1 OVARIAN CANCER Updated July 2015 by: Dr. Jenny Ko (PGY­5 Medical Oncology Resident, University of Calgary) Source: UpToDate 2015, ASCO/CCO/Alberta provincial guidelines, NCCN Reviewed by: Dr. Sarah Glaze (Gynecologic Oncologist, University of Calgary), Dr. Aalok Kumar (Gynecologic Oncologist, UBC), Dr. Stephanie Lhereux (Gynecologic Oncologist, University of Toronto) DISCLAIMER: The following are study notes compiled by the above PGY­5 medical oncology resident and reviewed by a staff gynecologic oncologist and medical oncologist. They reflect what we feel is relevant knowledge for graduating medical oncology residents preparing for their final examination. The information has not been surveyed or ratified by the Royal College. A) PUBLIC HEALTH

EPIDEMIOLOGY ­ Most common cause of cancer death among gyne CAs ­ Usually presents at advanced stage ­> 75% of women present with Stage III (spread through

peritoneal cavity or LN+) or Stage IV disease

RISK FACTORS ­ Increasing age ­ Reproductive: early menarche, late menopause, first pregnancy >30yo, nulliparity ­ Genetics: family history ovarian Ca, BRCA1 (40%) > BRCA2 (20%) mutations, Lynch II syndrome

(HNPCC) Overall 10% of ovarian cancer, nearly 20% in high grade serous subtype associated

with BRCA1/2 (Alsop JCO 2012) Genetic counselling for all women with non­mucinous pathology

PREVENTION & SCREENING ­ Screening is not recommended

For women with known genetic syndromes (CA­125 + trans­vaginal ultrasound) but not validated

OCPs decrease risk of ovarian Ca, but trade­off is increased risk of breast Ca Prophylactic BSO (+/­ hysterectomy) for patients with BRCA1 or 2 after childbearing

age B) PRESENTATION & DIAGNOSIS

SYMPTOMS & SIGNS ­ Asymptomatic initially, tend to present as stage III or IV disease ­ Abdominal/pelvic discomfort or pain, abdominal distention, bloating, early satiety ­ Urinary frequency, urgency ­ Bowel obstruction, ascites

INVESTIGATIONS ­ CA­125 tumour marker

o elevated in 50% of stage I tumours and 80­90% of stage II­IV o sensitive, but not specific (also elevated in breast cancer, endometrial cancer,

endometriosis, benign tumours, fibroids, pregnant/post­partum) o used as a surrogate for tumour response to treatment

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­ U/S abdo/pelvis then CT c/a/p for advanced cases ­ Tissue for diagnosis: if neoadjuvant chemotherapy is considered, obtain cytology from ascites or

biopsy for tissue confirmation prior to treatment ­ Full exploratory laparotomy with midline incision (most important)

TAH­BSO Omentectomy Pelvic and para­aortic lymph node sampling Biopsy suspicious lesions Peritoneal biopsies Peritoneal washings/ascites for cytology Debulking surgery ­ standard of care is microscopic (as much as possible, this

influences survival), goal is no residual disease. Consider appendicectomy – mandatory for mucinous OC

PATHOLOGY & MOLECULAR BIOLOGY (Cancer. 2015 Sep 15; 121(18): 3203–3211.) ­ Epithelial carcinomas (90%)

Common immunoprofile Common gene mutations Response to platinum chemotherapy

High­grade serous P53+ WT1+ Pax8+ High Ki67

TP53 BRCA1,2

Excellent

Low­grade serous WT1+ Pax8+ p53 wild type Low Ki67

BRAF KRAS

Poor

Endometrioid Estrogen receptor (ER)+ Pax8+ Vimentin+ WT1­ p53 wild type

PTEN CTNNB­1 (beta­catenin)

Good­excellent

Clear cell HNF beta+ WT1­ ER­

KRAS PTEN PIK3CA

Fair

Mucinous CK20+ cdx2+ CK7+ ER­ WT1­

KRAS Poor

o Mucinous and clear cell do notrespond well to chemo o 50% serous, 25% endometriod

­ Sex cord­stromal cell tumors (5%, granulosa cell) ­ Germ cell tumors (2%, teratoma, yolk­sac, embryonal, etc)

STAGING Reference:https://www.sgo.org/wp­content/uploads/2012/09/FIGO­Ovarian­Cancer­ Staging_1.10.14.pdf ­ 60% of epithelial ovarian CA present with stage III disease.

FIGO staging 2014

3 Stage I: confined to uterus IA Tumor limited to 1 ovary, capsule intact, no tumor on surface, negative

washings. IB Tumor involves both ovaries otherwise like IA. IC Tumor limited to 1 or both ovaries

IC1: Surgical spill IC2: Capsule rupture before surgery or tumor on ovarian surface IC3: Malignant cells in the ascites or peritoneal washings.

Stage II: Tumor involves 1 or both ovaries with pelvic extension (below the pelvic brim) or primary peritoneal cancer IIA Extension and/or implant on uterus and/or Fallopian tubes IIB Extension to other pelvic intraperitoneal tissues Stage III: Tumor involves 1 or both ovaries with cytologically or histologically confirmed spread to the peritoneum outside the pelvis and/or metastasis to the retroperitoneal lymph nodes IIIA Positive retroperitoneal lymph nodes and /or microscopic metastasis

beyond the pelvis IIIA1: Positive retroperitoneal lymph nodes only IIIA1(i) ­ Metastasis ≤ 10 mm IIIA1 (ii) ­ Metastasis > 10 mm

IIIA2: Microscopic, extrapelvic (above the brim) peritoneal involvement ± positive retroperitoneal lymph nodes

IIIB Macroscopic, extrapelvic, peritoneal metastasis ≤ 2 cm ± positive retroperitoneal lymph nodes. Includes extension to capsule of liver/spleen.

IIIC Macroscopic, extrapelvic, peritoneal metastasis > 2 cm ± positive retroperitoneal lymph nodes. Includes extension to capsule of liver/spleen

Stage IV: Distant metastasis excluding peritoneal metastasis IVA Pleural effusion with positive cytology IVB Hepatic and/or splenic metastasis, metastasis to extra­abdominal organs

(including inguinal LN and LN outside of abdominal cavity) C) TREATMENT Surgery

­ Reasons for surgery include: primary staging and primary/interval cytoreduction, obtain pathology – clear benefit of surgery in OC (AGO­OVAR, Cancer. 2009 Mar 15;115(6):1234­44.)

­ Components of a complete ovarian Ca surgery include:TAH­BSO, omentectomy, pelvic and para­aortic lymph node sampling, biopsy suspicious lesions, peritoneal biopsies, peritoneal washings/ascites for cytology – sometimes appendicectomy can be indicated

­ Primary/ interval debulking surgery microscopic(improves PFS and OS) Chemotherapy

­ Standard of care: carboplatin AUC 5 to 6 iv + paclitaxel 175mg/m2 iv q3weeks x 6 cycles if patient is continuing to respond and has not had a CR, may continue to 8­ cycles but no evidence to go beyond 6.

o IP chemotherapy may be beneficial and is the standard of care in most places if maximal debulking surgery (see below)

o Dose­dense chemotherapy may be superior, trials pending. This is controversial (see below)

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Adjuvant (i.e. after surgery or first­line) EARLY/LOCALIZED (Stage I & II) o Stage I

Surgical cytoreduction→ observation for low­risk stage IA, IB (grade 1, serous/endometriod) carbo/taxolx 3 to 6 cycles for high­risk IA & IB (≥grade 2, clear­cell histology)

and all IC ICON 1 (MRC): stage I ovarian Ca Tx with platinum­based chemo vs

observation showed 5Y­OS benefit of 8% (82% vs 74%) only in patients with high risk stage I

In BC and Ontario: In selected cases of stage IC patients, for clear cell and sometimes mucinous CA, can treat with 3 cycles of carbo/taxol followed by adjuvant abdo­pelvic XRT (J Clin Oncol. 2012 May 10;30(14):1656­62.)

o Stage II Surgical cytoreduction→ carboplatin AUC 6 + paclitaxel 175mg/m2 q3wks x

6 cycles

ACTION ­ Impact of adjuvant chemotherapy and surgical staging in early­stage ovarian carcinoma: European Organisation for Research and Treatment of Cancer­Adjuvant

ChemoTherapy in Ovarian Neoplasm trial. (J Natl Cancer Inst. 2003 Jan 15;95(2):113­25.)

Regimen Adjuvant platinum based chemotherapy (4­6 cycles) vs.

observation 47% Cisplat / cyclo ­33% single agent carboplatin

Primary Endpoint OS Inclusion/Exclusion Criteria

FIGO stage Ic and IIaOv ­Ia and Ib allowed if grade II­III or clear cell histology

Optimal staging strong advised (peritoneal washing, omentectomy, blind biopsies), although occurred in only 1/3

Size (N) 224 Results 5 yr RFS 76% vs. 68% (stat sig)

5 yr OS 85% vs. 78% (non­sig) Other comments Criticism: ­trial underpowered for survival ­only 1/3 pts received

optimal OR; restricted analysis of these pts showed no benefit to adjuvant Rx

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ICON1 ­ International Collaborative Ovarian Neoplasm Trial 1: A Randomized Trial of Adjuvant Chemotherapy in Women With Early­Stage Ovarian Cancer

(J Natl Cancer Inst. 2003 Jan 15;95(2):125­32.)

Regimen Adjuvant platinum based chemotherapy (6 cycles) vs. observation; Rx MD chose exact regimen

87% single agent carboplatin 11% cisplatin combination 2% carboplatin combination

Primary Endpoint OS

Inclusion/Exclusion Criteria

Histologically confirmed OvCA Clinician uncertain as to whether to offer immediate adjuvant

chemotherapy No visible residual cancer Optimal surgical staging advised but not mandated

Size (N) 241

Results 5 yr RFS 76% vs. 68% (stat sig) 5yr RFS 73% vs. 62% 10yr RFS 67% vs. 57%, HR0.7, p­sig

5 yr OS 79% vs. 70% 10yr OS 72% vs. 64%, HR 0.65, psig

Conclusion These results suggest that platinum­based adjuvant chemotherapy improves survival and delays recurrence in patients with early­stage ovarian cancer.

Other Comments Criticisms: lack of surgical staging, non­uniform choice of chemo, trial underpowered for accrual goal

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GOG 157 ­ Randomized phase III trial of three versus six cycles of adjuvant carboplatin and paclitaxel in early stage epithelial ovarian carcinoma: a Gynecologic Oncology Group study.

(Gynecol Oncol. 2006 Sep;102(3):432­9. Epub 2006 Jul 24.)

Regimen 3 or 6 cycles of chemotherapy consisting of P (175 mg/m2 over 3 h) and C (7.5 AUC over 30 min) every 21 days

Primary Endpoint OS

Inclusion/Exclusion Criteria

Surgically staged patients with stage IA grade 3, IB grade 3, clear cell, IC, and completely resected stage II epithelial ovarian cancer (EOC);

Size (N) 427

Results 5­yr DFS & OS from 3 cycles vs 6 cycles were: 75% vs 80% & 81% vs 83%, respectively HR after adjusted for stage & grade = 0.761 for PFS for 6 cycles arm (NS) and 1.02 for OS (NS) 5­year DFS= 83% vs 60% from 6 cycles vs. 3 cycles (p=0.007) HR for serous tumor having 6 cycles= 0.33 (p=0.04)

Toxicities Grade 3 or 4 neurotoxicity occurred in 4/211 (2%) and 24/212 (11%) treated patients on the 3­ and 6­cycle regimens, respectively (p<0.01); 6 cycles also caused significantly more severe anemia and granulocytopenia.

Conclusion Compared to 3 cycles, 6 cycles of C and P do not significantly alter the recurrence rate in high­risk early stage EOC but are associated with more toxicity.

Other Comments The recurrence rate for 6 cycles was 24% lower (hazard ratio [HR]: 0.761; 95% confidence interval [CI]: 0.51­1.13, p=0.18), and the estimated probability of recurrence within 5 years was 20.1% (6 cycles) versus 25.4% (3 cycles). The overall death rate was similar for these regimens (HR: 1.02; 95% CI: 0.662­1.57).

ADVANCED (Stage III & IV)

o Surgical cytoreduction→ carboplatin AUC 6 + paclitaxel 175mg/m2 q3wks x 6 cycles

Adjuvant carboplatin + paclitaxel

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GOG 158 ­ Phase III Trial of Carboplatin and Paclitaxel Compared With Cisplatin and Paclitaxel in Patients With Optimally Resected Stage III Ovarian Cancer: A Gynecologic Oncology Group Study

(J Clin Oncol 21:3194­3200)

Regimen Cisplatin 75mg/m2+taxol 175mg/m2 q 3 weeks Carboplatin ACU 7.5 +taxol 175mg/m2 q3 weeks

Primary Endpoint PFS, OS

Inclusion/Exclusion Criteria

Stage III with optimal cytoreduction, no prior chemotherapy or RT

Size (N) 792

Results Median RFS 20.7months (carbo) vs. 19.4 months (cis) non­significant Median OS 57.4 months (carbo) vs. 48.7 (cis) not significant

Toxicities Less toxicity of carboplatin arm

Conclusion Cis/paclitaxel = carbo/paclitaxel with less toxicity

ICON 3 ­ Paclitaxel plus carboplatin versus standard chemotherapy with either single­agent carboplatin or cyclophosphamide, doxorubicin, and cisplatin in women with ovarian cancer: the

ICON3 randomised trial. (Lancet. 2002 Aug 17;360(9332):505­15.)

Regimen Carbo/Taxol Vs. Non­taxol regimen based upon investigators’ choice (carbomonoRx or CAP ­> 70% chose carbomonoRx)

Inclusion/Exclusion Criteria

All stages, 20% stage I or II ­No previous chemo / RT ­N=2074

Results HR similar w. taxol/carbo vs. other for PFS (0.93) and OS (0.98) All arms determined equivalent

Toxicities Toxicity least in carbomonoRx arm

Other Comments Criticism: all stages, optimal surgery was not inclusion criteria, 85% received sequential carbo­>taxol (i.e. crossover)

o Adjuvant IP Chemotherapy for Stage III

High doses directly to tumor, only works if can take tumor bulk down since it can only diffuse across 2­3 layers of cells

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GOG 172 ­ Intraperitoneal cisplatin and paclitaxel in ovarian cancer. (N Engl J Med. 2006 Jan 5;354(1):34­43.)

Regimen Arm 1: 135mg of intravenous paclitaxel per square meter of body­surface area over a 24­hour period followed by either 75 mg of intravenous cisplatin per square meter on day 2 (intravenous­therapy group)

Arm 2: 100 mg of intraperitoneal cisplatin per square meter on day 2 and 60 mg of intraperitoneal paclitaxel per square meter on day 8 (intraperitoneal­therapy group).

Treatment was given every three weeks for six cycles.

Primary Endpoint OS

Inclusion/Exclusion Criteria

Patients with stage III ovarian carcinoma or primary peritoneal carcinoma with no residual mass greater than 1.0 cm

Size (N) 429

Results PFS: 18.3 vs. 23.8 months, respectively (P=0.05 by the log­rank test). OS: 49.7 vs. 65.6 months, respectively (P=0.03 by the log­rank test).

Toxicities Grade 3 and 4 pain, fatigue, and hematologic, gastrointestinal, metabolic, and neurologic toxic effects were more common in the intraperitoneal­therapy group than in the intravenous­therapy group (P≤0.001). Only 42 percent of the patients in the intraperitoneal­therapy group completed six cycles of the assigned therapy

Conclusion As compared with intravenous paclitaxel plus cisplatin, intravenous paclitaxel plus intraperitoneal cisplatin and paclitaxel improves survival in patients with optimally debulked stage III ovarian cancer. But not understood if it is because of intraperitoneal delivery of chemo OR more frequent taxol.

(Results similar for SWOG 9616, GOG 114, and a meta­analysis)

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o Adjuvant dose­dense IV chemotherapy ­ controversial

Long­term results of dose­dense paclitaxel and carboplatin versus conventional paclitaxel and carboplatin for treatment of advanced epithelial ovarian, fallopian tube, or primary peritoneal

cancer (JGOG 3016): a randomised, controlled, open­label trial (Lancet Oncology Volume 14, No. 10, p1020–1026, September 2013)

Regimen Carboplatin and paclitaxel (every three weeks)) or carboplatin (every three weeks) with weekly paclitaxel. In both arms, the regimen was repeated every three weeks for up to nine cycles

Primary Endpoint OS

Inclusion/Exclusion Criteria

Patients with stage II­IV ovarian cancer

Size (N) 429

Results PFS 28 versus 17.5 months (significant) For women with serous and other histologic types, dose­dense therapy

improved both PFS (median 28.7 versus 17.5 months, HR 0.70, 95% CI 0.57­0.86) and OS (median 100.5 versus 61.2 months, HR

OS 100.5 versus 62 months (significant) Subgroup analysis showed that the schedule of treatment did not influence

survival outcomes for patients with clear cell or mucinous cancers

Toxicities A higher rate of treatment discontinuation for toxicity (52 versus 37 percent) and higher proportion of patients who had at least one treatment cycle delayed because of toxicity (76 versus 67 percent).

A similar frequency of severe (grade 3 or 4) nonhematologic toxicity (including neurotoxicity) but no difference in the rate of febrile neutropenia (9 percent in both groups)

Other comments Women with at least one centimeter of residual disease following surgical cytoreduction appeared to benefit the most from dose­dense therapy.

Compared with conventional treatment every three weeks, dose­dense treatment resulted in an improvement in PFS (median 17.6 versus 12 months, HR 0.71, 95% CI 0.56­0.89) and OS (median, 51 versus 33 months, HR 0.75, 95% CI 0.57­0.97). There was no significant advantage to dose­dense treatment for patients with optimally cytoreduced disease.

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Carboplatin plus paclitaxel once a week versus every 3 weeks in patients with advanced ovarian cancer (MITO­7): a randomised, multicentre, open­label, phase 3 trial

(Lancet Oncology Volume 15, No. 4, p396–405, April 2014)

Regimen Arm 1: carboplatin (AUC 6 mg/mL per min) plus paclitaxel (175 mg/m(2)) every 3 weeks for six cycles

Arm 2: carboplatin (AUC 2 mg/mL per min) plus paclitaxel (60 mg/m(2)) every week for 18 weeks

Primary Endpoint PFS

Inclusion/Exclusion Criteria

Women with FIGO stage IC­IV ovarian cancer, an ECOG performance status of 2 or lower, and who had never received chemotherapy

Size (N) 822

Results 17.3 vs 18.3m (NS) With treatment every 3 weeks, FACT­O/TOI scores worsened at every

cycle (weeks 1, 4, and 7), whereas for the weekly schedule, after transient worsening at week 1, FACT­O/TOI scores remained stable.

Toxicities Fewer patients assigned to the weekly group than those allocated treatment every 3 weeks had grade 3­4 neutropenia (167 [42%]of 399 patients vs 200 [50%]of 400 patients), febrile neutropenia (two [0•5%]vs 11 [3%]), grade 3­4 thrombocytopenia (four [1%]vs 27 [7%]), and grade 2 or worse neuropathy (24 [6%]vs 68 [17%]).

Three deaths during the study were attributed to chemotherapy; two women died who were allocated treatment every 3 weeks and one death was recorded in the group assigned the weekly regimen.

Conclusions A weekly regimen of carboplatin and paclitaxel might be a reasonable option for first­line treatment of women with advanced ovarian cancer.

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GOG 262 ­ Weekly vs. Every­3­Week Paclitaxel and Carboplatin for Ovarian Cancer. (N Engl J Med. 2016 Feb 25;374(8):738­48.)

Regimen Either paclitaxel, administered intravenously at a dose of 175 mg per square meter of body­surface area every 3 weeks, plus carboplatin (dose equivalent to an area under the curve [AUC] of 6) for six cycles or paclitaxel, administered weekly at a dose of 80 mg per square meter, plus carboplatin (AUC, 6) for six cycles

Primary Endpoint PFS

Inclusion/Exclusion Criteria

Newly diagnosed, untreated, incompletely resected stage III or any stage IV epithelial ovarian, fallopian tube, or primary peritoneal cancer

Size (N) N=692

Results In the intention­to­treat analysis, weekly paclitaxel was not associated with longer progression­free survival than paclitaxel administered every 3 weeks (14.7 months and 14.0 months, respectively; hazard ratio for disease progression or death, 0.89; 95% confidence interval [CI], 0.74 to 1.06; P=0.18).

Among patients who did not receive bevacizumab, weekly paclitaxel was associated with progression­free survival that was 3.9 months longer than that observed with paclitaxel administered every 3 weeks (14.2 vs. 10.3 months; hazard ratio, 0.62; 95% CI, 0.40 to 0.95; P=0.03).

However, among patients who received bevacizumab, weekly paclitaxel did not significantly prolong progression­free survival, as compared with paclitaxel administered every 3 weeks (14.9 months and 14.7 months, respectively; hazard ratio, 0.99; 95% CI, 0.83 to 1.20; P=0.60).

A test for interaction that assessed homogeneity of the treatment effect showed a significant difference between treatment with bevacizumab and without bevacizumab (P=0.047).

Toxicities Patients who received weekly paclitaxel had a higher rate of grade 3 or 4 anemia than did those who received paclitaxel every 3 weeks (36% vs. 16%), as well as a higher rate of grade 2 to 4 sensory neuropathy (26% vs. 18%); however, they had a lower rate of grade 3 or 4 neutropenia (72% vs. 83%).

Conclusions Overall, weekly paclitaxel, as compared with paclitaxel administered every 3 weeks, did not prolong progression­free survival among patients with ovarian cancer.

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o Bevacizumab addition or maintenance – increases PFS but not OS (approximately 2­3m)

ICON7 ­ A Phase 3 Trial of Bevacizumab in Ovarian Cancer (N Engl J Med 2011; 365:2484­2496)

Regimen Carboplatin (area under the curve, 5 or 6) and paclitaxel (175 mg per square meter of body­surface area), given every 3 weeks for 6 cycles, or to this regimen plus bevacizumab (7.5 mg per kilogram of body weight), given concurrently every 3 weeks for 5 or 6 cycles and continued for 12 additional cycles or until progression of disease.

Primary Endpoint PFS

Inclusion/Exclusion Criteria

After surgery, women were eligible for enrollment if they had histologically confirmed, high­risk, early­stage disease (International Federation of Gynecology and Obstetrics [FIGO] stage I or IIA and clear­call or grade 3 tumors) or advanced (FIGO stage IIB to IV) epithelial ovarian cancer, primary peritoneal cancer, or fallopian­tube cancer (based on local histopathological findings).

Size (N) N=1528

Results Progression­free survival (restricted mean) at 36 months was 20.3 months with standard therapy, as compared with 21.8 months with standard therapy plus bevacizumab (hazard ratio for progression or death with bevacizumab added, 0.81; 95% confidence interval, 0.70 to 0.94; P=0.004 by the log­rank test).

Nonproportional hazards were detected (i.e., the treatment effect was not consistent over time on the hazard function scale) (P<0.001), with a maximum effect at 12 months, coinciding with the end of planned bevacizumab treatment and diminishing by 24 months.

Bevacizumab was associated with more toxic effects (most often hypertension of grade 2 or higher) (18%, vs. 2% with chemotherapy alone).

In the updated analyses, progression­free survival (restricted mean) at 42 months was 22.4 months without bevacizumab versus 24.1 months with bevacizumab (P=0.04 by log­rank test); in patients at high risk for progression, the benefit was greater with bevacizumab than without it, with progression­free survival (restricted mean) at 42 months of 14.5 months with standard therapy alone and 18.1 months with bevacizumab added, with respective median overall survival of 28.8 and 36.6 months.

Toxicities Bevacizumab improved progression­free survival in women with ovarian cancer. The benefits with respect to both progression­free and overall survival were greater among those at high risk for disease progression.

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GOG218 ­ Phase III trial of bevacizumab (BEV) in the primary treatment of advanced epithelial ovarian cancer (EOC), primary peritoneal cancer (PPC), or fallopian tube cancer (FTC): A

Gynecologic Oncology Group study. (J Clin Oncol 28:18s, 2010 (suppl; abstr LBA1))

Regimen The randomly allocated regimens were (1) CT (IV paclitaxel 175 mg/m2 + carboplatin AUC 6 cycles 1­6) + placebo cycles (C)2­22 (R1) (2) CT + concurrent BEV (15 mg/kg) C2­6 + placebo C7­22 (R2) (3) CT + concurrent BEV C2­6 + maintenance BEV C7­22 (R3) Infusions were administered d1 of a 21d cycle.

Primary Endpoint PFS

Inclusion/Exclusion Criteria

Newly diagnosed, previously untreated EOC, PPC or FTC following abdominal surgery for staging and maximal effort at tumor debulking; stage III (macroscopic residual disease) or stage IV disease

Size (N) 1873

Results Relative to R1, the hazard of first progression or death for R2 was 0.908 (95% CI: 0.795 ­ 1.04, p=0.16) and for R3 was 0.717 (95% CI: 0.625 ­ 0.824, p<0.0001).

Toxicities Grade 3 ­ 4 hypertension was reported in 1.6% (R1), 5.4% (R2), and 10.0% (R3). Grade ≥ 3 GI perforation, hemorrhage or fistula occurred in 0.8% (R1), 2.6% (R2) and 2.3% (R3).

Conclusions This study demonstrates that front­line treatment of EOC, PPC, and FTC patients with CT plus concurrent and maintenance BEV prolongs PFS. This is the first anti­angiogenic agent to demonstrate benefit in this population.

Neoadjuvant o Give 3­4 cycles of carbo/taxol then surgical cytoreduction in responding patients, then

follow­up with 3 cycles of chemo o Consider in patients who are not resectable at initial diagnosis to resection o Second look surgery does not add additional benefit.

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Primary chemotherapy versus primary surgery for newly diagnosed advanced ovarian cancer (CHORUS): an open­label, randomised, controlled, non­inferiority trial (Lancet Volume 386, No. 9990, p249–257, 18 July 2015)

Regimen Primary surgery or NACT first

Primary Endpoint OS

Inclusion/Exclusion Criteria

Women with stage III­IV EOC (25 percent with stage IV disease) Non­inferiority

Size (N) 670

Results NACT resulted in increase in the discharge rate within 14 days of hospitalization (92 versus 74 percent), similar PFS (median, 12 versus 10.7 months, respectively). Median operation time was 120 minutes in both. Among patients with available data on residual disease, debulking to < 1 cm was achieved in 73% vs 41% (P = .0001) and to no macroscopic disease in 39% vs 17% (P = .0001). The largest residual tumor was 1 cm or less in diameter in 41.6% of patients after primary debulking and in 80.6% of patients after interval debulking. Complete resection of all macroscopic disease (at primary or interval surgery) was the strongest independent variable in predicting overall survival.

The hazard ratio for death (intention­to­treat analysis) in the group assigned to neoadjuvant chemotherapy followed by interval debulking, as compared with the group assigned to primary debulking surgery followed by chemotherapy, was 0.98 (90% confidence interval [CI], 0.84 to 1.13; P=0.01 for noninferiority) 0.84 to 1.13; P=0.01 for noninferiority)

Toxicities Postoperative rates of adverse effects and mortality tended to be higher after primary debulking than after interval debulking.

Conclusion Neoadjuvant chemotherapy followed by interval debulking surgery was not inferior to primary debulking surgery followed by chemotherapy as a treatment option for patients with bulky stage IIIC or IV ovarian carcinoma in this study. Complete resection of all macroscopic disease, whether performed as primary treatment or after neoadjuvant chemotherapy, remains the objective whenever cytoreductive surgery is performed.

Other Comments The majority of these patients had extensive stage IIIC or IV disease at primary debulking surgery (metastatic lesions that were larger than 5 cm in diameter in 74.5% of patients and larger than 10 cm in 61.6%).

Biomarkers were not predictive of five­year survival rates (age, WHO performance status, tumor grade, tumor histology, serum CA­125, the presence of a pelvic mass, or the presence of an omental cake) The size of the largest mass was prognostic for survival following primary surgery.

Patients whose largest tumor size was <40 mm had a higher five­year OS rate compared with those with larger tumor sizes (40 versus 14 percent, respectively). However, there was no clear association between survival and tumor largest dimension among patients treated with NACT. The stage at presentation was also prognostic for survival.

Women with stage IV disease had higher five­year OS rates following NACT compared with primary surgery (22 versus 5 percent, respectively)

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Secondary Surgical Cytoreduction for Advanced Ovarian Carcinoma (N Engl J Med 2004; 351:2489­2497)

Regimen Enrolled within six weeks after primary surgery. If, after three cycles of postoperative paclitaxel plus cisplatin, a patient had no evidence of progressive disease, she was randomly assigned to undergo secondary cytoreductive surgery followed by three more cycles of chemotherapy or three more cycles of chemotherapy alone.

Primary Endpoint OS

Inclusion/Exclusion Criteria

Women with stage III­IV EOC (25 percent with stage IV disease) Non­inferiority

Size (N) 550

Results The likelihood of progression­free survival in the group assigned to secondary surgery plus chemotherapy, as compared with the chemotherapy­alone group, was 1.07 (non­significant)

Relative risk of death was 0.99 (95 percent confidence interval, 0.79 to 1.24; P=0.92).

Conclusion For patients with advanced ovarian carcinoma in whom primary cytoreductive surgery was considered to be maximal, the addition of secondary cytoreductive surgery to postoperative chemotherapy with paclitaxel plus cisplatin does not improve progression­free survival or overall survival.

Follow­Up After Adjuvant Tx ­ Hx and Px; no guidelines for routine imaging, ­ Frequent CA­125 monitoring for early recurrence and treating based on CA­125 does not improve

OS and decreases QoL compared to delaying treatment with standard chemotherapy until symptomatic recurrence

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MRC OV05; EORTC 55955 ­ Early versus delayed treatment of relapsed ovarian cancer (MRC OV05/EORTC 55955): a randomised trial

(Lancet Volume 376, No. 9747, p1155–1163, 2 October 2010)

Regimen Clinical examination and CA125 measurement were done every 3 months. Patients and investigators were masked to CA125 results, which were monitored by coordinating centres. If CA125 concentration exceeded twice the upper limit of normal, patients were randomly assigned (1:1) by minimisation to early or delayed chemotherapy

Patients assigned to delayed treatment continued masked CA125 measurements, with treatment commencing at clinical or symptomatic relapse

Primary Endpoint OS

Inclusion/Exclusion Criteria

Women with ovarian cancer in complete remission after first­line platinum­based chemotherapy and a normal CA125 concentration

Size (N) 1442

Results With a median follow­up of 56•9 months (IQR 37•4­81•8) from randomisation and 370 deaths (186 early, 184 delayed), there was no evidence of a difference in overall survival between early and delayed treatment (HR 0•98, 95% CI 0•80­1•20, p=0•85). Median survival from randomisation was 25•7 months (95% CI 23•0­27•9) for patients on early treatment and 27•1 months (22•8­30•9) for those on delayed treatment.

Conclusion Our findings showed no evidence of a survival benefit with early treatment of relapse on the basis of a raised CA125 concentration alone, and therefore the value of routine measurement of CA125 in the follow­up of patients with ovarian cancer who attain a complete response after first­line treatment is not proven.

Prognosis

­ Clinical CR (Stage III) = 75% ­ Relapse = 75% ­ Median survival (platinum + taxane) = 36 months

RECURRENT / METASTATIC DISEASE (mostly for high grade serous CA – for other subtypes, clinical trials strongly encouraged)

­ RR up to 60%, up to 25% pts achieving CR ­ Platinum Sensitive (>6m since last platinum Tx)

o Pts who respond to primary platinum Rx and have relapse free interval >6mo o If late relapse, important to consider discussion about repeat surgery o Re­treatment with platinum combination response rate up to 60% o Median survival duration up to 2 years

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o 6­12m considered platinum sensitivity intermediate o Bevacizumab adds PFS but not OS benefit (OCEANS) o Maintenance olaparib can be considered

Olaparib Maintenance Therapy in Platinum­Sensitive Relapsed Ovarian Cancer (N Engl J Med 2012; 366:1382­1392)

Regimen Olaparib, at a dose of 400 mg twice daily, or placebo

Mechanism of action Olaparib (AZD2281) is an oral poly(adenosine diphosphate [ADP]–ribose) polymerase inhibitor

Primary Endpoint PFS

Inclusion/Exclusion Criteria

Patients with platinum­sensitive, relapsed, high­grade serous ovarian cancer who had received two or more platinum­based regimens and had had a partial or complete response to their most recent platinum­based regimen

Size (N) 265

Results PFS 8.4 vs 4.8m (significant) An interim analysis of overall survival (38% maturity, meaning that 38% of

the patients had died) showed no significant difference between groups (hazard ratio with olaparib, 0.94; 95% CI, 0.63 to 1.39; P=0.75).

Toxicities Adverse events more commonly reported in the olaparib group than in the placebo group (by more than 10% of patients) were nausea (68% vs. 35%), fatigue (49% vs. 38%), vomiting (32% vs. 14%), and anemia (17% vs. 5%); the majority of adverse events were grade 1 or 2.

Conclusion Olaparib as maintenance treatment significantly improved progression­free survival among patients with platinum­sensitive, relapsed, high­grade serous ovarian cancer. Interim analysis showed no overall survival benefit. The toxicity profile of olaparib in this population was consistent with that in previous studies.

Update 2014 (Lancet Oncol)

BRCA status was known for 131 (96%) patients in the olaparib group versus 123 (95%) in the placebo group, of whom 74 (56%) versus 62 (50%) had a deleterious or suspected deleterious germline or tumour BRCA mutation.

Of patients with a BRCA mutation, median PFS was significantly longer in the olaparib group than in the placebo group (11∙2 months [95% CI 8∙3–not calculable] vs 4∙3 months [3∙0–5∙4]; HR 0∙18 [0∙10–0∙31]; p<0∙0001); similar findings were noted for patients with wild­type BRCA, although the difference between groups was lower (7∙4 months [5∙5–10∙3] vs 5∙5 months [3∙7–5∙6]; HR 0∙54 [0∙34–0∙85]; p=0∙0075).

At the second interim analysis of overall survival (58% maturity), overall survival did not significantly differ between the groups (HR 0∙88 [95% CI 0∙64–1∙21]; p=0∙44); similar findings were noted for patients with mutated BRCA (HR 0∙73 [0∙45–1∙17]; p=0∙19) and wild­type BRCA (HR 0∙99 [0∙63–1∙55]; p=0∙96).

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­ Platinum Refractory o Pts who do not even have a primary response to plat (i.e. progress on initial Rx) o Re­treatment rate with non­platinum agent affords RR 10­%

­ Platinum Resistant (<6m since last platinum Tx) o Pts who initially respond to platinum, but then relapse <6 mo post completion of primary Rx; o Re­treatment RR 15% o Bevacizumab: Again, adds PFS but not OS (AURELIA) although in GOG213, OS 42.2 vs

37.3 mos (significant) in women with platinum­sensitive recurrent ovarian cancer o Liposomal doxorubicin: effective first­line therapy either combined with platinum or as single

agent o Subgroup of weekly paclitaxel/bevacizumab in AURELIA trial improve significantly PFS and

OS – Indication approved but not covered o Enroll patients in clinical trials when possible: Several new pathways investigated in OC

19 Various Second­line Options Peglated liposomal doxorubicin

Recurrent epithelial ovarian carcinoma: a randomized phase III study of pegylated liposomal doxorubicin versus topotecan.

(J Clin Oncol. 2001 Jul 15;19(14):3312­22.)

Regimen Peglated liposomal doxorubicin 50 mg/m(2) as a 1­hour infusion every 4 weeks or topotecan 1.5 mg/m(2)/d for 5 consecutive days every 3 weeks

Primary Endpoint OS

Inclusion/Exclusion Criteria

Patients with epithelial ovarian carcinoma that recurred after or didn't respond to first­line, platinum­based chemotherapy.

Size (N) 474

Results The overall progression­free survival rates were similar between the two arms (P =.095). The overall response rates for PLD and topotecan were 19.7% and 17.0%, respectively (P =.390). Data analyzed in platinum­sensitive patients demonstrated a statistically significant benefit from PLD for progression­free survival (P =.037), with medians of 28.9 for PLD versus 23.3 weeks for topotecan.

Median overall survival times were 60 weeks for PLD and 56.7 weeks for topotecan. For overall survival, PLD was significantly superior to topotecan (P =.008), with a median of 108 weeks versus 71.1 weeks.

Toxicities Severe hematologic toxicity was more common with topotecan and was more likely to be associated with dosage modification, or growth factor or blood product utilization.

Conclusion The comparable efficacy, favorable safety profile, and convenient dosing support the role of PLD as a valuable treatment option in this patient population.

Other comments The platinum­refractory subgroup demonstrated a nonstatistically significant survival trend in favor of topotecan (P =.455)

Gemcitabine — Gemcitabine is a commonly used agent in recurrent ovarian cancer and appears to have equivalent activity to PLD. This was shown in a trial that included 195 women with platinum­resistant EOC, all of whom were randomly assigned to treatment with gemcitabine (1000 mg/m2 on days 1 and 8 of a 21­day cycle) or PLD (50 mg/m2 on day 1 of a 28­day cycle). Compared with PLD, treatment with gemcitabine resulted in: A similar ORR (9 versus 11 percent) A higher proportion of stable disease (55 versus 39 percent) Similar median progression­free survival (PFS, four versus three months) Similar median OS (13 versus 14 months)

20 Toxicity associated with gemcitabine included severe (grade 3/4) fatigue (11 percent), nausea/vomiting (13 percent), and neutropenia (38 percent) Weekly taxol ­ 21 percent response rate in a cohort of 48 women with platinum­resistant disease, stable disease in 46% Topotecan — Topotecan is a commonly used agent in recurrent ovarian cancer. Although it is historically administered as a once­daily infusion for five days of a 28­day cycle, it is more commonly used today on a weekly schedule because at least one randomized trial showed there was no difference in survival outcomes or quality of life between the two regimens. Etoposide — Oral etoposide (50 mg/m2 daily for 21 days every four weeks) was given to 41 women with an ORR of 27 percent. Serious (grade 3/4) toxicity consisted of neutropenia (45 percent) and leukopenia (41 percent). In this trial, two deaths were associated with neutropenic sepsis, and one patient died of bleeding associated with thrombocytopenia. Paclitaxel (nanoparticle albumin bound) – NAb­paclitaxel (100 mg/m2 given weekly for three weeks on/one week off) was administered to 51 women in a Gynecologic Oncology Group (GOG) study. The ORR was 23 percent, with stable disease in 36 percent. Moderate (grade 3) neutropenia was seen in 12 percent of women with mild­moderate neuropathy (grade 2/3). Otherwise, there was no significant toxicity. Pemetrexed – Pemetrexed (900 mg/m2 every 21 days) was given to 51 patients on a GOG study [18]. The ORR was 21 percent, with an additional 35 percent experiencing stable disease. Serious toxicities (grade 3/4) included neutropenia (42 percent) and constitutional deterioration (15 percent). A European study randomized 102 women to treatment using the standard dose used above or a lower dose (500 mg/m2 every 21 days). The ORR with either dose was lower than that seen in the GOG experience (9 and 10 percent for the standard and lower doses, respectively). The lower dose resulted in fewer side effects (17 versus 28 percent, respectively). Olaparib: PARP inhibitor, inhibits single strand base excision repair mechanism (especially effective in BRCA mutation) – approved for use after 3 lines of treatment in germline BRCA patients

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Olaparib Monotherapy in Patients With Advanced Cancer and a Germline BRCA1/2 Mutation (J Clin Oncol. 2015 Jan 20;33(3):244­50.)

Regimen Olaparib was administered at 400 mg twice per day, single arm multicentre phase 2

Primary Endpoint RR

Inclusion/Exclusion Criteria

Individuals with a germline BRCA1/2 mutation and recurrent cancer. Eligibility included ovarian cancer resistant to prior platinum; breast cancer with ≥ three chemotherapy regimens for metastatic disease; pancreatic cancer with prior gemcitabine treatment; or prostate cancer with progression on hormonal and one systemic therapy

Size (N) N=298

Results The tumor response rate was 26.2% (78 of 298; 95% CI, 21.3 to 31.6) overall and 31.1% (60 of 193; 95% CI, 24.6 to 38.1), 12.9% (eight of 62; 95% CI, 5.7 to 23.9), 21.7% (five of 23; 95% CI, 7.5 to 43.7), and 50.0% (four of eight; 95% CI, 15.7 to 84.3) in ovarian, breast, pancreatic, and prostate cancers, respectively.

Stable disease ≥ 8 weeks was observed in 42% of patients (95% CI, 36.0 to 47.4), including 40% (95% CI, 33.4 to 47.7), 47% (95% CI, 34.0 to 59.9), 35% (95% CI, 16.4 to 57.3), and 25% (95% CI, 3.2 to 65.1) of those with ovarian, breast, pancreatic, or prostate cancer, respectively.

Toxicities The most common adverse events (AEs) were fatigue, nausea, and vomiting. Grade ≥ 3 AEs were reported for 54% of patients; anemia was the most common (17%).

Conclusion Responses to olaparib were observed across different tumor types associated with germline BRCA1/2 mutations. Olaparib warrants further investigation in confirmatory studies.

Timing of Salvage (2nd Line) Therapy

o Treatment is palliative ­> generally OK to wait until patient is symptomatic, disease is rapidly growing, or CA­125 is rapidly rising

o Secodary/tertiary, etccytoredution should/may be considered in women with platinum sensitive disease with isolated disease

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Prospective validation study of a predictive score for operability of recurrent ovarian cancer: the Multicenter Intergroup Study DESKTOP II. A project of the AGO Kommission OVAR, AGO Study Group, NOGGO, AGO­Austria, and MITO.

(Int J Gynecol Cancer. 2011 Feb;21(2):289­95.)

Resectability was assumed if 3 factors were present: (1) complete resection at first surgery, (2) good performance status, and (3) absence of ascites. Resectability was assumed if 3 factors were present: (1) complete resection at first surgery, (2) good performance status, and (3) absence of ascites. A total of 516 patients were screened within 19 months; of these, 261 patients (51%) were classified as score positive, and 129 patients with a positive score and first relapse were operated on. The rate of complete resection was 76%, thus confirming the validity of this score regarding positive prediction of complete resectability in 2 or more of 3 patients. Complication rates were moderate including second operations in 11% and perioperative mortality in 0.8%.

o Caveat… pts who are platinum sensitive are more likely to respond to 2nd line Rx, and may benefit from retreatment

­ Poor prognostic factors: age >65 years (more aggressive disease), poor performance status,

clear cell histology, advanced stage III or IV, poorly differentiated, overexpression of HER2, high VEGF expression, suboptimal debulking