Cervix Part 2

Cervical Cancer
Written By Sydney Oesch

Episode Notes

  1. Definition of locally advanced cervical cancer

    1. Stage IB3 to IVA by FIGO 2018 staging system

      1. Except for stage IIA1 - considered early stage and treated accordingly

    2. IB3: confined to cervix, tumor > 4 cm, “bulky disease”

    3. Stage II: beyond uterus, but not to pelvic sidewall or lower one-third of vagina

    4. Stage III: extends to pelvic sidewall and/or the lower ⅓ of vagina and/or causes hydronephrosis and/or involves pelvic or para-aortic lymph nodes

    5. Stage IVA: involves the mucosa of the bladder or rectum and/or extends beyond the true pelvis

  2. Prognosis

    1. Very dependent on stage: 5-year OS 80% for stage IB vs 16% for stage IV

    2. Disease control and OS worse if LN involvement

    3. Recurrence risk 30-40% for LACC after primary treatment

  3. Workup

    1. PET CT

      1. Can biopsy avid nodes or use imaging if enlargement/avidity convincing

    2. Address urinary tract obstruction

  4. Chemoradiation is standard of care

    1. Chemoradiation: EBRT + concurrent platinum-based chemotherapy followed by brachytherapy

      1. Standard of care since GOG 123 in 1999

    2. GOG 123, 1999

      1. RCT

      2. N = 369, bulky stage IB w/ negative lymph nodes

      3. Randomized to EBRT + brachy vs EBRT w/ concurrent cisplatin + brachy; followed by hyst for both groups

      4. PFS and OS favored chemoRT

        1. 6-year PFS: 71% CRT vs 60% RT

        2. 6-year OS: 78% CRT vs 64% RT

      5. Late adverse events not different between two groups

    3. GOG 71

      1. Stage IB2 included

      2. PFS and OS not improved w/ addition of hysterectomy to radiation

  5. What is EBRT and brachytherapy?

    1. EBRT: external beam radiation therapy

      1. Delivered in fractions for a total dose, measured in Gray (Gy)

    2. Dosing?

      1. 40-50 Gy for microscopic or low volume disease

      2. 70+ Gy for gross disease

      3. Can consider boost to nodal disease

    3. Brachytherapy

      1. Local radiation doses to cervix and vagina

  6. Why EBRT + Brachy?

    1. Multiple retrospective, population-based studies support improved disease specific and OS w/ addition of brachy to EBRT

    2. Han et al., 2024

      1. Trends and practices in use of brachytherapy in LACC in US from 2000-2020

      2. N = 8500 pts w/ FIGO stage IB2 (correlates to FIGO 2018 stage IB3 disease) to IVA disease

      3. Improved 4-year OS (64 vs 51%)

  7. Nodal boost?

    1. RTOG 79-20, 1990, 1995

      1. Pts w/ bulky cervical cancer w/o evidence of PA disease and no plan for curative surgery

        1. Randomized to PLN radiation vs PLN + PALN radiation

      2. 5-year OS 65% vs 55% w/ addition of PALN radiation

      3. 10-year OS 55% VS 44% w/ addition of PALN radiation

      4. If prior abdominal surgery, grade 4 and 5 toxicities much higher (11% vs 2%)

      5. *note that this trial evaluated radiation alone, not chemoradiation

    2. RTOG 90-01, 1999, 2004

      1. N = 400, stage IIB-IVA to extended field RT vs pelvic RT w/ cisplatin and FU

      2. PFS and OS favored chemoRT arm

        1. 5-year OS 73% VS 58%

        2. Decreased local and distant recurrences

      3. Rate of serious late complications similar between groups

  8. ChemoRT Landmark Trials

    1. Alberts et al., 2010

      1. Meta-analysis of all RCTs of CRT vs RT

      2. 6% improvement in 5-yr OS w/ HR 0.81

    2. Zuliani et al., 2014

      1. RCT

      2. cis-RT vs RT in FIGO stage IIIB SCC

      3. DFS benefit in cisRT w/ HR 0.52

    3. Long-term survival of Zuliani paper - Fachini et al., 2020

      1. OS improved with cisRT; OS HR for RT 1.88

    4. Shrivastava 2018

      1. RCT, n = 850

      2. cis-RT vs RT in FIGO stage IIIB SCC

      3. 5-yr DFS 52 vs 44% favoring cisRT; 5-yr OS 54 vs 46% favoring cisRT

      4. Higher rates of acute hematologic events in cisRT arm

  9. Cisplatin as Choice of Chemo in ChemoRT Trials

    1. Preferred regimen: weekly cisplatin or carboplatin (AUC2)

      1. Use carbo if contraindication to cis (i.e. CKD)

      2. Limited retrospective data that suggests similar outcomes with cis vs carbo

    2. GOG 855, 1999

      1. Hydroxyurea alone not as effective as cisplatin + 5-FU

    3. GOG 120, 1999

      1. Any regimen which included cisplatin better than hydroxyurea alone

      2. Cisplatin alone has similar outcome to cisplatin + 5-FU or hydroxyurea

    4. Kim et al., 2007

      1. Cisplatin alone vs cis + 5-FU

      2. Equal survival outcomes with more favorable side effect profile, leading to improved completion rates

  10. Dosing of Cisplatin?

    1. Ryu et al. 2011

      1. Stage IIB-IVA SCC to cis 40 mg/m2 weekly x 6 cycles vs cisplatin 75/m2 every 3 weeks x 3 cycles

      2. Compliance w/ tri-weekly 92.5% vs 85% weekly

      3. Grade 3-4 neutropenia lower: 23% vs 39%

      4. 5 yr OS 88.7 mo vs 66.5 mo favoring tri-weekly

      5. However! Critiques of study:

        1. Substantial number of pts w/ pos paraaortic LN in both arms and radiation field not specified

        2. Reported para-aortic recurrences but didn’t states were originally treated

        3. Unclear definitions of cause-specific mortality (didn’t specify which salvage therapy used for recurrence)

          1. Recurrence rates not different, but survival was

    2. TACO trial

      1. Ongoing trial evaluating the above

  11. Alternatives to ChemoRT if cannot tolerate or contraindicated?

    1. Cat IIB rec for rad hyst w/ pelvic LND +/- paraaortic lnd

    2. Cat III rec for chemoRT followed by “selective completion hysterectomy”

    1. Examples of poor candidates for primary chemoRT

      1. Acute or chronic PID

      2. Coexisting pelvic mass that suggests possible dual malignancy

      3. Anatomic changes or Mullerian anomalies that would make optimizing radiation difficult

      4. Compliance issues

  12. Immunotherapy

    1. High rates of PD-L1 positivity in HPV-dependent disease (80-90%)

    2. CPS: combined positive score

      1. Calculated by determining the percentage of the total number of PD-L1 positive cells (including tumor, lymphocytes, macrophages) to the total number of tumor cells

    3. TAP: tumor area positivity

      1. Visual estimation of the area of tumor cells and immune cells that are positive for PD-L1 relative to the total tumor area

        1. TAP 5% roughly correlates to CPS 1

  13. Key Immunotherapy Trials

    1. KEYNOTE-A18, 2024

      1. Double-blinded, phase III RCT, n = 1060

      2. Pembro + chemoRT vs chemoRT alone

      3. FIGO 2014 stage IB2-IIB node positive and stage III-IVA regardless of nodal status

        1. Correlates to FIGO 2018 stage III-IV

      4. All patients received chemoRT +/- 5 cycles of pembrolizumab 200 mg every 3 weeks followed by pembrolizumab 400 mg every 6 weeks x 15 cycles

      5. First interim analysis w/o mature data published 2024

        1. 24 mo PFS: 68 vs 57% favoring pembro

        2. OS not different, but data only 43% mature

      6. No grade 3 adverse events that differed >=5% between the two groups

      7. Treatment completion rates identical

    2. CALLA, 2023

      1. Double-blinded phase III RCT, n = 770

      2. Similar patient population to KEYNOTE-A18

      3. Durvalumab + chemoRT vs chemoRT alone

      4. chemoRT +/- durvalumab with durvalumab maintenance, up to 24 cycles

      5. 12 mo PFS not different

      6. 5 treatment-related deaths in durvalumab group vs 1 in placebo group

      7. In exploratory analysis, the group that had a benefit from durvalumab were those with TAP score >= 20%, which was about 50% of the included patients

  14. Neoadjuvant Chemotherapy

    1. Majority of studies performed in stage IB2-IIB disease, and not LACC

    2. None have showed survival benefit; may be associated with worse DFS

      1. GOG 141, 2007

      2. Gupta et al., 2018

      3. EORTC-55994, 2023

  15. “Induction Chemotherapy”

    1. Induction chemotherapy refers to chemotherapy prior to primary chemoradiation. The important difference in these next two trials is that we aren’t changing the definitive treatment regimen of chemoradiation, but are adding extra chemotherapy prior to that treatment. 

    2. Costa et al., 2019

      1. Phase II study, n = 107

      2. NACT w/ cis/gem prior to chemoRT vs chemoRT alone

      3. 3 year OS 87% vs 61% w/ chemoRT alone

        1. authors concluded that the treatment agent choice and dosing ( cisplatin 50 mg/m2 + gem 1000 mg/m2,) may be affecting the potential benefit of induction chemotherapy, and pointed to the ongoing INTERLACE trial as another study which may provide answers.

    3. INTERLACE, 2023 abstract, 2024 publication

      1. N = 500

      2. FIGO 2008 stage IB1 node positive, IB2, IIIB, IVA disease (only 14% FIGO 2018 stage III-IV disease)

      3. ChemoRT alone with weekly cisplatin vs induction chemotherapy with carbo(AUC2)/taxol(80 mg/m2) for six cycles followed by chemoRT

      4. 5-year PFS 72% in IC/CRT vs 64% in CRT alone group.  

      5. 5-year OS was also improved in IC/CRT group - 80% vs 72%.

      6. Treatment completion: 

        1. 68% of patients in IC/CRT arm completed all five cycles of cisplatin, vs. 79% of patients in CRT alone arm

        2. 96% of patients in both groups completed CRT within 8 weeks

      7. Trial accrued over 10 years. Hard to know how application of this therapy regimen will be incorporated into standard of care in the setting of novel immunotherapy.

  16. Adjuvant Chemo?

    1. Dueñas-Gonzalez et al., 2011

      1. Phase III RCT

      2. Standard chemoRT (with cisplatin) vs chemoRT (with cisplatin + gemcitabine) followed by cisplatin + gemcitabine adjuvant chemo

      3. Combo group had improved PFS and OS w/ HR 0.68

      4. Toxicities also doubled in combo group (86% w/ grade 3-4 toxicity)

      5. Difficult to interpret whether the improved oncologic outcomes are due to addition of gem in chemoRT or adjuvant therapy

    2. OUTBACK, 2023

      1. Phase III RCT, n = 919

      2. LACC - FIGO stage 2008 stage IB1 w/ nodal involvement,stage IB2, II, IIIB, or IVA disease

      3. chemoRT + 4 cycles adjuvant carbo/taxol vs chemoRT alone

      4. No differences in 5-yr PFS or OS

      5. Toxicity much higher in combo group

    3. TLDR: adjuvant chemo following chemoRT not usually given

  17. Surveillance by ctDNA

    1. Han et al., 2023

      1. Evaluated impact of detectable HPV circulating tumor DNA (ctDNA) following completion of chemoRT

      2. Those w/ detectable HPV ctDNA had significantly worse 2 yr PFS (51% vs 77%)

        1. Association persisted when levels of ctDNA were measured at up to 3 months post chemoRT treatment

      3. Authors proposed ctDNA may help guide future studies to identify those at high risk for recurrence

References

1. Rose PG, Ali S, Whitney CW, Lanciano R, Stehman FB. Impact of hydronephrosis on outcome of stage IIIB cervical cancer patients with disease limited to the pelvis, treated with radiation and concurrent chemotherapy: A Gynecologic Oncology Group study. Gynecol Oncol. 2010;117(2):270-275. doi:10.1016/j.ygyno.2010.01.045

2. Keys H, Bundy BN, Stehman FB, et al. CISPLATIN, RADIATION, AND ADJUVANT HYSTERECTOMY COMPARED WITH RADIATION AND ADJUVANT HYSTERECTOMY FOR BULKY STAGE IB CERVICAL CARCINOMA A BSTRACT Background Bulky stage IB cervical cancers have. Published online 1999.

3. Stehman FB, Ali S, Keys HM, et al. Gynecologic Oncology Group trial. Am J Obstet Gynecol. 2007;197:503-504. doi:10.1016/j.ajog.2007.08.003

4. Keys HM, Bundy BN, Stehman FB, et al. Radiation therapy with and without extrafascial hysterectomy for bulky stage IB cervical carcinoma: a randomized trial of the Gynecologic Oncology Group. Published online 2003. doi:10.1016/S0090-8258(03)00173-2

5. Yamashita H, Okuma K, Kawana K, et al. Comparison between conventional surgery plus postoperative adjuvant radiotherapy and concurrent chemoradiation for FIGO stage IIB cervical carcinoma: A retrospective study. American Journal of Clinical Oncology: Cancer Clinical Trials. 2010;33(6):583-586. doi:10.1097/COC.0b013e3181cae5b7

6. Alberts DS, Brady M, Cikaric S, et al. Reducing uncertainties about the effects of chemoradiotherapy for cervical cancer: Individual patient data meta-analysis. Cochrane Database of Systematic Reviews. 2010;2010(1). doi:10.1002/14651858.CD008285

7. Morris M, Eifel P, Lu J, et al. Pelvic Radiation With Concurrent Chemotherapy Compared with Pelvic and Para-Aortic Radiation for High-Risk Cervical Cancer. NEJM. 1999;340.

8. Eifel PJ, Winter K, Morris M, et al. Pelvic Irradiation With Concurrent Chemotherapy Versus Pelvic and Para-Aortic Irradiation for High-Risk Cervical Cancer: An Update of Radiation Therapy Oncology Group Trial (RTOG) 90-01. J Clin Oncol. 2004;22:872-880. doi:10.1200/JCO.2004.07.197

9. Han K, Colson-Fearon D, Liu ZA, Viswanathan AN. Updated Trends in the Utilization of Brachytherapy in Cervical Cancer in the United States: A Surveillance, Epidemiology, and End-Results Study. Int J Radiat Oncol Biol Phys. 2024;119(1):143-153. doi:10.1016/j.ijrobp.2023.11.007

10. Morice P, Rouanet P, Rey A, et al. Results of the GYNECO 02 Study, an FNCLCC Phase III Trial Comparing Hysterectomy with No Hysterectomy in Patients with a (Clinical and Radiological) Complete Response After Chemoradiation Therapy for Stage IB2 or II Cervical Cancer; Results of the GYNECO 02 Study, an FNCLCC Phase III Trial Comparing Hysterectomy with No Hysterectomy in Patients with a (Clinical and Radiological) Complete Response After Chemoradiation Therapy for Stage IB2 or II Cervical Cancer. doi:10.1634/theoncologist.2011-0276

11. Shrivastava S, Mahantshetty U, Engineer R, et al. Cisplatin Chemoradiotherapy vs Radiotherapy in FIGO Stage IIIB Squamous Cell Carcinoma of the Uterine Cervix A Randomized Clinical Trial Supplemental content. JAMA Oncol. 2018;4(4):506-513. doi:10.1001/jamaoncol.2017.5179

12. Whitney CW, Sause W, Bundy BN, et al. Randomized comparison of fluorouracil plus cisplatin versus hydroxyurea as an adjunct to radiation therapy in stage IIB-IVA carcinoma of the cervix with negative para-aortic lymph nodes: a Gynecologic Oncology Group and Southwest Oncology Group study. J Clin Oncol. 1999;17(5):1339-1348. doi:10.1200/JCO.1999.17.5.1339

13. Thomas G. IMPROVED TREATMENT FOR CERVICAL CANCER-CONCURRENT CHEMOTHERAPY AND RADIOTHERAPY. NEJM. Published online 1999. Accessed April 28, 2024. http://www.sgo.org/meetings/

14. Carlos Zuliani A, Carlos Barros Esteves S, Carlos Teixeira L, et al. Concomitant Cisplatin Plus Radiotherapy and High-Dose-Rate Brachytherapy Versus Radiotherapy Alone for Stage IIIB Epidermoid Cervical Cancer: A Randomized Controlled Trial. J Clin Oncol. 2014;32:542-547. doi:10.1200/JCO.2013.50.1205

15. Maria Dias Fachini A, Carlos Zuliani A, Otávio Sarian L, et al. Long-term outcomes of concomitant cisplatin plus radiotherapy versus radiotherapy alone in patients with stage IIIB squamous cervical cancer: A randomized controlled trial. Published online 2020. doi:10.1016/j.ygyno.2020.11.029

16. Kim YS, Shin SS, Nam JH, et al. Prospective randomized comparison of monthly fluorouracil and cisplatin versus weekly cisplatin concurrent with pelvic radiotherapy and high-dose rate brachytherapy for locally advanced cervical cancer. Published online 2007. doi:10.1016/j.ygyno.2007.09.022

17. Ryu SY, Lee WM, Kim K, et al. RANDOMIZED CLINICAL TRIAL OF WEEKLY VS. TRIWEEKLY CISPLATIN-BASED CHEMOTHERAPY CONCURRENT WITH RADIOTHERAPY IN THE TREATMENT OF LOCALLY ADVANCED CERVICAL CANCER. doi:10.1016/j.ijrobp.2011.05.002

18. Eddy GL, Bundy BN, Creasman WT, et al. Treatment of (“bulky”) stage IB cervical cancer with or without neoadjuvant vincristine and cisplatin prior to radical hysterectomy and pelvic/para-aortic lymphadenectomy: A phase III trial of the gynecologic oncology group. Gynecol Oncol. 2007;106(2):362-369. doi:10.1016/J.YGYNO.2007.04.007

19. Lorusso D, Xiang Y, Hasegawa K, et al. Pembrolizumab or placebo with chemoradiotherapy followed by pembrolizumab or placebo for newly diagnosed, high-risk, locally advanced cervical cancer (ENGOT-cx11/ GOG-3047/KEYNOTE-A18): a randomised, double-blind, phase 3 clinical trial. www.thelancet.com. doi:10.1016/S0140-6736(24)00317-9

20. Mileshkin LR, Moore KN, Barnes EH, et al. Adjuvant chemotherapy following chemoradiotherapy as primary treatment for locally advanced cervical cancer versus chemoradiotherapy alone (OUTBACK): an international, open-label, randomised, phase 3 trial. www.thelancet.com/oncology. 2023;24. doi:10.1016/S1470-2045(23)00147-X

21. Dueñas-González A, Zarbá JJ, Patel F, et al. Phase III, Open-Label, Randomized Study Comparing Concurrent Gemcitabine Plus Cisplatin and Radiation Followed by Adjuvant Gemcitabine and Cisplatin Versus Concurrent Cisplatin and Radiation in Patients With Stage IIB to IVA Carcinoma of the Cervix. J Clin Oncol. 29:1678-1685. doi:10.1200/JCO.2009.25.9663

22. Gupta S, Maheshwari A, Parab P, et al. JOURNAL OF CLINICAL ONCOLOGY Neoadjuvant Chemotherapy Followed by Radical Surgery Versus Concomitant Chemotherapy and Radiotherapy in Patients With Stage IB2, IIA, or IIB Squamous Cervical Cancer: A Randomized Controlled Trial. Published online 2018. doi:10.1200/JCO

23. Kenter GG, Greggi S, Vergote I, et al. Randomized Phase III Study Comparing Neoadjuvant Chemotherapy Followed by Surgery Versus Chemoradiation in Stage IB2-IIB Cervical Cancer: EORTC-55994. Published online 2023. doi:10.1200/JCO.22.02852

24. Mccormack M, Gallardo Rincón D, Eminowicz G, et al. Gynaecological cancers LBA8 A randomised phase III trial of induction chemotherapy followed by chemoradiation compared with chemoradiation alone in locally advanced cervical cancer: The GCIG INTERLACE trial. Annals of Oncology. 2023;34:S1276. doi:10.1016/j.annonc.2023.10.028

25. Mccormack M, Eminowicz G, Gallardo D, et al. Articles Induction chemotherapy followed by standard chemoradiotherapy versus standard chemoradiotherapy alone in patients with locally advanced cervical cancer (GCIG INTERLACE): an international, multicentre, randomised phase 3 trial. Published online 2024. doi:10.1016/S0140-6736(24)01438-7

26. Monk BJ, Toita T, Wu X, et al. Durvalumab versus Placebo with Chemoradiotherapy for Locally Advanced Cervical Cancer (CALLA): A Randomised, Double-Blind, Phase 3 Trial. Vol 24.; 2023. www.thelancet.com/oncology

27. Han K, Zou J, Zhao Z, et al. Clinical Validation of Human Papilloma Virus Circulating Tumor DNA for Early Detection of Residual Disease After Chemoradiation in Cervical Cancer. Journal of Clinical Oncology. Published online November 16, 2023. doi:10.1200/jco.23.00954

Sydney Oesch
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