gynecology and obstetrics
Cervical Cancer
Treatment of Cervical Cancer
Surgery alone for microinvasive disease Surgery or curative radiation therapy if there is no spread to parametria or beyond Radiation therapy and chemotherapy (chemoradiation) if there is spread to parametria or beyond Chemotherapy for metastatic and recurrent cancer Treatment of cervical cancer may include surgery, radiation therapy, and chemotherapy. If radical hysterectomy is indicated but patients are not ideal candidates for it, chemoradiation is used and has similar oncologic outcomes. Treatment of stage IA1 involves Conization or simple hysterectomy Microinvasive cervical cancer, defined as FIGO stage IA1 with no lymphovascular space invasion (LVSI), has a < 1% risk of lymph node metastases and may be managed conservatively with conization using loop electrosurgical excision procedure (LEEP), laser, or cold knife. Conization is indicated for patients who are interested in preserving fertility (to obtain, if possible, a nonfragmented specimen with a 3-mm margin). A cold knife preserves the margins for pathology evaluation but cannot always be used. Simple hysterectomy should be done if patients are not interested in preserving fertility or if margins are positive after conization. If margins are positive, sentinel lymph node (SLN) mapping should be considered, and if patients are interested in preserving fertility, repeat conization is an alternative. Sentinel lymph node (SLN) mapping is an alternative to full pelvic lymphadenectomy for patients with early-stage (IA1 with lymphovascular space invasion, IB1, IB2, or IIA1) cervical cancer ( Treatment references ) because only 15 to 20% of these patients have positive nodes. SLN mapping therefore decreases the number of full pelvic lymphadenectomies, which can have adverse effects (eg, lymphedema, nerve damage). For SLN mapping, blue dye, technetium-99 (99Tc), orindocyanine green(ICG) is directly injected into the cervix, usually at 3 and 9 o’clock. During surgery, SLNs are identified by direct visualization of blue dye, by a camera to detect the fluorescence of ICG, or by a gamma probe to detect 99Tc. SLNs are commonly located medial to the external iliac vessels, ventral to the hypogastric vessels, or in the superior part of the obturator space. Ultrastaging of all SLNs is done to detect micrometastasis and isolated tumor cells (low-volume disease). Any grossly suspicious node must be removed regardless of mapping. If there is no mapping on a hemipelvis, a side-specific lymphadenectomy is done. In the 2018 FIGO staging system, only macrometastases and micrometastases are considered when classifying cases as IIIC; isolated tumor cells do not change the stage, they are considered pN0. Detection rates for SLN mapping are best for tumors < 2 cm. For stage IA1 with LVSI or stage IA2, recommended treatments include Modified radical hysterectomy and pelvic lymphadenectomy (with or without SLN mapping) External pelvic radiation therapy with brachytherapy Criteria used to determine whether pelvic radiation with concurrent chemotherapy should be done after radical hysterectomy include the following (see table): Presence of lymphovascular space invasion Depth of invasion Tumor size Patients with a combination of risk factors, such as large tumor size (> 4 cm), deep (> 1/3) stromal invasion, and/or lymphovascular space invasion (LVSI), have a risk of recurrence and death of up to 30% after surgery alone ( Treatment references , Risk factors such as positive margins and/or pathologically confirmed positive pelvic lymph nodes and/or microscopic involvement of the parametrium are considered higher risk. In a randomized trial, the estimated 4-year survival rates for patients with stage IB cervical cancer and high-risk factors were 81% for those treated with combined chemotherapy and radiation therapy and 71% for those treated with radiation therapy alone ( Treatment references , For stages IB1, IB2, and IIA1, the standard recommendation is Open radical hysterectomy with bilateral pelvic lymphadenectomy (with or without SLN mapping) Radical hysterectomy includes resection of the uterus (including the cervix), parts of the cardinal and uterosacral ligaments, the upper 1 to 2 cm of the vagina, the pelvic lymph nodes and parametrium. The Querleu & Morrow classification system describes four types of radical hysterectomy based on the lateral extent of resection; a few subtypes take nerve preservation and paracervical lymphadenectomy into account ( Treatment references ). Results from a randomized trial showed that minimally invasive surgery (laparoscopy or robot-assisted laparoscopy) resulted in a lower overall survival rate and a higher recurrence rate than total abdominal radical hysterectomy ( Treatment references ). Therefore, open radical hysterectomy is recommended as the appropriate approach. When patients are not considered ideal candidates for surgery because of comorbidities, another valid option is external pelvic radiation therapy and brachytherapy with or without concurrent platinum-based chemotherapy. Another treatment option is radical hysterectomy and bilateral pelvic lymphadenectomy (with or without para-aortic lymphadenectomy), sometimes with adjuvant radiation therapy (see table). If extracervical spread is noted during radical hysterectomy, the procedure should be aborted, and postoperative radiation therapy with concurrent chemotherapy is recommended to prevent local recurrence ( Treatment references ). The standard therapy for stages IB3, IIA2, IIB, III, and IVA cancer is External pelvic radiation therapy with brachytherapy and concurrent platinum-based chemotherapy To determine the extent of the radiation field, clinicians may evaluate spread to para-aortic lymph nodes clinically (abdominal CT and/or MRI) or surgically (pelvic and para-aortic lymphadenectomy). In a randomized trial, oncologic outcomes did not differ significantly in patients with stage IIB through IVA staged clinically compared with those staged surgically before chemoradiation. In this study, laparoscopic staging appeared to be safe, did not delay primary treatment, and resulted in upstaging in 33% of patients with locally advanced cervical cancer ( Treatment references ). When cancer is limited to the cervix and/or pelvic lymph nodes, the standard recommendation is External beam radiation therapy, followed by brachytherapy (local radioactive implants, usually using cesium) to the cervix Radiation therapy may cause acute complications (eg, radiation proctitis and cystitis) and, occasionally, late complications (eg, vaginal stenosis, intestinal obstruction, rectovaginal and vesicovaginal fistula formation). Chemotherapy (cisplatinorcarboplatin) is usually given with radiation therapy, often to sensitize the tumor to radiation. Although stage IVA cancers are usually treated with radiation therapy initially, pelvic exenteration (excision of all pelvic organs) may be considered. If after radiation therapy, cancer remains but is confined to the central pelvis, exenteration is indicated and cures up to 40% of patients. The procedure may include continent or incontinent urostomy, low anterior rectal anastomosis without colostomy or with an end-descending colostomy, omental carpet to close the pelvic floor (J-flap), and vaginal reconstruction with gracilis or rectus abdominis myocutaneous flaps. Chemotherapy is the primary treatment for stage IVB cervical cancer. Response rates are approximately 38% ( Treatment references ). ) resulted in an improvement of 3.7 months in median overall survival in patients with recurrent, persistent, or metastatic cervical cancer ( Treatment references ). Metastases outside the radiation field appear to respond better to chemotherapy than does previously irradiated cancer or metastases in the pelvis. A systematic review of observational studies included 2424 patients with stage IVB squamous cell, adenocarcinoma, or adenosquamous carcinoma of the cervix and found improved overall survival associated with definitive (≥ 45 Gy) pelvic radiotherapy compared with systemic chemotherapy (with or without palliative pelvic radiation) ( Treatment references ). Clinicians should consider testing for mismatch repair (MMR) and microsatellite instability (MSI), PD-L1 (programmed cell death-ligand 1) expression, and/orNTRKgene fusion if patients have recurrent, progressive, or metastatic cervical cancer. Results can help predict responses to immunotherapies such as PD-L1 inhibitors. Few effective second-line treatments exist for women with recurrent or metastatic cervical cancer. to chemotherapy, improved progression-free and overall survival in patients with persistent, recurrent, or metastatic cervical cancer ( Treatment references ). showed clinically meaningful and durable antitumor activity with a manageable and tolerable safety profile in women with previously treated recurrent or metastatic cervical cancer ( Treatment references ). Fertility-sparing surgery is an option in some patients who have early-stage cervical cancer (IA1 with LVSI, IA2, IB1, some cases of IB2) and who wish to preserve fertility. Surgical treatment of cervical cancer does not include oophorectomy unless ovaries appear abnormal. In young patients having surgery, ovarian preservation is particular important to avoid premature menopause. Before pelvic radiation, ovaries may be moved outside the radiation field (oophoropexy) to avoid toxic exposure. Patients should be counseled about the benefit of preserving ovary function versus the risk of potential ovarian metastases. In a study of 3471 patients who had stage Ib through IIb cervical cancer treated with a radical hysterectomy, the cancer metastasized to the ovaries in 1.5% of patients ( Treatment references ). Ovarian metastasis was more common among patients with adenocarcinoma (5.31%) than among those with squamous cell carcinoma (0.79%). Surgical options for uterine conservation include Radical trachelectomy with nodal evaluation Cervical conization Radical trachelectomy is removal of the cervix, parametria immediately adjacent to the cervix, upper 2 cm of the vagina, and pelvic lymph nodes. The uterus is conserved and is reattached to the upper vagina, preserving the potential for fertility. Candidates for this procedure are patients with the following: Histologic subtypes such as squamous cell carcinoma, adenocarcinoma, or adenosquamous carcinoma (not neuroendocrine or small cell carcinoma or sarcoma) Stage IA1/grade 2 or 3 with lymphovascular space invasion Stage IA2 Stage IB1 Invasion of the upper cervix and lower uterine segment should be excluded by MRI before surgery. Rates of recurrence and death are similar to those after radical hysterectomy. If patients who have this procedure plan to have children, delivery must be cesarean. After a radical trachelectomy, fertility rates range from 50 to 70%, and the recurrence rate is about 5 to 10%. Radical trachelectomy can be performed via vaginal surgery, laparotomy, laparoscopy, or robotic-assisted surgery. There has been concern about the safety of radical trachelectomy using minimally invasive approaches (laparoscopy or robotic-assisted surgery) compared with laparotomy. In one retrospective study of patients with early-stage cervical cancer (≤ 2 cm), laparotomy compared with minimally invasive approaches had comparable 4.5-year disease-free survival rates ( Treatment references ). For patients with low-risk, early-stage cervical cancer, conization with pelvic nodal evaluation may be an alternative to radical trachelectomy. In a single-arm, prospective study, conservative surgery (cervical conization or simple hysterectomy with nodal evaluation) appeared to be safe and feasible in women with low-risk, early-stage cervical cancer; the 2-year recurrence rate was 3.5% ( Treatment references ). Studies to determine the optimal treatment for patients with early-stage cervical cancer are ongoing (eg, SHAPE trial) ( An ongoing prospective study (CONTESSA) is evaluating the role of neoadjuvant chemotherapy followed by fertility-sparing surgery in patients who have tumors 2 to 4 cm and who wish to preserve fertility ( Treatment references ). 1.National Comprehensive Cancer Network (NCCN): NCCN Clinical Practice Guidelines in Oncology: Cervical Cancer. Version 1.2023. October 26, 2021. Accessed July 14, 2023. 2.Sedlis A, Bundy BN, Rotman MZ, et al: A randomized trial of pelvic radiation therapy versus no further therapy in selected patients with stage IB carcinoma of the cervix after radical hysterectomy and pelvic lymphadenectomy: A Gynecologic Oncology Group Study.Gynecol Oncol73 (2):177–183, 1999. doi: 10.1006/gyno.1999.5387 3.Rotman M, Sedlis A, Piedmonte MR, et al: A phase III randomized trial of postoperative pelvic irradiation in stage IB cervical carcinoma with poor prognostic features: Follow-up of a Gynecologic Oncology Group Study.Int J Radiat Oncol Biol Phys65 (1):169–176, 2006. doi: 10.1016/j.ijrobp.2005.10.019 4.Peters WA, Liu PY, Barrett RJ, et al: Concurrent chemotherapy and pelvic radiation therapy compared with pelvic radiation therapy alone as adjuvant therapy after radical surgery in high-risk early-stage cancer of the cervix.J Clin Oncol18 (8):1606–1613, 2000. doi: 10.1200/JCO.2000.18.8.1606 5.Monk BJ, Wang J, Im S, et al: Rethinking the use of radiation and chemotherapy after radical hysterectomy: a clinical-pathologic analysis of a Gynecologic Oncology Group/Southwest Oncology Group/Radiation Therapy Oncology Group trial.Gynecol Oncol96 (3):721–728, 2005. doi: 10.1016/j.ygyno.2004.11.007 6.Querleu D, Morrow CP: Classification of radical hysterectomy.Lancet Oncol9 (3):297–303, 2008. doi: 10.1016/S1470-2045(08)70074-3 7.Ramirez PT, Frumovitz M, Pareja R, et al: Minimally invasive versus abdominal radical hysterectomy for cervical cancer.N Engl J Med379 (20): 1895–1904, 2018. doi: 10.1056/NEJMoa1806395 8.Cibula D, Dostalek L, Hillemanns P, et al: Completion of radical hysterectomy does not improve survival of patients with cervical cancer and intraoperatively detected lymph node involvement: ABRAX international retrospective cohort study.Eur J Cancer143:88–100, 2021. doi: 10.1016/j.ejca.2020.10.037 9.Marnitz S, Tsunoda AT, Martus P, et al: Surgical versus clinical staging prior to primary chemoradiation in patients with cervical cancer FIGO stages IIB–IVA: Oncologic results of a prospective randomized international multicenter (Uterus-11) intergroup study.Int J Gynecol Cancer30:1855–1861, 2020. doi:10.1136/ijgc-2020-001973 10.Ruengkhachorn I, Leelaphatanadit C, Therasakvichya S, et al: Oncologic outcomes of stage IVB or persistent or recurrent cervical carcinoma patients treated with chemotherapy at Siriraj Hospital: Thailand's largest tertiary referral center.Int J Gynecol Cancer26(6):1154-1161, 2016. doi:10.1097/IGC.0000000000000712 11.Tewari KS, Sill MW, Long HJ III: Improved survival withbevacizumabin advanced cervical cancer.N Engl J Med370 (8):734-743, 2014. doi: 10.1056/NEJMoa1309748 12.Viveros-Carreño D, Vieira-Serna S, Grillo-Ardila CF, et al: Definitive pelvic radiotherapy for patients with newly diagnosed stage IVB cervical cancer: a systematic review.Int J Gynecol Cancer33(7):1057-1062, 2023. Published 2023 Jul 3. doi:10.1136/ijgc-2023-004465 13.Colombo N, Dubot C, Lorusso D, et al:Pembrolizumabfor persistent, recurrent, or metastatic cervical cancer.N Engl J Med385 (20):1856–1867, 2021. doi: 10.1056/NEJMoa2112435 14.Coleman RL, Lorusso D, Gennigens C, et al: Efficacy and safety oftisotumab vedotinin previously treated recurrent or metastatic cervical cancer (innovaTV 204/GOG-3023/ENGOT-cx6): a multicentre, open-label, single-arm, phase 2 study.Lancet Oncol22(5):609-619, 2021. doi:10.1016/S1470-2045(21)00056-5 15.Shimada M, Kigawa J, Nishimura R, Yamaguchi S, et al: Ovarian metastasis in carcinoma of the uterine cervix.Gynecol Oncol101 (2):234–237, 2006. doi: 10.1016/j.ygyno.2005.10.004 16.Salvo G, Ramirez PT, Leitao M, et al: Open vs minimally invasive radical trachelectomy in early-stage cervical cancer: International Radical Trachelectomy Assessment Study.Am J Obstet Gynecol226 (1):97.e1-97.e16, 2022. doi: 10.1016/j.ajog.2021.08.029 17.Schmeler KM, Pareja R, Aldo Lopez Blanco AL, et al: ConCerv: A prospective trial of conservative surgery for low-risk early-stage cervical cancer.Int J Gynecol Cancer31 (10):1317–1325, 2021. doi: 10.1136/ijgc-2021-002921 18.Plante M, Kwon JS, Ferguson et al: An international randomized phase III trial comparing radical hysterectomy and pelvic node dissection (RH) vs simple hysterectomy and pelvic node dissection (SH) in patients with low-risk early-stage cervical cancer (LRESCC): A Gynecologic Cancer Intergroup study led by the Canadian Cancer Trials Group (CCTG CX.5-SHAPE). [abstract taken fromJ Clin Oncol41(suppl 17; abstract LBA5511), 2023. doi: 10.1200/JCO.2023.41.17_suppl.LBA5511 19.Plante M, van Trommel NE, Schaafsma M, et al: 2022-RA-678-ESGO CONTESSA/NEOCON-F trial: Assessing the effectiveness and safety of neoadjuvant chemotherapy followed by fertility-sparing surgery in FIGO 2018 stage IB2 cervical cancer.International Journal of Gynecologic Cancer32:A20, 2022. http://dx.doi.org/10.1136/ijgc-2022-ESGO.45 