Radiation Oncology/Cervix/Early Stage Bulky

Surgery vs. RT

 * Milan, 1997 (1986-91) PMID 9284774 — "Randomised study of radical surgery versus radiotherapy for stage Ib-IIa cervical cancer." Landoni F et al. Lancet. 1997 Aug 23;350(9077):535-40.
 * Randomized. 343 patients. Stage IB-IIA (Ib1 61%, Ib2 27%, IIA 12%) Treated with radical hysterectomy (Class III) vs. radical RT. Median F/U 87 mo.
 * RT given: EBRT to median 47 Gy followed by LDR x1 for Point A median dose 76 Gy. Adjuvant RT allowed for pts who were surgical stage IIB or greater, <3mm of safe cervical stroma, positive margins, or positive LN (62/114 IB1, 46/55 IB2).
 * 63% of pts in surgery arm received RT.
 * 5-year outcome: no difference; Non-bulky: OS surgery 87% vs. RT 90% (NS), DFS surgery 80% vs. 82% (NS)
 * AdenoCA: significantly better outcomes with surgery; OS (70% vs. 59%), DFS (66% vs. 47%)
 * Complications (Grade 2-3): Surgery 28% vs RT 12% (SS). Severe leg edema surgery 0%, RT 1%, surgery + RT 9%
 * Conclusion: Primary surgery not a good option for bulky disease

Surgery +/- Post-op RT
25% of Stage IB pts may benefit from XRT because they have positive risk factors (from GOG 49). Sedlis criteria often simplified to needing 2 or more of these factors:
 * CLS (LVI) involvement
 * deep stromal invasion (middle or deep third); [i.e >1/3 stromal invasion]
 * Size > 4 cm


 * GOG 92 (1988-95)
 * 277 pts. Randomized. Stage IB, node negative, but with high estimated risk of recurrence (from GOG 49) s/p radical hysterectomy and lymphadenectomy randomized to +/- adjuvant pelvic XRT 50.4 Gy. Included pts with: 1) CLS involved, deep 1/3 stromal invasion, any size; 2) CLS involved, middle 1/3 invasion, size >= 2cm; 3) CLS involved, superficial 1/3 invasion, >= 5 cm; or 4) CLS not involved, deep or middle 1/3 invasion, >= 4 cm. These pts were estimated to have a 31% recurrence at 3 yrs.
 * 1999 PMID 10329031 &mdash; "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." Sedlis A et al. Gynecol Oncol. 1999 May;73(2):177-83.
 * Recurrences in 15% (RT) vs 28% (no RT). 2-year recurrence free rate 88% vs 79%. Hazard ratio=0.53. Grade 3/4 adverse effects were 6% vs 2.1% Distant mets 2% (RT) vs 7% (no RT). Follow up too short for survival analysis.
 * 2006 PMID 16427212 &mdash; "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." Rotman M et al. Int J Radiat Oncol Biol Phys. 2006 May 1;65(1):169-76.
 * Decreased rate of recurrence by 46%; local recurrence 13.9% (RT) vs 20.7% (no RT), distant 2.9% vs 8.6%. Improved PFS by 42%. Decreased death rate by 30% (28.6% vs 19.7%) but not S.S. (p=0.07). RT has improved benefit for adenocarcinoma or adenosquamous histologies (8.8% vs 44% recurrence).

Surgery + Post-op RT vs. Post-op CRT
High risk features:
 * microscopic involvement of the parametrium (upstaged to IIB)
 * positive pelvic lymph nodes (upstaged to IIIB)
 * positive surgical margins


 * GOG 109 / Intergroup 0107 / SWOG 8797 / RTOG 9112 (1991-96) -- RT vs chemo+RT
 * Randomized, 268 patients. Post-operative clinical stage IA2, IB, and IIA, s/p radical hysterectomy and pelvic lymphadenectomy, with high risk features (positive pelvic lymph nodes, positive margins, or microscopic involvement of the parametrium). Randomized to RT vs RT+CT.  Chemotherapy consisted of cisplatin 70 mg/m^2 and a 96-hour infusion of fluorouracil 1,000 mg/m^2/d every 3 weeks x four cycles (1st and 2nd cycles concurrent with RT). RT 49.3 Gy in 29 fractions (1.7 Gy/fx). 45 Gy (1.5 Gy/fx) given to paraaortic area if positive common iliac LN.
 * 2000 - PMID 10764420 &mdash; "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." (Peters WA 3rd et al. J Clin Oncol. 2000 Apr;18(8):1606-13.)
 * 4-year OS 71% (RT) vs 81% (RT+CT), HR=2.01; 4-year PFS 63% vs 80%, HR=1.96
 * Conclusion: Addition of cisplatin based chemotherapy to RT significantly improves progression free survival and overall survival following surgery for high-risk, early stage patients
 * 2005 PMID 15721417 &mdash; "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." Monk BJ et al. Gynecol Oncol. 2005 Mar;96(3):721-8.
 * Smaller benefit for chemo+RT when only 1 LN is positive.
 * Carbonic Anhydrase-IX; 2010 PMID 19913895 -- "Prognostic relevance of carbonic anhydrase-IX in high-risk, early-stage cervical cancer: a Gynecologic Oncology Group study." (Liao SY, Gynecol Oncol. 2010 Mar;116(3):452-8. Epub 2009 Nov 13.)
 * Retrospective. 166 patients, stained for CA-IX expression (high >80% staining).
 * Outcome: High CA-IX in 21%, associated with tumor size and depth of invasion. On MVA, independent prognostic factor for PFS (HR 2.1, SS), and OS (HR 2.4, SS)
 * Conclusion: Tumor hypoxia measured by CA-IX independent prognostic factor for PFS and OS

Primary RT vs. Pre-op RT + Surgery

 * GOG 71 / RTOG 84-12 (1984-91)
 * Randomized. 256 pts. "Suboptimal" or "bulky" stage IB, defined as: exophytic tumor >= 4 cm, a cervix expanded to >= 4 cm (and assumed to be tumor by the clinician), large or barrel-shaped tumors of >= 4 cm
 * Randomized to: RT alone vs RT followed by hysterectomy
 * EBRT to 40 Gy (RT alone) or 45 Gy (adjuvant hysterectomy). Followed in 1-2 weeks by brachy to 40 Gy (RT alone) or 30 Gy (hyst), for a total of 80 Gy vs 75 Gy to point A. Group 2 had extrafascial hysterectomy 2-6 wks after completing RT.
 * 2003 PMID 12798694 &mdash; "Radiation therapy with and without extrafascial hysterectomy for bulky stage IB cervical carcinoma: a randomized trial of the Gynecologic Oncology Group." Keys HM et al. Gynecol Oncol. 2003 Jun;89(3):343-53.
 * Median f/u 9.6 yrs. Lower incidence of local relapse with addition of hysterectomy (27% vs 14%). No difference in OS. Trend toward 5 year PFS 53% (RT) vs 62% (RT + surgery) (p=0.09). Disease progression in 46% (RT) vs 37% (RT + surgery) p=0.07. No difference in severe toxicity. Patients with 4-6 cm tumors may benefit from hysterectomy.

Pre-op RT vs. Pre-op CRT

 * GOG 123 (1992-97)
 * Randomized. 369 pts. Stage IB (at least 4 cm).
 * Randomized to: RT -> hysterectomy vs RT/chemo -> hysterectomy
 * 45 Gy EBRT followed by brachytherapy to total dose 75 Gy to point A. Cisplatin weekly at 40 mg/m2, maximum of 6 doses. Extrafascial hysterectomy 3-6 after RT.
 * 1999 PMID 10202166 &mdash; "Cisplatin, radiation, and adjuvant hysterectomy compared with radiation and adjuvant hysterectomy for bulky stage IB cervical carcinoma." Keys HM et al. N Engl J Med. 1999 Apr 15;340(15):1154-61.
 * Median f/u 36 mos. 3-yr OS 74% vs 83% (RT+chemo). RR=0.54. Recurrence rate 37% vs 21%, RR=0.51.
 * Conclusion: concomitant chemotherapy given with RT prior to hysterectomy improves survival.
 * Comment: authors felt that improved LC led to improved OS due to addition of cisplatin, and that adding hysterectomy did not impact OS
 * 2007 PMID 17980189 -- "Radiation therapy with or without weekly cisplatin for bulky stage 1B cervical carcinoma: follow-up of a Gynecologic Oncology Group trial." (Stehman FB, Am J Obstet Gynecol. 2007 Nov;197(5):503.e1-6.)
 * Median f/u 101 months (8.3 yr). Relative risk of progression 0.61; hazard ratio for death 0.63. 6-yr DFS 71% vs 60%; OS 78% vs 64%. Increased early hematologic and GI toxicity seen with RT+chemo. No difference in late effects.
 * Concurrent cisplatin improves long-term PFS and OS. Serious late effects were not increased. The inclusion of hysterectomy has been discontinued on the basis of another trial.

Surgery +/- Neoadjuvant chemotherapy

 * GOG 141
 * Study was closed prematurely due to slow accrual. Randomized. 288 patients with Stage IB2. Treated with exlap with radical hysterectomy and PPaLND +/- neoadjuvant vincristine-cisplatin x3 cycles
 * 2007 PMID 17493669 -- "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." (Eddy GL, Gynecol Oncol. 2007 Aug;106(2):362-9. Epub 2007 May 9.). Median F/U 5.2 years
 * Outcome: Comparable recurrence rate and death rate; post-op RT necessary in 52% vs. 45% (NS)
 * Conclusion: No benefit for neoadjuvant chemotherapy in IB2 prior to surgery; majority needed further radiation

(Surgery-RT or Primary RT) +/- Neoadjuvant chemotherapy

 * Argentina (1987-1992)
 * Randomized. 210 patients with IB (~50% bulky). Arm 1) Surgery + adjuvant pelvic RT 50 gy or if unresectable surgical staging + primary pelvic RT 60 Gy + LDR boost 25-35 Gy vs. Arm 2) Neoadjuvant chemo (VBP) with same treatment
 * 1997 PMID 9345358 -- "Long-term follow-up of the first randomized trial using neoadjuvant chemotherapy in stage Ib squamous carcinoma of the cervix: the final results." (Sardi JE, Gynecol Oncol. 1997 Oct;67(1):61-9.) Median F/U 5.6 years
 * Outcome: No difference in Ib1 (nonbulky). Benefit in IB2 (bulky) OS neoajduvant 80% vs. control 61% (SS)(due to increased operability 100% vs. 85%, SS).
 * Resectability: 7-year OS resectable 69% vs. unresectable 14% (SS)
 * Conclusion: Neoadjuvant chemo can improve OS because of improved resectability in Ib2 (bulky) patients

Neoadjuvant Chemotherapy + Surgery vs Definitive ChemoRT

 * EORTC-55994 (2002-2014)
 * Randomized. 626 with cervical cancer IB2-IIB. Arm 1) Neoadjuvant chemotherapy (investigator choice containing platinum) followed by surgery vs chemo-RT. Protocol treatment completed in 71% vs 82% of arms. Additional RT given in 48% of NACT-S arm. Additional surgery in 8% of CCRT arm
 * 2023 PMID 37656948 -- "Randomized Phase III Study Comparing Neoadjuvant Chemotherapy Followed by Surgery Versus Chemoradiation in Stage IB2-IIB Cervical Cancer: EORTC-55994" (Kenter GG, J Clin Oncol. 2023 Nov 10;41(32):5035-5043. doi: 10.1200/JCO.22.02852. Epub 2023 Sep 1.). Median F/U 8.7 years
 * Outcome: 5-year OS NACT-S 72% vs CCRT 76% (NS)
 * Toxicity: Short term grade 3+ NACT-S 41% vs CCRT 23%; long term 15% vs 21%
 * Conclusion: No superiority of NACT-S over CCRT, acceptable morbidity and QOL in both arms


 * Tata Memorial Center; 2018 (2003-2015) PMD 29432076 -- "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." (Gupta S, J Clin Oncol. 2018 Jun 1;36(16):1548-1555. doi: 10.1200/JCO.2017.75.9985. Epub 2018 Feb 12.)
 * Randomized. 635 patients with Stage IB2, IIA, or IIB squamous cell cervical cancer. Arm 1) Neoadjuvant paclitaxel/carboplatin x 3 cycles followed by radical hysterectomy; postop RT or chemoRT as indicated (21% crossed over into Arm 2) vs Arm 2) Definitive radiation with concurrent weekly cisplatin. Median F/U 5 years
 * Outcome: 5-year DFS NACT+S 69% vs CRT 77% (SS). 5-year OS 75% vs 75% (NS).
 * Toxicity: Rectal NACT+S 2.2% vs CRT 3.5%, bladder 1.6% vs 3.5%, vaginal 12% vs 26%
 * Conclusion: Superior DFS from chemoradiation compared with NACT followed by surgery; survival comparable. Concomitant chemoRT should remain the standard of care

PA Nodes

 * Gustave Roussy; 2008 (2004-2006) PMID 18487573 -- "Histologic results of para-aortic lymphadenectomy in patients treated for stage IB2/II cervical cancer with negative [18F]fluorodeoxyglucose positron emission tomography scans in the para-aortic area." (Boughanim M, J Clin Oncol. 2008 May 20;26(15):2558-61.)
 * Retrospective. 38 patients with cervix IB2/II with negative PET in PA LNs. Treated with Chemo-RT (cisplatin 40 mg/m2/wk + EBRT 45/25) + LDR BT >=15 Gy. Then PALND
 * Outcome: 3/38 (8%) had pathologically positive PA LN
 * Conclusion: 8% of patients with negative PA by PET have disease after chemo-RT therapy