Management of carcinoma cervix

Overview of FIGO 2018 staging and stage wise management in carcinoma cervix

1. Management of Carcinoma Cervix Dr. Varshu Goel Second Year Post-Graduate Resident Department of Radiation Oncology Maulana Azad Medical College, Delhi

2. FIGO 2018 Staging 2 FIGO 2018 FIGO stage Definition I Cervical carcinoma confined to uterus (extension to corpus should be disregarded) IA Invasive carcinoma diagnosed only by microscopy, with maximum depth of invasion < 5 mm IA1 Stromal invasion < 3.0 mm in depth (measured from the base of the epithelium) IA2 Stromal invasion  3.0 mm and < 5.0 mm in depth IB Clinically visible lesion confined to cervix or microscopic lesion with deepest invasion  5 .0 mm (greater than Stage IA) IB1 Invasive carcinoma  5 .0 mm in depth of stromal invasion and < 2.0 cm in greatest dimension IB2 Invasive carcinoma  2 .0 cm and < 4.0 cm in greatest dimension IB3 Invasive carcinoma  4 .0 cm in greatest dimension

3. 3 FIGO stage Definition II Cervical carcinoma invades beyond uterus, but has not extended onto the lower third of vagina or to the pelvic wall IIA Involvement limited to the upper two-thirds of vagina without parametrial involvement IIA1 Invasive carcinoma < 4.0 cm in greatest dimension IIA2 Invasive carcinoma  4.0 cm in greatest dimension IIB Tumor with parametrial involvement but not to the pelvic wall III The carcinoma involves the lower third of the vagina and/or extends to the pelvic wall and/or causes hydronephrosis or nonfunctioning kidney and/or involves pelvic and/or para-aortic lymph nodes IIIA Tumor involves lower third of vagina, no extension to pelvic wall FIGO 2018 Staging FIGO 2018

4. 4 FIGO stage Definition IIIB Tumor extends to pelvic sidewall and/or causes hydronephrosis or nonfunctioning kidney IIIC Involvement of pelvic and/or para-aortic lymph nodes, irrespective of tumor size and extent IIIC1 Pelvic lymph node metastasis only IIIC2 Para-aortic lymph node metastasis IV The carcinoma has extended beyond the true pelvis or has involved (biopsy proven) the mucosa of the bladder or rectum IVA Spread to adjacent organs IVB Spread to distant organs FIGO 2018 Staging FIGO 2018

5. Direct Invasion Lymphatic spread Blood-borne metastasis Corpus 10-30% Urinary Bladder Cervical Epithelium Cervical Stroma Parametrium Vagina Rectum Spread of tumor LN Involvement (%) Pelvic Stage Para-Aortic 0.5 IA1 0 5 IA2 < 1 16 IB 2.0 30 II 15 44 III 30 50 IV 40

6. Preinvasive disease FIGO stage Management Preinvasive Conization or loop electrosurgical excisional procedure (LEEP) or laser or cryotherapy ablation or simple hysterectomy Handbook of Evidence Based Radiation Oncology, 3 rd edition

7. Preinvasive Disease Shaw’s Textbook of Gynecology, 16 th edition and DC Dutta’s Textbook of Gynecology, 6 th edition

8. 8 Shaw’s Textbook of Gynecology, 16 th edition

9. 9 Shaw’s Textbook of Gynecology, 16 th edition

10. CIN1-2 has a spontaneous regression rate in 1 to 3 years of >50% and therefore observation may be an appropriate course Patients with no visible lesion undergo frequent serial exams Cold knife conization (CKC) may be used for diagnostic and therapeutic intent Loop electrosurgical excision procedure (LEEP) has become popular, although bleeding and stenosis may occur; pregnancy outcomes may be better with LEEP than with CKC Preinvasive Disease Perez & Brady's Principles and Practice of Radiation Oncology, 7 th edition

11. Persistent high-grade CIS = TAH with or without a small portion of the upper vagina removed. To preserve fertility : therapeutic conization, laser therapy, or cryotherapy. If surgery contraindicated or patient refuses it: intracavitary brachytherapy alone Carcinoma in situ Perez & Brady's Principles and Practice of Radiation Oncology, 7 th edition

12. Trachelectomy Conization

13. Total abdominal or modified radical hysterectomy with pelvic lymphadenectomy (or in some cases with simple conization or radical trachelectomy) Preserve fertility : Vaginal trachelectomy (removal of the cervix) and laparoscopic lymphadenectomy Inoperable patients may be treated with intracavitary radioactive sources alone : LDR 65–75 Gy or HDR 7 Gy/# x 5–6 #. If HR pathologic features, treat as IB Stage IA Perez & Brady's Principles and Practice of Radiation Oncology, 7 th edition 13

14. Perez & Brady's Principles and Practice of Radiation Oncology, 7 th edition 14

15. Hysterectomy

16. Stage IB 1 , IB 2 , IIA 1 FIGO stage Management IB 1 , IB 2 , IIA 1 Radical hysterectomy with bilateral pelvic LN dissection OR Definitive RT: External beam radiation therapy (EBRT) to WP (45 Gy) and brachy (HDR 6 Gy/# x 5 #, 7 Gy/# x 4 # or LDR 15–20 Gy/# x 2 #) Handbook of Evidence Based Radiation Oncology, 3 rd edition

17. 17 Lancet 1997 343 patients with stage Ib and IIa cervical carcinoma 1986-91 172 : surgery (class III radical abdominal hysterectomy) 171 : radical RT (XRT+BT) Total Point A dose 70-90 Gy adjuvant RT for surgical stage  pT2b, < 3 mm of safe cervical stroma, cut-through, or positive nodes 5-year overall and DFS were identical in surgery and RT groups (83% and 74%, respectively, for both groups) 17

18. Surgery vs RT : Outcome between radiation alone versus surgery is comparable Stage IB 1 , IB 2 < 4 cm or IIA 1 Perez & Brady's Principles and Practice of Radiation Oncology, 7 th edition 18

19. Post op RT or CTRT after radical hysterectomy: Stage IB 1 , IB 2 or IIA 1 Perez & Brady's Principles and Practice of Radiation Oncology, 7 th edition Peters et al. Any one of these factors : microscopic involvement of the parametrium positive pelvic lymph nodes positive surgical margins Sedlis et al. 2 or more of these factors: LVSI involvement Deep stromal invasion (middle or deep third) Size > 4 cm 19

20. 20 277 patients with stage IB after radical hysterectomy and pelvic lymphadenectomy with negative LNs 137 patients : pelvic RT 46 Gy/23# to 50.4 Gy/28#, no brachy 140 patients : no further treatment 46% reduction in risk of recurrence favoring RT arm GOG 92

21. Sedlis et al., 1999

22. 22 277 patients with stage IB after radical hysterectomy and pelvic lymphadenectomy with negative LNs but with 2 or more of the following features: more than one third (deep) stromal invasion, capillary lymphatic space involvement, and tumor diameter of 4 cm or more 137 : pelvic RT 140 : no further treatment RT is particularly beneficial in adenosquamous or adenocarcinoma: 9% recurrence with RT versus 44% recurrence without RT 22

23. 23 243 patients with clinical stage IA 2 , IB, and IIA carcinoma of the cervix, initially treated with radical hysterectomy and pelvic lymphadenectomy, and who had positive pelvic LNs and/or positive margins and/or microscopic involvement of the parametrium 116 patients : pelvic RT 49.3 Gy/29#, no brachy 127 patients : same pelvic RT with bolus Cisplatin 70 mg/m 2 and 5FU 1000 mg/m 2 /d as 96 hour infusion q 3wk x 4 SWOG 8797

24. Peters et al., 2000

25. 25 Overall survival at 4 years was 71% with RT and 81% with RT and chemo (Only 60% of patients received all 4 chemotherapy cycles)

26. 26 smaller absolute benefit when only one node is positive or when the tumor size is < 2 cm

27. Post op EBRT dose : metastatic pelvic lymph nodes = 45 Gy to the whole pelvis delivered with a four-field technique with concurrent weekly cisplatin Gross residual disease = dose escalation to 54 to 65 Gy, depending on small-bowel dose limits (D 5cc < 55 Gy) Common iliac or para-aortic node metastases = 45 Gy to the entire para-aortic region Gross residual nodal disease = nodal boost up to 65 Gy with IMRT Stage IB 1 , IB 2 or IIA 1 Perez & Brady's Principles and Practice of Radiation Oncology, 7 th edition

28. Post op Brachytherapy dose : Based on the ABS guidelines, vaginal cuff boost should be considered in patients with less-than-radical hysterectomy close or positive margins large or deeply invasive tumors parametrial or vaginal involvement extensive lymphovascular invasion Stage IB 1 , IB 2 or IIA 1 Perez & Brady's Principles and Practice of Radiation Oncology, 7 th edition

29. Stage IB 3 , IIA 2 to IVA FIGO stage Management IB 3 , IIA 2 Concurrent chemo-RT with cisplatin. WP RT (45 Gy). Brachy = HDR 6 Gy/# x 5 #, 7 Gy/# x 4# or LDR 15–20 Gy/# x 2# IIB Concurrent chemo-RT with cisplatin. WP RT (45, nodal boost 50–50.4 Gy). Brachy = HDR 6 Gy/# x 5 #, 7 Gy/# x 4# or LDR 15–20 Gy/# x 2 # IIIA Concurrent chemo-RT with cisplatin. RT to WP, vagina, and inguinal LN (45, nodal boost 50–50.4 Gy). Brachy = HDR 6 Gy/# x 5 #, 7 Gy/# x 4 # or LDR 17–20 Gy/# x 2 # IIIB, IVA Concurrent chemo-RT with cisplatin. WP RT (45, nodal boost 50–60 Gy). Brachy = HDR 6 Gy/# x 5#, 7 Gy/# 4 # or LDR 20 Gy/# x 2 #. If para-aortic LN+, add paraaortic LN IMRT (45–60 Gy) Handbook of Evidence Based Radiation Oncology, 3 rd edition

30. NCI Alert : In 1999, the National Cancer Institute (NCI) issued an alert recommending that concomitant (cisplatin-based) chemoradiotherapy should be considered instead of radiotherapy alone in women with cervical cancer Concurrent chemoradiation : 12% absolute survival benefit Stage IB 3 , IIA 2 to IVA Perez & Brady's Principles and Practice of Radiation Oncology, 7 th edition Gunderson Clinical Radiation Oncology, 4 th edition 30

31. 31 368 patients with stage IIB, III, or IVA (1986-1990), negative LN 177 patients : standard whole pelvic RT with concurrent 5-FU infusion and bolus Cisplatin stage IIB: 40.8/1.7 Gy/d; stage III–IVA: 51 Gy/1.7 Gy/d. 40 Gy (Point A) LDR BT, total Point A: 80–81 Gy; parametrial boost to 55–60 Gy P 50 mg/m 2 , days 1 , 21; F 100 mg/m 2 /day x 4 days 191 patients : same RT plus oral HU 80 mg/kg 2 x per week GOG 85

32. 32 significant changes in 5-year PFS 57% with PF versus 47% OS 62% with PF versus 50% less hematologic toxicity with PF no change in 3-year late complication rate Conclusion: P-based regimen superior to HU SWOG 8695

33. 33 526 patients : Randomized weekly P versus P F HU versus HU (1992–1997) Eligibility: IIB–IVA, negative LN by surgical staging weekly P 40 mg/m 2 GOG 120 P 50 mg/m 2 D 1 and D 29 F 4 g/m 2 as 96 hr infusion D 1 & D 29 , Oral HU 2 g/m 2 x twice weekly x 6 weeks HU 3 g/m 2 x twice weekly x 6 weeks RT: stage IIB: 40.8/1.7 Gy/day EBRT; stage III–IVA: 51 Gy/1.7 Gy/d 40 Gy (Point A) LDR BT, total Point A: 80–81 Gy; parametrial boost to 55–60 Gy

34. 34 GOG 120 P-based arms superior to HU, weekly P less toxic significant change in 3-year OS, 65% in P-based arms versus 47%; significant change in pelvic recurrence (20 versus 30%); less acute toxicity for weekly P

35. 35 IB2 (>4 cm), negative LN by CT, lymphangiogram, or surgical staging; 1992-1997 weekly P 40 mg/m 2 upto 6 cycles during EBRT or last dose during BT GOG 123 EBRT: 45 Gy/1.8 Gy/day; LDR BT, total Point A: 75 Gy Randomized concurrent weekly P versus RT alone followed by extrafascial hysterectomy

36. 36 36 weekly P superior to RT alone in bulky stage IB2 significant change in 3-year PFS, 79% with P versus 67%; OS 83 versus 74%; pelvic control 91 versus 79%, Complete pathologic response 52 versus 41%

37. 37 386 patients : stages IIB-IVA or stage IB-IIA (> 5 cm or involvement of pelvic lymph nodes); 1990-1997 193 patients : 45 Gy of radiation to the pelvis and para-aortic lymph nodes; 45 Gy/1.8 Gy/day, ≥40 Gy LDR BT, total Point A: ≥85 Gy; parametrial boost to 55–60 Gy RTOG 90-01 193 patients : 45 Gy of radiation to the pelvis and para-aortic lymph nodes with two cycles of 5FU 1,000 mg/m 2 and cisplatin 75 mg/m 2 (days 1 through 5 and days 22 through 26 of radiation)

38. 38 significant change in 8-year DFS, 61% with PF versus 46%; OS 67 versus 41%; reduction of locoregional failure 85 versus 35%; distant failure 20 versus 35%; no change in PA failure without PA RT; no change in complication rates 38 concurrent chemotherapy superior to pelvic/PA RT Patients were then to receive one or two applications of low-dose-rate intracavitary radiation, with a third cycle of chemotherapy planned for the second intracavitary procedure in the combined-therapy group

39. 39

40. 40

41. 41 41

42. 42 42 On the basis of 13 trials that compared chemoradiotherapy versus the same radiotherapy, there was a 6% improvement in 5-year survival with chemoradiotherapy Chemoradiotherapy also reduced local and distant recurrence and progression and improved disease-free survival Endorsed the recommendations of NCI alert, but also demonstrate their applicability to all women and a benefit of non-platinum-based chemoradiotherapy

43. 43 Twenty four trials (21 published, 3 unpublished) and 4921 patients Chemoradiation improves overall survival and progression free survival, whether or not platinum was used with absolute benefits of 10% and 13% respectively Chemoradiation also showed significant benefit for local recurrence and a suggestion of a benefit for distant recurrence. Acute hematological and gastrointestinal toxicity was significantly greater in the concomitant chemoradiation group

44. Trial Description NCI/Canada, Pearcey et al Randomized (1991–1996) Eligibility: IB,IIA (>5 cm or histologically + LN), IIB–IVA RT: EBRT: 45 Gy/1.8 Gy/day, BT (LDR or HDR) equivalent Point A dose of 35 Gy(LDR), total Point A: 80 Gy; RT to be completed within 7 weeks CT: weekly P 50 mg/m 2 x 5 cycles during EBRT Outcome: no change in 5-year PSF and OS, 62 versus 58% Conclusion: no benefit of concurrent weekly P. Possible reasons: shorter treatment duration, only imaging-based staging, more anemia in the chemotherapy arm, smaller sample size

45. Carboplatin AUC 2 Gemcitabine : 75-150 mg/m 2 with Cisplatin-RT Paclitaxel : 40 mg/m 2 with Cisplatin-RT Bevacizumab : 10 mg/kg q 2 weeks with Cisplatin-RT Alternative to Concurrent Cisplatin : Perez & Brady's Principles and Practice of Radiation Oncology, 7 th edition 46

46. GOG 165 : PVI 5FU : 35% failure rate Mitomycin C and oral 5FU Cisplatin, VCR and BLM Misonidazole : failed Hydroxyurea : failed Bevacizumab : Phase I study Intra-arterial Cisplatin Alternative to Concurrent Cisplatin Perez & Brady's Principles and Practice of Radiation Oncology, 7 th edition

47. BLM, VCR, mitomycin and Cisplatin BLM, Ifosfamide-mesna , Cisplatin Cisplatin and 5-FU CXII trial (Phase 2) INTERLACE trial (Phase 3) Neoadjuvant chemotherapy Perez & Brady's Principles and Practice of Radiation Oncology, 7 th edition 48

48. MD thesis protocol at MAMC : Neoadjuvant chemotherapy Perez & Brady's Principles and Practice of Radiation Oncology, 7 th edition   N (%) where N is out of 22 Complete Response 9 (40.9) Partial Response 11 (50) Stable Disease 1 (4.5) Progressive Disease - Assessment not done 1 (4.5) 49

49. Gemcitabine + Cisplatin Intensification CRT (Gem/Cisplatin) & adjuvant chemo ( GC x 2) 9% improvement PFS at 3 years OUTBACK trial CRT v CRT + 4 cycles adjuvant Carbo/Paclitaxel Adjuvant chemotherapy Perez & Brady's Principles and Practice of Radiation Oncology, 7 th edition 50

50. Bulky endocervical tumors and the barrel-shaped cervix have higher incidence of central recurrence, pelvic and PALN metastases, and distant dissemination Patients should receive definitive doses of chemoradiation, with hysterectomy reserved for salvage in patients with either gross residual disease or PET-positive disease that is biopsy proven at 3 months after completion of radiation Morice et al, 2012 : routine adjuvant hysterectomy is no longer practiced for patients who have no residual disease at 6 weeks after chemoradiation Need for salvage surgery after CTRT Perez & Brady's Principles and Practice of Radiation Oncology, 7 th edition 51

51. independent factors associated with PALN relapse SCC-Ag level of >40 ng/mL advanced parametrial involvement presence of pelvic lymphadenopathy pretreatment CEA of ≥10 ng/mL (for pretreatment SCC-Ag levels of <10 ng/mL) Role of prophylactic para-aortic radiation must be carefully weighed against the potential toxicities of para-aortic radiation Elective Para-Aortic LN Irradiation Perez & Brady's Principles and Practice of Radiation Oncology, 7 th edition

52. Average 5-year survival = 40% Toxicity to the small bowel (D 5cc < 55 Gy) is important to consider when treating para-aortic nodes Para-Aortic LN Irradiation Perez & Brady's Principles and Practice of Radiation Oncology, 7 th edition 54

53. Stage IVB FIGO stage Management IVB Combination chemotherapy Handbook of Evidence Based Radiation Oncology, 3 rd edition

54. Medial survival = 7 months Platinum doublets Paclitaxel and Cisplatin Paclitaxel and Carboplatin Ifosfamide , Paclitaxel and Carboplatin Vinorelbine Topotecan and Irinotecan Gemcitabine Cetuximab Pazopanib and Lapatinib Bevacizumab : GOG 240 Stage IVB Perez & Brady's Principles and Practice of Radiation Oncology, 7 th edition 57

55. Handbook of Evidence Based Radiation Oncology, 3 rd edition Stage Local Control (%) Disease Free Survival (%) IA 95-100 95-100 IB1 90-95 85-90 IB2 IB3 60-80 60-70 IIA 80-85 75 IIB 60-80 60-65 IIIC1 Depends on T stage IIIA 60 25-50 IIIB 50-60 25-50 IVA 30 15-30 IVB <10 LC and DFS 58

56. Median time to recurrence ranged from 7 to 36 months after primary treatment After previous surgery : Radiation may salvage 50% with localized pelvic recurrence Recommended : whole-pelvis external irradiation (45 to 50 Gy) with concurrent chemotherapy followed by interstitial brachytherapy After Definitive Irradiation : Reirradiation with caution Consider : beam energy, volume, doses delivered with external or intracavitary irradiation, time between two treatments external irradiation for recurrent tumor is given to limited volumes (40 to 45 Gy, 1.8-Gy tumor dose per fraction, preferentially using lateral portals Selected patients : Radical hysterectomy or pelvic exenteration Option : Gemcitabine and Cisplatin Recurrent Carcinoma Cervix Perez & Brady's Principles and Practice of Radiation Oncology, 7 th edition 59

57. Isolated PALN recurrence = 3% 5 year survival = 25% Concurrent chemoradiation Para-Aortic LN recurrence Perez & Brady's Principles and Practice of Radiation Oncology, 7 th edition

58. Recurrent or stage IVB 20 Gy in five fractions over 1 week 30 Gy in 10 fractions over 2 weeks 10 - Gy per fraction given at 3- to 4-week intervals for a total of three fractions New diagnosis 3 to 4 Gy for two or three fractions, followed by standard 1.8 Gy to approximately 39.6 Gy and then brachytherapy. 1 to 2 days of 1.8 Gy twice a day, switching to once-a-day treatment with 1.8 Gy per fraction after bleeding has stopped on day 2 or 3, completing treatment after 45 Gy and then commencing routine brachytherapy Urgent Bleeding and Palliative Irradiation Perez & Brady's Principles and Practice of Radiation Oncology, 7 th edition 61

59. H&P every 3–6 mo for 2 yrs , then every 6–12 mo for 3–5 yrs , then annually based on the risk of disease recurrence. Cervical/vaginal cytology annually as indicated for detection of lower genital tract lesions. Imaging (chest X-ray, CT, PET-CT, and MRI) and labs as indicated based on exam, symptoms and risk of recurrence. Patient education on sexual health, vaginal dilator use, and vaginal lubricants Follow up Handbook of Evidence Based Radiation Oncology, 3 rd edition 62

60. Gunderson’s Clinical Radiation Oncology, 4 th edition Conclusion 63

61. Carcinoma Cervix in pregnancy 64 Shaw’s Textbook of Gynecology, 16 th edition

62. True : first symptom occurs 3 or more years after subtotal hysterectomy (better prognosis) Coincidental : symptoms are noticed before the third postoperative year Aim is to bring the tumor dose to approximately 80 to 90 Gy for brachytherapy after completing a standard dose of 45 Gy to the whole pelvis Carcinoma Cervical Stump Perez & Brady's Principles and Practice of Radiation Oncology, 7 th edition 65

63. Lesions with deep stromal invasion = one or two vaginal intracavitary insertions to deliver a 65-Gy LDR mucosal dose to the vault Fully invasive tumor = 40 to 45 Gy to whole pelvis with cylinder brachytherapy to vaginal vault for an approx. 60-Gy mucosal dose Gross tumor in the vaginal vault or parametrium = 45 Gy dose to whole pelvis with concurrent weekly cisplatin chemotherapy, followed by an additional parametrial dose of 10 to 20 Gy. intracavitary insertion performed gross residual tumor = interstitial implant Carcinoma Cervix accidentally treated with a Simple Hysterectomy Perez & Brady's Principles and Practice of Radiation Oncology, 7 th edition

64. Thank You 67 In medical research, the most famous cell line known as HeLa was developed from cervical cancer cells of Henrietta Lacks in 1951