# Radiation Oncology/Cervix/Locally Advanced

* Front Page: Radiation Oncology | RTOG Trials | Randomized Trials
* Cervix: Main Page |
* Overview |
* Micro-invasive |
* Early Stage Non-Bulky |
* Early Stage Bulky |
* Locally Advanced |
* Brachytherapy |
* Cervix Randomized |
* GOG Trials |
* RTOG Cervix

## Overview

* No curative surgical options
* Primary RT alone fails often (Stage IIB ~20-50%, Stage III 50-75%)
* Early trials showed no difference, but RTOG 90-01 showed a benefit for CRT. Also, several other trials in other subgroups showed a benefit.
* As a result, in 1999 NCI recommended that "strong consideration should be given to adding chemotherapy to radiation therapy in the treatment of invasive cervical cancer"
* Cisplatin-based regimens appear best, but no firm conclusions yet

## RT vs. Chemo-RT
### Meta-Analysis

* Lanzhou University, China; 2010 PMID 20157716 -- "Radiochemotherapy versus radiotherapy in locally advanced cervical cancer: a meta-analysis." (Wang N, Arch Gynecol Obstet. 2010 Feb 16. [Epub ahead of print])
** Meta-analysis. 18 RCT involving 3,517 patients, locally advanced cervical CA. Comparison of RT vs chemo-RT
** Outcome: chemo-RT superior in response rate, 3-year OS and 5-year OS
** Toxicity: Chemo-Rt worse in GI, myelosuppression and leucopenia. No significant difference in rectitis, cystitis, nausea, or vomiting
** Conclusion: Chemo-RT superior outcome, no significant difference in toxicity

### Randomized Evidence

* NCI Canada, 2002 PMID 11844818 -- "Phase III trial comparing radical radiotherapy with and without cisplatin chemotherapy in patients with advanced squamous cell cancer of the cervix." (Pearcey R, J Clin Oncol. 2002 Feb 15;20(4):966-72.)
** Randomized. 259 patients with Stage IB-IVA squamous cell Cx, bulky >5cm or pathologically LN+. Treated with RT +/- cisplatin 40mg/m2 qw. Median F/U 6.8 years
** 5-year outcomes: no difference in PFS, or OS (62% vs. 58%)
** Conclusion: No difference, however balance of other evidence suggests CRT
** Editorial (PMID 11844807): No surgical staging of PA LN, anemia imbalance. Agree with authors conclusion that balance of evidence suggests combined-modality treatment
* Taiwan, 1997 (1990-1995) PMID 9234921 -- "A randomized trial of concurrent chemoradiotherapy versus radiotherapy in advanced carcinoma of the uterine cervix." (Tseng CJ, Gynecol Oncol. 1997 Jul;66(1):52-8.)
** Randomized. 122 patients with advanced Cx. Treated with RT alone vs. RT + concurrent chemo (cisplatin, vincristine, bleomycin q3w x4 cycles). Median F/U 3.8 years
** 3-year outcomes: DFS: 52% vs. 53% (NS), OS 62% vs. 64% (NS)
** Toxicity: higher in concurrent group 37% vs. 18% (SS)
** Conclusion: no difference
* RTOG 90-01 (1990-97)
** 403 pts. Stage IIB-IVA, or Stage IB-IIA with >5cm tumor, or LN+. Randomized to: 1) 45 Gy to pelvis + paraaortic nodes (both at 1.8 Gy/fx) with upper border at L1/L2, or 2) 45 Gy to pelvis alone plus 3 cycles 5-FU and cisplatin concurrent with RT. Intracavitary RT given in both arms. Chemotherapy was cisplatin (75 mg/m2) on Day 1 and 5-FU (4 g/m2 96-hr infusion,Days 1-5), repeated q3w.
** 3-years, 1999 PMID 10202164 — "Pelvic radiation with concurrent chemotherapy compared with pelvic and para-aortic radiation for high-risk cervical cancer." Morris M et al. N Engl J Med. 1999 Apr 15;340(15):1137-43. Median F/U 3.6 years.
*** Estimated 5-year outcome: DFS RT alone 40% vs CRT 67% (SS); OS 58% vs 73% (SS). Decreased DM and LRR in chemo+RT arm.
*** Toxicity: comparable, higher reversible hematologic in CRT
*** Conclusion: Significantly improved survival with concurrent cisplatin/5-FU
** 5-years, 2002: ASTRO Plenary #1, Eifel PJ et al. - Webcast:Eifel Webcast discussion:Greven
*** 5-yr OS 52% vs 72%, DFS 43% vs 67%, pelvic recurrence 34% vs 18%. No difference in paraaortic recurrence.
** 8-years, 2004: PMID 14990643 — "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." Eifel PJ et al. J Clin Oncol. 2004 Mar 1;22(5):872-80. Median F/U 6.6 yrs.
*** 8-yr OS 41% vs 67%. Decreased recurrences by 51%. Greatest improvement for Stage IB-IIB but were also substantial for stages III-IVA.
** Conclusion: addition of 5-FU and cisplatin improved survival
* GONO, Italy (1989-1991)
** Randomized. 64 patients, Stage IIB-III. Arm 1) RT 40/20 + 15-20 Gy parametrial boost + BT 40 Gy vs. Arm 2) sequential cisplatin 60 mg/m2 x2 cycles, then RT as in Arm 1, then cisplatin x 4 cycles
** 1994 PMID 8048390 -- "Randomized study comparing chemotherapy plus radiotherapy versus radiotherapy alone in FIGO stage IIB-III cervical carcinoma. GONO (North-West Oncologic Cooperative Group)." (Chiara S, Am J Clin Oncol. 1994 Aug;17(4):294-7.)
*** Outcome: 3 year OS RT 83% vs. C-RT 72% (NS); PFS 72% vs. 59% (NS)
*** Conclusion: No difference
* Chiang Mai, Thailand (1988-1994)
** Randomized. 926 patients with locally advanced Cx (FIGO IIB-IVA) randomized into 4 arms: 1) RT alone, 2) RT + adjuvant CT, 3) RT + concurrent CT, 4) RT + concurrent CT + adjuvant CT. Concurrent chemo was IV mitomycin C and oral 5-FU; adjuvant chemo was oral 5-FU. Median F/U 7.4 years
** 2003 PMID 12654431 -- "Concurrent mitomycin C, 5-fluorouracil, and radiotherapy in the treatment of locally advanced carcinoma of the cervix: a randomized trial." (Lorvidhaya V, Int J Radiat Oncol Biol Phys. 2003 Apr 1;55(5):1226-32.)
*** Toxicity: higher in concurrent arm, but tolerated well
*** 5-year DFS: 48% vs. 54% vs. 64% vs. 60%. 5-year LRR: 25% vs. 21% vs. 14% vs. 18%. Mets rate comparable
*** Conclusion: Concurrent chemo (mitomycin C + 5-FU) with RT showed improved DFS compared to RT alone
* Princess Margaret (1987-1995)
** Randomized. 234 patients with Stage IB/IIA bulky - IVA. Four arms. Arm 1) RT 50/25 vs. Arm 2) RT 50/25 + 5-FU 1000 mg/m2 vs. Arm 3) RT 52.8/33 (partially hyperfractionated 1st day and last 4 days BID) vs. Arm 4) RT 52.8/33 as Arm 3 + 5-FU 1000 mg/m2. All followed by BT 40 Gy.
** 1998 PMID 9600821 -- "A randomized trial of standard versus partially hyperfractionated radiation with or without concurrent 5-fluorouracil in locally advanced cervical cancer." (Thomas G, Gynecol Oncol. 1998 May;69(2):137-45.) Median F/U 5 years
*** Outcome: DFS 45% vs. 53% vs. 58% vs. 61% (NS); no difference in OS
*** Conclusion: No difference with concurrent 5-FU or partially hyperfractionated RT
* RTOG 80-05 (1980-1984)
** Randomized. 120 patients. Stage IIIB and IVA, squamous cell Cx. RT +/- misonidazole 400mg/m2 qd. RT technique' 46 Gy whole pelvis, 10 Gy parametrial boost, brachy/EBRT boost to tumor
** 1999 PMID 10348279 -- "Irradiation with or without misonidazole for patients with stages IIIB and IVA carcinoma of the cervix: final results of RTOG 80-05." (Grigsby PW, Int J Radiat Oncol Biol Phys. 1999 Jun 1;44(3):513-7.)
*** 5-year outcome: PFS RT 22% vs. CRT 29% (NS). No difference in patterns of failure
*** Toxicity: no difference
** Conclusion: No benefit for misonidazole
* Hong Kong (1982-83)
** Randomized. Advanced cervical CA. Treated with 1) RT alone, 2) RT + weekly cisplatin, or 3) RT + twice-weekly cisplatin
** 1989 PMID 2807006 -- "Long-term follow-up of potentiation of radiotherapy by cis-platinum in advanced cervical cancer." (Wong LC, Gynecol Oncol. 1989 Nov;35(2):159-63.)
*** Conclusion: Best central tumor control for twice-weekly group, but overall survival was similar.
* Roswell Park (1972-1976)
** Randomized. 130 patients. Stage IIB and IIIB Cx. Treated with continuous or split-course RT +/- hydroxyurea
** 1983 PMID 6359885 -- "Hydroxyurea: a radiation potentiator in carcinoma of the uterine cervix. A randomized double-blind study." (Piver MS, Am J Obstet Gynecol. 1983 Dec 1;147(7):803-8.)
*** 40 patients with IIB, PA lymphadenectomy negative. F/U >5 years
*** Toxicity: leukopenia significantly worse with HU, no other differences
*** OS: RT alone 53% vs. CRT 94% (SS); 45% of patients with placebo died of cervical cancer
** 1977 PMID 6359885 -- "Hydroxyurea as a radiation sensitizer in women with carcinoma of the uterine cervix." (Piver MS, Am J Obstet Gynecol. 1977 Oct 15;129(4):379-83.)
*** Outcome: Stage IIB: OS RT alone 43% vs. CRT 74% (SS); Stage IIIB: OS 33% vs. 52% (NS)
*** RT: continous RT 91% vs. split-course RT 29% (SS)
Retrospective
* Washington University, 2004 (1998-2003) - PMID 15667965 — "Lack of benefit of concurrent chemotherapy in patients with cervical cancer and negative lymph nodes by FDG-PET." Grigsby PW et al. Int J Radiat Oncol Biol Phys. 2005 Feb 1;61(2):444-9.
** Retrospective, 65 pts (15 without chemo, 50 with chemo). Stage IB2, IIB, and IIIB. All pts underwent PET with no evidence of lymph node metastases. Patients up until mid-1999 did not receive chemotherapy; thereafter, they received routine chemo. Chemo dose 40 mg/m^2 cisplatin weekly x 6 cycles. Radiation dose was curative intent with brachytherapy and external beam (mean dose 85 Gy to point A); no para-aortic XRT.
** Mean follow-up 32 months. Similar 5-year overall survival (85% vs 81%) and 5-year cause-specific survival (78% vs 74%).
** Conclusion: No benefit to concurrent chemotherapy in lymph node negative patients.

## Chemo-RT: various chemo combinations

* ENGOT-cx11 / GOG-3047 / KEYNOTE-A18 (2020 -2022) - Cisplatin-RT +/- pembrolizumab
** Phase III. 529 patients, 30 countries. High risk cervical cancer (IB2-IIBN+ or III/IVA regardless of nodal status), squamous/adeno/adenosquamous. Arm 1) Pembrolizumab 200 mg Q3 weeks x5 cycles with CRT, followed by 15 cycles 400 mg vs Arm 2) Placebo with CRT.
** Overall survival; 2024 PMID 39288779 -- "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): overall survival results from a randomised, double-blind, placebo-controlled, phase 3 trial. (Lorusso D, Lancet. 2024 Sep 13:S0140-6736(24)01808-7. doi: 10.1016/S0140-6736(24)01808-7.) Medium F/U 2.5 years, at 2nd interim analysis.
*** Outcome: 3 year OS Pembro 83% vs Placebo 75% (SS)
*** Toxicity: Grade3+ Pembro 78% vs Placebo 70%, primarily hematologic. Immune-mediated events 39% vs 17%
*** Conclusion: Pembrolizumab + chemoRT significantly improved overall survival in locally advanced cervical cancer
* Multinational B9E-MC-JHQS (2002-2004) -- A) gemcitabine + cisplatin + RT, then adjuvant gem/cis; B) cisplatin + RT only
** Randomized. 515 patients, Stage IIB - IVA. Arm 1) cisplatin 40 mg/m2 and gemcitabine 125 mg/m2 QW x6 + concurrent EBRT 50.4/28 followed by brachytherapy 30-35 Gy, followed by adjuvant cisplatin 50 mg/m2 + gemcitabine 1000 mg/m2 Q3w x2 cycles vs Arm 2) concurrent cisplatin 40 mg/m2 + RT with no adjuvant chemotherapy
** 2011 PMID 21444871 -- "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." (Duenas-Gonzalez A, J Clin Oncol -- online before print. 2011 Mar 28.) Median F/U 3.9 years
*** Outcome: 3-year PFS adjuvant GEM/CIS 74% vs control 65% (SS); 3-year OS ~80% vs 69% (SS). No difference in local failure rate (11% vs 16%)
*** Toxicity: Increased grade 3/4 toxicities (86% v 46%); 2 deaths attributed to treatment in Arm A.
*** Conclusion:"Gemcitabine plus cisplatin chemoradiotherapy followed by BCT and adjuvant gemcitabine/cisplatin chemotherapy improved survival outcomes with increased but clinically manageable toxicity when compared with standard treatment."
* GOG 165 (1997-2000)
** Randomized. 316 pts, Stage IIB, IIIB, or IVA. Randomized to: EBRT + brachytherapy (85 Gy total to point A) combined with 1) weekly cisplatin (40 mg/m2) x 6 cycles, or 2) continuous infusion 5-FU (225 mg/m2/d) 5 days/wk x 6 weeks. RT technique: EBRT to 45 Gy to pelvis, plus 5.4-9 Gy parametrial boost, followed by LDR or HDR brachytherapy. Brachytherapy: LDR 40 Gy (in 1-2 fractions) or HDR 30 Gy (in 5 fractions). HDR started on the 4th week of EBRT with at least 1 fx/week, then 2 fx/week after completion of EBRT.
** 2005 PMID 16230678 — "A Randomized Comparison of Weekly Cisplatin or Protracted Venous Infusion of Fluorouracil in Combination With Pelvic Radiation in Advanced Cervix Cancer: A Gynecologic Oncology Group Study." Lanciano R et al. J Clin Oncol. 2005. Epub ahead of print October 17, 2005; tentatively for 11/20/2005 print issue.
** Trial stopped early due to increase rate of progression in Arm 2. No S.S. difference in PFS. 4-yr OS 64% (arm 1) vs 55% (arm 2), N.S. Study not powered to detect an inferior outcome.
** Conclusion: 5-FU is not better than cisplatin
* GOG 120 (1992-97) - randomized to one of three concurrent chemotherapy regimens
** 526 pts. FIGO stage IIB, III, or IVA. Excluded those with positive para-aortic nodes or disease beyond the pelvis. All pts received RT. Randomized to receive concurrent chemotherapy with: 1) cisplatin (40 mg/m2, weekly x 6), 2) cisplatin / 5-FU / hydroxyurea (50 mg/m2, days 1+29; 4 g/m2 96-hr infusion, days 1+29; 2 g/m2 po twice weekly, weeks 1-6), 3) hydroxyurea (3 g/m2 po twice weekly, weeks 1-6). RT technique: whole pelvis 40.8 Gy/24 fx or 51 Gy/30 fx, followed by 1 or 2 intracavitary insertions for 40 Gy (stage IIB) or 30 Gy (Stage III-IV); total point A dose was 80.8 or 81 Gy; point B dose was 55 or 60 Gy, respectively.
** 10-years, 2007 PMID 17502627 -- "Long-term follow-up of a randomized trial comparing concurrent single agent cisplatin, cisplatin-based combination chemotherapy, or hydroxyurea during pelvic irradiation for locally advanced cervical cancer: a Gynecologic Oncology Group Study." (Rose PG, J Clin Oncol. 2007 Jul 1;25(19):2804-10.). Median F/U 8.8 years
*** 10-year outcome: PFS: Arm 1 46% vs. Arm 2 43% vs. Arm 3 26% (SS); OS 53% vs. 53% vs. 34%. Benefit seen for both Stage IIB and Stage III
*** Local progression: Arm 1 22% vs. Arm 2 21% vs. Arm 3 34% (SS). Prognosis for progression: stage, treatment arm
*** Conclusion: Cisplatin-based chemo during pelvic RT improves long-term PFS and OS
** 2-years, 1999 PMID 10202165 Full text, 1999 — "Concurrent cisplatin-based radiotherapy and chemotherapy for locally advanced cervical cancer." Rose PG e al. N Engl J Med. 1999 Apr 15;340(15):1144-53. Median F/U 3 years
*** 2-year outcome: PFS cisplatin 67% vs. cisplatin/5-FU/HU 64% vs. HU 47% (relative risk 0.56 for cisplatin groups); OS 75% vs. 75% vs. 60% (relative risk 0.60)
*** Improved PFS and OS in groups receiving cisplatin vs those only receiving hydroxyurea. Decreased local failures as well as distant mets.
*** Conclusion: cisplatin regimens improve overall survival and progression free survival for locally advanced cervical ca.
*** Editorial (PMID 10202172)
* GOG 85 / SWOG 8695 Intergroup (1986-1990) - RT + hydroxyurea vs cisplatin/5-FU
** Randomized. 368 pts. Stage IIB-IVA. All pts had staging para-aortic lymphadenectomy (from inferior mesenteric artery to mid common iliac arteries). Pelvic lymphadenectomy not required. Pts with para-A mets or positive washings were excluded. Randomized to hydroxyurea (80 mg/kg twice weekly ) vs cisplatin (50 mg/m2, days 1+29) + 5-FU (4 g/m2 96-hr infusion, days 2-5, 30-33) RT technique: IIB received 40.8/24 whole pelvis EBRT, then 40 Gy brachy boost to point A, point B 55 Gy; III-IVA received 51/30 EBRT + 30 Gy brachy boost, point B 60 Gy. If no implant, then 61.2 Gy EBRT
** 1999 PMID 10334517 - "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." Whitney CW et al. J Clin Oncol. 1999 May;17(5):1339-48. Median F/U 8.7 years
*** Outcome: PFS CF 57% vs. HU 47% (SS); OS CF 55% vs. HU 43% (SS)
*** Toxicity: leukopenia CF 4% vs. HU 24%
** Conclusion: cisplatin/5-FU better PFS, OS, and less toxicity than hydroxyurea
Meta-Analysis
* Canada, 2002 - PMID 12109823 — "Concurrent cisplatin-based chemotherapy plus radiotherapy for cervical cancer--a meta-analysis." Lukka H et al. Clin Oncol (R Coll Radiol). 2002 Jun;14(3):203-12.
** Relative risk of death for chemotherapy, 0.74; 0.78, for advanced stage; 0.56, for high-risk early stage disease.
* Liverpool, 2001 (UK) - PMID 11564482 — "Survival and recurrence after concomitant chemotherapy and radiotherapy for cancer of the uterine cervix: a systematic review and meta-analysis." Green JA et al. Lancet. 2001 Sep 8;358(9284):781-6.
** 4580 pts from randomized studies.
** Pts most likely to benefit from concurrent chemotherapy are those with: positive pelvic lymph nodes, large cervical lesions. Concurrent chemotherapy reduced incidence of distant mets.

## Para-aortic node RT

* EORTC (1977-81)
** 441 pts. Randomized. Stage IB-IIB with positive pelvic LN; or Stage IIB with distal vaginal and/or parametrial involvement; or any Stage III. Clinically involved PA nodes not allowed. Randomized to pelvic RT vs pelvic + PA RT (45 Gy).
** 1988 PMID 3281186 — "Is prophylactic para-aortic irradiation worthwhile in the treatment of advanced cervical carcinoma? Results of a controlled clinical trial of the EORTC radiotherapy group." Haie C et al. Radiother Oncol. 1988 Feb;11(2):101-12.
*** No difference in LC, DFS, or DM, but decreased PA metastases.
*** Conclusion: Routine PA RT is not indicated
* RTOG 79-20 (1979-86) - Prophylactic paraaortic RT.
** Randomized. 335 pts. Bulky Stage IB (now IB2) and IIA with tumor > 4 cm or Stage IIB (73%). Randomized to: 1) Pelvic RT alone (40-50 Gy), 2) Pelvic + PA RT (44-45 Gy). Both at 1.6-1.8 Gy/fx. For arm 2, gave maximum of 30 Gy AP/PA and paraaortic boosted with arc rotation technique or two posterior obliques or shaped laterals. Followed by parametrial and intracavitary RT.
** 1990 PMID 2211198 — "Prophylactic irradiation of the para-aortic lymph node chain in stage IIB and bulky stage IB carcinoma of the cervix, initial treatment results of RTOG 7920." Rotman M et al. Int J Radiat Oncol Biol Phys. 1990 Sep;19(3):513-21. Median F/U 3.6 years
*** Outcome: 2-yr OS 72% vs 81%, 5-yr OS 55% vs 66% (SS). No difference in LRC or DM
*** Toxicity: Grade 4/5 P-RT 4% vs. PA-RT 8% (primarily in patients with prior surgery 11% vs. 2%)
*** Conclusion: Improved survival, toxicity tolerable
** 1995 PMID 7616634 — "Prophylactic extended-field irradiation of para-aortic lymph nodes in stages IIB and bulky IB and IIA cervical carcinomas. Ten-year treatment results of RTOG 79-20." Rotman M et al. JAMA. 1995 Aug 2;274(5):387-93.
*** 10-yr OS 44% vs 55%. No difference in DFS.
** Conclusion: benefit for elective paraaortic radiation.
* GOG 125, 1998 (1992-3) - Phase II
** 95 pts. Any stage (except IIIA) with biopsy confirmed paraaortic nodal mets. Lymphadenectomy not required. Treatment: EBRT to the pelvis and PA with concurrent chemo. Doses: Pelvis (180 cGy/fx) to 39.6-48.6 Gy, paraaortic (150 cGy/fx) to 45 Gy. PA field border at L1/L2 interspace. Intracavitary application for point A dose of 80 Gy and pt B dose of 55-60 Gy. Chemo: Cisplatin (50 mg/m2) q28d + 96-hr 5-FU infusion (days 2-5), 2 cycles each.
** 1998 PMID 9869224 — "Cervical carcinoma metastatic to para-aortic nodes: extended field radiation therapy with concomitant 5-fluorouracil and cisplatin chemotherapy: a Gynecologic Oncology Group study." Varia MA et al. Int J Radiat Oncol Biol Phys. 1998 Dec 1;42(5):1015-23.
** Conclusion: feasible treatment regimen. PFS of 33% at 3 years demonstrated that a portion of patients with advanced disease can achieve control
* RTOG 90-01, Morris 1999 - see under Chemotherapy + RT above.

## Altered Fractionation

* RTOG 71-05 (1971-1980)
** Randomized. 301 patients. Stage IIB-IVA. Split course RT (25/10 + 25/10) vs. standard RT (51/30). Both followed by brachytherapy 30 Gy LDR or EBRT boost 16/8
** 1983 PMID 6406397 — "Split-course versus continuous pelvis irradiation in carcinoma of the uterine cervix: a prospective randomized clinical trial of the Radiation Therapy Oncology Group." (Marcial VA et al. Int J Radiat Oncol Biol Phys. 1983) Apr;9(4):431-6.
*** Outcome: 2-year pelvic control Split course 65% vs. continuous 59% (NS), no difference in DM or OS rate
*** 2-year survival: Stage IIB 70%, IIIA 58%, IIIB 46%, IVA 23%
*** Conclusion: No difference between split course and continuous RT

## Hyperthermia

* Maastro Clinic, Netherlands; 2010 PMID 20091593 -- "Combined use of hyperthermia and radiation therapy for treating locally advanced cervical carcinoma." (Lutgens L, Cochrane Database Syst Rev. 2010 Jan 20;(1):CD006377.)
** Cochrane meta-analysis. 6 RCTs. 74% FIGO IIIB
** Outcome: 3-year local recurrence improved (HR 0.48, SS); 3-year OS improved (HR 0.67, p=0.05)
** Toxicity: No difference
** Conclusion: Cannot draw definitive conclusions, but addition of hyperthermia likely improves local control and overall survival

## Hypoxia
### Anemia

* GOG 191 (2001-2003) -- Chemo-RT +/- EPO
** Randomized. Closed prematurely due to concerns about thromboembolic events. 109 patients accrued (<25% planned). Cervical cancer, Stage IIB-IVA, Hgb <14.0 Arm 1) Chemo-RT vs. Arm 2) Chemo-RT + recombinant Epo 40,000 units QW
** 3-years; 2008 PMID 18037478 -- "Phase III trial to evaluate the efficacy of maintaining hemoglobin levels above 12.0 g/dL with erythropoietin vs above 10.0 g/dL without erythropoietin in anemic patients receiving concurrent radiation and cisplatin for cervical cancer." (Thomas G, Gynecol Oncol. 2008 Feb;108(2):317-25. Epub 2007 Nov 26.) Median F/U 3 years
*** Outcome: 3-year PFS control 65% vs. EPO 58%; OS 75% vs. 61% (insufficient numbers)
*** Rate of thromboembolism: control 8% vs. EPO 19% (NS), no deaths
*** Conclusion: Thromboembolism common; impact of Hgb >12.0 remains undetermined

### Hyperbaric Oxygen

* RTOG 70-01 (1972-1975) -- RT in air vs. RT in HBO
** Randomized. Stopped early due to slow accrual. 58 patients with Stage IIB-IVA cervix. Arm 1) RT 50/25 in air vs. Arm 2) RT 40/10 in HBO. Brachytherapy in both arms. Only 19/29 HBO patients received most of their EBRT in the chamber
** 1981 PMID 7028700 -- "Hyperbaric oxygen therapy for carcinoma of the cervix--stages IIB, IIIA, IIIB and IVA: results of a randomized study by the Radiation Therapy Oncology Group." (Brady LW, Int J Radiat Oncol Biol Phys. 1981 Aug;7(8):991-8.)
*** Outcome: Local failure air 24% vs. HBO 26% (NS); DFS air 52% vs. HBO 73% (NS)
*** Complications: both arms 24% (NS)
*** Conclusion: Study too small; no difference; HBO technically difficult to administer
** Comment: Test of hypofractionation + HBO vs. standard fractionation; study too small

## Long-Term Outcome

* Florida, 2007 PMID 17234362 -- "Long-term Outcome after Radiotherapy for FIGO Stage IIIB and IVA Carcinoma of the Cervix." (Yeung AR, Int J Radiat Oncol Biol Phys. 2007 Apr 1;67(5):1445-50.)
** Retrospective. 91 patients IIIB/IVA treated with curative intent. Median F/U 8.8 years
** Outcome: 10-year LC 53%, RFS 26%, OS 21%; 5-year LC 53%, RFS 30%, OS 29%
** Failures: 90% within 2 years; 60% local, 29% regional, 17% para-aortic without pelvic
** Toxicity: Grade 3-5 rate 13%
** Conclusion: One-third can be cured, with 13% complication rate
* MDACC, 1999 (1965-74) PMID 10477014 -- "Mature results of a pilot study of pelvic radiotherapy with concurrent continuous infusion intra-arterial 5-FU for stage IIIB-IVA squamous cell carcinoma of the cervix." (Eifel PJ, Int J Radiat Oncol Biol Phys. 1999 Aug 1;45(1):113-8.)
** 27 pts; 22 Stage IIIB, 5 IVA. Treated with RT (median dose 50 Gy) + 5-FU. Only 4 pts received brachytherapy.
** Median f/u 190 mo (>15 yrs) -- 5-yr OS 37%; 41% for IIIB. 4 of 10 pts who received chemo + only 50 Gy were long term survivors.
** Conclusion: "While this series is small, the fact that 4 patients with massive Stage IIIB tumors survived after a total radiation dose of only 50 Gy suggests that RT with CI IA 5-FU deserves further study. Modifications in dose, technique, and route of administration should reduce toxicity, and the addition of intracavitary RT should improve the local effectiveness of combined treatment."

## PET Staging

* Washington U
** 2003 (1998-2002) PMID 12738325 -- "FDG-PET lymph node staging and survival of patients with FIGO stage IIIb cervical carcinoma." (Singh AK, Int J Radiat Oncol Biol Phys. 2003 Jun 1;56(2):489-93.)
*** 47 pts. Stage IIIB.
*** 13 (28%) were lymph node negative by PET, 20 (43%) had (+) pelvic LN only, 7 (15%) had both pelvic and para-aortic LN, 7 (15%) had pelvic, PA, and supraclavicular LNs. None had other distant mets.
*** 3-yr CSS 73% (LN-), 58% (pelvic LN), 29% (pelvic + PA), 0% (SCLV).
*** Conclusion: "The cause-specific survival for patients with FIGO Stage IIIb carcinoma is highly dependent on the extent of lymph node metastasis as demonstrated by whole-body FDG-PET."
** 2010 (2000-2009) [20308664] --"Lymph node staging by positron emission tomography in cervical cancer: relationship to prognosis." (Kidd EA, J Clin Oncol. 2010 Apr 20;28(12):2108-13.)
*** 560 pts. Stage IA2-IVA treated with curative intent (survival analysis on 513 pts)
*** 47% has lymph node involvement by PET, of those 100% had (+) pelvic, 35% had (+) PA, and 12% had (+) SCLV
*** Median F/U 45 mo--DSS HR: Pelvic LN 2.40 (SS); PA 5.9 (SS); SCLV 19.4 (SS). Recurrence HR: Pelvic LN 2.4 (SS); PA 5.9 (SS); SCLV 30.3 (SS)
*** Conclusion: "Nodal involvement detected by FDG-PET in cervical cancer relates to clinical stage, is comparable to historical data, and stratifies patient recurrence and survival outcomes.

## Review

* UC Irvine, 2007 PMID 17617527 -- "Multimodality therapy for locally advanced cervical carcinoma: state of the art and future directions." (Monk BJ, J Clin Oncol. 2007 Jul 10;25(20):2952-65.)

## RT Technique

* Example of an AP radiation therapy treatment field for Stage IB2+ Cervix used at Tufts/Brown residency program. Actual patient contours should guide field design.
* Superior border: L4/L5. If common illiac LN involvement, superior border should extend to L3/L4 or higher to cover the disease with 3 cm margin
* Inferior border: inferior edge of pubic ramus. If vaginal involvement, inferior border should extend 3-4 cm past the vaginal extent of the disease, as marked by a gold seed
* Lateral borders: ~2cm lateral to bony pelvis, in order to cover lymph nodes
* Red: cervix; Blue: uterus; Khaki: bladder; Brown: rectum
* Orange: common illiac LNs; Yellow: external illiac LNs; Light Green: obturator LNs; Purple: internal illiac LNs; Dark Green: presacral LNs
* Example of a lateral radiation therapy treatment field for Stage IB2+ Cervix used at Tufts/Brown residency program. Actual patient contours should guide field design and AP/PA vs. 4F decision.
* Superior border: same as AP field
* Inferior border: same as AP field
* Anterior border: ~1cm anterior to symphysis pubis
* Posterior border: cover entire sacrum to ensure coverage of presacral lymph nodes
* Red: cervix; Blue: uterus; Khaki: bladder; Brown: rectum
* Orange: common illiac LNs; Yellow: external illiac LNs; Light Green: obturator LNs; Purple: internal illiac LNs; Dark Green: presacral LNs