025 65 Trial (Year, Journal) Design / Setting Arms Compared Inclusion (Key Eligibility) Primary Endpoint Main Results Key Takeaway OUTBACK (TROG 0208, 2021, Lancet Oncol ) Phase III, adjuvant chemo after standard CCRT CCRT (cisplatin 40 mg/m² × 5 wks ) Same CCRT + 4 cycles carboplatin AUC 5 + paclitaxel 155 mg/m² q3 wks after RT FIGO 2008 stage IB1–IVA, planned for definitive or post-op CCRT OS 5-yr OS 72 % (CCRT) 71 % (CCRT + ACT ) HR 0.90 (p = 0.81) No survival benefit; do not add adjuvant chemotherapy after CCRT INTERLACE (2023 ESMO / Lancet) Phase III, induction chemo before CCRT Standard CCRT 6 weeks carboplatin AUC 2 + paclitaxel 80 mg/m² weekly → CCRT (cisplatin 40 mg/m² weekly + EBRT + BT)** FIGO 2009 IB2–IVA (no mets) PFS, OS 3-yr OS 86 % (IC+CCRT ) 80 % (CCRT ); 3-yr PFS 73 % 64% (HR 0.65, p = 0.016) Induction chemo improved OS & PFS without major delay → emerging new approach CALLA ( Durvalumab , 2023 JCO) Phase III, IO + CCRT CCRT + Placebo CCRT + Durvalumab (1,500 mg q4 wks × up to 24 mo ) FIGO 2014 IB2–IVA; cisplatin eligible PFS Median PFS 40 mo (DURVA) vs 41 mo (PLB ); HR 0.84 (p = 0.17) Negative; no PFS improvement KEYNOTE-A18 / ENGOT-cx11 / GOG-3047 (2024 NEJM) Phase III, IO + CCRT (+ maintenance) Standard CCRT + Placebo → Placebo maintenance CCRT + Pembrolizumab 200 mg q3 wks × 5 + maintenance 400 mg q6 wks up to 1 yr Newly diagnosed high-risk LACC (FIGO 2014 III–IVA or IIB with LN+) PFS (primary) and OS (dual primary) 24-mo PFS 68% 57 % (HR 0.59, p < 0.001 ); OS HR 0.67 ( significant update 2024) Positive; Pembrolizumab + CCRT → improved PFS and OS → FDA-approved Jan 2024 EORTC 55994 ( Neoadjuvant → Surgery vs CCRT, 2022 Lancet Oncol ) Phase III, neoadjuvant chemo + surgery vs definitive CCRT Standard CCRT (cisplatin 40 mg/m² weekly) NACT (cisplatin 75 mg/m² + paclitaxel 175 mg/m² × 3 cycles) → radical surgery ± post-op RT FIGO IB2–IIB (no para-aortic nodes) PFS 5-yr PFS 69 % (NACT + S) vs 76% (CCRT ); 5-yr OS 76 % vs 74% (p = 0.67) No OS benefit; PFS favored CCRT; many NACT pts still required adjuvant RT/CCRT

65. What we learn? 10/31/2025 66 Sequencing Strategy Representative Trial Outcome Clinical Implication Adjuvant chemo after CCRT OUTBACK No OS/PFS benefit Not recommended Induction chemo before CCRT INTERLACE OS & PFS benefit Promising; consider in fit patients if OTT maintained Neoadjuvant chemo → Surgery EORTC 55994 No OS gain; PFS favored CCRT Definitive CCRT preferred CCRT + Durvalumab CALLA Negative No role outside trials CCRT + Pembrolizumab KEYNOTE-A18 OS & PFS benefit New standard for high-risk LACC

66. Summary 10/31/2025 67 Start concurrent cisplatin-based chemoradiation promptly, integrate brachytherapy early, and finish ≤56 days. Consider IC → CCRT for select patients where logistics allow strict OTT control and team has experience with the INTERLACE regimen; discuss benefits and added AEs. Do not add adjuvant chemotherapy after CCRT outside a trial. Add pembrolizumab to CCRT for high-risk LACC when accessible and eligible, per KEYNOTE-A18 Cisplatin schedule: weekly 40 mg/m² is pragmatic; 3-weekly 100 mg/m² may increase LRC at the cost of more toxicity—choose based on patient fitness, renal function, and service logistics.

67. Who needs Neoadjuvant ? 10/31/2025 68

68. 10/31/2025 69 Large Paraaortic nodes

69. 10/31/2025 70 Large Paraaortic nodes

70. Iliac nodes 10/31/2025 71

71. Bladder base involvement 10/31/2025 72

72. Rectal wall involvement 10/31/2025 73

73. Who needs adjuvant? 10/31/2025 74

74. Adenocarcinoma –Need of adjuvant? 10/31/2025 75 Adenocarcinoma of the cervix does not automatically mandate more aggressive adjuvant chemotherapy after CCRT, in the absence of other high-risk factors . However , given its biologic behavior (often higher risk of distant relapse), you should be more vigilant, assess risk carefully, and have a low threshold for multi-disciplinary discussion . Optimize the core CCRT delivery first; if high-risk features are present, adjuvant chemo can be considered on a case-by-case basis . Document the discussion, involve the patient in decision-making, and monitor outcomes carefully

75. TAKE HOME MESSAGE Concurrent CTRT is the standard Prefer NACT in large nodes and bladder and rectal wall involvement Consider adjuvant chemo in adenocarcinoma Immunotherapy not the standard yet can be considered in patient is affordable. Consider adjuvant chemo in adenocarcinoma variant.{very low level-evidence} 10/31/2025 76

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