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Interferon after surgery for women with advanced (Stage II-IV) epithelial ovarian cancer

  1. Aramide O Lawal*,
  2. Alfred Musekiwa,
  3. Liesl Grobler

Editorial Group: Cochrane Gynaecological, Neuro-oncology and Orphan Cancer Group

Published Online: 6 JUN 2013

Assessed as up-to-date: 16 MAY 2013

DOI: 10.1002/14651858.CD009620.pub2


How to Cite

Lawal AO, Musekiwa A, Grobler L. Interferon after surgery for women with advanced (Stage II-IV) epithelial ovarian cancer. Cochrane Database of Systematic Reviews 2013, Issue 6. Art. No.: CD009620. DOI: 10.1002/14651858.CD009620.pub2.

Author Information

  1. Stellenbosch University, Centre for Evidence-based Health Care, Faculty of Medicine and Health Sciences, Cape Town, Western Cape, South Africa

*Aramide O Lawal, Centre for Evidence-based Health Care, Faculty of Medicine and Health Sciences, Stellenbosch University, PO Box 19063, Tygerberg, Cape Town, Western Cape, 7505, South Africa. aramide0319@yahoo.com.

Publication History

  1. Publication Status: Edited (no change to conclusions)
  2. Published Online: 6 JUN 2013

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Characteristics of included studies [ordered by study ID]
Alberts 2006

MethodsRandomised controlled trial

Trial duration: 11 years, from March 1988 to June 1999

Trial location: USA - 66 participants from South West Oncology Group (SWOG) and 4 from Gynecologic Oncology Group (GOG)


ParticipantsNumber of participants: 70 randomised (35 treatment group, 35 observation alone)

Inclusion criteria:

  • Histologically proven advanced (stage II or III) ovarian cancer
  • 120 days or less elapsed between completion of chemotherapy and second-look surgery
  • South West Oncology Group performance status of 0-2
  • White blood cell (WBC) ≥3500μl, platelet count ≥100,000/μl, adequate renal and hepatic function
  • Patent intraperitoneal space at the time of second-look surgery
  • Registered no later than 42 days following second-look surgery


Exclusion criteria: not specified


InterventionsIntervention:

Alpha-interferon (IFNα-26, Schering-Plough Kenilworth, NJ) in weekly doses of 50x106 IU (for 6 doses)

Control:

observation alone


Outcomes
  • Overall survival


  • Progression free survival, definition was not specified


  • Adverse events: abdominal pain/cramping, alopecia, anemia, arthralgia, catheter-related infection, diarrhea without colostomy, dizziness/lightheadedness, dyspenia, fatigue/malaise/lethargy, fever without neutropenia, fever, flu-like symptoms, headache, hypotension, leukopenia, local injection site reaction, myalgia/ arthralgia, nausea, neutropenia/granulocytopenia, pain, rigors/chills, SGOT (AST) increase, sensory neuropathy, urinary tract infection, vomiting


NotesEthics approval: the trial received local institutional review board (IRB) review and approval according to institutional guidelines

Informed consent: IRB approved consent forms were signed by the patients

Funding: source of funding/conflict of interest not declared

Correspondence with authors: dalberts@azcc.arizona.edu on the 3rd July 2012


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskIt is reported that patients were randomised but the method of randomisation is not described

Allocation concealment (selection bias)Unclear riskNot reported on

Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskNot reported on. Control group was merely observed

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNot described

Incomplete outcome data (attrition bias)
All outcomes
Low riskLoss to follow-up was minimal and similar in both groups (3/35 intervention, 0/35 control)

Selective reporting (reporting bias)Unclear riskProtocol was not obtained

Other biasUnclear riskTrial stopped early due to poor accrual of patients

Alberts 2008

MethodsThis was a multicentre, open-label, two-arm phase III randomised controlled trial

Trial duration: enrolment from January 29, 2002 to March 31, 2004. Trial duration not specified

Trial location: Europe, North and South America


ParticipantsNumber of participants: 847 participants (426 intervention, 421 control), 774 ovarian cancer (OC), 73 primary peritoneal carcinoma (PPC)

Inclusion criteria:

  • Previously untreated females with histologically confirmed epithelial ovarian cancer or PPC and FIGO Stage III or IV with either optimal or suboptimal residual disease following initial surgery
  • The majority of patients were Stage III O.C patients with 76.5% and 76.7% in the experimental group and comparison groups respectively. Stage IV 23.5% and 23.3% respectively
  • Randomisation within 12 weeks after initial surgery
  • Seven days or less between randomisation and first treatment dose
  • Adequate bone marrow, hepatic and renal function
  • Eastern Cooperative Oncology Group performance score of 0-2


Exclusion criteria: not stated


InterventionsIntervention:

Chemotherapy plus interferon-gamma 1b (IFN-γ 1b)

Chemotherapy included paclitaxel (175 mg/m2 over 3 hours) followed by carboplatin (AUC 6) every 3 weeks. A total of 6 cycles of chemotherapy were given unless disease progression or dose-limiting toxicity occurred or patients refused further treatment

Interferon therapy included 100μg administered subcutaneously, 3 times weekly (every other day; no more than 3 days in a 7-day period) continuously (including the 3 weeks following the last dose of chemotherapy)

Control:

Chemotherapy alone consisting of

Paclitaxel (175 mg/m2 over 3 hours) followed by carboplatin (AUC 6) every 3 weeks. A total of 6 cycles of chemotherapy were given unless disease progression or dose-limiting toxicity occurred or patients refused further treatment


Outcomes
  • Overall survival (OS): time (days) from the time of randomisation until death
  • Progression free survival (PFS): time (days) from randomisation until the earliest date of disease progression, death, or censoring
  • Treatment-failure free survival (TFFS): time (days) from randomisation until the earliest date of progressive disease, death, or the start of non-protocol carcinoma treatment for any reason
  • Adverse events (any, skin, blood, gastrointestinal, general, nervous system, musculoskeletal, infectious, psychiatric, metabolism, immune, investigations)


NotesEthics approval: this was not reported on

Informed consent: patients provided informed consent between January 29, 2002 and March 31, 2004

Funding: this was not reported on

Correspondence with authors: dalberts@azcc.arizona.edu on 3rd July 2012


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNot mentioned how randomisation was carried out

Allocation concealment (selection bias)Unclear riskNot reported on

Blinding of participants and personnel (performance bias)
All outcomes
Low riskOpen-label trial but unlikely to affect outcomes. Control group received chemotherapy alone

Blinding of outcome assessment (detection bias)
All outcomes
Low riskDisease progression was assessed by an endpoint review committee blinded to the treatment assignment using serial CT scans, MRIs, physical exams, and CA-125 levels

Incomplete outcome data (attrition bias)
All outcomes
High riskITT analysis was done

79% of participants adhered to treatment (i.e, undertook at least 5 out of 6 courses) in the treatment arm and 86% adhered in the control arm. 34% of adherent participants died in the intervention arm while 28% died in the control arm. 61% of non-adherent participants died in the intervention arm while 45% of non-adherent participants died in the control arm.

Selective reporting (reporting bias)Unclear riskProtocol was not available

Other biasUnclear riskStudy stopped early due to DSMB (data and safety monitoring board) recommendation - this was due to the study finding a statistically significant difference between treatment groups that crossed the pre-specified boundaries for inferiority and futility.

Bruzzone 1997

MethodsRandomised controlled trial

Trial duration: 4 years June 1990 to October 1992

Trial location: Italy (North West Oncology group)


ParticipantsNumber of participants: 111 randomised  (57 experimental group, 54 control)      

Inclusion criteria:

  • Patients with advanced epithelial ovarian cancer
  • Age between 18 and 75 years
  • ECOG performance status  0,1 or 2
  • Participant with FIGO Stage I/II, III, IV ovarian cancer in the intervention group to be 4%, 83% and 13% and the the control group patient in FIGO Stage III and IV were 86% and 14% respectively
  • Good renal, haematological, hepatic and cardiac function
  • More than 3 months life expectancy
  • Patients informed consent


Exclusion criteria:

  • Previous or concomitant malignancy
  • Extra-abdominal localisations of disease


InterventionsIntervention:

Intraperitoneal INF-alpha 25,000,000 U on day 1 followed by intraperitoneal carboplatin 400mg/m2 on day 2 every 28 days for 3 courses

Control:

Intraperitoneal carboplatin 400mg/m2 every 28 days


Outcomes
  • Overall survival
  • Progression free survival - assessment of PFS was first progression and death without a confirmed progression
  • Toxicity - leukopenia, anaemia, renal, neurologic and gastroenteric toxicity, flu-like syndrome


NotesEthics approval: not reported on

Informed consent: participants signed informed consent forms before enrolment into study

Funding: source of funding not reported on. Probably under auspices of North West Oncology Group

Correspondence with authors: National Institute for Cancer Research and Co-operative Centers of the North West Oncology Group on 3rd July 2012


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskRandomisation was performed using random number tables and specific lists of randomisation numbers

Allocation concealment (selection bias)Low riskTreatment allocation was conducted centrally by telephoning the trial office at the Cancer Institute whenever a patient was enrolled

 

Blinding of participants and personnel (performance bias)
All outcomes
Low riskBlinding of participants was not reported on but measured outcomes unlikely to be affected by lack of blinding as control group received chemotherapy only

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNot described

Incomplete outcome data (attrition bias)
All outcomes
Low riskLoss to follow-up low and similar in both groups (5/57 intervention, 5/54 control). Intention-to-treat analysis was also conducted

Selective reporting (reporting bias)Unclear riskTrial protocol not obtained

Other biasUnclear riskTrial stopped early due to due to toxicities and the higher costs in the interferon arm considering the absence of impressive survival advantage

Hall 2004

MethodsRandomised controlled trial

Trial duration: 7 years and 5 months, from February 1990 to July 1997

Trial location: 14 centres across the United Kingdom


ParticipantsNumber of participants: 300 randomised (interferon-149, control-151)

Inclusion criteria:

Patients had histologically proven epithelial ovarian cancer that showed no evidence of disease progression after post-operative chemotherapy.

The percentage of participants with FIGO stage I, II, III and IV ovarian cancer in the interferon group was 7%, 22%, 63% and 15% while in the chemotherapy group was 8%, 13%, 64% and 15% respectively

Exclusion criteria: not specified


InterventionsIntervention:

Interferon-alpha: INF-α 2a (Roferon-A, Roche) (4.5 mega-units subcutaneously 3 days per week). Interferon was continued until disease progression or in response to toxicity or patient request

Control:

No maintenance treatment


Outcomes
  • Overall survival (OS)
  • Progression free survival (PFS), definition was not given
  • Toxicity/adverse event (flu-like symptoms, fatigue, nausea/vomiting, neurological, dyspnoea, depression/anxiety, skin change/rash, alopecia, arthralgia/arthritis, insomnia, haematological, hepatic, injection site reaction, other, not stated)


NotesEthics approval: study was approved by the Local Research Ethics Commitee of each participating centre

Informed consent: written informed consent was obtained from patients prior to randomisation

Funding: not mentioned

Correspondence with authors: g.hall@leeds.ac.uk on date on 3rd July 2012


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNot described how randomisation was done

Allocation concealment (selection bias)Unclear riskNot mentioned

Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskNot described if participants were blinded to the treatment assigned. Control group did not receive any treatment

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNot described if outcome assessors were blinded to treatment assignment but inlikely to have any effect on the outcomes

Incomplete outcome data (attrition bias)
All outcomes
Low riskIntention-to-treat (ITT) analysis was done on all the patients. Eight patients (2 interferon and 6 observation) died without any follow-up visits). 144 of 149 participants in the interferon group received at least one injection

Selective reporting (reporting bias)Unclear riskProtocol was not available

Other biasLow riskNo reason to suspect other bias

Windbichler 2000

MethodsRandomised controlled trial

Trial duration: 7 years and 3 months, from December 1991 to March 1998

Trial location: 12 Austrian gynaecological and medical centres


ParticipantsNumber of participants: 148 randomized (75 intervention group, 73 control group)

Inclusion criteria:

  • Patients who had undergone primary surgical debulking of histologically confirmed invasive epithelial ovarian cancer in FIGO Stages Ic-III, with WHO performance status 0-2
  • The percentage of women with FIGO Stage Ic, II, III and IV ovarian cancer in the interferon group were 11%, 14%, 74% and 1% respectively while in the chemotherapy group were 16%, 9%, 69% and 6% respectively
  • Adequate renal function
  • Sufficient hepatic function
  • WBC > 3g/l, platelet count ≥ 100g/l
  • Age less than 75 years


Exclusion criteria:

Patients with concomitant severe cardiovascular disease, life expectancy of less than 3 months, recent second malignancy or history of thromboembolic disease


InterventionsIntervention:

Intraperitoneal treatment with interferon-gamma (IFN-γ) consisting of 0.1 mg subcutaneously on days 1,3,5, 15, 17 and 19 of each 28-day cycle PLUS standard chemotherapy given every 4 weeks consisting of 100mg/m2 cisplatin and 600mg/m2 cyclophosphamide

Control:

Standard chemotherapy given every 4 weeks consisting of 100mg/m2 cisplatin and 600mg/m2 cyclophosphamide


Outcomes
  • Overall survival (OS)
  • Progression free survival (PFS), PFS was defined as the interval between the initial surgery and last follow-up evaluation, diagnosis of progression or death from disease, whichever occurred first
  • Response
  • Toxicity (anaemia, neutropenia, thrombocytopenia, creatinine, bilirubin, SGOT, emesis, alopecia)


NotesEthics approval: study protocol was approved by the Ethical Committee of the University of Innsbruck Medical School as well as the respective committees of the other participating centres

Informed consent: all participants signed written consent forms before being enrolled

Funding: not mentioned

Correspondence with authors: To C Marth. Department of Obstetrics and Gynaecology, University Hospital, Anichstrasse 35, A-6020 Innsbruck, Austria 3rd July 2012


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskRandomisation lists were computer generated

Allocation concealment (selection bias)Low riskPatients were allocated to a treatment arm by the study centre by means of fax transmission

Blinding of participants and personnel (performance bias)
All outcomes
Low riskNot mentioned but unlikely to affect the study outcomes. Control group received chemotherapy only

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNot mentioned. Unlikely to affect the study as outcomes are objective. All slides were reviewed by one pathologist

Incomplete outcome data (attrition bias)
All outcomes
Low riskIntention-to-treat analysis was done. In the treatment group 6 of 65 patients discontinued due to disease progression. Of the remaining 59 participants, 32 completed 6 cycles of treatment. In the control group, 7 of the 68 participants discontinued due to disease progression. Of the remaining 61 patients, 39 completed 6 cycles of chemotherapy

Selective reporting (reporting bias)Unclear riskProtocol was not available

Other biasLow riskNo reason to suspect other bias

 
Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion

Berek 2000Not a randomised controlled trial

Cardamakis 1999Not a randomised controlled trial

Sumrit 1998Abstract or full article not found

 
Characteristics of studies awaiting assessment [ordered by study ID]
Kosmidis 1997

MethodsNot specified

Participants83 women with median age 56 years. 74% had stage III while 435 had serious and 25% had mucinous adenocarcinoma. 30% had an optimal operation with residual disease and treated with chemotherapy. Of the 86 women 44 had complete clinical remission (cCR) and they were randomised to receive either interferon-alpha 2b or observation alone

InterventionsIntervention:

Intraperitoneal interferon was given

Control:

Patients were observed

Outcomes
  • Overall survival
  • Feasibility of interferon
  • Tolerance of interferon

NotesThe full text article has been requested from authors but we have not received any response.

Zhyl'chuk 1998

MethodsNot specified

ParticipantsParticipants with different histologic forms of ovarian cancer

InterventionsAdjuvant interferon

OutcomesCA-125 levels

NotesThe full text article has been requested from authors but we have not received any response.

 
Comparison 1. Interferon versus observation alone

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Overall survival2370Hazard Ratio (Random, 95% CI)1.14 [0.84, 1.55]

 2 Progression-Free Survival2370Hazard Ratio (Random, 95% CI)0.99 [0.79, 1.24]

 3 Adverse event (flu-like symptoms)1293Risk Ratio (M-H, Random, 95% CI)2.25 [1.73, 2.91]

 4 Adverse event (fatigue)1293Risk Ratio (M-H, Random, 95% CI)1.54 [1.27, 1.88]

 5 Adverse event (nausea/ vomiting)1293Risk Ratio (M-H, Random, 95% CI)1.21 [0.91, 1.62]

 
Comparison 2. Interferon + chemotherapy versus chemotherapy alone

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Overall survival2244Hazard Ratio (Random, 95% CI)1.14 [0.74, 1.76]

 2 Progression-Free Survival2244Hazard Ratio (Random, 95% CI)1.43 [1.02, 2.00]

 3 Complete clinical response181Risk Ratio (M-H, Random, 95% CI)1.23 [0.87, 1.73]

 4 Adverse event (flu-like symptoms)2Risk Ratio (M-H, Random, 95% CI)Totals not selected

 5 Adverse event (fatigue)197Risk Ratio (M-H, Random, 95% CI)1.18 [0.82, 1.68]

 6 Adverse event (neurotoxicity)2230Risk Ratio (M-H, Random, 95% CI)0.87 [0.57, 1.33]

 7 Adverse event (alopecia)2230Risk Ratio (M-H, Random, 95% CI)0.96 [0.74, 1.23]

 8 Adverse event (anaemia)2230Risk Ratio (M-H, Random, 95% CI)1.13 [0.83, 1.55]

 
Summary of findings for the main comparison. Interferon + chemotherapy versus chemotherapy alone for women with advanced (Stage II-IV) epithelial ovarian cancer who have undergone surgery

Interferon + chemotherapy versus chemotherapy alone for women with advanced (Stage II-IV) epithelial ovarian cancer who have undergone surgery

Patient or population: Women with advanced (Stage II-IV) epithelial ovarian cancer who have undergone surgery
Settings: Secondary care settings
Intervention: Interferon + chemotherapy versus chemotherapy alone post-surgery for advanced ovarian surgery

OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of Participants
(trials)
Quality of the evidence
(GRADE)
Comments

Assumed riskCorresponding risk

ControlInterferon + Chemotherapy versus Chemotherapy alone

Overall survivalStudy populationHR 1.14
(0.74-1.76)
244
(2 trials)
⊕⊕⊝⊝
low1,4

318 per 1000378 per 1000
(295 to 483)

Moderate

309 per 1000368 per 1000
(287 to 470)

Progression-free survivalStudy populationHR 1.43
(1.02 to 2.00)
244
(2 trials)
⊕⊕⊝⊝
low,3,2

607 per 1000546 per 1000
(297 to 1000)

Moderate

603 per 1000543 per 1000
(295 to 1000)

Adverse event (flu-like symptoms)Study populationRR 6.49
(0.41 to 102.25)
230
(2 trials)
⊕⊕⊝⊝
low1,3

87 per 1000564 per 1000
(36 to 1000)

Moderate

100 per 1000649 per 1000
(41 to 1000)

Adverse event (fatigue)Study populationRR 1.17
(0.82 to 1.68)
97
(1 study)
⊕⊕⊝⊝
low3,4

511 per 1000597 per 1000
(419 to 858)

Moderate

511 per 1000598 per 1000
(419 to 858)

Adverse event (neurotoxicity)Study populationRR 0.87
(0.57 to 1.33)
230
(2 trials)
⊕⊕⊝⊝
low3, 4

270 per 1000235 per 1000
(154 to 359)

Moderate

244 per 1000212 per 1000
(139 to 325)

*The basis for the assumed risk (e.g. the median control group risk across trials) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; RR: Risk ratio

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

 1 High risk of bias due to study being stopped early
2 Significant heterogeneity between the trials
3 The method of randomisation was not described and allocation concealment was not mentioned
4 Small sample size, potentially underpowered study
 
Summary of findings 2. Interferon versus observation alone for women with advanced (Stage II-IV) epithelial ovarian cancer

Interferon versus observation alone for women with advanced (Stage II-IV) epithelial ovarian cancer

Patient or population: women with advanced (Stage II-IV) epithelial ovarian cancer who have undergone surgery
Settings: Secondary care settings
Intervention: Interferon versus observation alone post-surgery for advanced epithelial ovarian cancer

OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of Participants
(trials)
Quality of the evidence
(GRADE)
Comments

Assumed riskCorresponding risk

ControlInterferon versus observation alone

Overall survivalStudy populationHR 1.14
(0.84 to 1.55)
370
(2 trials)
⊕⊕⊝⊝1,3

low

140 per 100074 per 1000
(35 to 153)

Moderate

306 per 1000178 per 1000
(88 to 329)

Progression-free survivalStudy populationHR 0.99
(0.79 to 1.24)
370
(2 trials)
⊕⊕⊝⊝
low1,2

571 per 1000629 per 1000
(429 to 920)

Moderate

571 per 1000628 per 1000
(428 to 919)

Adverse event (flu-like symptoms)Study populationRR 2.25
(1.73 to 2.91)
293
(1 study)
⊕⊕⊝⊝
low1,2

315 per 1000710 per 1000
(546 to 918)

Moderate

315 per 1000709 per 1000
(545 to 917)

Adverse event (fatigue)Study populationRR 1.54
(1.27 to 1.88)
293
(1 study)
⊕⊕⊝⊝

low1,2

477 per 1000734 per 1000
(605 to 896)

Moderate

477 per 1000735 per 1000
(606 to 897)

Adverse event (nausea/ vomiting)Study populationRR 1.21
(0.91 to 1.62)
293
(1 study)
⊕⊕⊝⊝
low1,2

349 per 1000422 per 1000
(318 to 565)

Moderate

349 per 1000422 per 1000
(318 to 565)

*The basis for the assumed risk (e.g. the median control group risk across trials) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; RR: Risk ratio; OR: Odds ratio

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

 1Method of randomisation and allocation concealment were not reported on resulting in a potential high risk of selection bias. Participants were not blinded to the treatment which may have affected the performance of the control group resulting in a potentially high risk of performance bias.
2 Small sample size, potentially underpowered study
3 Imprecise effect estimate as evidenced by wide confidence interval.
 
Table 1. Table 1: FIGO staging for ovarian cancer

STAGE IThe cancer is limited to the ovaries

 

            IALimited to one ovary and the outer ovarian capsule is not ruptured. There is no tumor on the external surface of the ovary and there is no ascites and/or the washings are negative

            IBCancer is present in both ovaries, but the outer capsule is intact and there is no tumor on external surface. There is no ascites and the washings are negative

           ICThe cancer is either Stage IA or IB level but the capsule is ruptured or there is tumor on the ovarian surface or malignant cells are present in ascites or washings

  STAGE   IICancer involves one or both ovaries with spread to other pelvic organs or surfaces

               IIAExtension or implants onto the uterus and/or fallopian tube. The washings are negative washings and there is no ascites

              IIBExtension or implants onto other pelvic tissues. The washings are negative and there is no ascites

              IICPelvic extension or implants like Stage IIA or IIB but with positive pelvic washings

    STAGE III     Cancer spread outside the pelvis to the abdominal area, including metastases to liver surface

             IIIATumor is grossly confined to the pelvis but with micro-scopic peritoneal metastases beyond pelvis to abdominal peritoneal surfaces or the omentum

           IIIBSame as IIIA but with macro-scopic peritoneal or omental metastases beyond pelvis less than 2 cm in size

           IIICSame as IIIA but with peritoneal or omental metastases beyond pelvis, larger than 2 cm or lymph node metastases to inguinal, pelvic, or para-aortic areas

      STAGE IV Metastases or spread to the liver or outside the peritoneal cavity to areas such as the chest or brain