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SOLO-1: Maintenance Olaparib in Newly Diagnosed Advanced Ovarian Cancer

Title: Maintenance Olaparib in Newly Diagnosed Advanced Ovarian Cancer

Hypothesis: Maintenance PARP-i after initial therapy in high-grade ovarian carcinoma improves progression free survival.

Standard Arm: Placebo

Experimental Arm: Olaparib 300 mg bid daily x 2 years

Design: Double blinded randomized controlled phase 3 study

Inclusion Criteria: High-grade serous or endometrioid ovarian cancer, primary peritoneal cancer, or fallopian-tube cancer with mutation in BRCA1, BRCA2 (germline or somatic)

Primary Endpoint: PFS or death at 3 years

Outcomes: Experimental vs. Standard arm (p-value)

PFS/death at 3 years: 60% vs. 27% (p<0.001)

Median time to subsequent therapy: 51.8 months vs. 15.1 months (HR – 0.30, p<0.001)

Serious Adverse Events:Experimental vs. Standard arm (p-value)

Anemia (G3/G4): 22% vs. 2% (p=s.s.)

Neutropenia (G3/G4): 9% vs. 5% (p=s.s.)

AML: 3/260 (1%) vs. 0/130 (0%) (p=n.s)

New Primary Cancer: 5/260 (2%) vs. 3/130 (2%) (p=n.s.)

Pneumonitis/Interstitial Lung Disease: 5/260 (2%) vs. 0 (p=n.s)

Conclusion: Addition of Olaparib 300mg bid for two years maintenance after completion of primary chemotherapy and debulking surgery in BRCA 1/2 (both germline or somatic) increases progression free survival or risk of death at 3 years.

GOG 161

Phase III Trial of Ifosfamide With or Without Paclitaxel in Advanced Uterine Carcinosarcoma: A Gynecologic Oncology Group Study

Pubmed

Hypothesis:Addition of paclitaxel to ifosfamide improve OS/ PFS in carcinosarcoma (GOG 108 there was no advantage to the combination of ifosfamide and cisplatin vs. ifosfamide alone related to median survival. GOG 130-B revealed a substantial response rate of carcinosarcoma to single-agent paclitaxel.)

Site: Uterus

Experimental arm: Ifosfamide 1.6 g/m2 IV daily for 3 days (1.2 g/m2 for irradiated patients) plus Paclitaxel 135 mg/m2 by 3 hour infusion day 1

Standard Arm: Ifosfamide 2 g/m2 IV for 3 days

Mesna iv or oral 1

Primary Outcome: Overall survival (OS)

Results:

Outcome Ifos Ifos Taxol p-value
OS (months)2 8.4 13.5 SS
PFS (months) 3.6 5.8 SS
ORR3 29% 45% SS
Toxicity
G1-4 neuropathy 8% 30% SS
Alopecia 40% 58% SS
Thrombocytopenia 11% 46% SS
G3-G4 Neutropenia 53% 44% NS

CNS related toxicity was similar in two arms

Conclusions:

  • Combination chemotherapy with Ifosfamide Taxol improves OS.
  • Treatment effect not different based on prior radiation or previous site of disease
  • No Quality of life assessments in this study

  1. Read GOG 261 design and mesna dosing schedules ↩︎
  2. Hazard Ratio: 0.69 (95% CI, 0.49 to 0.97; P = .03) ↩︎
  3. Overall Response Rate ↩︎

GOG 141

Treatment of (bulky) stage IB cervical cancer with or without neoadjuvant vincristine and cisplatin prior to radical hysterectomy and pelvic/para-aortic lymphadenectomy: a phase III trial of the Gynecologic Oncology Group.

Pubmed

Study Reviewed by: Anthony Costales

First Author: Eddy GL

Study hypothesis: Addition of neoadjuvant chemotherapy prior to radical hysterectomy in bulky IB cervical cancer improves survival

Standard Arm: Type III radical hysterectomy, pelvic/para-aortic lymph node dissection

Experimental Arm: Neoadjuvant vincristine 1 mg/m2 and cisplatin 50 mg/m2 every 10 days x 3 cycles followed by type III radical hysterectomy and pelvic & para-aortic lymph node dissection

Both arms:

If positive pelvic lymph nodes or parametrial margins: 45 Gy to pelvis LDR VBT to raise point A to 85 Gy and point B to 60 Gy

If positive para-aortic Lymph nodes: Extended field RT LDR VBT to raise point A to 85 Gy and point B to 60 Gy

Study population:
Inclusion: Squamous or adeno-, IB, tumor diameter ≥4 cm
Exclusion: prior pelvic radiation, prior chemo, prior hyst, no extrauterine mets

Primary endpoint: PFS, OS
Secondary endpoints: Toxicity, sites of recurrence
Arm distribution:

-Arm 1 (Rad Hyst): 143 (Squamous- 77%, adeno- 18%); Post surgical RT: 52%

-Arm 2 (NACT Rad Hyst): 145 (Squamous- 78%, adeno- 22%); Post surgical RT: 45%

Of note, 29% (48 pts) in the surgery arm received adjuvant treatment

Results

Outcome Rad hyst NACT Rad hyst P value
3 yr PFS 60.4% 59.7% NS
3 yr OS 69.3% 67.7% NS
Outcome Rad hyst NACT Rad hyst P value
5 yr PFS 53.8% 56.2% NS
5 yr OS 60.7% 63.3% NS
Adverse events Rad hyst NACT Rad hyst SS
G3/ GU 7% 1% Yes

Summary:

-NACT followed by radical hysterectomy did not improve PFS or OS as compared to radical hysterectomy alone.

-The GOG recommends, based on this study, against NACT for patients with stage IB2 cervical cancer.

-This study was closed early because of slow accrual, likely secondary to the Sedlis criteria publication

For bulky IB (≥4 cm) that undergo radical hysterectomy, approximately 50% will require adjuvant radiation

GOG 218

Incorporation of bevacizumab in the primary treatment of ovarian cancer.

Pubmed

First Author: Burger RA

Hypothesis: Addition of bevacizumab improves progression free interval in previously untreated, incompletely resectable Stage III or any Stage IV EOC, surgery within 12 weeks. (PROTOCOL modification → Patients with Optimal debulking were included later in the trial)

Site: Ovary

Experimental arm – 1 (Bev-initiation): 175 mg/m2 paclitaxel (IV-3hrs) Carboplatin AUC 6 Bev 15 mg/m2 Cycle 2-6 followed by placebo cycle 7-22

Experimental arm – 2 (Bev-maintenance):175 mg/m2 paclitaxel (IV-3hrs) Carboplatin AUC 6 Bev 15 mg/m2 cycle 2-22

Standard Arm: 175 mg/m2 Paclitaxel (IV-3hrs) carboplatin AUC 6 IV x 6 cycle + placebo cycles 2-22

Primary Outcome: Originally planned was overall survival but changed to Progression free survival

Results:

Outcome Standard Bev-Inititation Bev-Maintenance p-value
PFS 10.3 11.2 14.1 SS
OS 39.3 38.7 39.7 NS
G3/4 – % cases
GI* 1.8 2.8 2.6 SS
HTN 7.2 16.5 23 SS
Neutropenia % 57 63 63 NS
VTE 5.8 5.3 6.7 NS
Arterial thrombosis 0.8 0.8 0.7 NS
CNS bleed 0 0 0.3 NS

*perforation, fistula, necrosis, or anastomotic leak

Conclusions: Marginal improvement in PFS, no significant improvement in OS

Important studies:

GOG Ancillary Study: Ascites predicts improved response to bevacizumab

Cost-effectiveness Study: Bevacizumab addition is not cost-effective

Other details

Arm Distribution:

Standard: 625 total - 83% serous,2.2% endometrioid, 3.7% clear cell and 10% other. 33% 1 cm disease, 26% stage IV


Experimental 1 (bev-inititation): 623 total - 84% serous,4% endometrioid, 3.2% clear cell, 1.3% mucinous, 7.5% other. 35%  1 cm disease, 26% stage IV


Experimental 2 (bev-maintenance): 625 total - 87% serous,3.4% endometrioid, 1.9% clear cell, 1% mucinous, 7.5% other. 35%  1 cm disease, 26% stage IV

GOG 152

Secondary surgical cytoreduction for advanced ovarian carcinoma

Pubmed

First Author: Rose PG

Hypothesis: Secondary debulking in sub optimally >1 cm tumor patients after 3 cycles of chemotherapy improves survival

Site: Ovary

Experimental arm: Suboptimal surgery –> 3 cycles of cisplatin 75 mg/m2 Paclitaxel 135 mg/m2 q-24 hr –>Secondary debulking –> 3 further cycles

Standard Arm: Suboptimal surgery –> 6 cycles of cisplatin 75 mg/m2 Paclitaxel 135 mg/m2 q-24 hr

Primary Outcome: OS

Arm Distribution:

Experimental arm (secondary debulking arm): N=208 (Serous 76%, Endometrioid 8%, Measurable disease at 3 cycles 1-2 cm 12%, 2-5 cm 43%, 5-10 cm 33%, > 10 cm 12%)

Standard arm (no secondary debulking): N=216 (Serous 76%, Endometrioid 5%, Measurable disease at 3 cycles 1-2 cm 12%, 2-5 cm 44%, 5-10 cm 38%, > 10 cm 6%)

Results:

Outcome Secondary debulking Chemotherapy only p-value
PFS (Months) 10.5 10.7 NS
OS 33.9 33.7 NS
Neuropathy G2/4 16% 26% SS
GI G2/4 7% 4% SS

Conclusions: If maximum surgical effort up front (by a gynecologic oncologist), no benefit to interval cytoreduction