Aebi, S.

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EditorialEndometrial cancer: a frequentorphan diseaseEndometrial cancer is the most frequent invasive cancer of thefemale genital tract, with an estimated annual incidence ofalmost 38 000 in the ‘old’ European Union (before 1 May2004) and a similar figure in the United States. It is substan-tially more frequent than ovarian cancer, but can be curedmore often by surgery and radiation therapy; this results inabout 9000 deaths per year in the EU and 7000 in the UnitedStates [1,2]. Epidemiological risk factors for endometrial can-cer are well known [3], but the optimal therapy of endometrialcancer has been poorly investigated. While there exists a cer-tain consensus for surgical therapy in so far as a total abdomi-nal hysterectomy and bilateral salpingo-oophorectomy shouldbe performed, the value of pelvic and paraaortic lympha-denectomy remains unproven. Indeed, the frequently citedrationale for retroperitoneal lymphadenectomy, namely theavoidance of adjuvant radiation therapy for node-negative dis-ease, may be wrong in the light of a recently published trial,GOG-99 [4].The role of adjuvant radiation therapy has been definedmuch more clearly in recent years, at least for patients withstage I and very early stage II disease. Pelvic radiation therapydramatically reduced the risk of locoregional recurrence inthree randomised controlled trials [4–6], regardless of whetheror not retroperitoneal lymphadenectomy was part of the stan-dard surgical procedure. None of these trials revealed a signifi-cant beneficial effect of radiotherapy on survival.The adjuvant medical therapy of endometrial cancerremains poorly investigated. A systematic review and meta-analysis of the Cochrane Collaboration revealed that the adju-vant use of progestational agents may indeed be dangerous.They do not significantly reduce the risk of recurrence andendometrial cancer-related death, but significantly increase therisk of non-cancer-related death [7]. Numerous small trialshave investigated the efficacy of adjuvant chemotherapy inendometrial cancer, but were not adequately powered to detecta difference in survival (reviewed in [8]). Adjuvant chemo-therapy with doxorubicin and cisplatin has been comparedwith whole abdominal radiation therapy in stage III and IVdisease, and chemotherapy turned out to be superior to radio-therapy with regards to progression-free (hazard ratio 0.81)and overall survival (hazard ratio 0.71; P < 0.05) [9].Similarly, the knowledge base for the therapy of recurrentand metastatic endometrial cancer is small at present. Highdoses of oral medroxyprogesterone acetate were not found tobe more active than lower doses [10]. For cytotoxic chemother-apy, phase I and II trials are abundant, but while they are usefulto estimate the efficacy of drugs, they do not contribute todefining the best choice of therapy. A few major randomisedcontrolled trials are nevertheless available (Table 1) in additionto numerous small trials (reviewed in [8]). The combination ofdoxorubicin and cisplatin is considered standard therapy basedupon two trials [11,12] that revealed a very moderate advan-tage of the combination over single drug doxorubicin, despitethe greater toxicity experienced with the combination.An important trial reported in this issue of Annals of Onco-logy builds upon this foundation and on the promising activityof paclitaxel in phase II trials. The randomised comparison ofthe standard three-weekly doxorubicin (60 mg/m2) plus cispla-tin (50 mg/m2) with doxorubicin (50 mg/m2) plus paclitaxel(150 mg/m2 as a 24-h infusion) plus filgrastim was performedin an exemplary manner, based upon sound principles of clini-cal trial design. The randomisation yielded comparable groupsof patients, and the selection of patients represented the popu-lation of endometrial cancer patients. Despite promisingresults from preliminary trials and the activity of paclitaxel ina phase III trial [13], the chemotherapy regimens did not differsignificantly in terms of activity and toxicity. While this mayseem disappointing, at least two points are illustrated:(i) promising observations in phase II trials may be due topatient selection bias and need not be confirmed in random-ised trials; and (ii) cisplatin or carboplatin may be essential inthe therapy of endometrial cancer. The latter hypothesis issupported by two very recent trials [13,14].A more general issue, however, also deserves a mention:certain neoplasias that are much rarer than endometrial cancerhave been far better investigated. For instance, only 8000cases of Hodgkin’s disease are diagnosed annually in theUnited States, and a similar number is expected for the Euro-pean Union; a substantial majority of these patients can becured by chemotherapy and/or radiotherapy, such that  1300patients a year die from Hodgkin’s disease in the UnitedStates [2]. A long series of trials organised by many collabora-tive groups in different countries have optimised chemother-apy and radiotherapy to the current state of the art, whichallows the majority of patients, even with advanced stageHodgkin’s disease, to be cured. By comparison, endometrialcancer appears to be a poorly investigated orphan diseaseindeed, despite its frequent occurrence. A substantial decreasein the incidence of endometrial cancer is unlikely in the nextfew years, and early detection methods have not been provento have a major impact on mortality [15]. Thus, our effortsshould be focused on improving all treatment modalities forendometrial cancer. Such progress will have to begin in theminds of those who care for patients with endometrial cancer.This tumour is neither rarer nor less interesting than otherneoplasias that have been studied successfully. In addition toelucidating the molecular events that lead to and characteriseendometrial cancer, the oncology community is obliged to setAnnals of Oncology 15: 1149–1150, 2004DOI: 10.1093/annonc/mdh325q 2004 European Society for Medical Oncologyup and complete clinical trials of endometrial cancer surgery,radiation therapy and medical therapy. At present, the NorthAmerican Gynecologic Oncology Group is leading the way,but despite regulatory agencies increasingly threatening clinicalresearch, similar contributions will have to be made in Europe.S. AebiInstitute of Medical Oncology, University Hospital,Inselspital, 3010 Bern, Switzerland(E-mail: stefan.aebi@insel.ch)References1. Cancer Incidence, Mortality and Prevalence in the European Union(1998 Estimate). The European Commission Health MonitoringProgramme; http://www-dep.iarc.fr/hmp/camon.htm (27 April 2004,date last accessed).2. Jemal A, Tiwari RC, Murray T et al. Cancer statistics, 2004. CACancer J Clin 2004; 54: 8–29.3. Kaaks R, Lukanova A, Kurzer MS. Obesity, endogenous hormones,and endometrial cancer risk: A synthetic review. Cancer EpidemiolBiomarkers Prev 2002; 11: 1531–1543.4. Keys HM, Roberts JA, Brunetto VL et al. A phase III trial of surgerywith or without adjunctive external pelvic radiation therapy in inter-mediate risk endometrial adenocarcinoma: a Gynecologic OncologyGroup study. Gynecol Oncol 2004; 92: 744–751.5. Aalders J, Abeler V, Kolstad P, Onsrud M. Postoperative externalirradiation and prognostic parameters in stage I endometrial carci-noma: clinical and histopathologic study of 540 patients. ObstetGynecol 1980; 56: 419–427.6. Creutzberg CL, van Putten WLJ, Koper PCM et al. Surgery and post-operative radiotherapy versus surgery alone for patients with stage-1endometrial carcinoma: multicentre randomised trial. Lancet 2000;355: 1404–1411.7. Martin-Hirsch PL, Jarvis G, Kitchener H, Lilford R. Progestagens forEndometrial Cancer (Cochrane Review). The Cochrane Library, Issue1. Oxford: Update Software 2003.8. Steer C, Harper P. Is there any place for cytotoxic chemotherapy inendometrial cancer? Best Pract Res Clin Obstet Gynaecol 2001; 15:447–467.9. Randall ME, Brunetto G, Muss H et al. Whole abdominal radio-therapy versus combination doxorubicin-cisplatin chemotherapy inadvanced endometrial carcinoma: a randomized phase III trial ofthe Gynecologic Oncology Group. Proc Am Soc Clin Oncol 2003;22: 2.10. Thigpen JT, Brady MF, Alvarez RD et al. Oral medroxyprogesteroneacetate in the treatment of advanced or recurrent endometrial carci-noma: a dose-response study by the Gynecologic Oncology Group.J Clin Oncol 1999; 17: 1736–1744.11. Thigpen JT, Blessing J, Homesley H et al. Phase III trial of doxorubi-cin+/- cisplatin in advanced or recurrent endometrial carcinoma: aGynecologic Oncology Group (GOG) study. Proc Am Soc Clin Oncol1993; 12: 261.12. van Wijk FH, Aapro MS, Bolis G et al. Doxorubicin versus doxorubi-cin and cisplatin in endometrial carcinoma: definitive results of a ran-domised study (55872) by the EORTC Gynaecological Cancer Group.Ann Oncol 2003; 14: 441–448.13. Fleming GF, Brunetto VL, Cella D et al. Phase III trial of doxorubicinplus cisplatin with or without paclitaxel plus filgrastim in advancedendometrial carcinoma: a Gynecologic Oncology Group study. J ClinOncol 2004; 22: 2159–2166.14. Weber B, Mayer F, Fargeot P et al. What is the best chemotherapyregimen in recurrent or advanced endometrial cancer? Proc Am SocClin Oncol 2003; 22: 453.15. Smith RA, Cokkinides V, Eyre HJ. American Cancer Society guide-lines for the early detection of cancer, 2003. CA Cancer J Clin 2003;53: 27–43.16. Thigpen JT, Blessing JA, DiSaia PJ et al. A randomized comparisonof doxorubicin alone versus doxorubicin plus cyclophosphamide inthe management of advanced or recurrent endometrial carcinoma: aGynecologic Oncology Group study. J Clin Oncol 1994; 12:1408–1414.17. Gallion HH, Brunetto VL, Cibull M et al. Randomized phase III trialof standard timed doxorubicin plus cisplatin versus circadian timeddoxorubicin plus cisplatin in stage III and IV or recurrent endometrialcarcinoma: a Gynecologic Oncology Group Study. J Clin Oncol 2003;21: 3808–3813.18. Fleming GF, Filiaci VL, Bentley RC et al. Phase III randomized trialof doxorubicin + cisplatin versus doxorubicin + 24-h paclitaxel + fil-grastim in endometrial carcinoma: a Gynecologic Oncology Groupstudy. Ann Oncol 2004; 15: 1173–1178.Table 1. Major randomised controlled trials of chemotherapy for advanced endometrial cancerTrial No. ofpatientsRandomised chemotherapy regimens Median progression-free survivalMedian survival CommentThigpen et al.,1993 [11]223 Doxorubicin versus doxorubicin + cisplatin 3.9 versus 6.2 monthsvan Wijk et al.,2003 [12]177 Doxorubicin versus doxorubicin + cisplatin 7 versus 8 months 7 versus 9 months Significant survival benefitfor patients with goodperformance statusThigpen et al.,1994 [16]356 Doxorubicin versus doxorubicin +cyclophosphamide3.2 versus 3.9 months 6.7 versus 7.3 monthsFleming et al.,2004 [13]266 Doxorubicin + cisplatin versus doxorubicin +cisplatin + paclitaxel + G-CSFAt 5 months, 50%versus 67%At 12 months, 50%versus 58%Gallion et al.,2003 [17]342 Standard timed doxorubicin + cisplatin versuscircadian timed doxorubicin + cisplatin6.5 versus 5.9 months 11.2 versus 13.2 monthsWeber et al.,2003 [14]63 Doxorubicin + cisplatin versus carboplatin +paclitaxelAt 15 months, 24%versus 35%At 15 months, 27%versus 41%Randomised phase II trialFleming et al.,2004 [18]317 Doxorubicin + cisplatin versus doxorubicin +paclitaxel + G-CSF7.2 versus 6.0 months 12.6 versus 13.6 monthsG-CSF, granulocyte colony-stimulating factor.1150

Endometrial cancer: a frequent orphan disease

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