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National Collaborating Centre for Cancer (UK). Ovarian Cancer: The Recognition and Initial Management of Ovarian Cancer. Cardiff (UK): National Collaborating Centre for Cancer (UK); 2011 Apr. (NICE Clinical Guidelines, No. 122.)

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Ovarian Cancer: The Recognition and Initial Management of Ovarian Cancer.

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4Management of suspected early (stage I) ovarian cancer

The two objectives of this chapter were:

  1. to determine whether the systematic removal of the retroperitoneal lymph nodes during surgical treatment for suspected early stage ovarian cancer confers any added benefit as opposed to conventional surgical staging which includes lymph node sampling.
  2. to determine the clinical benefits and toxicity of first-line adjuvant chemotherapy for women with stage I ovarian cancer.

4.1. The role of systematic retroperitoneal lymphadenectomy

In women whose disease is thought to be confined to the ovary(s), optimum surgical staging comprises midline laparotomy to allow thorough assessment of the abdomen and pelvis; a total abdominal hysterectomy, bilateral salpingo-oophorectomy and infracolic omentectomy; biopsies of any peritoneal deposits; random biopsies of the pelvic and abdominal peritoneum and retroperitoneal lymph node assessment (Winter-Roach et al., 2009). In women where the disease appears to be confined to one ovary and who wish to conserve fertility, then conservative surgery can be considered where the uterus and contra-lateral ovary are conserved.

It is recognised that around 22% of women considered to have stage I ovarian cancer, will in fact have occult retroperitoneal lymph node metastases which can only be identified by removing affected nodes (Maggioni et al., 2006). Current surgical staging guidelines advocate only sampling a number of pelvic and/or para-aortic nodes but inevitably less will be sampled than in a systematic retroperitoneal lymphadenectomy, which aims to remove all pelvic and para-aortic lymph nodes up to the renal vessels as a block dissection on both sides. Removing all affected nodes will improve staging and might be therapeutic.

Systematic retroperitoneal lymphadenectomy is a major surgical procedure which carries the potential risks of prolonged anaesthesia and surgical complications such as increased blood loss and transfusion, ureteric injury, lymphoedema, lymphocysts, damage to nerves and major vessels. In addition to concerns about morbidity, there are resource implications. The use of peri-operative frozen section to confirm malignancy has been proposed. This might be a way of selecting only those patients with ovarian cancer for systematic retroperitoneal lymphadenectomy, thereby reducing the risks and costs of this strategy.

There is, however, no international agreement on whether the potential survival benefits of systematic retroperitoneal lymphadenectomy outweigh the risks.

Clinical question: For women with ovarian cancer whose disease appears confined to the ovaries, what is the effectiveness of systematic retroperitoneal lymphadenectomy in surgical management?

Clinical evidence

The evidence for this topic was generally of low quality, comprising two retrospective observational studies, one non-randomised comparative study and a small randomised controlled trial (RCT) (Table 4.1). Across all studies, the majority of women had stage I ovarian cancer. Only the RCT reported the incidence of post-surgical morbidity and none of the papers reported on patient quality of life. The results of survival outcomes were inconsistent between studies.

Table 4.1. GRADE profile: For women with ovarian cancer whose disease appears confined to the ovaries, what is the effectiveness of systematic retroperitoneal lymphadenectomy in surgical management?.

Table 4.1

GRADE profile: For women with ovarian cancer whose disease appears confined to the ovaries, what is the effectiveness of systematic retroperitoneal lymphadenectomy in surgical management?.

Maggioni et al., (2006) presented results from a small, underpowered study that was unable to demonstrate a difference in short or long term survival between patients having surgery alone or surgery with systematic lymphadenectomy (SL). But the more extensive operation was associated with increased morbidity. Conversely, Yokoyama et al., (1999) found a significant difference in the rates of 5 and 10 year survival for women with stage I/II disease who had received SL compared with those who had not (100% vs. 71.4% (P<0.05) and 83.9% vs. 61.1% (P<0.05) respectively). These results may have been confounded by the addition of different chemotherapy regimens to the study arms.

The retrospective studies also reported conflicting results for survival. The largest study (Chan et al., 2007; N=6,686) found a significant improvement in the rate of 5 year disease-specific survival for women who underwent SL as part of staging compared with women who did not (92.6% ± 0.6 vs. 87% ± 0.6 P<0.001). However, during the study period participants had unrecorded treatments including surgery and/or chemotherapy which could have confounded these results. The smaller study (Yang et al., 2007) found no significant differences in survival after 1, 3, 5 or 10 years between women that had undergone SL after primary surgery and those who had not. Again, some participants had subsequently received chemotherapy which could have confounded the results.

Kim et al., (2010) conducted a thorough systematic review and meta-analysis of RCTs and observational studies to determine the possible benefit of systematic retroperitoneal lymphadenectomy to women with all stages of ovarian cancer. A sub-set of patients had stage I-II disease and these data showed a survival advantage with SL (HR: 0.80 [95%CI: 0.70-0.92] (P=0.001) with no between studies heterogeneity. However, the included studies were not of high evidential quality consisting of Chan et al., 2007; Maggioni et al., 2006 and a small retrospective observational study (Suzuki et al., 2008).

Recommendation

1

Lymph node assessment involves sampling of retroperitoneal lymphatic tissue from the para-aortic area and pelvic side walls if there is a palpable abnormality, or random sampling if there is no palpable abnormality.

2

Optimal surgical staging constitutes: midline laparotomy to allow thorough assessment of the abdomen and pelvis; a total abdominal hysterectomy, bilateral salpingo-oophorectomy and infracolic omentectomy; biopsies of any peritoneal deposits; random biopsies of the pelvic and abdominal peritoneum; and retroperitoneal lymph node assessment [Winter Roach BA, Kitchener HC, Dickinson HO (2009) Adjuvant (post-surgery) chemotherapy for early stage epithelial ovarian cancer. Cochrane Database of Systematic Reviews issue 3: CD004706].

Linking evidence to recommendations

The GDG acknowledged that evidence on the basis of study quality assessed according to GRADE was limited and of poor quality. There was no demonstrable survival benefit from systematic retroperitoneal lymphadenectomy compared to lymph node sampling. They also noted that no studies reported on quality of life.

The GDG reaffirm the need for accurate staging, particularly in women with suspected early ovarian cancer, but were not convinced that the greater risks and costs of systematic retroperitoneal lymphadenectomy compared to conventional lymph node sampling were justifiable. Therefore they were unable to recommend its use in women whose disease appears to be confined to the ovaries.

This clinical question was agreed as a low priority for health economic evaluation because of the lack of good quality RCT data in this area. Also, given that an economic evaluation would be unlikely to clarify the uncertain health benefits associated with these interventions, the added value of such an analysis was lower than for other clinical questions.

Research recommendation

  • A prospective randomised trial should be undertaken to evaluate the therapeutic effect, associated risks and cost effectiveness of systematic retroperitoneal lymphadenectomy in women with ovarian cancer whose disease appears to be confined to the ovaries.

4.2. Adjuvant systemic chemotherapy for stage I disease

No surgical staging procedure is perfect and in a proportion of women in whom the disease is thought to be confined to the ovaries and completely removed at operation there may, in fact, be occult residual disease.

In women with apparent stage I disease, chemotherapy can be given in certain circumstances, such as poorly differentiated tumours and in certain histological sub-types (for example, clear cell carcinomas). This is done to treat residual disease that is suspected but may not, in fact, exist. Therefore some women without residual disease will receive chemotherapy with its associated risks.

Given that women with stage I ovarian cancer have significantly less disease it is possible that less chemotherapy will be required for cure. Currently NICE technology appraisal guidance 55 (NICE, 2003) recommends a choice of either platinum based compound on its own or in combination with paclitaxel (see section 5.3) but does not stipulate the number of cycles to be given. It is logical that reducing the number of cycles of chemotherapy is likely to reduce toxicity but could compromise effectiveness. The GDG felt that establishing the evidence base for reducing chemotherapy cycles should be investigated in order to quantify any risk-benefit assessment.

Clinical question: For women with stage I ovarian cancer, what is the most effective first line chemotherapy?

Clinical evidence

The evidence for this topic consisted of one high quality Cochrane review and a lower quality randomised controlled trial (RCT) (Table 4.2). Across these studies, women had undergone primary surgery and had stage I or II ovarian cancer.

Table 4.2. GRADE profile: For women with stage I ovarian cancer, what is the most effective first line chemotherapy.

Table 4.2

GRADE profile: For women with stage I ovarian cancer, what is the most effective first line chemotherapy.

Winter-Roach et al., (2009) conducted a review which investigated whether adjuvant therapy with mainly platinum-containing regimens was associated with a survival advantage compared to withholding chemotherapy until disease progression, and whether certain sub-groups of patients gained more or less from this approach. After an average follow-up of nearly ten years it was found that women receiving adjuvant therapy had a considerable advantage in overall survival (HR=0.71 [95%CI: 0.53 to 0.93] P=0.015) and progression-free survival (HR=0.67 [95%CI: 0.53-0.84] P=0.00046). In particular, those women who had been adequately staged gained no survival advantage from immediate adjuvant chemotherapy (HR=1.22 [95%CI: 0.63-2.37] P=0.56) whereas women who had been inadequately staged did (HR=0.63 [95%CI: 0.46 to 0.85] P=0.0031).

Bell et al., (2006) compared six vs. three cycles of adjuvant carboplatin and paclitaxel in women with early stage ovarian cancer (N=457). Across all patients and after an average follow-up of 6.8 years, there were no statistically significant differences in the risk of death (HR=1.02 [95%CI: 0.66-1.57] P=0.94) or the rate of disease recurrence (HR=0.76 [95%CI: 0.51-1.13] P=0.18). The higher number of treatment cycles was associated with significantly increased morbidity.

The systematic review (Winter-Roach et al., 2009) included evidence from the Adjuvant Chemotherapy in Ovarian Neoplasm (ACTION) trial which has now been updated by Trimbos et al., (2010). The results showed that, even with observation, optimally surgically staged patients had a significantly better prognosis compared with patients who had been non-optimally staged: cancer-specific survival (risk of death: HR 3.28 [95%CI: 1.47-7.33] (P=0.002); recurrence-free survival (risk of death: HR 1.91 [95%CI: 1.17-3.11] P=0.009). In non-optimally staged patients only, adjuvant chemotherapy provided significantly improved cancer-specific survival (risk of death: HR 0.58 [95%CI: 0.35-0.95] P=0.029) and recurrence-free survival (risk of death: HR 0.60 [95%CI: 0.41-0.87] P=0.007) when compared with observation. The authors concluded, therefore, that the benefit of adjuvant chemotherapy appeared to be limited to patients with non-optimal staging who, perhaps, had a greater risk of unidentified residual disease.

The results of Bell et al., 2006 were re-analysed in a more recent report (Chan et al., 2010) after a median follow-up of 91 months. The authors grouped data by tumour type (i.e. serous or non-serous) and showed that only women with serous cancer derived a significant benefit from six cycles compared with three cycles of adjuvant carboplatin and paclitaxel chemotherapy (HR=0.33 [95%CI: 0.14-0.77] P=0.007). Although interesting, the original study was underpowered for sub-group analyses which, in any event, have been performed post hoc.

Recommendations

  • Do not offer adjuvant chemotherapy to women who have had optimal surgical staging3 and have low-risk stage I disease (grade 1 or 2, stage Ia or 1b).
  • Offer women with high-risk stage I disease (grade 3 or stage Ic) adjuvant chemotherapy consisting of six cycles of carboplatin.
  • Discuss the possible benefits and side effects of adjuvant chemotherapy with women who have had suboptimal surgical staging3 and appear to have stage I disease.
3

Optimal surgical staging constitutes midline laparotomy to allow thorough assessment of the abdomen and pelvis; a total abdominal hysterectomy, bilateral salpingo-oophorectomy and infracolic omentectomy; biopsies of any peritoneal deposits; random biopsies of the pelvic and abdominal peritoneum and retroperitoneal lymph node assessment [Winter Roach et al. (2009) Adjuvant (post-surgery) chemotherapy for early stage epithelial ovarian cancer. Cochrane Database of Systematic Reviews 2009, Issue 3: CD004706]

Linking evidence to recommendations

Interventions that improve the likelihood of disease free survival are very important, but that benefit needs to be weighed against the morbidity and effects on overall quality of life. The GDG noted that there was some evidence suggesting adjuvant chemotherapy in stage I disease could reduce the risk of relapse and death from ovarian cancer. This evidence was limited and of varying quality on the basis of study quality assessed according to GRADE. The GDG was aware that there was a lack of data on both the toxicity associated with adjuvant chemotherapy and on how this affected quality of life.

In women whose risk of relapse was small the GDG felt the adverse effects and costs of adjuvant treatment would significantly outweigh any benefit from treatment and therefore did not recommend adjuvant chemotherapy.

The GDG was also aware that different women might place different personal value on the short-term adverse effects of treatment as well as on the possible long-term benefits. Therefore discussion of treatment options, as well as the option of no treatment was important.

The GDG noted that single agent platinum-based therapy, using 6 cycles of carboplatin, had demonstrated a survival benefit in women with early stage ovarian cancer. They were also aware that combination therapy had been shown to be more toxic than monotherapy and has not been evaluated in this setting. The GDG therefore decided to recommend 6 cycles of adjuvant carboplatin for most women.

This clinical question was considered a low priority for health economic evaluation because of the small patient numbers involved.

References

  • Bell J, Brady MF, Young RC, Lage J, Walker JL, Look KY, Rose GS, Spirtos NM., Gynaecologic Oncology Group. Randomized phase III trial of three versus six cycles of adjuvant carboplatin and paclitaxel in early stage epithelial ovarian carcinoma: a Gynaecologic Oncology Group study. Gynaecol Oncol. 2006;102:432–439. [PubMed: 16860852]
  • Chan JK, Munro EG, Cheung MK, Husain A, Teng NN, Berek JS, Osann K. Association of lymphadenectomy and survival in stage I ovarian cancer patients. Obstetrics and Gynecology. 2007;109:12–19. [PubMed: 17197582]
  • Chan JK, Tian C, Fleming GF, Monk BJ, Herzog TJ, Kapp DS, et al. The potential benefit of 6 vs. 3 cycles of chemotherapy in subsets of women with early-stage high-risk epithelial ovarian cancer: an exploratory analysis of a Gynecologic Oncology Group study. Gynecol Oncol. 2010;116(3):301–306. [PubMed: 19945740]
  • Kim HS, Ju W, Jee BC, Kim YB, Park NH, Song YS, et al. Systematic lymphadenectomy for survival in epithelial ovarian cancer a meta-analysis. Int J Gynecol Cancer. 2010;20(4):520–528. [PubMed: 20686371]
  • Maggioni A, Benedetti PP, Dell'Anna T, Landoni F, Lissoni A, Pellegrino A, Rossi RS, Chiari S, Campagnutta E, Greggi S, Angioli R, Manci N, Calcagno M, Scambia G, Fossati R, Floriani I, Torri V, Grassi R, Mangioni C. Randomised study of systematic lymphadenectomy in patients with epithelial ovarian cancer macroscopically confined to the pelvis. Br J Cancer. 2006;95:699–704. [PMC free article: PMC2360519] [PubMed: 16940979]
  • National Institute for Health and Clinical Excellence. NICE technology appraisal guidance 55. London: National Institute for Health and Clinical Excellence; 2003. Guidance on the use of paclitaxel in the treatment of ovarian cancer.
  • Suzuki S, Kajiyama H, Shibata K, Ino K, Nawa A, Sakakibara K, Matsuzawa K, Takeda A, Kinoshita Y, Kawai M, Nagasaka T, Kikkawa F. Is there any association between retroperitoneal lymphadenectomy and survival benefit in ovarian clear cell carcinoma patients? Ann.Oncol. 2008;19:1284–1287. [PubMed: 18356137]
  • Trimbos B, Timmers P, Pecorelli S, Coens C, Ven K, van der Burg M, et al. Surgical staging and treatment of early ovarian cancer: long-term analysis from a randomized trial. J Natl Cancer Inst. 2010;102(13):982–987. [PMC free article: PMC2911043] [PubMed: 20445161]
  • Winter-Roach BA, Kitchener HC, Dickinson HO. Adjuvant (post-surgery) chemotherapy for early stage epithelial ovarian cancer. Cochrane Database Sys Rev. 2009;(3):CD004706. [PubMed: 19588360] [Cross Ref]
  • Yang X, Hou M, Yang K, Wang H, Peng, Cao Z, Mingrong X. Prognosis in epithelial ovarian cancer: clinical analysis of 287 pelvic and para-aortic lymphadenectomy. Chinese-German Journal of Clinical Oncology. 2007;6(5):492–496.
  • Yokoyama Y, Sakamoto T, Sato S, Saito Y. Evaluation of cytoreductive surgery with pelvic and para-aortic lymphadenectomy and intermittent cisplatin-based combination chemotherapy for improvement of long-term survival in ovarian cancer. Eur J Gynaecol Oncol. 1999;20:361–366. [PubMed: 10609495]

Lymph node assessment involves sampling of retroperitoneal lymphatic tissue from the para-aortic area and pelvic side walls if there is a palpable abnormality, or random sampling if there is no palpable abnormality.

Optimal surgical staging constitutes: midline laparotomy to allow thorough assessment of the abdomen and pelvis; a total abdominal hysterectomy, bilateral salpingo-oophorectomy and infracolic omentectomy; biopsies of any peritoneal deposits; random biopsies of the pelvic and abdominal peritoneum; and retroperitoneal lymph node assessment [Winter Roach BA, Kitchener HC, Dickinson HO (2009) Adjuvant (post-surgery) chemotherapy for early stage epithelial ovarian cancer. Cochrane Database of Systematic Reviews issue 3: CD004706].

Optimal surgical staging constitutes midline laparotomy to allow thorough assessment of the abdomen and pelvis; a total abdominal hysterectomy, bilateral salpingo-oophorectomy and infracolic omentectomy; biopsies of any peritoneal deposits; random biopsies of the pelvic and abdominal peritoneum and retroperitoneal lymph node assessment [Winter Roach et al. (2009) Adjuvant (post-surgery) chemotherapy for early stage epithelial ovarian cancer. Cochrane Database of Systematic Reviews 2009, Issue 3: CD004706]

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