Radiation Oncology/Ovary/Epithelial ovarian

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Epithelial Ovarian Cancer

Epidemiology

CA-125 elevated in >80% of patients (though can be also elevated in endometriosis, pelvic inflammatory disease, or pregnancy)
Hereditary: 5-10% (majority due to BRCA1/BRCA2 mutations, some HNPCC)
- Lifetime risk BRCA1: 20-60%
- Lifetime risk BRCA2: 10-35%
Stage I-II in ~30%

BRCA Mutations

Impact of oophorectomy:

Toronto
- 2014 PMID 24567435 -- "Impact of Oophorectomy on Cancer Incidence and Mortality in Women With a BRCA1 or BRCA2 Mutation." (Finch AP, J Clin Oncol. 2014 Feb 24. [Epub ahead of print])
  - 5,783 pts from international registry with BRCA1 or BRCA2 mutations.
  - Average f/u 5.6 yrs. 186 women developed either ovarian (n = 132), fallopian (n = 22), or peritoneal (n = 32) cancer, of whom 68 have died. Bilateral oophorectomy associated with HR 0.20 for development of cancer, HR 0.23 for all-cause mortality.
  - Conclusion: "Preventive oophorectomy was associated with an 80% reduction in the risk of ovarian, fallopian tube, or peritoneal cancer in BRCA1 or BRCA2 carriers and a 77% reduction in all-cause mortality."

Pathology

Most likely arise from the surface epithelium covering the ovary (contiguous with peritoneal mesothelium)
Malignant transformation likely occurs within epithelium that becomes trapped within ovarian inclusion cysts during ovulation
Mutations: p53 in ~50%, her2 in 8%

Patterns of Spread

Intraperitoneal Spread
- Cells exfoliate from the ovarian surface, and spread into peritonum
- Papillary serous has highest predilection
Direct extension
- Bladder or rectosigmoid
Lymphatics
- 10-15% of Stage I patients are LN+
- Along blood supply through infundibulopelvic ligmanent to para-aorticl LNs
- Through broad ligament to pelvic sidewall LNs (including external illiac, and obturator)
- Rarely along round ligament to inguinal LNs
- Paraortic and Pelvic LNs
- Occasionally Inguinal LNs via round ligament
Hematogenous (2-3%)
- Lung and Liver

Serous Tumors

Harvard; 2008 PMID 18854563 -- "New insights into the pathogenesis of serous ovarian cancer and its clinical impact." (Levanon K, J Clin Oncol. 2008 Nov 10;26(32):5284-93. Epub 2008 Oct 14.)
- Review. Fallopian tube fimbria as origin for high-grade ovarian serous carcinomas

Overall Survival

Stage	5-year OS
Stage IA - IB	90%
Stage IC - II	70-80%
Stage IIIA	60%
Stage IIIB	40%
Stage IIIC	30%
Stage IV	<20%

Treatment Overview

Surgical resection and staging with TAH/BSO is the first step; goal is maximum cytoreduction (<1cm)
NCCN Guidelines (v2.2010)

Stage	Adjuvant Therapy
Stage IA - IB G1	Observe
Stage IA - IB G2	Observe or IV taxane/carboplatin 3-6 cycles
Stage IC or G3	IV taxane/carboplatin 3-6 cycles
Stage II-IV	IV taxane/carboplatin 6-8 cycles or IP chemo in optimally debulked Stage II and Stage III

Role for adjuvant radiation therapy appears minimal at this time
Whole abdominal RT was removed as a treatment option from NCCN guidelines in the 2007 version
Typical role for RT is in palliative care

Whole Abdomen Irradiation (WAI)

Several randomized trials generally found that WAI was less effective and/or more toxic than chemotherapy, particularly platinum-containing regimens
As a result, adjuvant RT is no longer routinely used for patients with high-risk, early stage ovarian cancer

Adjuvant treatment

WAI vs. Chemo

GONA (Italy)(1985-1989) -- adjuvant WAI vs. cyclophosphamide
- Randomized. Closed prematurely due to poor compliance. 70 patients, high-risk Stage I-II. Arm 1) chemo cisplatin 50 mg/m2 + cyclophosphamide 600 mg/m2 x6 courses vs. Arm 2) WAI open field 30.2 Gy upper abdomen and 43.2/24 pelvis
- 5-years; 1994 PMID 8311013 -- "High-risk early-stage ovarian cancer. Randomized clinical trial comparing cisplatin plus cyclophosphamide versus whole abdominal radiotherapy." (Chiara S, Am J Clin Oncol. 1994 Feb;17(1):72-6.)
  - Outcome: 5-year RFS chemo 74% vs. WAI 50% (p=0.07); OS 71% vs. 53% (NS)
  - Toxicity: WAI Grade 3-4 diarrhea 28%, late GI toxicity requiring surgery in 1 patient
  - Conclusion: No difference, but chemotherapy appears safe in comparison with WAI

West Midlands; UK (1981-1987) -- adjuvant WAI vs. cisplatin
- Randomized. 40 patients, surgery, with no macroscopic residual disease. Treated with Arm 1) cisplatin vs. Arm 2) WAI moving strip
- 5-years; 1993 PMID 8424908 -- "The West Midlands epithelial ovarian cancer adjuvant therapy trial." (Redman CW, Clin Oncol (R Coll Radiol). 1993;5(1):1-5.)
  - Outcome: 5-year OS 58% vs 62% (NS)
  - Toxicity: 11% long-term disability
  - Conclusion: No difference between chemo and WAI

MD Anderson -- adjuvant WAI vs. melphalan
- 2-years; 1975 PMID 1234631 -- "Postoperative treatment of early cancer of the ovary: a random trial between postoperative irradiation and chemotherapy." (Smith JP, Natl Cancer Inst Monogr. 1975 Oct;42:149-53.)
- Randomized. 149 patients, Stage I-II. Arm 1) WAI vs. Arm 2) melphalan. RT technique moving strip
  - Outcome: Stage I RFS 85% vs. 90% (NS); Stage II 55% vs. 58% (NS)
  - Toxicity: melphalan well tolerated, WAI 7 patients with GI toxicity requiring surgery
  - Conclusion: Significant toxicity for moving-strip WAI, no outcome difference

WAI vs. Pelvic RT + chemo

Denmark (1981-1987) -- WAI vs. pelvic RT + cyclophosphamide
- Randomized. 118 patients, Stage IB-IIC epithelial ovarian CA. Arm 1) WAI vs. Arm 2) pelvic RT + cyclophosphamide
- 4-years; 1990 PMID 2351321 -- "Randomized study of whole-abdomen irradiation versus pelvic irradiation plus cyclophosphamide in treatment of early ovarian cancer." (Sell A, Gynecol Oncol. 1990 Jun;37(3):367-73.)
  - Outcome: 4-year OS: 63% (NS), RFS 55% (NS)
  - Toxicity: in pelvic RT + cyclophosphamide arm, 25% hemorrhagic cystis; 8% late GI toxicity requiring surgery
  - Conclusion: No difference

NCIC Canada (1975-1984)
- Randomized. Arm C discontinued early due to toxicity. 257 patients, Stage I-III ovarian, surgery + whole pelvis RT 45/20, then Arm A) WAI 22.5/20 vs. Arm B) melphalan 8 mg/m2/d vs. Arm C) intraperitoneal chromic phosphate 10-20 mCi
- 5-years; 1988 PMID 3045264 -- "Early stage ovarian cancer: a randomized clinical trial comparing whole abdominal radiotherapy, melphalan, and intraperitoneal chromic phosphate: a National Cancer Institute of Canada Clinical Trials Group report." (Klaasen D, J Clin Oncol. 1988 Aug;6(8):1254-63.) Median F/U 8 years
  - Outcome: 5-year OS 62% vs. 61% vs. 66% (NS); marginally better DFS with melphalan over WAI
  - Toxicity: melphalan - 4 patients developed MDS/AML
  - Conclusion: No difference

Princess Margaret -- WAI vs. pelvic RT + chlorambucil
- Randomized. 190 patients, TAH/BSO, Stage IB-III. Arm 1) WAI vs. Arm 2) pelvic RT alone vs. Arm 3) pelvic RT + chlorambucil
- 10-years; 1979 PMID 463982 -- "Ovarian carcinoma: improved survival following abdominopelvic irradiation in patients with a completed pelvic operation." (Dembo AJ, Am J Obstet Gynecol. 1979 Aug 1;134(7):793-800.)
  - Outcome: 10-year RFS WAI 64% vs. pelvic RT +/- C 40% (SS); chlorambucil delayed time to treatment failure but not number of treatment failures
  - Failure patterns: 20-25% pelvis regardless of RT, 0% abdomen alone in WAI vs. 25% abdomen alone in pelvic RT
  - Conclusion: Whole abdomen RT superior to pelvic RT with/without chlorambucil

Dose Evaluation

Princess Margaret (1981-1990) -- 22.5 Gy vs. 27.5 Gy abdomen
- Randomized. 125 patients, optimally debulked Stage I-III. Arm 1) whole pelvis 22.5/10 + WART 22.5/22 vs. Arm 2) whole pelvis 22.5/10 + WART 27.5/27
- RT technique: most superior diaphragm excursion + 1-1.5cm margin; lateral peritoneum; pelvic floor + 1.5cm margin. Pelvic field at L5/S1 and 1.5 cm bony pelvis lateral margin. Renal dose <20 Gy.
- 5-years; 1998 PMID 9635700 -- "A randomized study of two doses of abdominopelvic radiation therapy for patients with optimally debulked Stage I (n=43), II (n=71), and III (n=11) ovarian cancer." (Fyles AW, Int J Radiat Oncol Biol Phys. 1998 Jun 1;41(3):543-9.). Median F/U 6.6 years
  - 5-year outcome: OS: low-dose 83% vs. high-dose 72% (NS); DFS 74% vs. 67% (NS)
  - Sites of failure: pelvis alone 39%, abdomen alone 18%, pelvis+abdomen 15%, distant 28%
  - Toxicity: no difference, GI Grade 3 2%, Bladder Grade 3 2%
  - Conclusion: No difference in outcome, no benefit to higher WART dose

Consolidative treatment

Swedish-Norwegian OCSG (1988-1993) -- WAI vs. cisplatin + doxorubicin/epirubicin vs. observation
- Randomized. 172 patients, Stage III, primary surgery, then cisplatin 50 mg/m2 + doxorubicin 50 mg/m2 or epirubicin 60 mg/m2, followed by second look surgery. Randomized to Arm 1) WAI vs. Arm 2) same chemo consolidation x6 cycles vs. Arm 3) no further treatment. WAI 20/20 + pelvic boost to L3/L4 20.4/12
- 5-years; 2003 PMID 12801256 -- "Consolidation treatment of advanced (FIGO stage III) ovarian carcinoma in complete surgical remission after induction chemotherapy: a randomized, controlled, clinical trial comparing whole abdominal radiotherapy, chemotherapy, and no further treatment." (Sorbe B, Int J Gynecol Cancer. 2003 May-Jun;13(3):278-86.)
  - Outcome: 5-year PFS WAI 56% vs. chemo 36% vs. control 35% (SS)
  - Subset analysis: If microscopic residual disease, no difference between groups
  - Toxicity: 10% late GI in WAI group
  - Conclusion: WAI may be beneficial in consolidative setting, if pCR after chemo

North Thames (UK) -- consolidative WAI vs. carboplatin
- Randomized. 254 patients, Stage IIB-IV, surgery followed by carboplatin 400 mg/m2. If residual disease <2cm at second look surgery, randomized to Arm 1) carboplatin 400 mg/m2 x5 courses vs. Arm 2) WAI 24 Gy
- 2-years; 1993 PMID 8445418 -- "A randomized trial comparing single-agent carboplatin with carboplatin followed by radiotherapy for advanced ovarian cancer: a North Thames Ovary Group study." (Lambert HE, J Clin Oncol. 1993 Mar;11(3):440-8.)
  - Outcome: Median OS 2 years, no OS or DFS difference between groups
  - Toxicity: Chemo well tolerated. WAI reasonably well tolerated, but one treatment-related death from fecal fistulae
  - Conclusion: No advantage to WAI over more chemo

West Midlands Trial II (UK) -- consolidative WAI vs. chlorambucil
- Randomized. 109 patients, ovarian cancer, treated with surgery, cisplatin 100 mg/m2 x5 courses, and second look laparotomy. Then randomized to Arm 1) WAI moving strip vs. Arm 2) chlorambucil x1 year
- 2-years; 1990 PMID 2261388 -- "A randomized trial comparing whole abdominal radiotherapy with chemotherapy following cisplatinum cytoreduction in epithelial ovarian cancer. West Midlands Ovarian Cancer Group Trial II." (Lawton F, Clin Oncol (R Coll Radiol). 1990 Jan;2(1):4-9.)
  - Outcome: 2-year OS 35%, no difference between arms
  - Toxicity: considerable, ~50% unable to complete treatment in both arms
  - Conclusion: No indication for consolidation with WAI or chlorambucil after primary surgery and cisplatin

GONA (Italy) -- consolidative WAI vs. chemo(type?)
- Randomized. Stopped early due to poor outcome in WAI arm. 41 patients, treated with surgery, chemotherapy, and second look laparotomy. Randomized to Arm 1) more chemotherapy vs. Arm 2) WAI
- 1990 PMID 2227553 -- "Chemotherapy versus radiotherapy in the management of ovarian cancer patients with pathological complete response or minimal residual disease at second look." (Bruzzone M, Gynecol Oncol. 1990 Sep;38(3):392-5.) Median F/U 1.8 years
  - Outcome: progression WAI 55% vs. chemo 29% (SS), death 45% vs. 14%
  - Conclusion: Significant advantage for chemo over WAI

RT Technique

There are multiple techniques, but typically Whole Abdomen RT is given to 22.5-25 Gy, followed by boost to PA LNs and whole pelvis to 45-50.4 Gy
Dose: 22.5-25Gy in 130-150cGy/fx.
Simulation: Supine with Alpha cradle.
Fields: AP/PA single fields or 4-field technique
Blocks:
- Kidneys – 50% transmission block or block after 15Gy.
- Liver – Block at 25Gy. Block not used by some institutions.

Example of a AP whole abdomen/pelvis radiation therapy treatment field used at Tufts/Brown residency program. Actual patient contours should guide field design.

Superior border: Above the top of the diaphragm
Inferior border: Inferior edge of pubic ramus
Lateral borders: Lateral to peritoneal reflection
Red: cervix; Blue: uterus; Khaki: bladder; Brown: rectum & liver; Teal: kidney; Light Blue: peritoneal reflection
Orange: common illiac LNs; Yellow: external illiac LNs; Light Green: obturator LNs; Purple: internal illiac LNs; Dark Green: presacral LNs

Example of a PA whole abdomen/pelvis radiation therapy treatment field used at Tufts/Brown residency program. Actual patient contours should guide field design.

Superior border: Above the top of the diaphragm
Inferior border: Inferior edge of pubic ramus
Lateral borders: Lateral to peritoneal reflection
Red: cervix; Blue: uterus; Khaki: bladder; Brown: rectum & liver; Teal: kidney; Light Blue: peritoneal reflection
Orange: common illiac LNs; Yellow: external illiac LNs; Light Green: obturator LNs; Purple: internal illiac LNs; Dark Green: presacral LNs

Chemotherapy

AGO-Ovar/AIO & EBMT
- Randomized. 149 patients, untreated ovarian CA, s/p debulking surgery. Arm 1) standard combination chemo vs. Arm 2) HD chemo with stem cell rescue. Median F/U 3.2 years
- 2007 17698804 -- "Phase III trial of high-dose sequential chemotherapy with peripheral blood stem cell support compared with standard dose chemotherapy for first-line treatment of advanced ovarian cancer: intergroup trial of the AGO-Ovar/AIO and EBMT." (Mobus V, J Clin Oncol. 2007 Sep 20;25(27):4187-93.)
  - Outcome: Median OS standard chemo 5.2 years vs. HD chemo 4.5 years (NS)
  - Conclusion: No benefit to HD chemo with stem cell rescue