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BMJ Clinical Evidence logoLink to BMJ Clinical Evidence
. 2009 Jan 16;2009:0816.

Ovarian cancer (advanced)

Sean Kehoe 1,#, Jo Morrison 2,#
PMCID: PMC2907795  PMID: 19445772

Abstract

Introduction

Ovarian cancer is the fourth most common cause of cancer deaths in the UK. The 5-year relative survival rate in the UK at diagnosis for women aged 15-39 years is nearly 70%. In comparison, it is only 12% for women diagnosed aged over 80 years.

Methods and outcomes

We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of surgical treatments for ovarian cancer that is advanced at first presentation? What are the effects of platinum-based chemotherapy for ovarian cancer that is advanced at first presentation? What are the effects of taxane-based chemotherapy for ovarian cancer that is advanced at first presentation? What are the effects of intraperitoneal chemotherapy for ovarian cancer that is advanced at first presentation? We searched: Medline, Embase, The Cochrane Library, and other important databases up to September 2007 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).

Results

We found 31 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.

Conclusions

In this systematic review we present information relating to the effectiveness and safety of the following interventions: adding taxanes to platinum-based chemotherapy, carboplatin plus a taxane, cisplatin plus a taxane, combination or single-agent platinum-based chemotherapy, docetaxel, intravenous and intraperitoneal chemotherapy, interval debulking, paclitaxel, primary surgery, and second-look surgery.

Key Points

Ovarian cancer is the fourth most common cause of cancer deaths in the UK.

  • Incidence rises with age, and peaks in the seventh and eighth decades of life.

  • Risk factors include family history of ovarian cancer, increasing age, and low parity. Risks are reduced by using the oral contraceptive pill for more than 5 years, tubal ligation, hysterectomy, breastfeeding, increased age at menarche, decreased age at menopause, and use of NSAIDs.

  • In the UK, the 5-year relative survival rate at diagnosis for women aged 15-39 years is nearly 70%. In comparison, it is only 12% for women diagnosed over 80 years of age.

Standard treatment for advanced ovarian cancer is primary surgical debulking, followed by chemotherapy.

  • We found no direct evidence on the effects of primary surgery versus no surgery, or primary surgery plus chemotherapy versus surgery or chemotherapy alone.

  • Although we found no direct evidence, subgroup analysis comparing groups by the degree to which maximal surgical debulking was acheived or not, suggests that maximal surgical cytoreduction at primary surgery is strongly associated with improved survival in advanced ovarian cancer.

  • Subsequent debulking and second-look surgery seem unlikely to improve survival, especially if initial surgery achieved optimal cytoreduction.

Platinum-based regimens are now standard first-line chemotherapy and have been shown to be beneficial in prolonging survival compared with non-platinum-based regimens.

  • Platinum compounds seem to be the main beneficial agent, with little additional survival benefit from adding non-platinum (excluding taxanes) chemotherapeutic agents to platinum.

  • Carboplatin is as effective as cisplatin in prolonging survival, but with less-severe adverse effects.

Taxanes may increase survival if added to platinum chemotherapy compared with platinum-based regimens alone, but studies have given conflicting results.

  • One RCT suggests paclitaxel is as effective at prolonging survival as docetaxel when combined with a platinum drug.

Platinum-based chemotherapy can also be delivered directly into the intraperitoneal cavity, as well as by the intravenous route.

We found limited evidence that intraperitoneal platinum-based chemotherapy may increase survival compared with intravenous administration but at the cost of increased adverse effects, both those associated with the use of an intraperitoneal catheter and from increased doses of chemotherapy.

  • Any benefit seen with intraperitoneal rather than intravenous administration may be due to different chemotherapy doses, rather than the route of administration.

Limited evidence suggests that consolidation treatment given intraperitoneally does not confer any survival benefit compared with no further treatment in women who have undergone primary surgery and chemotherapy and who have no disease at second-look laparotomy.

  • However, consolidation treatment may be associated with increased adverse effects.

About this condition

Definition

Ovarian tumours are classified according to the assumed cell type of origin (surface epithelium, stroma, or germ cells). Epithelial tumours account for over 90% of ovarian cancers. These can be further grouped into histological types (serous, mucinous, endometroid, and clear cell). Epithelial ovarian cancer is staged using the FIGO classification (see table 1 ). This review is limited to first-line treatment in women with advanced (FIGO stage 2-4) invasive epithelial ovarian cancer at first presentation.

Table 1.

FIGO staging for carcinoma of the ovary.

Stage Criteria
1 Growth limited to the ovaries
1A Growth limited to one ovary, no malignant ascites present, capsule intact, no surface tumour
1B Growth limited to both ovaries, no malignant ascites present, capsule intact, no surface tumour
1C Growth limited to one or both ovaries but with a ruptured capsule, tumour on the surface, malignant ascites, or positive peritoneal washings
2 Growth involving one or both ovaries, with pelvic extension
2A Extension, metastases, or both to the uterus, fallopian tubes, or both
2B Extension to other pelvic tissues
2C Stage 2A or 2B with a ruptured capsule, tumour on the surface, malignant ascites, or positive peritoneal washings
3 Tumour involving one or both ovaries with peritoneal implants outside the pelvis and/or positive retroperitoneal or inguinal nodes. Tumour is limited to the true pelvis, but with histologically proved malignant extension to small bowel or omentum. Surface liver metastases equals stage 3
3A Tumour grossly limited to the true pelvis with negative nodes, but with histologically confirmed microscopic seeding of the abdominal peritoneal surfaces
3B Tumour of one or both ovaries with histologically confirmed implants of abdominal peritoneal surfaces, less than 2 cm in diameter, nodes are negative
3C Abdominal implants greater than 2 cm in diameter, positive retroperitoneal or inguinal nodes, or both
4 Growth involving one or both ovaries, with distant metastases. If pleural effusion is present, there must be positive cytological findings to allot a case to stage 4. Parenchymal liver metastases equates to stage 4
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Incidence/ Prevalence

The worldwide incidence of ovarian cancer according to the GLOBOCAN database was 204,499 cases in 2002. There is a worldwide variation: the highest rates are in Lithuania, Denmark, and Estonia, and the lowest rates are in Egypt, Malawi, and Mali. This variation may be due to differences in reproductive practice, use of the oral contraceptive pill, breastfeeding habits, and age of menarche and menopause. The incidence of ovarian cancer rises steadily with increasing age and peaks in the seventh and eighth decades of life. In the UK, it is the fourth most common cause of cancer deaths, with about 6900 new cases diagnosed annually, and 4600 deaths from the disease each year. The incidence of ovarian cancer seems to be stabilising in some other countries, and declining in some resource-rich countries (Finland, Denmark, New Zealand, and the USA).

Aetiology/ Risk factors

Risk factors include family history of ovarian cancer, increasing age, and low parity. More controversial risk factors are subfertility and use of fertility drugs. Use of the oral contraceptive pill for more than 5 years reduces the risk by 30-40%. Other factors associated with risk reduction are tubal ligation, hysterectomy, breastfeeding, increasing age of menarche, decreasing age of menopause, and use of NSAIDs.

Prognosis

Survival rates vary according to age, disease stage, and residual tumour after surgery. The most important determination of survival seems to be disease stage at diagnosis. Early disease stage has a 5-year survival rate of greater than 70%, but for those diagnosed with advanced disease stage, it is about 15%. Younger women survive longer than older women, even after adjustments for general life expectancy. In the UK, the 5-year relative survival rate at diagnosis for women aged 15-39 years is nearly 70%. It is only 12% for women diagnosed over 80 years of age.

Aims of intervention

To prolong survival and reduce disability; to minimise adverse effects of treatment.

Outcomes

Mortality; disease-free survival; disease-related symptoms; quality of life; adverse effects of treatment.

Methods

Clinical Evidence search and appraisal September 2007. The following databases were used to identify studies for this systematic review: Medline 1966 to September 2007, Embase 1980 to September 2007, and The Cochrane Database of Systematic Reviews and Cochrane Central Register of Controlled Clinical Trials 2007, Issue 3. Additional searches were carried out using these websites: NHS Centre for Reviews and Dissemination (CRD) — for Database of Abstracts of Reviews of Effects (DARE) and Health Technology Assessment (HTA), Turning Research into Practice (TRIP), and NICE. Abstracts of the studies retrieved were assessed independently by an information specialist using pre-determined criteria to identify relevant studies. Study design criteria for evaluation in this review were: published systematic reviews and RCTs in any language, at least single blinded, and containing more than 20 individuals of whom more than 80% were followed up. There was no minimum length of follow-up required to include studies. We excluded all studies described as "open", "open label", or not blinded unless blinding was impossible. In addition we use a regular surveillance protocol to capture harms alerts from organisations such as the FDA and the UK Medicines and Healthcare products Regulatory Agency (MHRA), which are added to the review as required. We have performed a GRADE evaluation of the quality of evidence for interventions included in this review (see table ). To aid readability of the numerical data in our reviews, we round many percentages to the nearest whole number. Readers should be aware of this when relating percentages to summary statistics such as RRs and ORs.

Table.

GRADE evaluation of interventions for ovarian cancer

Important outcomes Mortality, adverse effects
Number of studies (participants) Outcome Comparison Type of evidence Quality Consistency Directness Effect size GRADE Comment
What are the effects of surgical treatments for advaced ovarian cancer at first presentation?
3 (781) Mortality Interval debulking surgery plus chemotherapy v chemotherapy alone 4 0 –1 0 0 Moderate Consistency point deducted for conflicting results
1 (102) Mortality Second-look surgery v watchful waiting 4 –2 0 0 0 Low Quality points deducted for sparse data and incomplete reporting of results
What are the effects of platinum-based chemotherapy for advanced ovarian cancer at first presentation?
3 (1798) Mortality Carboplatin plus taxane v cisplatin plus taxane 4 0 0 0 0 High
3 (1798) Adverse effects Carboplatin plus taxane v cisplatin plus taxane 4 –1 –1 0 0 Low Quality points deducted for incomplete reporting of results. Consistency point deducted for conflicting results for some adverse effects
at least 11 (at least 3298) Mortality Combination platinum-based chemotherapy (non-taxane) v single-agent platinum chemotherapy 4 –1 0 0 0 Moderate Quality point deducted for incomplete reporting of results
What are the effects of taxane-based chemotherapy for advanced ovarian cancer at first presentation?
5 (3685) Mortality Taxane plus platinum-based regimen v platinum-based non-taxane regimen or platinum alone 4 0 –1 –1 0 Low Consistency point deducted for conflicting results. Directness point deducted for different interventions
1 (1077) Mortality Paclitaxel plus platinum v docetaxel plus platinum 4 0 0 0 0 High
What are the effects of intraperitoneal chemotherapy for advanced ovarian cancer at first presentation?
At least 8 (1819) Mortality Intraperitoneal platinum-based chemotherapy v intravenous platinum-based chemotherapy 4 0 0 0 –2 Low Directness point deducted for heterogeneity among included RCTs, and limited generalisability of included chemotherapy regimens compared with current standard therapy
At least 8 (1819) Adverse effects Intraperitoneal platinum-based chemotherapy v intravenous platium-based chemotherapy 4 0 0 0 –2 Low Directness point deducted for heterogenity among included RCTs, and limited generalisability of included chemotherapy regimens compared with current standard therapy
4 (875) Mortality Intraperitoneal consolidation treatment following first-line treatment v no further treatment 4 –2 0 0 0 Low Quality points deducted for incomplete reporting of results and premature discontinuation of RCTs
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Type of evidence: 4 = RCT. Consistency: similarity of results across studies. Directness: generalisability of population or outcomes. Effect size: based on relative risk or odds ratio.

Glossary

Debulking

is removal of a major proportion of the tumour. Initial and primary debulking both refer to surgery performed at first presentation.

High-quality evidence

Further research is very unlikely to change our confidence in the estimate of effect.

Interval debulking

is a second operation to remove residual tumour after a specified number of cytotoxic chemotherapy cycles, which is then followed by further chemotherapy.

Low-quality evidence

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.

Moderate-quality evidence

Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.

Routine second-look surgery

is an operation to assess the response to cytotoxic chemotherapy in women who have already had primary surgery.

Disclaimer

The information contained in this publication is intended for medical professionals. Categories presented in Clinical Evidence indicate a judgement about the strength of the evidence available to our contributors prior to publication and the relevant importance of benefit and harms. We rely on our contributors to confirm the accuracy of the information presented and to adhere to describe accepted practices. Readers should be aware that professionals in the field may have different opinions. Because of this and regular advances in medical research we strongly recommend that readers' independently verify specified treatments and drugs including manufacturers' guidance. Also, the categories do not indicate whether a particular treatment is generally appropriate or whether it is suitable for a particular individual. Ultimately it is the readers' responsibility to make their own professional judgements, so to appropriately advise and treat their patients.To the fullest extent permitted by law, BMJ Publishing Group Limited and its editors are not responsible for any losses, injury or damage caused to any person or property (including under contract, by negligence, products liability or otherwise) whether they be direct or indirect, special, incidental or consequential, resulting from the application of the information in this publication.

Contributor Information

Sean Kehoe, Nuffield Department of Obstetrics and Gynaecology, Women's Centre, John Radcliffe Hospital, Oxford, UK.

Jo Morrison, Nuffield Department of Obstetrics and Gynaecology, Women's Centre, John Radcliffe Hospital, Oxford, UK.

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BMJ Clin Evid. 2009 Jan 16;2009:0816.

Primary surgery

Summary

We found no direct information about whether primary surgery is better than no active treatment in women with advanced ovarian cancer. We found no direct information about the effects of primary surgery plus chemotherapy compared with surgery or chemotherapy alone.

Benefits

Primary surgery alone versus no surgery:

We found four systematic reviews (search date 2002; search date 2005;search date 2006;search date not stated) which identified no RCTs (see comment below).

Primary surgery plus chemotherapy versus surgery alone:

We found no systematic review or RCTs.

Primary surgery plus chemotherapy versus chemotherapy alone:

We found no systematic review or RCTs.

Harms

Primary surgery alone versus no surgery:

The four systematic reviews gave no information on adverse effects.

Primary surgery plus chemotherapy versus surgery alone:

We found no RCTs.

Primary surgery and chemotherapy versus chemotherapy alone:

We found no RCTs.

Comment

Two systematic reviews identified observational studies assessing the role of maximal debulking surgery. One review, which included 12 studies (one of high quality, 11 of low quality) concluded that there are no data to support the role of cytoreductive surgery and that the beneficial effect of cytoreductive surgery is based on "indirect documentation from uncontrolled, retrospective patient groups from which no firm conclusions could generally be drawn." The second review performed linear regression models on cohort studies (22 cohorts of 835 people) and concluded that each 10% increase in the proportion of people in each cohort undergoing maximal interval cytoreduction was associated with a 1.9 - month increase in median survival time (95% CI 0.23 to 3.5 months; P = 0.027). The definition of maximal cytoreduction has changed over time from no tumour nodules over 2 cm in diameter, to now being no residual macroscopic disease following surgery.

Clinical guide:

We found no RCTs directly testing the effects of primary surgery or no surgery in ovarian cancer. The available evidence supporting surgery comes from clinical trials of chemotherapy for ovarian cancer. Subgroup analyses comparing groups by the degree to which maximal surgical debulking was achieved or not, suggest that maximal surgical cytoreduction at primary surgery is strongly associated with improved survival in advanced ovarian cancer. However, rates of achieving maximal cytoreduction vary considerably between studies. There are ongoing trials addressing surgery timing, but none that have randomised to no surgery. Current standard treatment should include surgery with the aim of maximal debulking until evidence is available to show otherwise.

Substantive changes

Primary surgery Three systematic reviews added which found no relevant RCTs. Background data added to comments section of the option. Categorisation of "primary surgery" unchanged (Unknown effectiveness).

BMJ Clin Evid. 2009 Jan 16;2009:0816.

Interval debulking plus chemotherapy (after primary surgery)

Summary

MORTALITY Interval debulking surgery plus chemotherapy compared with chemotherapy alone: We don't know whether interval debulking surgery plus chemotherapy improves overall survival or progression-free survival compared with chemotherapy alone in women with advanced ovarian cancer, who have at least 1 cm residual intraperitoneal tumour after primary surgery, and no disease progression after an initial three to five cycles of chemotherapy ( moderate-quality evidence ).

Benefits

Interval debulking surgery plus chemotherapy versus chemotherapy alone:

We found one systematic review (search date 2006)which identified three RCTs comparing interval debulking plus chemotherapy versus chemotherapy alone in women with advanced ovarian cancer. The review did not pool data. All women included in the RCTs had at least 1 cm residual intraperitoneal tumour after primary surgery, and no disease progression after an initial three to five cycles of chemotherapy (see table 2 ). Those considered fit for surgery were randomised to have interval debulking plus chemotherapy, or chemotherapy alone. Interval debulking included total abdominal hysterectomy, bilateral salpingo-oophorectomy, and omentectomy (if it had not been previously performed). The first included RCT (278 women) found a significant increase in progression-free and overall survival with interval debulking plus chemotherapy compared with no interval debulking (median progression-free survival: 18 months with interval debulking plus chemotherapy v 13 months with chemotherapy alone; P = 0.01; median overall survival: 26 months with interval debulking plus chemotherapy v 20 months with chemotherapy alone; P = 0.01; adjusted HR for death for interval debulking plus chemotherapy v chemotherapy alone 0.67, 95% CI 0.50 to 0.90). The second included RCT (79 women) found no significant difference between interval debulking plus chemotherapy and chemotherapy alone in median overall survival (see table 2 ). The third included RCT (424 women) found no significant difference in progression-free and overall survival between interval debulking plus chemotherapy compared with chemotherapy alone (progression-free survival: RR 1.07, 95% CI 0.87 to 1.31; P = 0.54; overall survival: RR for mortality 0.99, 95% CI 0.79 to 1.24; P = 0.92). A follow-up study of this RCT compared survival outcomes, including quality-of-life scores, for the two treatments. Quality of life was measured using a multidimensional questionnaire (Functional Assessment of Cancer Therapy-Ovarian) developed for women with ovarian cancer. Questions were scored using a 5-point response scale (0 = not at all to 4 = very much). The RCT found similar improvements in quality-of-life scores for both interval debulking surgery plus chemotherapy and chemotherapy alone (significance not assessed). However, there were significant improvements in quality-of-life scores from baseline for both interventions at 6 months' follow-up (no other data reported; P less than 0.001), which was sustained at 12 months (reported as significant; P value not reported).

Table 2.

Details of RCTs comparing interval debulking plus chemotherapy versus chemotherapy alone.

Ref Regimen FIGO stage and population Size of residual tumour after initial surgery Median overall survival Harms
  Debulking surgery (including TAH, BSO, and omentectomy, if not already done) plus cisplatin 75 mg/m2 plus cyclophosphamide 750 mg/m2 vcisplatin 75 mg/m2 plus cyclophosphamide 750 mg/m2 319 women aged less than 75 years Stage 2B–4 Mean follow-up: 42 months IDS within 28 days of third cycle of chemotherapy No tumour progression after first 3 cycles of chemotherapy Greater than 1 cm 26 months with IDS v 20 months without IDS; P = 0.012 Surgery group: 5% intraoperative complications; 14% postoperative complications Non-surgery group: no information on adverse effects reported
  Debulking surgery (including TAH, BSO, and omentectomy, if not already done) plus chemotherapy vChemotherapy alone: either cisplatin 75 mg/m2 plus cyclophosphamide 750 mg/m2 for 8 cycles or cisplatin 75 mg/m2 plus doxorubicin 50 mg/m2 plus bleomycin 50 mg/m2 for 3 cycles plus cyclophosphamide 0.5–2.5 mg/m2 for up to 5 cycles 79 women Stage 2–4 Mean follow-up: 48 months IDS within median of 13 weeks after primary surgery No tumour progression or static disease after first 3 cycles of chemotherapy Greater than 2 cm 15 months with IDS v 12 months without IDS; HR 0.71, 95% CI 0.44 to 1.13 Surgery group: 54% had complications Non-surgery group: no information on adverse effects
  Debulking surgery (including TAH, BSO, and omentectomy, if not already done) plus cisplatin 75 mg/m2 plus paclitaxel 135 mg/m2 vcisplatin 75 mg/m2 plus paclitaxel 135 mg/m2 424 women Stage 3–4 initially (stage 4 patients excluded towards end of recruitment period) Mean follow-up: 46.6 months with IDS v47.6 months without IDS IDS within 6 weeks of third cycle of chemotherapy No tumour progression after first 3 cycles of chemotherapy Greater than 1 cm intraperitoneal, but less than 1 cm extraperitoneal 33.9 months with IDS v 33.7 months without IDS; P = 0.92 Peripheral neuropathy (grade 2 or greater): 35/216 (16%) with IDS v 54/208 (26%) without IDS; P = 0.01 Gastrointestinal (grade 3– 4): 7% with IDS v 4% without IDS; absolute numbers not reported; P value not reported Cardiorespiratory: 5/216 (3%) with IDS v 1/208 (0.5%) without IDS; P value not reported
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BSO, bilateral salpingo-oophorectomy; IDS, interval debulking surgery; TAH, total abdominal hysterectomy.

Harms

Interval debulking surgery plus chemotherapy versus chemotherapy alone:

The systematic review did not report on harms. The first included RCT found that 5% of women who had interval debulking plus chemotherapy had intraoperative complications, and 14% had postoperative complications (see table 2 ). The complication rate was considered similar to that of primary surgery. The second included RCT found that, of 26 women who had interval debulking, 11 received a blood transfusion, two developed intestinal fistulae, and one developed DVT. The third included RCT found a higher incidence of gastrointestinal, cardiovascular, and respiratory adverse effects with interval debulking plus chemotherapy compared with chemotherapy alone (see table 2 ). However, there was a significantly lower rate of grade 2 or higher peripheral neuropathy with interval debulking plus chemotherapy compared with chemotherapy alone (see table 2 ). This difference may have been due to the brief respite from chemotherapy after surgery. In two women, study treatment after randomisation may have contributed to the cause of death (1 developed renal insufficiency and the other developed pneumonia and respiratory failure). The follow-up RCT found a significant reduction in neurotoxicity at 6 months with interval debulking plus chemotherapy compared with chemotherapy alone (61/159 [38%] with interval debulking plus chemotherapy v 87/161 [54%] with chemotherapy alone; P = 0.012). However, this difference was not significant 12 months after surgery (38/132 [29%] with interval debulking plus chemotherapy v 49/154 [32%] with chemotherapy alone; P = 0.542).

Comment

Clinical guide:

Interval debulking surgery could be beneficial in situations where optimal debulking is not achieved at primary surgery. However, if initial surgery was optimal, there is no evidence that interval surgery improves survival. Interval debulking surgery increases the risks of intraoperative and postoperative complications.

Substantive changes

Interval debulking plus chemotherapy (after primary surgery) Option title clarified and changed from "interval debulking" to "interval debulking plus chemotherapy (after primary surgery)". One systematic review added which did not pool data and which identified three already-reported RCTs.No new data added. Categorisation of "interval debulking in women who have residual tumours after primary surgery" unchanged (Unlikely to be beneficial).

BMJ Clin Evid. 2009 Jan 16;2009:0816.

Second-look surgery (following primary surgery and chemotherapy)

Summary

MORTALITY Second-look surgery compared with watchful waiting: Second-look surgery (followed by salvage chemotherapy if necessary) may not improve overall survival at 5 years compared with watchful waiting in women with advanced ovarian cancer who are thought to be in complete remission following primary surgery and first-line chemotherapy ( low-quality evidence ).

Benefits

Second-look surgery versus watchful waiting:

We found one RCT in women with advanced ovarian cancer (102 women in complete remission after primary debulking surgery and first-line chemotherapy consisting of cisplatin plus cyclophosphamide or doxorubicin plus cyclophosphamide every 3 weeks for 5 cycles) comparing second-look surgery (including visual inspection and biopsy) versus watchful waiting. Complete remission before trial entry was confirmed by clinical and biochemical assessment, computed tomography, and laparoscopy. Of the women having second look surgery, 11/46 (24%) women had positive macroscopic or microscopic findings at laparotomy and biopsy that were not detectable at laparoscopy. These women were given salvage chemotherapy with 5-fluorouracil plus cisplatin. The RCT found no significant difference between second-look surgery and watchful waiting in overall survival after 60 months (65% with second-look laparotomy v 78% with watchful waiting; absolute numbers not reported; P = 0.14).

Harms

Second-look surgery versus watchful waiting:

The RCT gave no information on harms.

Comment

Clinical guide:

There is no evidence that second-look surgery alters survival. The role of second-look surgery would seem best placed within the context of pertinent clinical trials.

Substantive changes

No new evidence

BMJ Clin Evid. 2009 Jan 16;2009:0816.

Carboplatin plus taxane versus cisplatin plus taxane

Summary

MORTALITY Carboplatin plus taxane compared with cisplatin plus taxane: Carboplatin plus paclitaxel and cisplatin plus paclitaxel seem to be equally effective at improving overall survival and median progression-free survival in women with advanced ovarian cancer who have undergone primary surgery ( high-quality evidence ). ADVERSE EFFECTS Carboplatin plus taxane compared with cisplatin plus taxane: Carboplatin plus paclitaxel may be associated with less gastrointestinal toxicity and fewer metabolic and genitourinary adverse effects compared with cisplatin plus paclitaxel, but may be associated with more haematological adverse effects ( low-quality evidence ).

Benefits

Carboplatin plus taxane versus cisplatin plus taxane:

We found no systematic review. We found three RCTs comparing carboplatin (5.0–7.5 AUC) plus paclitaxel (175–185 mg/m2) versus cisplatin (75 mg/m2) plus paclitaxel (135–185 mg/m2) as first-line treatment of women with advanced ovarian cancer (see table 3 ). All the women had undergone primary surgery. Each RCT found no significant difference between carboplatin plus paclitaxel and cisplatin plus paclitaxel in median progression-free survival (which ranged from 16–21 months) and overall survival (which ranged from 30–57 months). However, one RCT found that quality-of-life scores at the end of treatment were significantly better in women taking carboplatin plus paclitaxel than in those taking cisplatin plus paclitaxel (65.25 with carboplatin plus paclitaxel v 51.97 with cisplatin plus paclitaxel; difference –13.28, 95% CI –18.88 to –7.68).

Table 3.

RCTs comparing carboplatin plus taxane regimens versus cisplatin plus taxane regimens.

Ref Regimen FIGO stage and population Median survival % with adverse effects
  Carboplatin 5 AUC plus paclitaxel 175 mg/m2 vcisplatin 75 mg/m2 plus paclitaxel 175 mg/m2 208 women FIGO stage 2B–4 Median follow-up: 37 months Progression-free survival: 16 months with carboplatin plus taxane v 16 months with cisplatin plus taxane; HR 1.07, 95% CI 0.78 to 1.48 Overall survival: 32 months with carboplatin plus taxane v 30 months with cisplatin plus taxane; HR 0.85, 95% CI 0.59 to 1.24 Gastrointestinal (grade 2–3):26% with carboplatin plus taxane v 57% with cisplatin plus taxane; P less than 0.01 Haematological (grade 3–4):Platelets: 6% with carboplatin plus taxane v 1% with cisplatin plus taxane; P less than 0.01 Granulocytes: 40% with carboplatin plus taxane v 23% with cisplatin plus taxane; P less than 0.01 Neurological (grade 3–4):2% with carboplatin plus taxane v 6% with cisplatin plus taxane; P = 0.10
  Carboplatin 7.5 AUC plus paclitaxel 175 mg/m2 vcisplatin 75 mg/m2 plus paclitaxel 135 mg/m2  * 792 women FIGO stage 3 Less than 1 cm residual disease 90% follow-up for 48 months Progression-free survival: 20.7 months with carboplatin plus taxane v 19.4 months with cisplatin plus taxane; RR 0.88, 95% CI 0.75 to 1.03 Overall survival: 57.4 months with carboplatin plus taxane v 48.7 months with cisplatin plus taxane; RR 0.84, 95% CI 0.70 to 1.02 Gastrointestinal (grade 2–3):10% with carboplatin plus taxane v 23% with cisplatin plus taxane; P less than 0.05 Haematological (grade 3–4):Thrombocytopenia: 39% with carboplatin plus taxane v 5% with cisplatin plus taxane; P less than 0.05 Granulocytopenia: 90% with carboplatin plus taxane v 93% with cisplatin plus taxane; reported as not significant; P value not reported Leukopenia: 59% with carboplatin plus taxane v 63% with cisplatin plus taxane; P less than 0.05 Neurological (grade 3–4):7% with carboplatin plus taxane v 8% with cisplatin plus taxane; reported as not significant; P value not reported Metabolic:2% with carboplatin plus taxane v 8% with cisplatin plus taxane; P less than 0.05 Genitourinary:1% with carboplatin plus taxane v 3% with cisplatin plus taxane; P less than 0.05
  Carboplatin 6 AUC plus paclitaxel 185 mg/m2 vcisplatin 75 mg/m2 plus paclitaxel 185 mg/m2 798 women FIGO stage 2B–4 Median follow-up 48.5–49.9 months Progression-free survival: 17.2 months with carboplatin plus taxane v 19.1 months with cisplatin plus taxane; HR 1.05, 95% CI 0.89 to1.23 Overall survival: 43.3 months with carboplatin plus taxane v 44.1 months with cisplatin plus taxane; HR 1.05, 95% CI 0.87 to1.26 Gastrointestinal (grade 2–3):Nausea: 6% with carboplatin plus taxane v 14% with cisplatin plus taxane; difference 8.4, 95% CI 4.2 to 12.6 Vomiting: 3% with carboplatin plus taxane v 10% with cisplatin plus taxane; difference 7.6, 95% CI 4.1 to 11.1 Haematological (grade 3–4):Platelets: 13% with carboplatin plus taxane v 1% with cisplatin plus taxane; P less than 0.05 Neutrophils: 37% with carboplatin plus taxane v 22% with cisplatin plus taxane; P less than 0.05 Leukocytes: 32% with carboplatin plus taxane v 11% with cisplatin plus taxane; P less than 0.05 Peripheral sensory neuropathy:7% with carboplatin plus taxane v 14% with cisplatin plus taxane; P less than 0.05 Oedema:2% with carboplatin plus taxane v 0 with cisplatin plus taxane; P less than 0.05 Quality-of-life scores:65.25 with carboplatin plus taxane v 51.97 with cisplatin plus taxane; difference –13.28, 95% CI –18.88 to –7.68
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*Note different doses of paclitaxel in the two groups.

Harms

Carboplatin plus taxane versus cisplatin plus taxane:

All three RCTs found that gastrointestinal adverse effects, such as nausea and vomiting, were significantly decreased with carboplatin-based regimens compared with cisplatin-based regimens (see table 3 ). However, haematological adverse effects, especially thrombocytopenia and leukopenia, significantly increased with carboplatin plus paclitaxel compared with cisplatin plus paclitaxel (see table 3 ). One RCT found a significant decrease in metabolic and genito-urinary adverse effects with carboplatin plus paclitaxel compared with cisplatin plus paclitaxel (see table 3 ). One RCT found a significant decrease in peripheral sensory neuropathy, and a significant increase in oedema with the carboplatin-based regimen compared with the cisplatin-based regimen.

Comment

Clinical guide:

Carboplatin is used routinely in women with advanced ovarian cancer, reflecting similar efficacy but different toxicity compared with cisplatin. Platinum-based regimens are now standard first-line chemotherapy, and have been shown to be beneficial in prolonging survival compared with non-platinum-based regimens.

Substantive changes

No new evidence

BMJ Clin Evid. 2009 Jan 16;2009:0816.

Combination platinum-based chemotherapy (non-taxane) versus single-agent platinum chemotherapy

Summary

MORTALITY Combination platinum-based chemotherapy (non-taxane) compared with single-agent platinum chemotherapy: Combination platinum-based, non-taxane chemotherapy seems to be no more effective than single-agent platinum based chemotherapy at improving survival ( moderate-quality evidence ).

Benefits

Combination platinum-based regimen (non-taxane) versus single-agent platinum:

We found two systematic reviews (search date 1998, 9 RCTs, 1095 women with advanced ovarian cancer;search date 2006, 11 RCTs, 3928 women) comparing a combination regimen of platinum plus non-platinum (excluding taxanes) chemotherapy agents with single-agent platinum chemotherapy, which used different data sources and provided slightly different analysis. We found no subsequent RCTs. The first review found no significant difference between treatments for risk of death (9 RCTs, 1095 women, HR 0.91, 95% CI 0.79 to 1.05). Separate subgroup analyses of regimens containing cisplatin and carboplatin yielded similar findings (HR of death for single-agent v combination cisplatin regimens: 5 RCTs, 759 women, 0.86, 95% CI 0.72 to 1.01; HR of death for single-agent v combination carboplatin regimens: 4 RCTs, 336 women, 1.05, 95% CI 0.82 to 1.35). The review sought data for all women randomised in eligible RCTs, published or unpublished, and was based on individual patient data obtained directly from the responsible trialist or data centre. Hence, the meta-analysis included unpublished data.

The second systematic review included only published RCTs, four of which were published subsequent to the first review. It reported data based on direct comparisons in RCTs, and also compared regimens by indirect comparisons; we have reported data based only on direct comparisons here. The review found no significant difference in survival between platinum monotherapy and platinum-based non-taxane combinations (11 RCTs, HR 0.99, 95% CI 0.88 to 1.10; absolute numbers in analysis and timeframe not reported). Of the 11 included, 10 of the RCTs compared a single-agent platinum regimen versus the same platinum agent plus other non-taxane agents, while one RCT (1526 women) compared a carboplatin alone regimen versus a combination cisplatin regimen. One RCT included people solely with recurrent disease (356 people) while another RCT included people both at first presentation and with recurrent disease (190 people in total, proportion with recurrent disease not specified).

Harms

Combination platinum-based regimen (non-taxane) versus single-agent platinum:

Neither systematic review reported on adverse effects. One of the RCTs included in the second review assessed 875 (57%) women for adverse effects. Leukopenia, alopecia, and nausea and vomiting were more common with combination treatment than with carboplatin alone (AR; leukopenia: 10% with carboplatin alone v 36% with combination; alopecia: 4% with carboplatin alone v 70% with combination; nausea and vomiting: 9% with carboplatin alone v 20% with combination; P values not reported). Thrombocytopenia was more common with carboplatin (AR: 16% with carboplatin alone v 6% with combination treatment; P value not reported). Renal, cardiac, and neurotoxicity were rare in both groups (less than 2% in both groups for each category; P values not reported). Another RCT included in the second review reported similar toxicity between the two cisplatin regimens, but gave no further information.

Comment

Clinical guide:

Platinum may be the most effective agent in these combination regimens, and there seems little benefit in adding other non-platinum (excluding taxanes) agents, with increased risks of adverse effects.

Substantive changes

Combination platinum-based chemotherapy (non-taxane) versus single-agent platinum chemotherapy Option title clarified from "combination platinum-based chemotherapy versus single-agent platinum chemotherapy" to "combination platinum-based chemotherapy (non-taxane) versus single-agent platinum chemotherapy". One systematic review (search date 2006) added which included a meta-analysis and reached similar conclusions to an already reported systematic review. Categorisation of "combination platinum-based chemotherapy versus single-agent platinum chemotherapy (cisplatin or carboplatin alone may be as effective as platinum plus non-platinum [excluding taxanes] combination regimens)" unchanged (Unlikely to be beneficial).

BMJ Clin Evid. 2009 Jan 16;2009:0816.

Adding a taxane to platinum-based regimen as first-line treatment

Summary

MORTALITY Taxane plus platinum regimen compared with platinum non-taxane regimen or platinum alone: We don't know whether combination taxane plus platinum regimens reduce mortality or increase progression-free survival compared with platinum-based non taxane chemotherapy or platinum alone ( low-quality evidence ). NOTE Taxanes are associated with increased haematological and neurological toxicity.

Benefits

Taxane plus platinum regimen versus platinum non-taxane regimen or platinum alone:

We found three systematic reviews (search date not reported, 4 RCTs; search date 2003, 4 RCTs; search date 2006, 4 RCTs ) and one subsequent RCT.The three reviews identified the same four RCTs (see table 4 ). The third systematic review also identified two further RCTs. However, these were in people with relapsed disease rather than in first-line treatment. The third review pooled data, but did not undertake a separate analysis of platinum–taxane combination versus platinum-based treatment in women at first presentation alone, so we have not reported these results further (see comment below). The first RCT (410 women, 216 with advanced disease) compared cisplatin (75 mg/m2) plus paclitaxel (135 mg/m2 over 24 hours) versus cisplatin plus cyclophosphamide (750 mg/m2). The RCT found that progression-free and overall survival were significantly longer with cisplatin plus paclitaxel compared with cisplatin plus cyclophosphamide (see table 4 ). The second RCT (680 women) compared paclitaxel (175 mg/m2 over 3 hours instead of 24 hours) plus cisplatin (75 mg/m2) versus cyclophosphamide (750 mg/m2) plus cisplatin (75 mg/m2 ). The RCT found a significantly longer progression-free and overall survival with cisplatin plus paclitaxel compared with cisplatin plus cyclophosphamide at a median follow-up of 38.5 months. This was despite a high rate of crossover (48%) from the cyclophosphamide group to the paclitaxel group at first detection of disease progression. The third RCT (401 women) compared cisplatin alone (100 mg/m2) versus paclitaxel alone (200 mg/m2 over 24 hours) versus paclitaxel (135 mg/m2 over 24 hours) plus cisplatin (75 mg/m2). Only the comparison of cisplatin alone versus cisplatin and paclitaxel results are discussed. There was no significant difference in median progression-free or overall survival for paclitaxel plus cisplatin compared with cisplatin alone (see table 4 ). Overall survival was similar in all groups, but combination treatment had lower toxicity. Although these results were markedly different from the first two RCTs, the authors also recommend that combined chemotherapy with cisplatin and paclitaxel remain the preferred initial treatment option because of its better toxicity profile. The fourth RCT (2074 women) compared paclitaxel (175 mg/m2) plus carboplatin (minimum 5 x [glomerular filtration rate + 25] mg by Calvert's method) versus either cyclophosphamide (500 mg/m2) plus doxorubicin (50 mg/m2) plus cisplatin (50 mg/m2) or carboplatin alone. The RCT found no significant difference between paclitaxel plus carboplatin and either carboplatin alone or cyclophosphamide plus doxorubicin plus cisplatin in progression-free or overall survival after a median follow-up of 51 months (see table 4 ).

Table 4.

Addition of taxane to platinum-based regimen.

Ref Regimen FIGO stage and population Median survival % with adverse effects
First-line therapy
Platinum-based regimens versus taxane-based regimens
  Cisplatin 75 mg/m2 plus paclitaxel 135 mg/m2 over 24 hours vcisplatin 75 mg/m2 plus cyclophosphamide 750 mg/m287% of paclitaxel group and 78% of non-taxane group completed study regimen 386 women, median age 59–60 years Mean follow-up: 37 months 65% stage 335% stage 4 Greater than 1 cm residual tumour Progression-free survival: 18 months with taxane v 13 months without taxane; RR 0.7, 95% CI 0.5 to 0.8; P less than 0.001 Overall survival: 38 months with taxane v 24 months taxane; RR 0.6, 95% CI 0.5 to 0.8; P less than 0.001 Gastrointestinal:15% with taxane v 11% without taxane; reported as not significant; P value not reported Haematological:Neutropenia: 92% with taxane v 83% without taxane; RR 1.12, 95% CI 1.04 to 1.21 Anaemia: 8% with taxane v 8% without taxane; reported as not significant; P value not reported Thrombocytopenia: 3% with taxane v 3% without taxane; reported as not significant; P value not reported Neurological:4% with taxane v 4% without taxane; reported as not significant; P value not reported Alopecia: 63% with taxane v 37% without taxane; RR 1.71, 95% CI 1.38 to 2.12 Others: Reported as not significant; P value not reported
  Paclitaxel 175 mg/m2 as 3-hour infusion plus cisplatin 75 mg/m2 vcisplatin 75 mg/m2 plus cyclophosphamide 750 mg/m248% crossover between treatment groups 680 women, median age 58 years Mean follow-up: 30 months 7% stage 2B–2C74% stage 319% stage 4 With or without successful debulking Progression-free survival: 15.5 months with taxane v 11.5 months without taxane; P = 0.0005 Overall survival: 35.6 months with taxane v 25.8 months without taxane; P = 0.0016 Gastrointestinal:26% with taxane v 38% without taxane; P value not reported Neutropenia (grade 3–4):64% with taxane v 73% without taxane; P value not reported Thrombocytopenia (grade 3–4):2% with taxane v 8% without taxane; P value not reported Neurological:20% with taxane v 9% without taxane; RR 21.48, 95% CI 6.82 to 67.64 Arthralgia/myalgia:7% with taxane v less than 1% without taxane; RR 11.72, 95% CI 2.79 to 49.18 Allergy:7% with taxane v 2% without taxane; RR 3.35, 95% CI 1.46 to 7.66 Quality-of-life score:Subgroup of 152 women: Worse scores for muscle pain and neurotoxicity in taxane group. Differences ‘clinically and statistically significant', P value not reported
  Cisplatin 100 mg/m2 vPaclitaxel 135 mg/m2 over 24 hours plus cisplatin 75 mg/m269% in cisplatin only group and 81% in combination group completed the treatment 401 women, median age 59–60 years Mean follow-up: not reported 66% stage 334% stage 4 Greater than 1 cm residual tumour Progression-free survival: 14.1 months with cisplatin plus paclitaxel v 16.4 months with cisplatin; HR 1.06, 95% CI 0.86 to 1.30 Overall survival: 26.3 months with cisplatin plus paclitaxel v 30.2 months with cisplatin only; HR 0.99, 95% CI 0.79 to 1.23 Gastrointestinal (grade 3–4):33% with cisplatin v 18% with cisplatin plus paclitaxel; P less than 0.001* Haematological (grade 3–4):Granulocytes: 96% with cisplatin v 94% with cisplatin plus paclitaxel; P less than 0.001* Anaemia: 11% with cisplatin v 8% with cisplatin plus paclitaxel; Pless than 0.001* Neurological (grade 3–4):11% with cisplatin v 5% with cisplatin plus paclitaxel; P = 0.13 Renal (grade 3–4):4% with cisplatin v less than 1% with cisplatin plus paclitaxel; P less than 0.001* All others reported as not significant
  Paclitaxel 175 mg/m2 over 3 hours plus carboplatin (minimum 5 × [glomerular filtration rate + 25] mg by Calvert's method) vCarboplatin (minimum 5 × [glomerular filtration rate + 25] mg by Calvert's method) OR Paclitaxel 175 mg/m2 over 3 hours plus Carboplatin (minimum 5 × [glomerular filtration rate + 25] mg by Calvert's method) vCAP (cyclophosphamide 500 mg/m2 plus doxorubicin 50 mg/m2 plus cisplatin 50 mg/m2) 2074 women, median age 59 years Mean follow-up: 51 months 20% stage 1–264% stage 316% stage 4 Progression-free survival: 17.3 months with paclitaxel plus carboplatin v 16.1 months with carboplatin alone/cisplatin plus cyclophosphamide plus doxorubicin HR for paclitaxel plus carboplatin v carboplatin alone: 0.92, 95% CI 0.81 to 1.04; P = 0.19 HR for paclitaxel plus carboplatin v cisplatin plus cyclophosphamide plus doxorubicin 0.95, 95% CI 0.78 to 1.15; P = 0.57 Overall survival: 36.1 months with paclitaxel plus carboplatin v 35.4 months with carboplatin alone/carboplatin plus cyclophosphamide plus doxorubicin HR for paclitaxel plus carboplatin v carboplatin alone 0.98, 95% CI 0.85 to 1.12; P = 0.73 HR for paclitaxel plus carboplatin v cisplatin plus cyclophosphamide plus doxorubicin 0.99, 95% CI 0.81 to 1.22; P = 0.94 Significance not assessed for adverse effectsGastrointestinal:9% with paclitaxel plus carboplatin v 9% with carboplatin alone 10% with paclitaxel plus carboplatin v 23% with cisplatin plus cyclophosphamide plus doxorubicin All haematological:25% with paclitaxel plus carboplatin v 32% with carboplatin alone 29% with paclitaxel plus carboplatin v 33% with cisplatin plus cyclophosphamide plus doxorubicin Alopecia:73% with paclitaxel plus carboplatin v 4% with carboplatin alone 80% with paclitaxel plus carboplatin v 76% with cisplatin plus cyclophosphamide plus doxorubicin Infection/fever:10% with paclitaxel plus carboplatin v 3% with carboplatin alone 13% with paclitaxel plus carboplatin v 23% with cisplatin plus cyclophosphamide plus doxorubicin Neurological:22% with paclitaxel plus carboplatin v 2% with carboplatin alone 19% with paclitaxel plus carboplatin v 4% with cisplatin plus cyclophosphamide plus doxorubicin
Cisplatin (75 mg/m2) plus cyclophosphamide (700 mg/m2) v cisplatin (75 mg/m2) plus paclitaxel (175 mg/m2, 3-hour continous infusion) 128 women 25% stage IIB-C28% stage III46.7% stage IV8 people ineligible after randomisationMedian ages 59 and 57 years for cisplatin/cyclophosphamide and cisplatin/paclitaxel groups respectivelyMedian follow-up not reported Progression-free survival (median): 9 months with cisplatin plus cyclophosphamide v 12 months with cisplatin plus paclitaxel (log-rank test, P = 0.215; no HR or CI reported)Overall survival (median): 20 months with cisplatin plus cyclophosphamide v 24 months with cisplatin plus paclitaxel (log-rank test, P = 0.350; no HR or CI reported) Haematological: Neutropaenia (grade 3–4) 49/60 [82%] with cisplatin plus cyclophosphamide v 54/60 [90%] with cisplatin plus paclitaxel Thrombocytopaenia (grade 3–4) 3/60 [5%] with cisplatin plus cyclophosphamide v 4/60 [6.6%] with cisplatin plus paclitaxelGastrointestinal: Nausea and vomiting (grade 3–4) 17/60 [28%] with cisplatin plus cyclophosphamide v 16/60 [27%] with cisplatin plus paclitaxelNeurological: Neurological symptoms (grade 3–4): 2/60 [3%] with cisplatin plus cyclophosphamide v 13/60 [22%] with cisplatin plus paclitaxel
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* P value reported for comparison of cisplatin alone versus paclitaxel alone versus cisplatin plus paclitaxel.

The second systematic review also reported on results of the two meta-analyses, one carried out by the Medical Research Council (MRC) and one by the manufacturer of paclitaxel (Bristol–Myers Squibb). The meta-analyses found no significant benefit from the addition of a taxane to platinum treatment, although there was a trend in the favour of the combination (progression-free survival: HR 0.84, 95% CI 0.70 to 1.02 in the MRC meta-analysis; HR 0.87, 95% CI 0.72 to 1.05 in the manufacturer's meta-analysis; overall survival: HR 0.82, 95% CI 0.66 to 1.01 in the MRC meta-analysis; HR 0.82, 95% CI 0.68 to 1.00 in the manufacturer's meta-analysis). The subsequent RCT (128 women) was smaller than the other four RCTs and compared cisplatin (75 mg/m2) plus cyclophosphamide (700 mg/m2) versus cisplatin (75 mg/m2) plus paclitaxel (175 mg/m2 3-hour continuous infusion). It was also subsequent to the two meta-analyses reported above. The RCT found a small but significant increase in response rates with paclitaxel plus cisplatin compared with cisplatin plus cyclophosphamide in evaluable women (complete or partial response: 39/60 [65%] with paclitaxel plus cisplatin v 35/60 [58%] with cisplatin plus cyclophosphamide; P less than 0.05). However, there was no significant difference between groups in progression-free survival or overall survival (see table 4 ). The RCT did not report the method of randomisation or level of blinding. It is unlikely that this RCT was adequately powered to demonstrate any clinically significant differences.

Harms

Taxane plus platinum regimen versus platinum non-taxane regimen or platinum alone:

The systematic reviews found that taxanes were associated with increased risks of neurosensory and neuromotor toxicity, alopecia, arthralgia, myalgia, and hypersensitivity reactions. The first RCT identified by the reviews found the incidence of alopecia was significantly increased with paclitaxel plus cisplatin compared with cisplatin plus cyclophosphamide. However, rates of other adverse effects were similar (see table 4 ).

The second RCT identified by the reviews found significantly higher rates of neurological, allergic, and musculoskeletal adverse effects with paclitaxel plus cisplatin compared with cisplatin plus cyclophosphamide. In a study of quality of life in women with ovarian cancer in this RCT, 152 eligible women completed the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire 30 with three further questions (EORTC QLQ C30+3) and a trial-specific checklist. They were required to complete the questionnaire at baseline (after surgical debulking) and at regular intervals at the end of up to nine cycles of chemotherapy, and at 3-monthly follow-up for 2 years. The research staff completed a case report form on every visit. Women taking paclitaxel reported clinically and statistically worse scores for muscle pain and neurotoxicity than those not taking a taxane. However, overall quality of life was not adversely affected, and was similar in both groups. The study found a close agreement between reporting adverse effects to be mild or none, and reporting quality of life to be mildly or not impaired across most categories of symptoms. The study found that 68% of the variance in baseline quality-of-life scores could be explained by motor weakness, anorexia, altered mood, vomiting, and gastrointestinal pain. However, as few women reported moderate or severe adverse effects, or moderate or severe quality-of-life impairment, it is unclear how informative these findings can be.

The third RCT identified by the reviews found significantly lower rates of gastrointestinal, haematological, and renal adverse effects with cisplatin plus paclitaxel compared with cisplatin alone. However, there was no significant difference in neurological adverse effects between the two treatments. Monotherapies were more frequently stopped compared with combination therapy (cisplatin because of toxicity or patient refusal: 17% with cisplatin v 7% with combination treatment; paclitaxel because of progression: 20% with paclitaxel v 6% with combination treatment; P values not reported).

The fourth RCT found significantly increased rates of alopecia, fever requiring antibiotics, and neuropathy with paclitaxel plus carboplatin compared with carboplatin alone and cisplatin plus cyclophosphamide plus doxorubicin, but lower risks of haematological toxicity compared with carboplatin alone (see table 4 ). The fourth RCT identified by the reviews also found higher rates of neurological adverse effects with paclitaxel, but lower rates of gastrointestinal adverse effects, infection, or fever compared with non-taxane combination regimens.The fifth RCT found similar haematological toxicities between the study arms (see table 4 ). However, neurological toxicities were higher in the taxane-containing arm (see table 4 ). It reported that neutropenia (see table 4 ), alopecia (12 women in cisplatin arm v 16 women in paclitaxel arm), arthralgia (2 women v 17 women), and myalgia (1 woman v 15 women) occured significantly more frequently in those women treated with the paclitaxel-containing regimen (P less than 0.05).

Comment

The two systematic reviews on treatment at first presentation reported only slightly different outcome data from each other and from the original reports of the RCTs, although the overall conclusions did not differ. In one of the RCTs, clinicians were allowed to choose the control regimen (either carboplatin alone or a combination doxorubicin with cyclophosphamide and cisplatin) before randomisation. However, three other RCTs assessed the efficacy of the combination of cisplatin plus cyclophosphamide in the treatment of advanced ovarian cancer. It may be that the combination of cisplatin and cyclophosphamide given in these three RCTs is inferior to the single-agent platinum control groups used in other RCTs. In addition, three of the RCTs included a higher proportion of women with stage IV ovarian cancer compared with the other RCTs. One systematic review estimated the crossover rate of the fourth RCT was about 83%, although this was based on data for the proportion of women eligible for crossover based on disease progression. If this is correct, it could have contributed to differences in results. The most recent systematic review included data from people with relapsed disease in the meta-anlaysis, which is likely to have skewed the results in favour of the platinum–taxane arm.

Clinical guide:

The finding that the addition of paclitaxel to platinum did not significantly improve outcomes compared with platinum alone led to the consensus that taxane–platinum combination treatment should not be exclusively recommended as first-line treatment. Current recommendations consider both platinum therapy alone and combination of taxanes and platinum-based compounds as appropriate first-line treatments, although there is a trend in favour of adding taxanes.

Substantive changes

Adding a taxane to platinum-based regimen as first-line treatment One systematic review added which identified the same previously reported four RCTs. One small subsequent RCT (128 women) addedcomparing cisplatin plus cyclophosphamide versus cisplatin plus paclitaxel to existing reporting of four larger RCTs (410, 680, 401, and 2074 women) and two meta-analyses. The new small RCT does not change the overall conclusions. Categorisation of "adding a taxane to a platinum-based compound" unchanged (Unknown effectiveness).

BMJ Clin Evid. 2009 Jan 16;2009:0816.

Paclitaxel versus docetaxel

Summary

MORTALITY Paclitaxel plus platinum agent compared with docetaxel plus platinum agent: Paclitaxel plus carboplatin is as effective as docetaxel plus carboplatin at reducing mortality and increasing disease-free survival at 2 years ( high-quality evidence ).

Benefits

Comparison of different taxanes (paclitaxel versus docetaxel) added to a platinum agent:

One RCT included 1077 women from 83 centres who were randomly assigned to receive intravenous docetaxel (75 mg/m2) over 1 hour or intravenous paclitaxel (175 mg/m2) over 3 hours (see table 5 ). Both were followed by carboplatin to an area under the curve of 5. The groups had a median follow-up of 23 months showing a similar progression-free survival (see table 5 ). The RCT found no significant difference between groups in overall survival at 2 years (see table 5 ). Global quality-of-life scores were similar in both treatment combinations.

Table 5.

Docetaxel plus carboplatin versus paclitaxel plus carboplatin.

Ref Regimen FIGO stage and population Median survival % with adverse effects
  Docetaxel 75 mg/m2 plus carboplatin 5 AUC vpaclitaxel 175 mg/m2 plus carboplatin 5 AUC 1077 women, median age 59 years 19% stage 1C–281% stage 3–4 Mean follow-up 23 months Progression-free survival: 15.0 months with docetaxel v 14.8 months with paclitaxel; HR 0.97, 95% CI 0.83 to 1.13; P = 0.707 Overall 2-year survival: 64.2% with docetaxel v 68.9% with paclitaxel; HR 1.13, 95% CI 0.92 to 1.39; P = 0.238 Nausea:2% with docetaxel v 1% with paclitaxel group; P less than 0.001 Vomiting (grade 3–4):1% with docetaxel v 2% with paclitaxel; P  greater than 0.05 Neutropenia (grade 3–4):94% with docetaxel v 84% with paclitaxel; P less than 0.001 Neurosensory (grade 2–4):11% with docetaxel v 30% with paclitaxel group; P less than 0.001 Neuromotor (grade 2–4):3% with docetaxel v 7% with paclitaxel; P less than 0.001 Significantly more oedema, hypersensitivity reactions, and nail changes with docetaxel; significantly more arthralgia, myalgia, and alopecia with paclitaxel; P less than 0.001 for all comparisons Global quality-of-life scores were similar for both treatments
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AUC, area under the curve.

Harms

Comparison of different taxanes (paclitaxel versus docetaxel) added to a platinum agent:

The RCT found that women taking docetaxel plus carboplatin had significantly less grade 2 or higher neurosensory toxicity or grade 2 or higher neuromotor toxicity overall (see table 5 ). However, women taking docetaxel plus carboplatin had significantly more grade 3–4 neutropenia (see table 5 ). Women taking docetaxel plus carboplatin also had more gastrointestinal adverse effects, peripheral oedema, hypersensitivity reactions, and nail changes. Women taking paclitaxel plus carboplatin had more arthralgia, myalgia, alopecia, and abdominal pain.

Comment

None.

Substantive changes

No new evidence

BMJ Clin Evid. 2009 Jan 16;2009:0816.

Intraperitoneal platinum-based chemotherapy versus intravenous platinum-based chemotherapy following primary cytoreductive surgery

Summary

MORTALITY Intraperitoneal compared with intravenous platinum-based chemotherapy: Intraperitoneal platinum-based chemotherapy may be more effective than intravenous platinum-based chemotherapy at increasing overall survival and disease-free survival in women with advanced ovarian cancer following primary cytoreductive surgery ( low-quality evidence ). ADVERSE EFFECTS Intraperitoneal compared with intravenous platinum-based chemotherapy: Intraperitoneal platinum-based chemotherapy may be associated with more adverse effects (such as fever and infection) than intravenous platinum-based chemotherapy, although interpretation of results is complicated by different doses of chemotherapy used in intraperitoneal and intravenous chemotherapy regimens in RCTs. The use of an intraperitoneal catheter may be associated with blockage and infection (low-quality evidence).

Benefits

Intraperitoneal versus intravenous platinum-based chemotherapy:

We found six systematic reviews (search date not stated; search date 2006; search date 2007)comparing intraperitoneal versus intravenous platinum-based chemotherapy for advanced ovarian cancer. We found no additional or subsequent RCTs. The reviews all found similar RCTs, pooled data, and reached similar overall conclusions. We have reported one good-quality systematic review with the latest search date in detail in order to illustrate the findings.The review (search date 2007) only included RCTs, and the included studies were published between 1986–2002. It included women with a new diagnosis of ovarian cancer following primary cytoreductive surgery. The primary outcomes reported were disease-free and overall survival. The included RCTs were in women with FIGO stage 2–4 disease (1819 women, mainly stage 3). One included RCT was published in abstract form only, but further mature data was supplied to the review from the study chair, and this RCT included in the review has subsequently been fully published. Of eight included RCTs, six RCTs included cisplatin-based regimens, and the remaining two RCTs included carboplatin-based regimens. The review found that intraperitoneal chemotherapy significantly prolonged survival compared with intravenous chemotherapy (time to death: 7 RCTs, 1728 women, HR 0.8, 95% CI 0.71 to 0.90; P = 0.0003). It also found that intraperitoneal chemotherapy significantly reduced risk of recurrence compared with intravenous chemotherapy (time to reccurrence: 4 RCTs, 1070 women, HR 0.79, 95% CI 0.69 to 0.90; P = 0.0004). Quality-of-life data were collected and reported for one included RCT. This RCT compared intravenous paclitaxel followed by either intravenous cisplatin or intraperitoneal cisplatin plus paclitaxel. The RCT found that ovarian cancer symptoms, as well as physical and functional wellbeing, were significantly poorer before cycle four (of 6 cycles), and 3–6 weeks after treatment in the intraperitoneal treatment group compared with the intravenous treatment group (mean Functional Assessment of Cancer Therapy — Trial Outcome Index [FACT-TOI] questionnaire scores: before cycle 4; 71.0 with intravenous v 61.5 with intraperitoneal, P less than 0.001; 3–6 weeks post-treatment: 75.0 with intravenous v 68.6 with intraperitoneal, P = 0.001). The FACT-TOI measure included physical, functional, and specific ovarian subscales. The review reported that RCTs employed very different chemotherapy regimens, and that no conclusion could be drawn about the best method of treatment. It also noted an important caveat that in two included RCTs, it could not be certain that the survival advantage in the intraperitoneal arm was due to the route of administration, but could also be explained due to higher total chemotherapy dose initially administered in the intraperitoneal arm. However, it also reported that increased dosage in one arm was unlikely to account solely for all the difference in survival. The review also noted that the analysis did not address the current primary treatment of ovarian cancer (the review stated the standard therapy to be carboplatin with or without a taxane; see comment below).

Harms

Intraperitoneal versus intravenous platinum-based chemotherapy:

The systematic review with the most recent search date included data on adverse effects. However, it reported that the meta-analysis could not draw conclusions on haematological (leukopenia, thrombocytopaenia), renal, neurological, and pulmonary toxicity as the data were substantially heterogeneous, and adverse effects would vary according to the regimen used. In two included RCTs, increased haematological, renal, and neurological toxicity were observed in the intraperitoneal arm, which were less obvious in the other included RCTs. The review suggested that differences were likely to be secondary to higher doses of platinum-based chemotherapeutic agents received in the intraperitoneal arms of these RCTs. The review found that intraperitoneal chemotherapy significantly increased pain (grade 3–4), infection (grade 3–4), and fever (grade 3–4) compared with intravenous chemotherapy (pain: 2 RCTs, 68/455 [15%] with intraperitoneal v 9/486 [2%] with intravenous, RR 8.13, 95% CI 4.11 to 16.10; infection: 2 RCTs, 44/440 [10%] v 16/437 [4%], RR 2.78, 95% CI 1.60 to 4.82; fever: 4 RCTs, 47/736 [6%] v 26/767 [3%], RR 1.92, 95% CI 1.20 to 3.06). The review found no significant difference between groups in grade 3–4 anaemia (4 RCTs, 812 women, RR 0.97, 95% CI 0.74 to 1.26). Overall, the review found more complications in the intraperitoneal arms (many secondary to catheter-related problems) that were not observed in the intravenous arms. It reported that catheter-related complications were discussed in all the RCTs, but data were insufficient to undertake a meta-analysis. In the intraperitoneal arms, the review stated that abdominal pain (grade 3–4) was reported in 11%, 18%, and 22% of women in 3 RCTs and 42% of women (including all grades of abdominal pain) in a further RCT; catheter blockage was reported in 7%, 9%, 10%, and 26% in four RCTs; and catheter-related infection in 5%, 13%, and 20% in 3 RCTs.

Comment

Clinical guide:

Intraperitoneal-therapy RCTs have not been blinded, and some of the increased complications are associated with the intraperitoneal catheter, as these are only inserted in women who receive intraperitoneal treatment. The theoretical advantage of intraperitoneal treatment is that changed pharmacokinetics of the intraperitoneal administration route allow increased doses of chemotherapy to be given, resulting in improvements in survival. However, it is not possible to determine whether the improvements in survival (and increases in toxicity from non-catheter-related adverse effects) are due to the route of administration or the increased dose of chemotherapy. The platinum agent used intraperitoneally in all but one RCT included in the meta-analysis of disease-free or overall survival undertaken in the review was cisplatin, which is known to have more harmful effects (without additional beneficial effects) to carboplatin. Future RCTs should examine the role of intraperitoneal carboplatin in similar doses to intravenous administration, so that meaningful comparisons can be made which may more fully inform clinical practice.

Substantive changes

Intraperitoneal platinum-based chemotherapy versus intravenous platinum-based chemotherapy following primary cytoreductive surgery New option. Six systematic reviews identified (search date not stated; search date 2006; search date 2007)which included women with a new diagnosis of ovarian cancer following primary cytoreductive surgery, and compared intraperitoneal platinum-based chemotherapy versus intravenous platinum chemotherapy. "Intraperitoneal platinum-based chemotherapy versus intravenous platinum-based chemotherapy following primary cytoreductive surgery" categorised as Unknown effectiveness.

BMJ Clin Evid. 2009 Jan 16;2009:0816.

Intraperitoneal consolidation treatment versus no further treatment in women following primary surgery and intravenous platinum-based chemotherapy

Summary

MORTALITY Intraperitoneal consolidation treatment after first-line treatment compared with no further treatment: In women who have had primary surgery and intravenous platinum-based chemotherapy and have no residual disease at second-look surgery, we don't know whether further intraperitoneal consolidation treatment is more effective than no further treatment at improving overall survival or progression-free survival ( low-quality evidence ). NOTE Intraperitoneal consolidation treatments have increased toxicities compared with observation only; these toxicities will vary depending on the type of treatment used.

Benefits

Intraperitoneal consolidation treatment after first-line treatment versus no further treatment:

We found no systematic review but found four RCTs. The first RCT (152 women) evaluated the role of consolidation treatment with intraperitoneal cisplatin. Women were randomised following a second-look laparotomy, where pathological complete remission was confirmed. They were then allocated to observation only, or four courses of intraperitoneal cisplatin (90 mg/m2 every 3 weeks). The RCT found no significant difference between groups in progression-free or overall survival after a median follow-up of 8 years (152 women, progression-free survival: HR 0.89, 95% CI 0.6 to 1.3, P = 0.57; overall survival: HR 0.82, 95% CI 0.5 to 1.3, P = 0.39; absolute results not reported). The RCT had a low accrual rate and was closed before reaching adequate numbers to power the study (power calculation required 312 people to demonstrate a 15% difference in 5-year survival). The second RCT (74 women) evaluated the use of interferon-alfa delivered intraperitoneally following conventional primary surgery and platinum-based chemotherapy. It compared intraperitoneal interferon-alfa (6 cycles of 50 x 106 IU) versus no further treatment in people with no pathological evidence of residual disease at second-look surgery. The RCT had slow accrual and was closed after 74 women were recruited. Of 70 evaluable women, it found no significant difference between groups in progression-free survival (absolute results presented graphically, P = 0.56). By the time the trial was closed, overall median survival was not met in the interferon-alfa group and was estimated at 87 months in the observation-only group (absolute results presented graphically, P = 0.09). The planned size of the trial was 165 women.The third RCT (202 women) assessed radioactive chromic phosphate (32P) for intraperitoneal consolidation treatment of advanced ovarian cancer. Women with no residual disease at second-look laparotomy were randomised to receive either intraperitoneal 32P or observation only.The RCT found no significant difference between groups in recurrence-free survival at 5 years (absolute results presented graphically; RR 0.90, 90% CI 0.68 to 1.19). It also found no significant difference between groups in overall 5-year survival (absolute results presented graphically; RR 0.85, 90% CI 0.62 to 1.16). The fourth RCT (447 women) evaluated a yttrium-labelled HMFG1 murine monoclonal antibody delivered intraperitoneally for consolidation treatment of advanced ovarian cancer.The HMFG1 murine monoclonal antibody binds to a large, heavily glycosylated mucin on the surface of most secretory epithelial cells, and is overexpressed by most ovarian cancers. The antibody is labelled with a radioactive compound, thereby delivering radiotherapy directly to target cells. In the RCT, women who had no residual disease at second-look laparoscopy were randomised to receive a single intraperitoneal dose of 90Y-muHMFG1or observation only. The RCT found no significant difference between groups in time to relapse (absolute results presented graphically; Kaplan–Meier analysis, RR 0.90, 95% CI 0.68 to 1.19; P = 0.48). The RCT also found no significant difference between groups in overall survival (absolute results presented graphically; Kaplan–Meier analysis, RR 1.16, 95% CI 0.82 to 1.63; P = 0.40).

Harms

Intraperitoneal consolidation treatment after first-line treatment versus no further treatment:

The first RCT, which evaluated the role of consolidation treatment with intraperitoneal cisplatin, found higher toxicity in women receiving consolidation treatment compared with no further treatment. In total, only 43/77 [56%] women received the scheduled four doses of cisplatin, largely because of harmful effects of treatment. The major reasons for discontinuation were excessive toxicity (7 women, mainly neurological) or patient refusal (16 women). Harmful effects were not reported in the no further treatment arm, so no direct statistical comparison between groups was reported. However, toxicities in the intraperitoneal cisplatin arm (76 women) included: nausea and vomiting (82% of women; grade 2); rise in creatinine (45% of women; grade 2); abdominal pain (38% of women; grade 1–2); infection (26% of women; grade 1); and neurotoxicity (15% of women; grade 2–3). In the second RCT involving interferon-alfa (which was terminated prematurely), 14/35 [40%] women in the intraperitoneal interferon-alfa arm experienced a grade 3 toxicity, and 20/35 [57%] experienced a grade 2 toxicity or greater, which was thought to be treatment related. Main toxicities were fever, malaise and flu-like symptoms, and leukopaenia. Adverse effects in the observation arm were not reported. In the third RCT assessing 32P intraperitoneal consolidation treatment, there were significantly more grade 1–2 gastrointestinal toxicity events in the intraperitoneal 32P arm compared with the no further treatment arm (16/104 [15%] women with 32P intraperitoneal consolidation treatment v 5/98 [5%] women with no further treatment, reported as significant, P value not reported). In the fourth RCT, women treated with intraperitoneal 90Y-muHMFG1 had increased haematological toxicities compared with women in the observation arm.In total, 26% of women had a grade 3–4 thrombocytopaenia in the 90Y-muHMFG1 arm (absolute numbers not reported for the no further treatment arm). Nausea was also more common in the 90Y-muHMFG1 group (moderate or severe nausea: 34/224 [16%] with 90Y-muHMFG1 v 17/223 [7%] with no further treatment, statistical analysis between groups for adverse effects not reported).

Comment

Clinical guide:

Many women with advanced ovarian cancer will have a complete response to first-line treatment (debulking surgery and platinum-based chemotherapy), yet will go on to relapse and die from their disease. The aim of administering different agents intraperitoneally to women who have completed standard first-line treatment is to destroy the microscopic deposits of tumour, reducing the rate of recurrence, thereby improving survival. We found no RCT evidence to support the use of intraperitoneal consolidation treatment with carboplatin, interferon-alfa, radioactive chromic phosphate (32P), or 90Y-muHMFG1. The RCTs did not demonstrate any benefit in terms of survival, although due to slow accrual rates, many were underpowered. However, all RCTs demonstrated increased toxicity in people receiving intraperitoneal consolidation treatments compared with observation only. Current evidence suggests that use of intraperitoneal consolidation treatment should be done within the context of a clinical trial only.

Substantive changes

Intraperitoneal consolidation treatment versus no further treatment in women following primary surgery and intravenous platinum-based chemotherapy New option. Four RCTs identified, two of which were terminated prematurely. All the RCTs used different regimens and found no significant difference in survival between groups. "Intraperitoneal consolidation treatment versus no further treatment in women following primary surgery and intravenous platinum-based chemotherapy" categorised as Unknown effectiveness.

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