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Key clinical trials in gynaecological oncology
EJSO 32 (2006) 887e891
www.ejso.com
Key clinical trials in gynaecological oncology* J. Morrison*, S. Kehoe 1 Nuffield Department of Obstetrics and Gynaecology, John Radcliffe Hospital, Headington, Oxford OX3 9DU, UK Accepted 23 March 2006 Available online 4 May 2006
Abstract Aims: To review the most important clinical trials which have impacted the management of gynaecological cancers, in conjunction with some ongoing studies of interest. Methods: PubMed and Cochrane databases were searched to find clinical trials and meta-analyses in vulva, cervical, endometrial and ovarian cancers. Other pertinent literature was also used. Results: The majority of trials related to ovarian and cervical cancers, and the least associated with vulval cancer. Conclusions: To ensure evidence based medicine, trials in gynaecological cancers must be supported. Notably, surgical trials are on the increase in the last decade, but are still a minority when compared with non-surgical interventions. Ó 2006 Elsevier Ltd. All rights reserved. Keywords: Gynaecological cancer; Clinical trial; Surgery; Chemotherapy
Introduction Evidence based medicine recognises the need for robust non-biased data with which to guide practice in order to optimise patient outcome. Clinical trials in gynaecological oncology, dominated by the Gynaecological Oncology Group (GOG) in America and the European Organisation for Research and Treatment of Cancer (EORTC) and Medical Research Council in Europe, have previously focussed on non-surgical treatments. This is partly because for many surgical treatments the effects of surgery/no surgery were obvious and randomised trials are unnecessary or unethical, e.g. hysterectomy for endometrial cancer. However, the need for randomised controlled trials (RCTs) for comparing different surgical or non-surgical treatments, where the differences between groups may be more modest, has been recognised and is being addressed. This review will highlight some of the key trials that inform clinical practice, in both surgical and non-surgical gynaecological oncology, *
Conflicts of Interest: JM is sponsored by grants from Macmillan Cancer Relief and WellBeing for Women. SK is the principle investigator for CHORUS. * Corresponding author. Tel.: þ44 1865 228626; fax: þ44 1865 791712. E-mail addresses: [email protected] (J. Morrison), [email protected] (S. Kehoe). 1 Tel.: þ44 1865 857942; fax: þ44 1865 221001. 0748-7983/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved. doi:10.1016/j.ejso.2006.03.038
but with a more surgical bias, and include details of ongoing trials which we hope will provide a solid evidence base for gynaecological oncology management in the future. Ovarian cancer Ovarian cancer is the leading cause of death from gynaecological cancer in the developed world.1 Symptoms are vague and non-specific and 75% of women will present once their disease has spread outside the pelvis when surgery alone is unlikely to be curative (FIGO stages III and IV).2 Current management in advanced disease is a debulking laparotomy, which acts to diagnose, stage and treat, followed by platinum-based chemotherapy for advanced disease. Primary surgery In early stage disease (FIGO stages IAeIIA) surgery alone can be curative, although results from randomised clinical trails demonstrated that there may be a subgroup of women who would benefit from adjuvant chemotherapy.3 The International Collaborative Ovarian Neoplasm trial 1 (ICON1) and Adjuvant ChemoTherapy In Ovarian Neoplasm trial (ACTION) randomised 925 women with
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early stage ovarian cancer to either platinum-based adjuvant chemotherapy or observation. Women receiving chemotherapy had an improved overall survival at 5 years (82% vs. 74%) with a hazard ratio for chemotherapy of 0.67 (95% confidence intervals (CI): 0.5e0.9; p ¼ 0.008). However, less than 25% of women were optimally staged, and so there is the possibility that improved outcome was due to appropriate treatment of more advanced ovarian cancer. In addition, these data indicate that the majority of women with early stage ovarian cancer do well and do not require chemotherapy. The ideal would be a test that could differentiate those women who would benefit from chemotherapy from those who would do well otherwise. Current diagnostic and prognostic indicators cannot identify these women, although advances in genomics and proteomics may make this possible in the future.4 Management of advanced stage disease is currently based on the results of a retrospective series of 102 women, in whom univariate analysis revealed a better outcome for those women who had optimally debulked cancer (no disease more than 1.6 cm diameter). Results of meta-analyses of non-randomised trials of debulking have confirmed an improved outcome for women with optimally debulked disease. Nevertheless, these data do not inform us whether the outcome is improved due to surgery or due to the nature of the cancer, which may make better prognostic cancers more amenable to optimal debulking (now defined as no macroscopic disease). Currently recruiting are two randomised clinical trials which aim to determine whether the effect of maximal debulking in advanced ovarian cancer is due to surgery or disease (Chemotherapy or Up-front Surgery (CHORUS); a Royal College of Obstetricians and Gynaecologists/MRC study, and one from the Gynaecological Cancer Co-operative of the EORTC). The results of these trials are likely to have a major impact on current clinical practice and are eagerly awaited.
Interval debulking surgery Interval debulking surgery (IDS) is a surgery performed to optimally debulk the tumour following unsuccessful primary surgery mid-way through optimal chemotherapy. An EORTC trial to assess the value of IDS randomised women with residual disease following primary surgery, who had shown some response to three cycles of chemotherapy, to secondary surgery or no further surgery unless clinically indicated. Women randomised to IDS had an improved median survival of 6 months ( p ¼ 0.01). In contrast, the GOG152 study from North America demonstrated no significant improvement in median survival (32 vs. 33 months). It is argued that these studies are not directly comparable due to differences in chemotherapeutic regimens: in the GOG study women received cisplatin and paclitaxel, whereas in the EORTC study women received a platinum agent and cyclophosphamide.
Platinum agents The alkylating platinum agents, carboplatin and cisplatin, are the principle chemotherapeutic agents for ovarian cancer. Cisplatin was developed in the 1970s, and carboplatin was subsequently developed and shown to be a less toxic alternative with similar therapeutic effect.5 A meta-analysis of individual patient data from 45 clinical trials by the Advanced Ovarian Cancer Trialists Group (AOCTG) compared platinum to non-platinum agents.6 Although the results did not reach significance (overall relative risk (RR): 0.93; 95% CI: 0.83e1.05), there was a trend towards superiority of platinum agents and results for cisplatin and carboplatin were equivalent. A more recent update in the form of a Cochrane Collaboration systematic review by the AOCTG included individual patient data from 8763 women in 49 different trials.7 They were able to demonstrate statistically significant improved survival in the group who received platinum agents (hazard ratio (HR): 0.88, 95% CI: 0.79e0.98). They confirmed the earlier finding of no significant difference between carboplatin and cisplatin in terms of survival. Carboplatin is therefore the agent of choice as the side effects are less severe, without impairing efficacy. Paclitaxel The taxanes are derived from the bark of the Pacific yew (Taxus brevifolia). First tested in relapsed ovarian cancer, it was found to have activity as a single agent. It was then combined with platinum agents for first-line treatment of advanced ovarian cancer in several randomised clinical trials. The GOG111 trial demonstrated improved overall survival in the paclitaxel arm (38 vs. 24 months; p < 0.001) in women with suboptimally debulked advanced ovarian cancer.8 These findings were supported by those of the European/Canadian Intergroup OV10 study.9 However, the GOG132 three-armed study, which compared paclitaxel, cisplatin and cisplatin/paclitaxel in combination, found that there was no difference between single agent cisplatin and cisplatin/paclitaxel in combination (30.2 vs. 26.0 months overall survival; not significant).10 Paclitaxel alone was not as effective as regimens that included a platinum agent. The International Collaborative Ovarian Neoplam Group trial (ICON3) compared carboplatin or CAP (cyclophosphamide/doxorubicin/cisplatin) with carboplatin/paclitaxel in combination in a randomised controlled trail of 2074 women.11 The results confirmed those of GOG132; there was no improved survival with the addition of paclitaxel and there were fewer side effects from carboplatin alone. These results are still the source of much debate. Indeed, the National Institute of Clinical Excellence (NICE), the government medical advisory group in the UK, did not make a recommendation either for or against the use of paclitaxel in first-line treatment. In an attempt to reconcile
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the results of these four large clinical trials, a meta-analysis was performed.12 There was difficulty in combining the data due to heterogeneity in the study arms. However, these data demonstrated a non-significant trend towards superiority of platinum/paclitaxel combination therapy (HR: 0.82; 95% CI: 0.66e1.02). This study then went on to test statistically different theories as to why the results of GOG111, OV10, GOG132 and ICON3 differed. They concluded that the only theory which was consistent with the observed results was that there may have been suboptimal therapy in the platinum alone arms of trials that concluded an improvement for platinum/paclitaxel combination. The debate continues.
Endometrial cancer Endometrial cancer is a disease of peri- and postmenopausal women, with 91% of cases worldwide in women aged 50 years or older.13 Endometrial cancer is common in the Western world with incidences of 22 per 100,000 in North America, but much less common in African and eastern Asia (less than 3.5 per 100,000) largely due to differences in risk factors and life expectancy. Endometrial cancer largely presents at an early stage where cure rates from surgery alone are high and so, although it accounts for 3.9% of cancers in women worldwide, it causes only 1.7% of female cancer deaths. Nevertheless, a retrospective study of patients with stage I endometrial cancer demonstrated that there were very variable death rates, dependent on tumour differentiation and depth of myometrial involvement.14 However, there is great variation in treatment of women with stage I endometrial cancer with regard to pelvic lymph node dissection, arguably required for adequate staging, and use of adjuvant radiotherapy.15 The PORTEC study examined the role of post-operative radiotherapy in women with FIGO stage I endometrial cancer with either high grade or deeply invasive disease who had not undergone pelvic lymphadenectomy.16 Seven hundred and fifteen women were randomised to pelvic radiotherapy or no further treatment. Although there was higher local recurrence in the non-radiotherapy group (14% vs. 4%; p < 0.001), there was no significant difference in 5-year overall survival (85% vs. 81%; p ¼ 0.31) or endometrial cancer related deaths (9% vs. 6%; p ¼ 0.37). Complications in the treatment group were much higher (25% vs. 6%; p < 0.001) although most were grade 1 or 2 toxicities. The conclusions of this study were that women with stage I endometrial cancer under 60 years or those with grade 2 tumours with only superficial invasion did not require adjuvant radiotherapy, as it did not improve survival and increased toxicity. Pelvic lymphadenectomy Data from retrospective caseecontrol study suggested a role for pelvic lymphadenectomy in endometrial cancer.17
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Six hundred and forty-nine women with endometrial cancer over a 20-year period were divided into three groups: multiple site lymph node sampling, limited lymph node sampling, and no lymph node sampling. Histological prognostic features such as stage and grade were similar between the three groups. Patients receiving multiple site pelvic node sampling had a significant improvement in survival other those not receiving multiple site pelvic node sampling in both high and low risk groups. However, these data were not randomised, leaving the potential for bias. Thus, was the rationale for the surgical arm of the AZTEC trial.18 ASTEC was designed to investigate whether extensive pelvic lymph node dissection in addition to standard hysterectomy and bilateral salpingo-oophorectomy improved survival in women with endometrial disease thought to be confined to the uterine corpus (FIGO stage I). In addition, there was a second randomisation point following surgery to examine the role of external beam radiotherapy in women with early stage disease who had any of the following risk factors on histology: Grade 3 tumour, invasion into the outer half of the myometrium, serous papillary or clear cell histological type, or FIGO stage IIa. The trial has completed recruitment in May 2005 and results from follow up are awaited.
Cervical cancer Carcinoma of the cervix is still the leading cause of death from cancer in women in the developing world despite now being less prevalent than breast cancer, as rates in countries with adequate screening policies have dramatically decreased over the past 20 years.13 There is a relatively long lag phase from detecting carcinoma in situ to the development of squamous carcinoma of the cervix and the role of human papilloma virus in the aetiology is well established. Women with early stage disease (stage 1a1) can be treated with cone biopsy or simple hysterectomy. However, treatment of women with more advanced disease is changing in response to recent clinical data. Radiation vs. surgery Survival rates for women with stage Ib and IIa carcinoma of the cervix treated with either radical surgery (Wertheim’s hysterectomy and pelvic lymph node clearance) or pelvic radiotherapy were previously known to be similar. However, these two treatment modalities were directly compared in a randomised controlled trial of 367 women with stages IbeIIa cervical carcinoma.19 One hundred and eight patients in the surgery group required adjuvant radiotherapy following surgery. Overall five-year survival rates for women with squamous cell carcinoma were 84% in the surgical group and 88% in the radiotherapy group ( p ¼ not significant). For adenocarcinoma of the cervix, there was improved overall five-year survival rates in the
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surgery arm compared to radiotherapy (70% vs. 59%; p ¼ 0.05). Those patients who required radiotherapy following surgery had a poorer survival rate than either those receiving surgery or radiotherapy alone and also had a higher rate of complications. Current practice is therefore to restrict radical surgery to those who have, or are likely to have, negative lymph nodes, and offer radiotherapy to the rest. Concomitant chemotherapy Chemotherapy was demonstrated to have a synergistic effect with radiotherapy in cervical cancer cells in vitro. There have now been several RCTs which have examined the role of concomitant chemotherapy in the treatment of cervical cancer. These were analysed in a Cochrane Collaboration systematic review.20 They concluded that chemoradiation gave an improved overall survival (hazard ratio: 0.71, p < 0.0001) with an absolute survival benefit of 12% for women with at least bulky stage Ib cervical cancer. The potential improvement in survival may be more marked for those women with earlier stage disease. The studies included in the review covered a wide range of patient populations and types of chemotherapy regimens, although cisplatin was the most commonly used. However, improved survival was accompanied by increased side effects, which were significantly higher in the chemoradiation group. They concluded that chemoradiation gives improved survival in selected patients, but that further studies are required to examine the role of different chemotherapeutic agents, radiation regimens and the effect of haemoglobin levels. Fertility conserving surgery Increasingly, younger women are being diagnosed with cervical cancer at a relatively early stage. Many of these women will not have completed their family and therefore are concerned about preserving their fertility. A radical trachelectomy is an operation in which the cervix and paracervical tissue is excised but the uterine body is conserved, so leaving the possibility of pregnancy for women with stage IA2 or IB cervical cancer. There is a possibility of lymphatic spread in these women and so pelvic lymph node dissection is performed prior to the conservative surgery. As yet there have been no RCTs published on this approach. In a case series of 82 women who planned to have vaginal radical trachelectomy following laparoscopic pelvic lymph node dissection, nine were abandoned due to positive lymph nodes or endocervical margins.21 During a mean follow up of 60 months (6e156), there were two recurrences and one death (1.4%) with a calculated actuarial survival of 95%. In a more recent follow up paper, there were 50 pregnancies in 31 of the 72 women.22 Thirty-six of the pregnancies (72%) reached the third trimester and 28 (78%) delivered at term. In another series of 30 women
who had radical trachelectomy for early cervical cancer, there were no recurrences in a mean follow up of 23 months (range 1e64 months).23 Eight of 13 women trying to conceive achieved a total of 14 pregnancies and nine live births. They concluded that for a small subset of women fertility sparing surgery may be a safe and relatively successful alternative to radical surgery. The largest case series is that of 82 patients who underwent laparoscopic lymph node dissection and a modified Schauta procedure.24 There were three recurrences, all in women who had a primary tumour larger than 2 cm diameter. Twenty-nine of 38 women who tried to conceive achieved 47 pregnancies, resulting in 27 live births. All of these series suggest that this may be a reasonable alternative in well counseled women who are very keen to preserve their fertility. However, it is unlikely that these women would be happy to be randomised to radical hysterectomy and a large multi-national multicentre cohort study may be the best evidence we can collect to decide on the safety of this more conservative approach.
Vulval cancer Vulval cancer is relatively rare which therefore makes large clinical trials somewhat a challenge. The pioneering work of Taussig and Way25e27 in the early 20th century lead to the development of the en bloc radical vulvectomy due to the recognition of the need to adequately treat the inguinal lymph nodes in all but the very earliest of vulval cancer. However, there was high morbidity from the ‘butterfly’ incision, and therefore more recently efforts have focussed on reducing morbidity without compromising survival (reviewed in ref. [28]). A pilot study comparing different surgical techniques for groin dissection demonstrated that a less radical, more anatomically based method was equally successful in terms of lymph node retrieval, with reduced short-term morbidity and no evidence in this small study of increased mortality of the conservative approach.29 The concept that there is a primary or ‘sentinel’ lymph node to which the tumour first drains has been investigated for breast cancer. By injecting labels at the primary tumour site, e.g. coloured dyes or radiolabels, it is possible to track the lymphatic drainage and locate the sentinel lymph node. Whether this is a reliable method to select patients for conservative treatment or radical groin node dissection is the subject of current investigation for vulval cancer (reviewed by Van der Zee).
Conclusions Gynaecological malignancy is relatively rare and meaningful clinical trials are dependent on multi-centre international collaboration. However, the international gynaecological oncology community is committed to improving outcome for women and recent trials have been
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well supported. It is hoped that this collaboration will lead to robust data which will inform and improve clinical practice. Nevertheless, despite evidence from well performed trials, it can be difficult to change practice; for example, cisplatin remained the standard treatment in America, despite data from the 1980s demonstrating the advantages of carboplatin. In addition, the paclitaxel trials illustrate how modest changes in outcomes can be difficult to demonstrate even with large RCTs. It is likely that increasing knowledge about the genetic and proteomic basis for cancer will influence inclusion criteria of trials and translation of their results to the care of individual patients. These changes will be a challenge for the future, but one that must be addressed by both surgeons and oncologists. References 1. Quinn M, Babb B, Brock A, Jones J. Cancer trends in England and Wales. London: Office for National Statistics, The Stationery Office; 2001. 2. Shepherd JH. Revised FIGO staging for gynaecological cancer. Br J Obstet Gynaecol 1989;96:889–92. 3. Trimbos JB, Parmar M, Vergote I, et al. International Collaborative Ovarian Neoplasm trial 1 and Adjuvant ChemoTherapy In Ovarian Neoplasm trial: two parallel randomized phase III trials of adjuvant chemotherapy in patients with early-stage ovarian carcinoma. J Natl Cancer Inst 2003;95:105–12. 4. Bingham C, Roberts D, Hamilton TC. The role of molecular biology in understanding ovarian cancer initiation and progression. Int J Gynecol Cancer 2001;11(Suppl. 1):7–11. 5. Wiltshaw E, Subramarian S, Alexopoulos C, Barker GH. Cancer of the ovary: a summary of experience with cis-dichlorodiammineplatinum(II) at the Royal Marsden Hospital. Cancer Treat Rep 1979;63:1545–8. 6. Chemotherapy in advanced ovarian cancer: an overview of randomised clinical trials. Advanced Ovarian Cancer Trialists Group. BMJ 1991;303:884–93. 7. Advanced Ovarian Cancer Trialists Group. Chemotherapy for advanced ovarian cancer. Cochrane Database Syst Rev 1999;Issue 1. 8. McGuire WP, Hoskins WJ, Brady MF, et al. Cyclophosphamide and cisplatin compared with paclitaxel and cisplatin in patients with stage III and stage IV ovarian cancer. N Engl J Med 1996;334:1–6. 9. Piccart MJ, Bertelsen K, Stuart G, et al. Long-term follow-up confirms a survival advantage of the paclitaxelecisplatin regimen over the cyclophosphamideecisplatin combination in advanced ovarian cancer. Int J Gynecol Cancer 2003;13(Suppl. 2):144–8. 10. Muggia FM, Braly PS, Brady MF, et al. Phase III randomized study of cisplatin versus paclitaxel versus cisplatin and paclitaxel in patients with suboptimal stage III or IV ovarian cancer: a gynecologic oncology group study. J Clin Oncol 2000;18:106–15. 11. Paclitaxel plus carboplatin versus standard chemotherapy with either single-agent carboplatin or cyclophosphamide, doxorubicin, and cisplatin in women with ovarian cancer: the ICON3 randomised trial. Lancet 2002;360:505–15.
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12. Sandercock J, Parmar MK, Torri V, Qian W. First-line treatment for advanced ovarian cancer: paclitaxel, platinum and the evidence. Br J Cancer 2002;87:815–24. 13. Parkin DM, Bray F, Ferlay J, Pisani P. Global cancer statistics 2002. CA Cancer J Clin 2005;55:74–108. 14. DiSaia PJ, Creasman WT, Boronow RC, Blessing JA. Risk factors and recurrent patterns in Stage I endometrial cancer. Am J Obstet Gynecol 1985;151:1009–15. 15. Maggino T, Romagnolo C, Landoni F, Sartori E, Zola P, Gadducci A. An analysis of approaches to the management of endometrial cancer in North America: a CTF study. Gynecol Oncol 1998;68:274–9. 16. Creutzberg CL, van Putten WL, Koper PC, et al. Surgery and postoperative radiotherapy versus surgery alone for patients with stage-1 endometrial carcinoma: multicentre randomised trial. PORTEC Study Group. Post Operative Radiation Therapy in Endometrial Carcinoma. Lancet 2000;355:1404–11. 17. Kilgore LC, Partridge EE, Alvarez RD, et al. Adenocarcinoma of the endometrium: survival comparisons of patients with and without pelvic node sampling. Gynecol Oncol 1995;56:29–33. 18. Kitchener H, Blake P. AZTEC: a randomised trial of lymphadenectomy and of adjuvant external beam radiotherapy in the treatment of endometrial cancer (ISRCTN number 16571884): MRC Clinical Trials Unit. London: Medical Research Council; 2003. 19. Landoni F, Maneo A, Colombo A, et al. Randomised study of radical surgery versus radiotherapy for stage IbeIIa cervical cancer. Lancet 1997;350:535–40. 20. Green JA, Kirwan JM, Tierney JF, et al. Survival and recurrence after concomitant chemotherapy and radiotherapy for cancer of the uterine cervix: a systematic review and meta-analysis. Lancet 2001;358: 781–6. 21. Plante M, Renaud MC, Francois H, Roy M. Vaginal radical trachelectomy: an oncologically safe fertility-preserving surgery. An updated series of 72 cases and review of the literature. Gynecol Oncol 2004; 94:614–23. 22. Plante M, Renaud MC, Hoskins IA, Roy M. Vaginal radical trachelectomy: a valuable fertility-preserving option in the management of early-stage cervical cancer. A series of 50 pregnancies and review of the literature. Gynecol Oncol 2005;98:3–10. 23. Shepherd JH, Mould T, Oram DH. Radical trachelectomy in early stage carcinoma of the cervix: outcome as judged by recurrence and fertility rates. BJOG 2001;108:882–5. 24. Dargent D. Radical trachelectomy: an operation that preserves the fertility of young women with invasive cervical cancer. Bull Acad Natl Med 2001;185:1295–304. discussion 1305e6. 25. Taussig F. Cancer of the vulva: an analysis of 155 cases. Am J Obstet Gynecol 1940;40:764–70. 26. Way S. The anatomy of the lymphatic drainage of the vulva and its influence on the radical operation for carcinoma. Ann R Coll Surg Engl 1948;3:187–97. 27. Way S. Carcinoma of the vulva. Am J Obstet Gynecol 1960;79:692–9. 28. DiSaia PJ. The case against the surgical concept of en bloc dissection for certain malignancies of the reproductive tract. Cancer 1987;60: 2025–34. 29. Kehoe S, Luesley D, Chan KK. A pilot study on early post-operative morbidity and technique of inguinal node dissection in vulval carcinoma. Eur J Gynaecol Oncol 1998;19:374–6.
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Key clinical trials in gynaecological oncology* J. Morrison*, S. Kehoe 1 Nuffield Department of Obstetrics and Gynaecology, John Radcliffe Hospital, Headington, Oxford OX3 9DU, UK Accepted 23 March 2006 Available online 4 May 2006
Abstract Aims: To review the most important clinical trials which have impacted the management of gynaecological cancers, in conjunction with some ongoing studies of interest. Methods: PubMed and Cochrane databases were searched to find clinical trials and meta-analyses in vulva, cervical, endometrial and ovarian cancers. Other pertinent literature was also used. Results: The majority of trials related to ovarian and cervical cancers, and the least associated with vulval cancer. Conclusions: To ensure evidence based medicine, trials in gynaecological cancers must be supported. Notably, surgical trials are on the increase in the last decade, but are still a minority when compared with non-surgical interventions. Ó 2006 Elsevier Ltd. All rights reserved. Keywords: Gynaecological cancer; Clinical trial; Surgery; Chemotherapy
Introduction Evidence based medicine recognises the need for robust non-biased data with which to guide practice in order to optimise patient outcome. Clinical trials in gynaecological oncology, dominated by the Gynaecological Oncology Group (GOG) in America and the European Organisation for Research and Treatment of Cancer (EORTC) and Medical Research Council in Europe, have previously focussed on non-surgical treatments. This is partly because for many surgical treatments the effects of surgery/no surgery were obvious and randomised trials are unnecessary or unethical, e.g. hysterectomy for endometrial cancer. However, the need for randomised controlled trials (RCTs) for comparing different surgical or non-surgical treatments, where the differences between groups may be more modest, has been recognised and is being addressed. This review will highlight some of the key trials that inform clinical practice, in both surgical and non-surgical gynaecological oncology, *
Conflicts of Interest: JM is sponsored by grants from Macmillan Cancer Relief and WellBeing for Women. SK is the principle investigator for CHORUS. * Corresponding author. Tel.: þ44 1865 228626; fax: þ44 1865 791712. E-mail addresses: [email protected] (J. Morrison), [email protected] (S. Kehoe). 1 Tel.: þ44 1865 857942; fax: þ44 1865 221001. 0748-7983/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved. doi:10.1016/j.ejso.2006.03.038
but with a more surgical bias, and include details of ongoing trials which we hope will provide a solid evidence base for gynaecological oncology management in the future. Ovarian cancer Ovarian cancer is the leading cause of death from gynaecological cancer in the developed world.1 Symptoms are vague and non-specific and 75% of women will present once their disease has spread outside the pelvis when surgery alone is unlikely to be curative (FIGO stages III and IV).2 Current management in advanced disease is a debulking laparotomy, which acts to diagnose, stage and treat, followed by platinum-based chemotherapy for advanced disease. Primary surgery In early stage disease (FIGO stages IAeIIA) surgery alone can be curative, although results from randomised clinical trails demonstrated that there may be a subgroup of women who would benefit from adjuvant chemotherapy.3 The International Collaborative Ovarian Neoplasm trial 1 (ICON1) and Adjuvant ChemoTherapy In Ovarian Neoplasm trial (ACTION) randomised 925 women with
888
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early stage ovarian cancer to either platinum-based adjuvant chemotherapy or observation. Women receiving chemotherapy had an improved overall survival at 5 years (82% vs. 74%) with a hazard ratio for chemotherapy of 0.67 (95% confidence intervals (CI): 0.5e0.9; p ¼ 0.008). However, less than 25% of women were optimally staged, and so there is the possibility that improved outcome was due to appropriate treatment of more advanced ovarian cancer. In addition, these data indicate that the majority of women with early stage ovarian cancer do well and do not require chemotherapy. The ideal would be a test that could differentiate those women who would benefit from chemotherapy from those who would do well otherwise. Current diagnostic and prognostic indicators cannot identify these women, although advances in genomics and proteomics may make this possible in the future.4 Management of advanced stage disease is currently based on the results of a retrospective series of 102 women, in whom univariate analysis revealed a better outcome for those women who had optimally debulked cancer (no disease more than 1.6 cm diameter). Results of meta-analyses of non-randomised trials of debulking have confirmed an improved outcome for women with optimally debulked disease. Nevertheless, these data do not inform us whether the outcome is improved due to surgery or due to the nature of the cancer, which may make better prognostic cancers more amenable to optimal debulking (now defined as no macroscopic disease). Currently recruiting are two randomised clinical trials which aim to determine whether the effect of maximal debulking in advanced ovarian cancer is due to surgery or disease (Chemotherapy or Up-front Surgery (CHORUS); a Royal College of Obstetricians and Gynaecologists/MRC study, and one from the Gynaecological Cancer Co-operative of the EORTC). The results of these trials are likely to have a major impact on current clinical practice and are eagerly awaited.
Interval debulking surgery Interval debulking surgery (IDS) is a surgery performed to optimally debulk the tumour following unsuccessful primary surgery mid-way through optimal chemotherapy. An EORTC trial to assess the value of IDS randomised women with residual disease following primary surgery, who had shown some response to three cycles of chemotherapy, to secondary surgery or no further surgery unless clinically indicated. Women randomised to IDS had an improved median survival of 6 months ( p ¼ 0.01). In contrast, the GOG152 study from North America demonstrated no significant improvement in median survival (32 vs. 33 months). It is argued that these studies are not directly comparable due to differences in chemotherapeutic regimens: in the GOG study women received cisplatin and paclitaxel, whereas in the EORTC study women received a platinum agent and cyclophosphamide.
Platinum agents The alkylating platinum agents, carboplatin and cisplatin, are the principle chemotherapeutic agents for ovarian cancer. Cisplatin was developed in the 1970s, and carboplatin was subsequently developed and shown to be a less toxic alternative with similar therapeutic effect.5 A meta-analysis of individual patient data from 45 clinical trials by the Advanced Ovarian Cancer Trialists Group (AOCTG) compared platinum to non-platinum agents.6 Although the results did not reach significance (overall relative risk (RR): 0.93; 95% CI: 0.83e1.05), there was a trend towards superiority of platinum agents and results for cisplatin and carboplatin were equivalent. A more recent update in the form of a Cochrane Collaboration systematic review by the AOCTG included individual patient data from 8763 women in 49 different trials.7 They were able to demonstrate statistically significant improved survival in the group who received platinum agents (hazard ratio (HR): 0.88, 95% CI: 0.79e0.98). They confirmed the earlier finding of no significant difference between carboplatin and cisplatin in terms of survival. Carboplatin is therefore the agent of choice as the side effects are less severe, without impairing efficacy. Paclitaxel The taxanes are derived from the bark of the Pacific yew (Taxus brevifolia). First tested in relapsed ovarian cancer, it was found to have activity as a single agent. It was then combined with platinum agents for first-line treatment of advanced ovarian cancer in several randomised clinical trials. The GOG111 trial demonstrated improved overall survival in the paclitaxel arm (38 vs. 24 months; p < 0.001) in women with suboptimally debulked advanced ovarian cancer.8 These findings were supported by those of the European/Canadian Intergroup OV10 study.9 However, the GOG132 three-armed study, which compared paclitaxel, cisplatin and cisplatin/paclitaxel in combination, found that there was no difference between single agent cisplatin and cisplatin/paclitaxel in combination (30.2 vs. 26.0 months overall survival; not significant).10 Paclitaxel alone was not as effective as regimens that included a platinum agent. The International Collaborative Ovarian Neoplam Group trial (ICON3) compared carboplatin or CAP (cyclophosphamide/doxorubicin/cisplatin) with carboplatin/paclitaxel in combination in a randomised controlled trail of 2074 women.11 The results confirmed those of GOG132; there was no improved survival with the addition of paclitaxel and there were fewer side effects from carboplatin alone. These results are still the source of much debate. Indeed, the National Institute of Clinical Excellence (NICE), the government medical advisory group in the UK, did not make a recommendation either for or against the use of paclitaxel in first-line treatment. In an attempt to reconcile
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the results of these four large clinical trials, a meta-analysis was performed.12 There was difficulty in combining the data due to heterogeneity in the study arms. However, these data demonstrated a non-significant trend towards superiority of platinum/paclitaxel combination therapy (HR: 0.82; 95% CI: 0.66e1.02). This study then went on to test statistically different theories as to why the results of GOG111, OV10, GOG132 and ICON3 differed. They concluded that the only theory which was consistent with the observed results was that there may have been suboptimal therapy in the platinum alone arms of trials that concluded an improvement for platinum/paclitaxel combination. The debate continues.
Endometrial cancer Endometrial cancer is a disease of peri- and postmenopausal women, with 91% of cases worldwide in women aged 50 years or older.13 Endometrial cancer is common in the Western world with incidences of 22 per 100,000 in North America, but much less common in African and eastern Asia (less than 3.5 per 100,000) largely due to differences in risk factors and life expectancy. Endometrial cancer largely presents at an early stage where cure rates from surgery alone are high and so, although it accounts for 3.9% of cancers in women worldwide, it causes only 1.7% of female cancer deaths. Nevertheless, a retrospective study of patients with stage I endometrial cancer demonstrated that there were very variable death rates, dependent on tumour differentiation and depth of myometrial involvement.14 However, there is great variation in treatment of women with stage I endometrial cancer with regard to pelvic lymph node dissection, arguably required for adequate staging, and use of adjuvant radiotherapy.15 The PORTEC study examined the role of post-operative radiotherapy in women with FIGO stage I endometrial cancer with either high grade or deeply invasive disease who had not undergone pelvic lymphadenectomy.16 Seven hundred and fifteen women were randomised to pelvic radiotherapy or no further treatment. Although there was higher local recurrence in the non-radiotherapy group (14% vs. 4%; p < 0.001), there was no significant difference in 5-year overall survival (85% vs. 81%; p ¼ 0.31) or endometrial cancer related deaths (9% vs. 6%; p ¼ 0.37). Complications in the treatment group were much higher (25% vs. 6%; p < 0.001) although most were grade 1 or 2 toxicities. The conclusions of this study were that women with stage I endometrial cancer under 60 years or those with grade 2 tumours with only superficial invasion did not require adjuvant radiotherapy, as it did not improve survival and increased toxicity. Pelvic lymphadenectomy Data from retrospective caseecontrol study suggested a role for pelvic lymphadenectomy in endometrial cancer.17
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Six hundred and forty-nine women with endometrial cancer over a 20-year period were divided into three groups: multiple site lymph node sampling, limited lymph node sampling, and no lymph node sampling. Histological prognostic features such as stage and grade were similar between the three groups. Patients receiving multiple site pelvic node sampling had a significant improvement in survival other those not receiving multiple site pelvic node sampling in both high and low risk groups. However, these data were not randomised, leaving the potential for bias. Thus, was the rationale for the surgical arm of the AZTEC trial.18 ASTEC was designed to investigate whether extensive pelvic lymph node dissection in addition to standard hysterectomy and bilateral salpingo-oophorectomy improved survival in women with endometrial disease thought to be confined to the uterine corpus (FIGO stage I). In addition, there was a second randomisation point following surgery to examine the role of external beam radiotherapy in women with early stage disease who had any of the following risk factors on histology: Grade 3 tumour, invasion into the outer half of the myometrium, serous papillary or clear cell histological type, or FIGO stage IIa. The trial has completed recruitment in May 2005 and results from follow up are awaited.
Cervical cancer Carcinoma of the cervix is still the leading cause of death from cancer in women in the developing world despite now being less prevalent than breast cancer, as rates in countries with adequate screening policies have dramatically decreased over the past 20 years.13 There is a relatively long lag phase from detecting carcinoma in situ to the development of squamous carcinoma of the cervix and the role of human papilloma virus in the aetiology is well established. Women with early stage disease (stage 1a1) can be treated with cone biopsy or simple hysterectomy. However, treatment of women with more advanced disease is changing in response to recent clinical data. Radiation vs. surgery Survival rates for women with stage Ib and IIa carcinoma of the cervix treated with either radical surgery (Wertheim’s hysterectomy and pelvic lymph node clearance) or pelvic radiotherapy were previously known to be similar. However, these two treatment modalities were directly compared in a randomised controlled trial of 367 women with stages IbeIIa cervical carcinoma.19 One hundred and eight patients in the surgery group required adjuvant radiotherapy following surgery. Overall five-year survival rates for women with squamous cell carcinoma were 84% in the surgical group and 88% in the radiotherapy group ( p ¼ not significant). For adenocarcinoma of the cervix, there was improved overall five-year survival rates in the
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surgery arm compared to radiotherapy (70% vs. 59%; p ¼ 0.05). Those patients who required radiotherapy following surgery had a poorer survival rate than either those receiving surgery or radiotherapy alone and also had a higher rate of complications. Current practice is therefore to restrict radical surgery to those who have, or are likely to have, negative lymph nodes, and offer radiotherapy to the rest. Concomitant chemotherapy Chemotherapy was demonstrated to have a synergistic effect with radiotherapy in cervical cancer cells in vitro. There have now been several RCTs which have examined the role of concomitant chemotherapy in the treatment of cervical cancer. These were analysed in a Cochrane Collaboration systematic review.20 They concluded that chemoradiation gave an improved overall survival (hazard ratio: 0.71, p < 0.0001) with an absolute survival benefit of 12% for women with at least bulky stage Ib cervical cancer. The potential improvement in survival may be more marked for those women with earlier stage disease. The studies included in the review covered a wide range of patient populations and types of chemotherapy regimens, although cisplatin was the most commonly used. However, improved survival was accompanied by increased side effects, which were significantly higher in the chemoradiation group. They concluded that chemoradiation gives improved survival in selected patients, but that further studies are required to examine the role of different chemotherapeutic agents, radiation regimens and the effect of haemoglobin levels. Fertility conserving surgery Increasingly, younger women are being diagnosed with cervical cancer at a relatively early stage. Many of these women will not have completed their family and therefore are concerned about preserving their fertility. A radical trachelectomy is an operation in which the cervix and paracervical tissue is excised but the uterine body is conserved, so leaving the possibility of pregnancy for women with stage IA2 or IB cervical cancer. There is a possibility of lymphatic spread in these women and so pelvic lymph node dissection is performed prior to the conservative surgery. As yet there have been no RCTs published on this approach. In a case series of 82 women who planned to have vaginal radical trachelectomy following laparoscopic pelvic lymph node dissection, nine were abandoned due to positive lymph nodes or endocervical margins.21 During a mean follow up of 60 months (6e156), there were two recurrences and one death (1.4%) with a calculated actuarial survival of 95%. In a more recent follow up paper, there were 50 pregnancies in 31 of the 72 women.22 Thirty-six of the pregnancies (72%) reached the third trimester and 28 (78%) delivered at term. In another series of 30 women
who had radical trachelectomy for early cervical cancer, there were no recurrences in a mean follow up of 23 months (range 1e64 months).23 Eight of 13 women trying to conceive achieved a total of 14 pregnancies and nine live births. They concluded that for a small subset of women fertility sparing surgery may be a safe and relatively successful alternative to radical surgery. The largest case series is that of 82 patients who underwent laparoscopic lymph node dissection and a modified Schauta procedure.24 There were three recurrences, all in women who had a primary tumour larger than 2 cm diameter. Twenty-nine of 38 women who tried to conceive achieved 47 pregnancies, resulting in 27 live births. All of these series suggest that this may be a reasonable alternative in well counseled women who are very keen to preserve their fertility. However, it is unlikely that these women would be happy to be randomised to radical hysterectomy and a large multi-national multicentre cohort study may be the best evidence we can collect to decide on the safety of this more conservative approach.
Vulval cancer Vulval cancer is relatively rare which therefore makes large clinical trials somewhat a challenge. The pioneering work of Taussig and Way25e27 in the early 20th century lead to the development of the en bloc radical vulvectomy due to the recognition of the need to adequately treat the inguinal lymph nodes in all but the very earliest of vulval cancer. However, there was high morbidity from the ‘butterfly’ incision, and therefore more recently efforts have focussed on reducing morbidity without compromising survival (reviewed in ref. [28]). A pilot study comparing different surgical techniques for groin dissection demonstrated that a less radical, more anatomically based method was equally successful in terms of lymph node retrieval, with reduced short-term morbidity and no evidence in this small study of increased mortality of the conservative approach.29 The concept that there is a primary or ‘sentinel’ lymph node to which the tumour first drains has been investigated for breast cancer. By injecting labels at the primary tumour site, e.g. coloured dyes or radiolabels, it is possible to track the lymphatic drainage and locate the sentinel lymph node. Whether this is a reliable method to select patients for conservative treatment or radical groin node dissection is the subject of current investigation for vulval cancer (reviewed by Van der Zee).
Conclusions Gynaecological malignancy is relatively rare and meaningful clinical trials are dependent on multi-centre international collaboration. However, the international gynaecological oncology community is committed to improving outcome for women and recent trials have been
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well supported. It is hoped that this collaboration will lead to robust data which will inform and improve clinical practice. Nevertheless, despite evidence from well performed trials, it can be difficult to change practice; for example, cisplatin remained the standard treatment in America, despite data from the 1980s demonstrating the advantages of carboplatin. In addition, the paclitaxel trials illustrate how modest changes in outcomes can be difficult to demonstrate even with large RCTs. It is likely that increasing knowledge about the genetic and proteomic basis for cancer will influence inclusion criteria of trials and translation of their results to the care of individual patients. These changes will be a challenge for the future, but one that must be addressed by both surgeons and oncologists. References 1. Quinn M, Babb B, Brock A, Jones J. Cancer trends in England and Wales. London: Office for National Statistics, The Stationery Office; 2001. 2. Shepherd JH. Revised FIGO staging for gynaecological cancer. Br J Obstet Gynaecol 1989;96:889–92. 3. Trimbos JB, Parmar M, Vergote I, et al. International Collaborative Ovarian Neoplasm trial 1 and Adjuvant ChemoTherapy In Ovarian Neoplasm trial: two parallel randomized phase III trials of adjuvant chemotherapy in patients with early-stage ovarian carcinoma. J Natl Cancer Inst 2003;95:105–12. 4. Bingham C, Roberts D, Hamilton TC. The role of molecular biology in understanding ovarian cancer initiation and progression. Int J Gynecol Cancer 2001;11(Suppl. 1):7–11. 5. Wiltshaw E, Subramarian S, Alexopoulos C, Barker GH. Cancer of the ovary: a summary of experience with cis-dichlorodiammineplatinum(II) at the Royal Marsden Hospital. Cancer Treat Rep 1979;63:1545–8. 6. Chemotherapy in advanced ovarian cancer: an overview of randomised clinical trials. Advanced Ovarian Cancer Trialists Group. BMJ 1991;303:884–93. 7. Advanced Ovarian Cancer Trialists Group. Chemotherapy for advanced ovarian cancer. Cochrane Database Syst Rev 1999;Issue 1. 8. McGuire WP, Hoskins WJ, Brady MF, et al. Cyclophosphamide and cisplatin compared with paclitaxel and cisplatin in patients with stage III and stage IV ovarian cancer. N Engl J Med 1996;334:1–6. 9. Piccart MJ, Bertelsen K, Stuart G, et al. Long-term follow-up confirms a survival advantage of the paclitaxelecisplatin regimen over the cyclophosphamideecisplatin combination in advanced ovarian cancer. Int J Gynecol Cancer 2003;13(Suppl. 2):144–8. 10. Muggia FM, Braly PS, Brady MF, et al. Phase III randomized study of cisplatin versus paclitaxel versus cisplatin and paclitaxel in patients with suboptimal stage III or IV ovarian cancer: a gynecologic oncology group study. J Clin Oncol 2000;18:106–15. 11. Paclitaxel plus carboplatin versus standard chemotherapy with either single-agent carboplatin or cyclophosphamide, doxorubicin, and cisplatin in women with ovarian cancer: the ICON3 randomised trial. Lancet 2002;360:505–15.
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