Endometriosis and ovarian cancer

Endometriosis and ovarian cancer

Correspondence We declare that we have no conflicts of interest. Diana Pignalosa, *Marco Durante [email protected] GSI Helmholtzzentrum für Schwerione...

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Correspondence

We declare that we have no conflicts of interest.

Diana Pignalosa, *Marco Durante [email protected] GSI Helmholtzzentrum für Schwerionenforschung, Biophysics Department (DP, MD); and Technische Universität Darmstadt (MD), Darmstadt, Germany 1

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Vermeulen L, de Sousa e Melo F, Richel DJ, Medema JP. The developing cancer stem-cell model: clinical challenges and opportunities. Lancet Oncol 2012; 13: e83–89. Durante M, Loeffler J. Charged particles in radiation oncology. Nat Rev Clin Oncol 2010; 7: 37–43. Halperin EC. Particle therapy and treatment of cancer. Lancet Oncol 2006; 7: 676–85. Baumann M, Krause M, Hill R. Exploring the role of cancer stem cells in radioresistance. Nat Rev Cancer 2008; 8: 545–54. Cui X, Oonishi K, Tsujii H, et al. Effects of carbon ion beam on putative colon cancer stem cells and its comparison with X-rays. Cancer Res 2011; 71: 3676–87.

Placebo effect in hot flush research We commend Eleanor Mann and colleagues1 for their excellent Article about the use of cognitive behavioural therapy (CBT) to decrease the negative and debilitating effects of hot flushes and night sweats (HFNS) in patients who had been treated for breast cancer. The methods for this study were strong and well described, including both physiological and selfreport measures, and they represent a novel approach to management of a challenging side-effect. Two large meta-analyses did not specifically identify any studies using CBT for management of hot flushes.2,3 Patients in both the control and intervention groups were assessed at baseline, during the intervention, and 6 months later. As the investigators noted, the number of hot flushes did not decrease significantly in either group, but CBT seemed to make them more tolerable.1 Of interest, no significant differences in the frequency of HFNS were reported at either 9 or 26 weeks in either group. Women in the usual care group had access to high-quality support services and symptom management strategies provided by breast cancer nurses, e188

which might have led to reductions in HFNS in that group. The researchers noted that the benefits in the CBT group could be related to the placebo effect of additional attention.1 We suggest that the placebo effect might not be limited to the intervention group alone and could be associated with control group results as well. Significant reductions in hot flush activity have been reported in placebo intervention or control groups in several randomised studies.4,5 In one review,4 about 25% of 1174 patients who received a placebo or control intervention reported a reduction in hot flushes of at least 50%; 15% had greater than 75% reduction. In another review of data from seven randomised trials which had a placebo group (375 patients),5 results showed that patients receiving the placebo intervention reported an average decrease of 25% in hot flush frequency and intensity. The effect of placebo on the control group needs to be considered when interpreting results of research related to hot flush interventions. This finding also suggests that offering even a little advice on management, together with high-quality support services and acknowledgement of the importance of hot flushes might have a positive clinical effect. We declare that we have no conflicts of interest.

*Suzanne M Mahon, Marcelle Kaplan [email protected] Saint Louis University, St Louis, MO, USA (SMM); and Adjunct Faculty Adelphi University School of Nursing, Garden City, NY, USA (MK) 1

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Mann E, Smith MJ, Hellier J, et al. Cognitive behavioural treatment for women who have menopausal symptoms after breast cancer treatment (MENOS 1): a randomised controlled trial. Lancet Oncol 2012; 13: 309–18. Kaplan M, Mahon S, Cope D, Keating E, Hill S, Jacobson M. Putting evidence into practice. Clin J Oncol Nurs 2011; 15: 149–57. Rada G, Capurro D, Pantoja T, et al. Non-hormonal interventions for hot flushes in women with a history of breast cancer. Cochrane Database Syst Rev 2010; 9: CD004923. Boekhout AH, Beijnen JH, Schellens JHM. Symptoms and treatment in cancer therapy-induced early menopause. Oncologist 2006; 11: 641–54.

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Sloan JA, Loprinzi CL, Novotny PJ, Barton DL, Lavasseur BI, Windschitl H. Methodologic lessons learned from hot flash studies. J Clin Oncol 2001; 19: 4280–90.

Endometriosis and ovarian cancer The findings of Pearce and collaborators1 regarding the association between endometriosis and ovarian cancer have pathogenic and clinical implications. A relation between endometriosis and low-grade serous invasive ovarian cancer was reported for the first time, in addition to confirmation of the well known association with clearcell and endometrioid histotypes. These results suggest a relation between endometriosis and the entire type I ovarian cancer group. Available evidence suggests that most endometrioid and clear-cell ovarian cancers are derived from endometriosis.2 Furthermore, findings support the hypothesis that lowgrade serous ovarian cancers develop through papillary tubal hyperplasia, sloughing and implantation of tubal epithelium on the ovarian surface or peritoneum, and progression to atypical endosalpingiosis and eventually low-grade serous adenocarcinoma.3 If this association is confirmed, type I invasive ovarian cancers could be classed as a type of pelvic contamination disorder secondary to sloughing of müllerian cells from the fallopian tubes. In this regard, the association between endometriosis and low-grade serous ovarian cancers could be explained by independent pelvic contamination by both endometrial and tubal epithelial cells. However, the definition of endometriosis in general as the precursor lesion of clear-cell and endometriotic ovarian cancers raises issues because only atypical endometriosis should be regarded as a precursor lesion2—not any form of ectopic endometrium independent www.thelancet.com/oncology Vol 13 May 2012

Correspondence

www.thelancet.com/oncology Vol 13 May 2012

We declare that we have no conflicts of interest.

*Paolo Vercellini, Edgardo Somigliana, Laura Buggio, Giorgio Bolis, Luigi Fedele [email protected] Clinica Ostetrica e Ginecologica, Istituto Luigi Mangiagalli, Università Statale di Milano, Milan, Italy (PV, LB, LF); Fondazione Istituto di Ricovero e Cura a Carattere Scientifico Ca’ Granda, Ospedale Maggiore Policlinico, Milan, Italy (ES); and Gynaecologic Oncology Unit, Department of Obstetrics and Gynaecology, University of Milan, Milan, Italy (GB) 1

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Pearce CL, Templeman C, Rossing MA, et al, on behalf of the Ovarian Cancer Association Consortium. Association between endometriosis and risk of histological subtypes of ovarian cancer: a pooled analysis of case–control studies. Lancet Oncol 2012; 13: 385–94. Prat J. Ovarian carcinomas: five distinct diseases with different origins, genetic alterations, and clinicopathological features. Virchows Arch 2012; 460: 237–49. Kurman RJ, Vang R, Junge J, Gerd Hannibal C, Kjaer SK, Shih IM. Papillary tubal hyperplasia: the putative precursor of ovarian atypical proliferative (borderline) serous tumors, noninvasive implants, and endosalpingiosis. Am J Surg Pathol 2011; 35: 1605–14. Bedaiwy MA, Hussein MR, Biscotti C, Falcone T. Pelvic endometriosis is rarely associated with ovarian borderline tumours, cytological and architectural atypia: a clinicopathologic study. Pathol Oncol Res 2009; 15: 81–88. van Leeuwen FE, Klip H, Mooij TM, et al. Risk of borderline and invasive ovarian tumours after ovarian stimulation for in vitro fertilization in a large Dutch cohort. Hum Reprod 2011; 26: 3456–65.

In a pooled analysis of 13 case–control studies, Pearce and colleagues1 noted a two-fold to three-fold increase in the risk of clear-cell, low-grade serous, and endometrioid invasive ovarian cancer, but not high-grade serous invasive ovarian cancer, in association with self-reported endometriosis. The investigators ultimately seek improved risk stratification methods to individualise prevention and early detection strategies. We think that this study is a small step towards that goal; however, several methodological and statistical considerations should temper the enthusiasm for surveillance at this stage. First, Pearce and colleagues’ study lacked information about specific subtypes of endometriosis, making pathogenic inference difficult.

Although ovarian endometriomas can generate a proinflammatory microenvironment conducive to ovarian cancer development because of proximity, whether peritoneal or vaginorectal deep-infiltrating endometriosis would increase the risk of ovarian cancer more than for other gynaecological cancers is unclear. Second, no information was available regarding treatments received, which makes assessment of a potential effect modification by surgery or danazol treatment impossible.2,3 Third, although dismissed by the authors, a recall bias is likely. Recall bias should not affect the histological type of the ovarian cancer, but could inflate the strength of the association. Recall bias is shown by the finding that two of the 13 included studies had a prevalence of endometriosis in controls lower than 5% and ten had a prevalence lower than 10% (widely used as a benchmark estimate).4 An additional piece of evidence that brings the association into question is the decrease, rather than increase, in the risk of ovarian cancer with the removal of patients with specific length of exposure duration.1 Finally, this study should be put in perspective, and should not serve as a call for universal screening of women with endometriosis. The yearly incidence of all types of ovarian cancer in the USA is 13 per 100 000 women,5 and the data from Pearce and coworkers’ study raise this incidence to roughly 39 per 100 000. If a screening test is optimistically assumed to be 99% sensitive and 99% specific, the corresponding positive predictive value in this population is only 3·7%. In other words, of 100 women who test positive, 96 would have falsepositive results and have to undergo more tests, some of which might be invasive. Although the investigation by Pearce and co-workers is a meaningful advance towards defining the role of endometriosis in the development

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from histological characteristics. Similarly, the epithelium of tubal fimbria is not thought to be a precursor of high-grade serous ovarian cancers, but rather P53 signatures or even only serous intraepithelial carcinomas.2,3 Atypical endometriosis has been reported in 2–3% of excised ovarian endometriomas although its prevalence might be much lower.4 Many low-risk patients might request unnecessary extirpative surgery because they are worried about having premalignant disease, unless only specifically patients with atypical endometriosis are deemed at high risk. Pearce and colleagues suggest more definitive endometriosis treatment and risk-reduction surgery as potential treatment options in women at otherwise undefined high oncological risk. Alternatively, the chemopreventive use of oral contraceptives, which substantially reduces the risk of ovarian cancer in women with endometriosis, could be considered. Women with endometriosis have around 98·5% lifetime probability of not developing invasive ovarian cancer, compared with 99% in the general female population. Having endometriosis seems much less risky than undergoing in-vitro fertilisation, which is associated with a three-fold increase in risk of invasive ovarian cancer.5 The notion that all forms of endometriosis are precursor lesions of most type I epithelial ovarian cancers implies the need for strict surveillance, serial screening, and systematic surgical exploration of suspected disease. The psychological consequences for millions of women persuaded to live with a potentially serious disease are not determinable. In view of the high prevalence of endometriosis, the low incidence of clear-cell and endometrioid ovarian cancers, and the modest increase in the small lifetime risk of all invasive forms, would the enormous organisational efforts reduce mortality or result in inappropriate investment of scarce health-care resources?

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