# Radiation Oncology/Cervix/Early Stage Nonbulky

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* RTOG Cervix
Cervical Cancer - Early Stage Non-bulky (IB1 and IIA <4cm)

## Surgery vs. RT

* No survival or DFS difference
* Severe toxicity (Grade 2-3) significantly higher in surgery
* Advantages to surgery: preserve gonadal function (and avoid early menopause), avoid shortening/fibrosis of vagina, assess LN status
* Advantages to RT: easy to deliver if poor surgical candidate, lower risk of complications
* Combined surgery + RT highest rate of complications
* Milan (1986-91)
** Randomized. 343 patients. Stage IB-IIA (IB1 61%, IB2 27%, IIA 12%). Squamous 83%, adenoCA 14%, small cell 3%. Treated with radical hysterectomy (Class III) vs. radical RT.
** RT given: EBRT using 18 MV photon to median 47 Gy followed by LDR x 1 for Point A median dose 76 Gy. Adjuvant RT allowed for pts who were surgical stage IIB or greater, < 3 mm of safe cervical stroma, positive margins, or positive LN (62/114 IB1, 46/55 IB2).
** 63% of pts in surgery arm received RT.
** 5 years 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.
*** Median F/U 87 mo. Non-bulky: OS surgery 87% vs. RT 90% (NS), DFS surgery 80% vs. RT 82% (NS). Bulky: OS surgery 70% vs. RT 72% (NS), DFS surgery 63% vs. RT 57% (NS).
*** AdenoCA: significantly better outcomes with surgery; OS (70% vs. 59%), DFS (66% vs. 47%). Squamous not differ.
*** Complications (Grade 2-3): Surgery 28% vs RT 12% (SS). Severe leg edema surgery 0%, RT 1%, surgery + RT 9%
*** Conclusion: Surgery and RT are both acceptable treatments for early stage cervical ca; (for bulky, primary surgery not a good option)
** 20 years PMID 28382797 — "Randomized study between radical surgery and radiotherapy for the treatment of stage IB-IIA cervical cancer: 20-year update." Landoni F, et al. J Gynecol Oncol. 2017 May;28(3):e34.
*** Shortest F/U 19 years. 20-year OS: surgery 72% vs. RT 77% (NS).
*** Squamous: RT better for whole cohort (OS 82% vs. 72%, SS); but subgroup showed that RT was not better for size <= 4 cm.
*** AdenoCA OS surgery 71% vs. RT 47% (NS)
*** Relapse 28% in both arms. No difference in pattern and timing. More likely to cure in RT arm (salvage surgery option available).
*** Complications: More hydroureteronephrosis and legs edema in surgery + adjuvant RT. Proctitis presence only in RT arm (8.8%).
*** Conclusion: No treatment of choice; should individualize based on histology, tumor size, etc.

## Surgery +/- Post-op RT

25% of Stage IB pts may benefit from XRT because they have positive risk factors, which were originally delineated in a surgical series from GOG 49.
* GOG 49, Delgado (1981-1984)
** Prospective cohort study of 732 patients (645 evaluated) with stage 1 squamous cell carcinoma of the cervix with greater than or equal to 3mm of invasion required to undergo radical hysterectomy, paraaortic and pelvic lymphadenectomy and peritoneal cytology. Analysis was performed to identify independent prognostic factors associated with disease-free interval (DFI), or the time between study entry to physical or radiological evidence of disease recurrence or date last seen.
** 1990 PMID 2227547 — "Prospective Surgical-Pathological Study of Disease-Free Interval in Patients with Stage IB Squamous Cell Carcinoma of the Cervix: A Gynecologic Oncology Group Study." Delgado, et al. GYNECOLOGIC ONCOLOGY 38, 352-357 (1990)
** Disease free interval (DFI) correlated strongly with depth of tumor invasion (both in absolute mm and in fractional thirds), tumor size, and capillary-lymphatic space (CLS) invasion [ie, LVSI].
*** Depth of Invasion
**** DFI 94.1% for superficial third invasion
**** DFI 84.5% for middle third invasion
**** DFI 73.6% for deep third invasion
*** Tumor Size
**** DFI 94.8% for occult tumor
**** DFI 88.1% for tumor <=3cm
**** DFI 67.6% for tumor >3cm
*** CLS [LVSI]
**** DFI 77.0% if present
**** DFI 88.9% if absent
* GOG 92, Sedlis, (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 46-50.4 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 — "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 — "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).
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

## 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)
** 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.
** 4-years; 2000 - PMID 10764420 — "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.)
*** Outcome: 4-year OS RT 71% vs CRT 81%, HR=2.0 (SS); 4-year PFS 63% vs 80%, HR=2.0 (SS). Local failure 17% vs 6%. No difference in outcome based on histology (squamous vs adeno) for patients who underwent chemo-RT
*** Toxicity: Grade 4+ RT 4% vs CRT 17% (mainly hematologic)
*** Conclusion: Addition of cisplatin based chemotherapy to RT significantly improves progression free survival and overall survival following surgery for high-risk, early stage patients
** LN; 2005 PMID 15721417 — "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 (79% versus 83% OS at 5 years) or if tumor was ≤2 cm (77% versus 82%).

## Adjuvant RT vs Adjuvant Chemo

* Gachon University (Korea); 2008 PMID 18021218 -- "Comparison of adjuvant chemotherapy and radiation in patients with intermediate risk factors after radical surgery in FIGO stage IB-IIA cervical cancer." (Lee KB, Int J Gynecol Cancer. 2008 Sep-Oct;18(5):1027-31. Epub 2007 Nov 16.)
** Retrospective. 80 patients, FIGO Stage IB-IIA cervical cancer, s/p radical hysterectomy and PLND, with intermediate risk factors (>50% stromal invasion, LVI, bulky, or close SM). Treated with RT (n=42) or chemo (n=38). Comparable risk factors
** Outcome: No difference in DFS, OS not reached
** Conclusion: Adjuvant chemo in Stage IB-IIA cervical cancer with intermediate risk factors after surgery may be effective

## RT Technique

* Example of an AP radiation therapy treatment field for Stage IB1 Cervix used at Tufts/Brown residency program. Actual patient contours should guide field design.
* Superior border: L5/S1
* Inferior border: superior edge of pubic ramus
* Lateral borders: ~2cm lateral to bony pelvic, 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 IB1 Cervix used at Tufts/Brown residency program. Actual patient contours should guide field design, and decision on 4F vs. AP/PA treatment.
* Superior border: same as AP (L5/S1)
* Inferior border: same as AP
* Anterior border: ~1cm anterior to symphysis pubis
* Posterior border: historically at S2/S3, but need to cover enough of presacral LNs and cervix volume.
* 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