Management of endometrial cancer

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Management of endometrial cancer Frank Lawton Traditionally endometrial cancer has been considered a relatively benign disease with an overall five-year survival rate of around 75%.

Randomised controlled trials of radiotherapy in this disease are rare and many patients at little risk of recurrent disease, cured by surgery alone, are still referred for adjuvant radiotherapy.

1 Management of endometrial cancer Frank Lawton Traditionally endometrial cancer has been considered a relatively benign disease with an overall five-year survival rate of around 75%. However, one-quarter of patients with this disease are dead within five years of diagnosis. Randomised controlled trials of radiotherapy in this disease are rare and many patients at little risk of recurrent disease, cured by surgery alone, are still referred for adjuvant radiotherapy. Lymph node status is a known prognostic factor but it is not yet known whether lymphadenectomy is of therapeutic significance. The roles of chemotherapy and hormonal therapy remain to be defined. Most patients are treated outside of trials and this situation must be addressed if improvements in treatment are to be seen. REVIEW 2003; 5: Keywords endometrial cancer, lymp hadenectomy, prognostic factors, radiotherapy, surgery. Introduction ~~~ According to the International Federation of Gynecology and Obstetrics (FIGO) staging system, a number of factors are deemed to be of prognostic significance for patients with endometrial cancer (Table 1). These include tumour differentiation, depth of myometrial invasion, tumour spread to the cervix, serosal or adnexal metastases, the presence of tumour cells in peritoneal fluid and involvement of retroperitoneal nodes. Studies by The Gynecologic Oncology Group (GOG) in the USA have been paramount in defining the importance of these various parameters and Morrow et al. have published data on their fiequency, relative risk and impact on survival.' Prognostic factors Overall five-year survival for patients with endometrial cancer is usually quoted at around 75%. Nearly 20% of patients with apparent clinical stage I and I1 disease, that is confined to the uterus/cervix, will have poorly differentiated tumours. These patients have a corresponding five-year survival rate of 66%. Of the 17% of patients with deeply invasive tumours, the sutvival rate is 64%. One-quarter of patients will have evidence of extrauterine disease, which is either gross or microscopic, with survival ranging from 40% (positive para-aortic nodes) to 65% (positive pelvic nodes). The& is a strong correlation between these factors. When a grade 1 tumour is confined to the myometrium one can predict a positive pelvic node rate of less than 3%. compared with a 34% rate for patients with poorly differentiated tumours with outerthird myometrial invasion.the greatest effect on survival can be determined by combining risk factors: grade 3 versus grade 1 and 2, less than versus more than inner third myoinvasion, the presence or absence of cervical stromal invasion and negative versus positive lymphvascular space invasion.* Three risk groups can be identified; patients with either no risk factors or only one risk factor, those with two or three risk factors and those with four. Five-year survival is 97%, 66% and 17% respectively.' Surgery and staging Traditionally, surgery for early endometrial cancer has been limited to total abdominal hysterectomy, bilateral salpingo-oophorectomy (TAH-BSO) plus excision of vaginal cuff. The latter was performed because of the erroneous belief that vaginal vault recurrence was due to local, intraoperative seeding of tumour cells. More extensive surgery was thought to be contraindicated because of the advanced age and concurrent medical problems commonly encountered in patients with endometrial cancer and also because overall sumval with simple hysterectomy is so good.while these belie6 are true, almost half of the cases in the USA are seen in women over 65 years old and two-thirds of them have medical problems which could increase surgical morbidity.' Studies have shown that biological rather than chronological age should be considered in such cases.' The FIGO staging classification demands knowledge of Author details Frank Lawton MD FRCOG, Consultant Gynaecologicel Cancer Surgeon, King's College Hospital, Denmark Hill, London SES 9RS. UK. fglawtonodoctonorg.uk Royal College of Obstetricians and Gynaecologists 79

2 REVIEW Table 1. FIGO classification of endometrial carcinoma Sbgb la Tumour limited to the endometrium Ib Invasion of the inner half of the myometrium 2003;5:79-83 Ic Invasion to the outer half of the myometrium Ila Endocervical glandular involvement IIb Cervical stromal invasion IlIa IlIb Vaginal metastases llic IVa IVb Tumour invasion of serosa and/or adnexa and/or positive peritoneal cytology Metastases to pelvic and/or para-aortic nodes Tumour invasion of bladder and/or bowel mucosa Distant metastases including inm-abdominal disease and/or inguinal nodes In addition each stage is further subdivided (grade 1, gnde 2 or grade 3) based on tumour grade lymph node status, but it is apparent that many gynaecologists are still reluctant to recommend lymphadenectomy on the grounds that this will lead to an even greater increase in morbidity. Studies suggest that less than 50% of patients undergo lymphadene~tomy.~ The literature contains many studies regarding this aspect of management and the consensus is that pelvic and para-aortic lymphadenectorny can be added to TAH-BSO without a significant effect on morbidity and mortality. Larson et al. presented data on 35 patients who had TAH-BSO compared with 42 patients who underwent lymphadenectomy in addition to TAH-BSO. Operative time was increased in the latter group, with a mean of two hours and nine minutes compared with one hour 2J minutes, and there was a longer inpatient stay. However, there was no difference in transfusion rate, infective episodes, postoperative problems or mortality? Notwithstanding the above problems, the extent of surgical endeavour to remove pelvic and paraaortic nodes is also controversial.the GOG has defined a selective pelvic lymphadenectomy as the removal of nodal tissue h m the distal half of the common iliac vessels, the anterior and medial aspects of the external iliacs and removal of fat in the obturator fossa anterior to the obturator nerve; a mean harvest of nodes per patient would be expected (there is also a definition of selective para-aortic lymphadenectorny). In reality, about half of all patients who have some sort of nodal surgery will have node sampling only Therefore, in a, patient with endometrial cancer the following surgical approach should be adopted as it addresses all significant surgicopathological variables. On opening the abdomen peritoneal fluid or saline washings should be collected for cytology. Since all peritoneal surfaces need to be examined and upper abdominal surgery may be necessary to remove any suspicious lesions, a vertical midline incision is recommended. If imaging studies have shown minimal myometrial penetration, or if on sectioning the uterus the disease appears superficial (see below), and the tumour is well differentiated then TAH-BSO alone is probably su5cient (despite FIGO recommendations). For all other tumour grades, histology other than pure adenocarcinoma or evidence of deeper myometrial penetration, pelvic and para-aortic lymphadenectomy should be carried out. Occult omental metastases occur in around 10% of patients with clinical stage I disease and, therefore, omentectomy should also be considered? Is lymphadenectomy beneficial? There are no data h m prospective, randomised studies to address this question and studies to date have produced conflicting results. Kilgore et al. showed that the overall sumval did seem to be superior for those patients who had undergone lymphadenectomy. However, it was not possible to ascertain why some patients had undergone nodal surgery while others had not. This was probably due to either surgeon preference and/or skill or patient characteristics, other prognostic factors were not taken into account. In the large multicentre COSA-NZ- UK endometrial cancer study, which was initially designed as a trial to assess adjuvant hormonal therapy in high-risk patients but in which many of the patients underwent lymphadenectomy, the recurrence rate was hgher for node-positive patients (45% versus 14% for node-negative patients) with a significant difference in disease-ke interval and sumval.9 However, others have suggested that lymphadenectomy has no effect on mortality. The therapeutic role of lymphadenectomy may 80

be defined by the results of the continuing ASTEC (A Study in the Treatment of Endometrial Cancer) study coordinated by the Medical Research Council.

Should routine lymph node surgery be recommended when only about 8% of patients with apparent stage I disease will be node positive?

3 be defined by the results of the continuing ASTEC (A Study in the Treatment of Endometrial Cancer) study coordinated by the Medical Research Council. Nevertheless, even if lymphadenectomy is proven to be therapeutic, two important factors must be considered. Should routine lymph node surgery be recommended when only about 8% of patients with apparent stage I disease will be node positive? Since pelvic radiotherapy influences rates of local recurrence but not distant recurrence and survival, is it not likely that pelvic wall surgery will produce similar results? Knowledge of lymph node status may also have a positive impact on overall treatment morbidity. In a study of 40 consecutive patients with clinical stage I disease, eight of 18 patients with high-risk disease were node negative." Without knowledge of nodal status all these patients would receive postoperative radiotherapy, with such knowledge their radiotherapy field could be planned appropriately with a possible reduction in morbidity. There is clearly a role for laparoscopic surgery in endometrial cancer, especially in reducing operative morbidity and inpatient stay. The completeness of lymphadenectomy is similar using the two techniques and laparoscopic assisted vaginal hysterectomy is a less morbid procedure. Stage II disease Dogmatic treatment recommendations are impossible because of the lack of randomised data and small patient numbers in any series. With a node-positive rate of more than 30% lymphadenectomy is mandatory and, clearly, the uterus and adnexae should be removed.i2 Parametrial excision (radical hysterectomy) has been endorsed but, since almost all patients with stage I1 disease will receive radiotherapy, the parametrium and vaginal vault will be included in the treatment field. Another approach is to offer presurgical radiotherapy (external and intracavitary) followed by 'completion hysterectomy' after six to ten weeks. Survival rates for either approach are similar, but most papers relating to the combined approach report significant bowel morbidity. Recurrences are rarely seen at the vault alone and pelvic relapse tends to be accompanied by evidence of distant metastases. Clinical stage Ill disease The nature, and indeed the operability, of an adnexal mass can usually only be determined at laparotomy. Excision of all macroscopic disease is of major prognostic importance in stage 111 disease and enlarged lymph nodes should be excised if possible.the prognosis is confbsed by the FIG0 staging system, since only those patients with positive peritoneal cytology are included in the same stage as those with serosal or peritoneal disease, vaginal metastases and para-aortic disease. Five-year sumval is around 55%. Abdominal recurrence is common but is rarely the only site of failure (vault, pelvis, intrahepatic, lung) suggesting that after surgery the whole abdomen should be treated either with radiotherapy or chemotherapy as part of a randomised clinical trial, the problems of small patient numbers of this stage at presentation not withstanding. Radiotheram ~ ~~~ As with so many aspects of gynaecological cancer, the role of adjuvant radiotherapy in patients with endometrial cancer has not been established on the basis of data h m randomised trials. In order to show a good overall prognosis for patients with this disease such studies would need to be very large to show any benefit from radiotherapy. However, in a review of over 6000 patients (in 23 reports) the five-year sumval for patients with clinical stage I disease treated by surgery alone was 75% compared with 78% for those treated by surgery and radi~therapy.'~ A study of patients with medium-risk stage I disease treated by surgery, without lymphadenectomy, and randomised to receive no further treatment or pelvic radiotherapy reported similar five-year survival for both groups (85% for the surgery-only group compared with 81% for the irradiated group), but a reduction in locoregiomal recurrence rates for those treated with adjuvant radiotherapy (14% and,%).i' In this study medium-risk stage I disease was defined as well differentiated tumours with 50% myometrial penetration or more, moderately differentiated tumoun with any degree of myoinvasion or poorly differentiated tumours with <50% invasion. In the study 40 non-irradiated patients developed a vault recurrence but only four died fiom it. Since radiotherapy is successu in treating reourrent vault disease, with cure rates of nearly 70??,15 the routine practice of offering medium-risk patients radotherapy must be questioned. REVIEW

REVIEW 2003;5:79-83 Radiotherapy _- has been shown to reduce the risk of vault and vaginal recurrence and it would therefore seem logical to offer high-risk patients vault and pelvic radiotherapy.".

Such treatment has little or no toxicity and therefore has a high patient acceptability, but response rates are rarely greater than 20%.

4 REVIEW 2003;5:79-83 Radiotherapy _- has been shown to reduce the risk of vault and vaginal recurrence and it would therefore seem logical to offer high-risk patients vault and pelvic radiotherapy."." Hormonal therapy Hormonal therapy has been used at almost every stage of adjuvant and at recurrence) but, once again, proven efficacy has not been established. Such treatment has little or no toxicity and therefore has a high patient acceptability, but response rates are rarely greater than 20%. Response is more common in patients with positive steroid receptors (progesterone and oestrogen) with rates of 40% reported for receptor-positive patients compared with 12% for the receptor-negative group.'" Response is also seen more commonly in patients with well-differentiated tumours and in those patients with a surgery-hormone treatment interval of more than three years. Tamoxifen, a known mutogenic agent in the endometrium, has been used both as a single agent and in combination with progestogens in the disease. Its efficacy stems h m its ability to block oestradiol receptor sites and to increase the number of progesterone receptors. Response rates are variable, 043% with a mean of 22%, and seem related to tumour grade and receptor status. Chemotherapy Many cytotoxic agents, alone and in combination, have been evaluated in endometrial carcinoma but only a few drugs (cisplatin, carboplatin and ' doxorubicin hydrochloride) consistently produce response rates of greater than 20%. Most responses are only partial and of short duration, generally averaging about six months. These drugs in combination produce somewhat higher response rates.the medan survival for almost all patients treated with cytotoxics is less than 12 months, but many patients do gain symptomatic benefit. In this group of patients (elderly, many with coexisting medical problems) toxicity may be considerable and the potential benefit e m cytotoxic therapy that will only offer temporary palliation must be weighed against the adverse effects. The addition of progestogens to combination chemotherapy has little or no effect on response, duration of response and survival. Uncommon clinical circumstances Occasionally, the diagnosis is only made afler hysterectomy has been carried out for other reasons. It has been proposed that this scenario could be avoided if the uterus was opened in theatre to inspect the cavity, but histopathologists consider that this reduces the fixing of the specimen prior to transport to the laboratory. In general, patients with grade 1 or 2 tumours with minimal myometrial invasion require no further treatment, although if the ovaries were conserved a further laparotomy or lapamcopy should be carried out to remove the adnexae and to perform surgical staging. For all other lesions radiotherapy should be considered. A rare occurrence is the finding of synchronous endometrial and ovarian tumours. It may be difficult to determine whether the clinical picture is one of metastatic spread from the endometrium, particularly since about 50% of patients will have endometrioid tumours in both organs. In general it should be assumed that each is a primary tumour and treatment should address this; for example, the patients may well need chemotherapy and pelvic radiotherapy, The issue regarding the use of hormone replacement therapy after treatment for endometrial cancer is controversial, but data would suggest that combination oestrogen and progestogen therapy has no effect on the incidence of tumour recurrence. This should especially be offered to young women (5% of women are under the age of forty years at diagnosis). Conclusion Despite the thirty years since the original publication relating to the incidence of nodal metastases in endometrial cancer,i9 we remain ignorant of the best way to treat patients with endometrial cancer. Most surgical regimens do not address risk factors appropriately, we cannot define the place of radiotherapy and have no cytotoxic regimens that provide proven longterm benefit. Advances in molecular medicine may lead to an improved outlook (in many years time) but, at present, optimal surgical staging is the most likely means by which to improve the management of women with endometrial cancer. H 82

5 References Morrow CP, Bundy BN, Kurman RJ. Creasman WT, Heller P, Homesley HD, er a/. Relationship between surgical-pathological risk factors and outcome in clinical stage I and II carcinoma of the endometrium: a Gynecologic Oncology Group study. Cynecol GKOI 1991;405%5. Kadar N. Malfetano JH. Homesley HD. Determinants of survival of surgically staged patients with endonietrial carcinoma histologicauy confined to the uterus: implications for therapy. Obsrer Gynecol 1992;80:655-Y, Lawton FG. Early endometrial carcinoma - no more TAH. BSO and cuff. In: Studd JWW, editor. hofress iii Obstetrics and Cyimerolo~y. Vol 10. London: Churchill Livingstone; p Lawton FG. Hacker NF. Surgery for invasive gynecologic cancer in the elderly female population. Ohtet Gyiiecol 1990;76: Lanon DM. Johnson K. Olson KA. Pelvic and panaortic lymphadenectomy for surgical staging of endometrial cancer: morbidity and mortality. Obsrer Cynecol 1992;79: Girardi F. Pecru E. Heydarfadai M. Haas J,Winter R. Pelvic lymphadenectomy in the surgical matment of endometrial cancer. Gynecol Oiicol 1993;49: Kilgore LC. Partridge EE.Alvucz RQAusrin JM, Shingleton HM. Noojin F 3rd, el al. Adenoarcinoma of the endometrium: sumval comparisons of patients with and without pelvic node umpling. Cynecol Oncol 1995; Chen SS, Speigel G. Stage I endometrial carcinoma. Role of omend biopsy and omentectomy J Reprod Med 1991; COSA-NZ-UK Endometrial Cancer Study Groups. Pelvic lymphadenectomy in high risk endometrial cancer. Int J Cynecol Cancer 1996; Belinson JL. Lee KR, Badger GJ. Pretoriur RG. JarreU MA. Clinical stage I adenocarcinoma of the endometrium - analysis of recurrence and the potential benefit of staging lymphadenectomy. Gynecol Onrol 1992;44: Lawton FG.The management of endometrial cancer. BrJ Obsrer Gyiiaecol 1997; Morrow CP, Di Saia PJ,Townsend DE. Current management of endometrial carcinoma. Obsrer Cynecol 1973;42: Jones HW Ill.Treatment of adenocarcinoma of the endometrium. Obstrr Gynecol Suw 1975; Creutzberg CL, van Punen WLJ, Koper PCM. Lybeert ML. Jobsen JJ, Warlam-Rodenhuis CC, er al. Surgery and pompaxk tdkhaqy -rgrg alone for patieno with -1 edamuid carcinoma: multicenhc nndomrced aid.portbc Study Gmup. Port Opentivc RadiationThenpy in Endometrial Carcinoma. Luwf 2000,355:14oc Ackerman 1. Malone $Thomas G. Fnnrcen E, Balogb J. Dembo A. Endometrial cvcinoma - m k eltectiveness of adjuvant irradiation vs thmpy reserved for relapse. Cynecol Oncol 19%,60: Aalden JG. AbelerV, Kolstad P, Onsrud M. Postoperative external irradiation and pmgnostic parameters in stage I endometrial carcinoma: clinical and histopathologic study of 540 patients. Obstet Cynecol 1980; Lotocki RJ. Copeland LJ. DePetrillo AD, Muirhcad W. Stage I endometrial adenocarcinoma: treatment mdts in 835 patients. Am J Obsfet Cynecol 1983; Lentz SS. Advanced and recurrent endometrial carcinoma: hormonal therapy. %in Oncol 1994;21: Lewis BY StaUworthy JA Cowdell R. Adenocarcinoma of the body of the uterus. J 0brk-l Gynaecol Br Commonw :

Chapter 2: Initial treatment for endometrial cancer (including histologic variant type)

Chapter 2: Initial treatment for endometrial cancer (including histologic variant type) CQ01 Which surgical techniques for hysterectomy are recommended for patients considered to be stage I preoperatively?