Prognosis and treatment of endometrial cancer

CURRENT DEVELOPMENTS

Prognosis and treatment of endometrial cancer MICHAEL SAMUEL LEO

D.

L. C.

BALLON,

LAGASSE,

WATSON Pittsburgh,

BERMAN,

M.D. M.D.

G. WATRING, Pennsylvania,

M.D.

M.D.

and Los Angeles,

Calforuia

An understanding of the patterns of spread and prognostic factors influencing survival Ls necessary to develop rational treatment programs for patients with endometrial cancer. The most important risk factors include the stage of tumor, status of pelvic lymph nodes, depth of myometrial penetration, tumor grade, cell type, and patient age. Because of the inherent inaccuracies of staging based on pelvic examination and the inability to assess the status of lymph nodes or myometrial penetration clinically, errors in management often result when radiation therapy is delivered prior to operation. Therefore, a rationale is offered for primary operative management of patients with Stage I disease, with consideration of adjunctive radiation therapy following operation based on extent of disease and a thorough evaluation of the high-risk factors. It is suggested that patients with more advanced stages of disease be considered for pretreatment operative evaluation. Data are presented which refute theoretical objections to this approach. (AM. J. OBSTET. GYNECOL. 136:679, 1960.)

is the most common site of invasive cancer of the female genital tract and the third most frequent site of malignancy in American women. Approximately 27,000 new cases of endometrial cancer and 3,300 deaths from this disease occurred during 1977.’ Clinical assessment of women with endometrial cancer shows that 75% of new cases are confined to the uterus2 Frequent early detection results from the evaluation of abnormal uterine bleeding by a physician before metastases occur. Paradoxically, because survivaI statistics suggest high curability and because therapeutic measures often include operations commonly performed for benign disease, many patients with en-

THE

ENDOMETRIUM

From the University of Pittsburgh School of Medicine, Magee-Womens Hospital, Departnwnt of Obstetrics and Gynecology, Division of Gynecologic Oncology, and the University of California, Los Angeles, Medical Center, Department of Obstettics and Gynecology,Division of Gynecologic Oncology. Reprint requests: Michael L. Berman, M.D., University of Pittsburgh School of Medicine, Magee- Womens Hospital, Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Pittsburgh, Pennsylvania 15213. 0002-9378/80/050679+10$01.00/0

@-I 1980 The C. V. Mosby

Co.

dometrial cancer are treated without benefit of careful staging and without consultation with physicians who are trained in the management of gynecologic malignancies. Treatment should be initiated only after careful staging and evaluation of factors which place a patient at high risk of failure of standard therapy.3

Biology Endometrial cancer disseminates: (1) by direct extension to adjacent structures, (2) through the lymphatic system to regional and distant lymph nodes, and (3) by the hematogenous route to remote sites (Fig. 1). When tumor is confined to the endometrium, lymphatic, and hematogenous metastases rarely occur. With increasing myometrial penetration there is a progressive increase in the incidence of lymph node metastases from approximately 3% with superficial tumors to more than 40% with deeply invasive tumors.4-7 Similarly, hematogenous spread and extension to adjacent organs is usually seen with deeply invasive tumors. Tumors which involve myometrium can ultimately extend to the serosa of the uterus. When this occurs 679

660

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et al

March 1. 1980 Am. J. Obstet. Gynecol.

Endwrtrlun

(cuff,

AiLzikLm uterln

subunthrrl)

i.,

sites

sagmnt 1 kmsa

*

I Ovarie5

I Pcrlaortic

3 Perltoneal

nodes

I

Cavity

t

L

Fig. 1. Patterns ot‘ spread of endometrial tumor c ‘III spr~acl throughout the peritoneal cavity to invohr the omrntum. liver, diaphragm, and other visceral surfacrs. Metastases to the ovaries by the lymphatic route can also result in peritoneal seeding with tumor. Such patients can present with ascites or bowel ctbsrruction. but c%xtensive intraperitoneal tumor is genrrall) an unexpected finding at operatic-m. Bec:ause the lympharics frotn the uterus accompany both the uterine and ovarian blood vessels. metastases can follow rhe uterine lymphatics to the h\;pogastric. external iliac. common iliac, and periaortic lymph nodes ok- can drain directly into the periaortic nodes via the lymphatics around the ovarian vessels. Autops) data suggest that periaortic nodes are the most common sites of’ nodal metastases and that these are frequently found in the absence of pelvic lymph node involvement.’ This conflicts with data from patients with endometrial carcinoma who undergo primary operation including pelvic and periaortic lymphadenectomies. In 74 such patients only one had aortic lymph node involvement without metastases to pelvic lymph nodes. while six of 10 patients with spread to pelvic lymph nodes also had periaortic nodal metastases.” These preliminary data have been expanded based on pelvic and periaortic lymphadenectomies in 228 patients with Stage I cancers. Again, pelvic lymph node metastases were seen more frequently than periaortic metastases, and periaortic lymph node metastases in the absence of positive pelvic nodes were rarely seen.” The conflicting autopsy data might reflect many patients who died from extrapelvic metastases despite local and regional control of tumor by operation and radiation. The intraoperative data suggest that the most common route of lymphatic spread is to the pelvic

cancer.

lymph nodes with frequent secondary involvement of‘ the periaortic nodes. Local spread to the cervix (Stage II) occ~~rs in 104 to 157~ of women with endometrial cancer. The biologic behavior of such tumors resembles that of primal.) cervical carcinoma with an increased risk of lymph node metastases and further extension to the vagina OI parametria. The overall frequency of pelvic lymph node tnetastases is reported to increase from lO.(i’% in tumors confined to the uterine fundus 10 36.39 in tumors with cervical extension.” This increase in part reflects the high incidence of deep myometrial penetration and high tumor grade seen with Stage II carcinomas, both of which are associated with an increased likelihood of lymph node metastases.” Similarly, involvement of the uterine isthmus increases the risk of lymph node metastases.‘. ” The vagina can be a site of metastases b\ l?mphatit spread or possibly seeding of the vaginal c.uff at the time of hysterectomy. In patients who had preopetative intrauterine radium therapy, the incidence of subsequent vaginal metastases was independent of the presence or absence of residual tumor at the time of hysterectomy.” These data suggest that rumor implantation at operation is an infrequent source of hagina spread of endometrial cancer and that a more likeI> source of these metastases might be spread through paracervical and paravaginal lymphatics. The OC‘CLI~rence of isolated metastases in the distal vagina also supports this hypothesis. Endometrial cancer spreads to the ovaries in approximately 5rc of women. The most likely route ofokarian involvement is the Iymphatics in the mesosalpinx and mesovarium. Because primary ovarian neoplasms are

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Table

I. Staging

Prognosis

of’ carcinoma

Stage Stage 0

Table

G3 Stage II Stage III Stage IV

malignancy;

cases

of

Stage

0

should not be included in any therapeutic statistics The carcinoma is confined to the corpus The length of the uterine cavity is 8 cm or less The length of the uterine cavity is more than 8 cm

Differentiated adenomatous carcinoma with partly solid areas Predominantly solid or entirely undifferentiated carcinoma The carcinoma has involved the corpus and the cervix but has not extended outside the uterus The carcinoma has extended outside the uterus but not outside the true pelvis The carcinoma has extended outside the true pelvis or has obviously involved the mucosa of the bladder or rectum. Bullous edema as such does not permit a case to be allotted to Stage

IVA Stage IVB Stage

Stage

Carcinoma in situ. Histologic findings are susof

IV

of endometrial

carcinoma:

No. of batients

It is desirable that the Stage I Casey be subgrouped with regard to the hirtologic type of the adenocarcinoma (IS follows: Cl Highly differentiated adenomatous carcinoma

G2

II. Endometrial

Criteria picious

stage I: Stage IA Stage IB

of the corpus uteri

and treatment

-

Spread of the growth to adjacent organs Spread to distant organs

often seen with endometrial cancer, careful histologic evaluation of the ovaries is necessary to distinguish between coexisting and metastatic ovarian tumors. In some instances this distinction cannot be made. Distant spread to involve the lung, liver, and skeleton is infrequent and usually occurs hematogenously. The lung is the most common site of distant metastases and is involved in 2?& to 3% of patients, often concurrently with other sites. Although poorly differentiated tumors represent less than 25% of endometrial cancer, 60% of patients with distant spread have anaplastic cancers.

Prognosis Prognosis is a function of several interrelated variables including stage of tumor, lymph node involvement, depth of myometrial penetration, histologic grade, cell type, uterine size, and patient age.*, ‘3--15 Although endometrial cancer is seen most frequently in women of low parity, survival does not correlate with this factor.” Each prognostic factor must be assessed independently to determine its relative importance. Stage of tumor. The stage of tumor at the time of diagnosis provides important prognostic information based on clinical and limited radiographic assessment of the extent of tumor. Since July 1, 1974, staging conforms to the recommendations of the Cancer Committee of the International Federation of Gynaecology and

1 12,655 2,185 1,596 585 17,021

I II

III IV

Total *Compiled

Stage

I

681

5-year survival* 5-vr survival

1

‘m

(74.4) (12.8) (9.4) (3.4)

9,670 1,089 480 54 11,293

from Kottmeier* and Morrow

Table III. Lymph cancer*

cancer

(76.4) (49.8) (30.1) (9.2) (66.3)

et al.‘O

node metastases in endometrial

Incidence of metastasest

I II

69/841 40/136

(8.2%) (29.4%)

III and IV

14/32 (43.8%)

I

5-yr suroival with metasta.ses$. 14/34

(41.2%)

6127 (22.2%) -

*In most series preoperative intracavitary radiation was used. tData from references 4, 6, 11, and 19 to 28.

therapy

SData from references 4, 11, 19, 26, and 29 to 31, Obstetrics (FIGO), as shown in Table I.‘” The prognosis for each stage of endometrial cancer as measured by 5-year survival statistics is shown in Table II. Lymph node involvement. Although operative findings cannot change clinical staging, they can provide useful prognostic information which influences subsequent treatment with radiation or chemotherapy. In some patients with Stage I carcinomas at high risk for lymph node metastases, the operative procedure of choice is a total abdominal hysterectomy and bilateral salpingo-oophorectomy with pelvic and periaortic lymphadenectomy.g In this way it is possible to evaluate the lymph nodes, detect occult ovarian or intraperitoneal spread, and evaluate prognostic factors including depth of myometrial penetration and occult cervical or isthmic extension.” Other selected patients with more advanced clinical stages have undergone pretreatment operative evaluation including abdominal exploration with pelvic and periaortic lymphadenectomy as described for advanced cervical carcinoma.‘* As expected, patients with more advanced stages of disease have a greater frequency of lymph node metastases, ranging from approximately 8% in Stage I to 44% in Stages III and IV (Table III). The importance of detecting lymph node metastases results from the poor prognosis associated with them. An initial operative approach for either beginning treatment or pretreatment evaluation permits subsequent management to be tailored to the extent of disease. Less invasive measures including lymphangiography have not been assessed systematically to determine the

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March 1, 1980 Am. J. Obstet. Gynecol.

Table IV. Lymph node metastases in Stage I endometrial cancer Incidence

*Data

from

references

of metashes

101339 6/43 31175

(3%) (14%) (41%)

4/132 15/139 16162

(3%) (11%) (26%)

4 to 7.

*Data from references 4 and 6. presence ot‘ 1).mph node metastases. Such metastases are often microscopic when present and, therefore, the potent.ial value nf this diagnostic tool seems to be limited in this disease.“? Because operative evaluation of pelvic lymph nodes can be difficult and morbid in elderl), infirm. and obese patients and because less invasive means are unproved, factors which frequently are associated with these metastases are utilized to estimate their risk. Depth of myometrial invasion. In Stage I endometrial cancer, depth of myometrial penetration appears to correlate best with the risk of lymphatic spread and hence prognosis. Data from L,ewis and associates,d Carmichael and Bean,” Creasman and associates.6 and Javert7 show a tow incidence of lymph node metastases with superficial cancers and a much higher incidence with deep+ invasive tumors (Table IV). Based on data from Cheon:‘:’ and L.ewis and associates.’ BoronoQ concluded that up to 50% of patients with deep myometrial penetration of tumor, independent of histologic grade. can be expected to have pelvic lymph node metastases. Differences in defining superficial. moderate, and deep invasion between these studies make an accurate assessment of risk of metastases for a given depth of myometrial invasion difficult. In addition, because some patients in the studies had “selective” lymphadenectomies performed, with removal of only- enlarged or suspicious lymph nodes. metastases might be mot-c prevalent than reported. The greater incidence of’ nodal spread with more deeply imasive tumors is reflected in the reported cure rates. Patients with noninvasive or superficially invasive tumor have an 80% to 85(X j-year cure rate, while those with deeply invasive tumors have a 60% survival rate.‘“. “.’ In addition to a greater risk of pelvic lymph node metastases, the risk of vaginal vault recurrences and distant metastases is also increased with deeply invasive tumors. Brown and associates3j reported vaginal recurrences in two of 196 patients (1%) without myometrial

invasion, in seven of 179 patients (4%) with invasion less than 5 mm, and in 13 of 171 patients (8%) with deeper invasion. Although clinical assessment of m,-ometrial penetration generally has not been feasible, a recent study reported this use for hysterography which can also localize the primary tumor.“” Grade of tumor. Of the factors which can be assessed reliably before operation in patients with Stage I cancers, the grade of tumor has the greatest prognostic importance because it correlates best with the risk of deep myometrial penetration. Cheon33 showed that low-grade tumors had less likelihood of deep myometrial penetration than those of high grade, ranging from 12% in grade I to 46% in grade 3 tumors. The grade of tumor indirectly reflects the risk of not only deep myometrial invasion and pelvic lymph node metastases (Table IV) but also vaginal vault recurrence and cervical extension. Vaginal metastases following hysterectomv appear to occur more frequently- and earlier with more anaptastic tumors,“’ although the difference is less apparent from metastases confined to the vaginal apex,:‘5. :3RSimilarly, the risk of cervical extension is increased with high-grade tumors.” In addition, risk of hematogenous spread to distant sites is increased with poorly differentiated tumors. Data from the University of California Los Angeles Medical Center and MageeWomens Hospital, Pittsburgh, Pennsylvania, found that 20 of 33 patients with pulmonary metastases had grade 3 cancers.“” In 48 patients dying of endometrial carcinoma, De MuelenaeresY also found a greater likelihood of hematogenous spread for poorly differentiated tumors; however, he found a similar risk of intraabdominal spread for all tumor grades. As expected, there is a progressive decline in cure rates of patients with poorly differentiated tumors as compared with those having well-differentiated tumors. Collected series show 5-year survival rates of 80%’ with grade 1, 66% to 74% with grade 2, and 50% with grade 3 tumors.“. “’ Cell type. The cell type can influence the prognosis of patients with endometrial cancer. Ng and associatesl” found an incidence of 67.1% adenocarcinoma, 20.3% adenoacanthoma, and 12.6% adenosquamous carcinoma in 542 cases seen from 1942 to 197 1. There were no squamous cell or clear cell tumors reported in that series, although these cell types have been reported infrequently. Confusion exists concerning the interpretation and implications of adenoacanthoma, adenosquamous carcinoma, and adenocarcinomas because the terminology is not uniform and precise criteria in establishing the proper diagnosis are tacking. Adenoacanthoma represents an adenocarcinoma with benign squamous metaplasia; adenosquamous carci-

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noma contains malignant both glandular and squamous elements, while adenocarcinoma has malignant glandular elements and no squamous componems. Attempts to subdivide adenosquamous carcinoma further by the degree of differentiation of the malignant squamous component have compounded the confusion without providing useful prognostic information.41, 42 The prognosis appears worse for adenosquamous tumors than for adenoacanthomas or pure adenocarcinemas. The most important factor which determines the prognosis of these tumors appears to be the differentiation of the malignant glandular elements.‘* Because approximately 75% of adenoacanthomas are well differentiated, they appear to have the best prognosis of the group with 7 1% overall 5-year survival and 84% survival rates in Stage I. Less than 20% of adenosquamous tumors, however, are well differentiated and 5-year survival rates range between 20% and 50%. Overall, adenocarcinomas without squamous elements have a 5-year survival rate of approximately 60%.34 Nevertheless, for a given grade of malignant glandular epithelium, the prognosis for a patient with any of these three types of tumor appears to be similar. The rarer tumors of the endometrium, which include clear cell or epidermoid carcinoma, have a uniformly poor prognosis with 5-year cure rates of less than 25%.43* 4J Uterine size. While uterine enlargement can result from extensive tumor growth which might impart a poor prognosis, uterine myomas and adenomyosis frequently cause this change and make this a less reliable prognostic indicator than depth of invasion or grade of tumor. Reported series have documented a 5-year survival rate of 85% with Stage IA disease but only 67% with Stage IB. 1h This difference in outcome appears to occur because higher grade tumors are found more frequently in Stage IB and lower grade tumors, more frequently in Stage IA. Therefore, when Stage I tumors are corrected for histologic grade, uterine size has little influence on survival.45 Patient age. Older patients present more often with an advanced stage of disease, more anaplastic cancers, more extensive myometrial invasion in early stages, and a poorer 5-year survival rate even when the rate is corrected for intercurrent disease.i4* ig, 46 Up to 90% of patients less than 60 years of age with tumor confined to the uterus on clinical assessment survive at least 5 years, while only 65% of those at least 60 years old survive 5 years. When corrected for intercurrent disease the survival rate is 95% versus 75% for the two broad age groups. 46 The risk of distant metastases to lung and multiple extrapelvic sites is increased in older patients. The median age of 33 patients with endometrial cancer at the University of California Los Angeles

Prognosis

and treatment

of endometrial

cancer

683

Medical Center and Magee-Womens Hospital, who subsequently developed pulmonary metastases, was 67 years as compared with a median age of 57 years for al! patients newly diagnosed as having endometrial carcinoma. The poorer survival also results from selective modification of therapy in some patients because of advanced age and coexisting medical conditions. When possible, optimal therapy should be chosen irrespective of the patient’s age.

Treatment The best approach to the management of patients with endometrial cancer must provide satisfactory treatment of the primary tumor, known metastases. and those areas at increased risk for metastases. Knowledge of the risk factors cited previously permits a rational approach to the treatment of the various stages and substages of this disease. Unfortunately, many questions concerning optimal treatment regimens remain unanswered because of difficulty in interpreting published data. The magnitude of this problem is great because many reports either demonstrate bias in patient selection for a specific treatment regimen or fail to control within each treatment group for the factors which influence prognosis.‘7 Prospective controlled studies have been found to be difficult to perform. The absence of such studies has inevitably resulted in the systematic inclusion of patients in treatment groups because of age, weight, or other medical conditions, thereby preventing meaningful comparison of data so generated. In addition, there is a lack of uniformity within and among studies concerning definitions of stage of disease, determination of tumor grade, means of detecting cervical involvement, and quantification of myometrial invasion. In some reports extent of disease conforms to the older League of Nations staging; in some, to FIG0 staging, and in others, to no standardized staging system. Many studies modify staging by operative findings, such as occult cervical spread, while most conform to accepted standards of clinical staging. Determination of tumor grade remains subjective, and comparison of histologic grading between studies is often meaningless. Some authors utilize Broder’s grading system (grades I to IV), based on both cellular pleomorphism and the glandular patterns, while others use that system recommended by FIG0 (grades 1 to 3). based solely on the glandular pattern and relative quantity of solid tumor with poorly preserved glandular architecture. Cervical involvement might be evaluated by clinical examination alone, cervical punch biopsy, endocervical curettage, cervical conization, or examination of the hysterectomy specimen. Myometrial penetration has been deter-

684

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March 1, 1980 Am. J. Obstet. Gynecol.

Total

Abdominal

Hysterecto:ny

and

Bilateral

Salpitlgo-oophorectomy

I

Grade 1

none or nyometrial

superficial penetration

Grade

intermediate deep myometrial penetration

I

no further treatment

2 or

3

none or superficial myometrial penetration

br if pelvic lymphadenectomy perfowed

I II i

I

I

I

I

whole pelvis radiation including upper half of vagina - 5000 rads in 5 weeks

I

G--L.-'t nodes

nodes

-

I

.I

‘$inal cuff radiation (7000 rads to mucosa providing approximately 2500 rads to a depth 5 millimeters)

Fig.

2. 7‘reatment

ofendometrialcancer-Stage

mined by dividing the uterine wall in half or in thirds or hv otherwise defining superficial, intermediate, and deep invasion. Often unclear is the means of reporting patients lost to follow-up or dying of intercurrent disease. ‘These problems are compounded by the inability LO standardize radiation therapy or operation between studies or even within studies which include patients who often span the experience of an institution over two or three decades. Hence, there is a great need for prospective controlled studies designed to minimize the man) variables cited. Despite a lack of such studies. optimal management of most patients can be recommended based on the extent of disease determined at operation. Stage I. The recommended approach to managing patients wit11 Stage I endometrial cancer employs operation which. when possible, consists of total abdominal hysterectomy and bilateral salpingo-oophorectomy (Fig. 2). Although many publications have reported the use of preoperative or postoperative radiation therapy. including external beam and intrauterine or vaginal radium, none has compared the various approaches in a prospective randomized fashion controlled for various risk factors. Nonetheless. S-year survival rates between studies show remarkable similarities when these nonhomogenous groups of patients are compared. Overall survival rates in 30 of 38 studies reviewed by

of

I.

Jones” and by Plentl and Friedmar? ranged from 65% to 85% with no clear improvement in survival rates for women treated with combined radiation and operation as compared with operation alone. In these studies the .i-year cure seen in nearly 4,000 patients treated with operation alone was 70.5% while the cure rate in 5,900 women treated by combined therapy was just under 75%. Despite the possibility that groups of patients managed with operation alone might include a larger number of “low-risk” patients with a better prognosis selected for less aggressive therapy, it has not been proved that radiation therapy improves survival. Hence the rationale for using radiation therapy in combination with operation includes both theoretical considerations and the proved ability to cure some patients, control recurrent tumor, and prevent recurrence in the pelvis and in regional lymph nodes with radiation alone. Initial management preferred by the authors consists of abdominal exploration, total hysterectomy, and bilateral salpingo-oophorectomy. Although some investigators have advocated radical hysterectomy with pelvic lymphadenectomy”’ there are no data substantiating improved survival with more extensive resection3. 47. a’ and there is no decrease in the risk of subsequent vaginal metastases. 49 Because endometrial cancer rarely spreads to the parametria without cervical

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involvement, removal of parametria in Stage I disease is not warranted. In addition, radical surgery in patients who are often obese and elderly is associated with increased morbidity and mortality rates. There is renewed interest, however, in sampling the pelvic and periaortic lymph nodes at the time of hysterectomy in some patients with Stage I disease.g Information gained can reduce the need for adjuvant whole-pelvis radiation therapy when lymph nodes are negative and can help to direct radiation therapy when they are positive. It is unclear whether the benefits of the additional information outweigh the risks of this more extensive operation and the complications of retroperitoneal dissection followed by radiation in those patients with lymph node metastases. When lymphadenectomy is not performed, the decision to administer radiation therapy is based on the depth of myometrial penetration and the histologic grade of tumor. Well-differentiated tumors confined to the endometrium or with minimal invasion rarely metastasize to lymph nodes or vagina and can be managed with operation alone. All other patients receive vaginal cuff irradiation or external beam therapy to include the pelvic lymph nodes and upper vagina. Because adjuvant radiation reduces the incidence of vaginal vault recurrence from 10% to 15% to 2% to 3%, therapy to this area is standard today.2g’ 5o, 5’ Unfortunately, no studies exist which show convincingly that survival is improved in patients so treated. Patients with poorly differentiated tumors, even without myometrial penetration, have a reduced 5-year survival rate despite infrequent metastases by the lymphatic route. Ng and Reagan5’ reported that 64% of 22 patients with Stage I endometrial carcinoma, Broder’s grades III and IV, confined to the endometrium survived 5 years, while 94% of 107 patients with grades I and II tumors survived. It is assumed that these patients have an increased risk of vaginal metastases and therefore are managed with radiation to the vaginal cuff. Because these superficial tumors rarely metastasize to pelvic lymph nodes, whole-pelvis radiation is avoided. Presumably the poorer survival reflects hematogenous spread even prior to myometrial penetration, indicating the possible need for adjuvant chemotherapy. To date no report of chemotherapy in this group of patients has been published. Patients with any grade of tumor invading one third of the myometrial wall are treated with radiation to the whole pelvis in an attempt to sterilize occult lymph node metastases. In such patients the upper half of the vagina is also included to prevent vaginal cuff recurrences. Because so many patients with anaplastic tumors have myometrial invasion or occult cervical ex-

Prognosis and treatment of endometrial cancer

685

tension and need whole pelvis radiation therapy, some investigators use preoperative radiation therapy for this entire group. Operation should precede radiation in all Stage I patients because this approach provides prognostic information not available with clinical staging alone which can serve as a basis to modify therapy. For example, unsuspected, disseminated intraperitoneal disease would preclude utilization of radiation therapy except for palliation; the absence of myometrial penetration might eliminate the need for radiation directed at the pelvic lymph nodes, and the presence of positive pelvic or periaortic lymph nodes would necessitate extension of radiotherapeutic ports and consideration of adjuvant chemotherapy. In addition, operation prior to radiation prevents unnecessary delays in the treatment of some radioresistant tumors and might reduce the risk of intraoperative bowel injury. A theoretical objection to postoperative radiation is the concern that intraoperative spread of viable tumor to the vaginal cuff occurs, which might be prevented by preoperative treatment. Since vaginal metastases usually result from lymphatic dissemination rather than intraoperative seeding,” postoperative radiation therapy should be equally effective in preventing vaginal vault recurrences. Indeed, patients treated with postoperative radiation demonstrate a similar risk of vaginal vault recurrences to that of patients treated with preoperative radiation.t4 A second objection to an approach of initial operation is the potential for an increased risk of radiation complications from adhesions induced by the pelvic surgery. Bowel complications are infrequent, however, with either preoperative or postoperative radiation. On the other hand, if preoperative intrauterine radiation is delivered, the risk of bowel complications can be increased in those patients where operative findings necessitate additional postoperative wholepelvis radiation therapy. Ten of 63 patients (16%) so treated experienced radiation injury to the bowel or urinary tract as compared with two of 113 patients (2%) treated with radiation to the whole pelvis following abdominal hysterectomy. 53 Five-year survival rates with radiation therapy alone in patients controlled for stage of disease, coexistent medical disease, and uterine size are significantly lower than those reported with operation or a combination of operation and radiation. s4 In 190 matched pairs of patients there was a significantly higher cure rate for operation with or without radiation as compared with radiation alone (p < 0.01) for each stage of disease. The 5- and lo-year survival rates in Stage I were 87% and 76%, respectively, for the group of patients treated with hysterectomy as compared with 69% and 52% for

686

Berman et al

the irradiated group. Therefore, radiation therapy without operation in Stage I is reserved only for the patients at poorest medical risk. L\%en radiation therapy alone is employed in the managemen! of medically inoperable patients with Stag? 1. grade I tumors, intrauterine packing with Hc)man capsules is utilized to deliver a total of approximareh 6,000 mg hours of radium in two applications sepax ated b\, 2 weeks.“: When &e uterine cavity is large or irregular ,md the tumor is well differentiated. three packings each qcparated by 2 weeks can deliver up to 8,000 mg hours. In addition, 7.000 to 8,000 rads can be delivered simultaneously to the vaginal mucosa with coipostats. Thr use of multiple applications minimizes variables such as the size and shape of the uterine cavit! and tumor volume within the uterus, which can preciucle the homogeneous delivery of radiation. Patients with anaplastic tumors receive an initial 4,000 to 5,000 rads of external whole-pelvis therapy over 4 to 6 weeks, followed by 3.000 to 4,000 mg hours of intracavitar). therapy in ant’ or two applications and a surface dose ol 3.000 to ~i,OOO rads to the vaginal mucosa with colpostats.““i Stage II. When cndometrial cancer extends to the cervix (Stage l 1). treatment must include the parametria, vagina. md pelvic ly-mph nodes in addition to the uterine fundus. Three treatment regimens currently advocated in&de radical hysterectomy with bilateral pelvic I~niphadenectom)-,I’ radiation therapy alone, consisting of both intracavitary treatment and external whole-pelvis therapy ,5i or a combination of radiation and operation.” Because pelvic lymph node metastases appear to br managed best with radiotherapy” and because the risk of metastases in Stage 11 disease is apprcIximatc$ 30% (Table III). radiotherapy to the whole pelvi\ is preferred to primary operation for management of the pelvic lymph nodes. Since disease in the uterim tundus appears to be managed less successfully with radiation, operation is preferred for disease in the uterine cavity. sq Hence, the approach we prefer for Stage II disease employs both radiation therapy and surgery. Radiation is delivered to the whole pelvis with external beam while intracavitar) therapy utilizes Suit-Fletcher afterloading applicators. In order to minimize the risk of ureteral and bladder injuries, whir h can occur when hysterectomy follows maximal radiation, the total dose of radiation is limited to provide approximately 7,000 rads to Point A and 5,500 rads to Point B. A total abdominal hysterectomy with bilateral salpingo-oophorectom); follows 6 to 10 weeks after the completion of radiation therapy. Stages III and IV. The treatment of Stage III carcinoma when associated with vaginal or parametrial

March 1, 1980 Am. J. Obstet. Gynecol.

metastases is similar to that outlined for Stage II disease. When bulky tumor is present in the cervix and parametria. more extensive whole-pelvis radiation is delivered in conjunction with brachytherapy with tandem and ovoids and subsequent operation is abandoned. A total of 8,500 rads to Point A and 6,000 rads to Point B can be given safely, but subsequent operation carries an unacceptably high risk of intestinal and urologic injuries. The treatment of Stage IV disease is designed primarily for palliation, although a few patients with tumor invading bladder or rectum will survive 5 years when treated with radiation therapy, sometimes combined with pelvic exenteration or chemotherapy (Table II). Pretreatment operative evaluation should be considered in patients with tumor outside of the uterine <‘orpus because of the high risk of occult lymph node metastases and intraperitoneal spread. Operative evaluation should include extraperitoneal pelvic and periaortic lymphadenectom);, abdominal washings, and biopsy of any suspicious areas in the peritoneal cavity. Postoperative radiation therapy can then be tailored to the extent of disease and can be given with curative intent if tumor is limited to the pelvis or for palliation if extrapelvic spread is detected. If lymph node metastases are found, the dose of radiation therapy should be augmented on the involved side and the radiation ports should be extended appropriately.‘” Recurrent carcinoma. When vaginal vault recurrences are encountered, treatment should consist of radiation therapy when possible.“” In patients with no prior external beam therapy, treatment should consist of 4,500 to 6.000 rads to the whole pelvis and vagina over 5 to 6 weeks followed by 4,000 to 5,000 rads to the vaginal mucosa with colpostats.j’j If prior external beam therapy was used during treatment of the primary tumor, transvaginal therapy followed by partial vaginectomy can often treat a small recurrence successfully. The 5-year survival rate for apparently isolated vaginal vault recurrences is between 35% and 50’%.:%“. .iH Metastatic endometrial carcinoma is best treated with chemotherapy. Various progestational compounds, including megestrol acetate and 17a-hydroxyprogesterone in a wide range of dosages, have produced objective response rates ranging from 25% to 40%.““, “’ Objective responses include measurable reduction of tumor volume, persistent decrease in the size of’ effusions, and relief of urinary tract obstruction. Patients most likely to achieve palliation with these compounds characteristically are young, have well-differentiated tumors metastatic to the lung in the absence of other metastases, and have a long disease-free interval after initial treatment.61 Nearly half of these patients will

Volume Number

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5

show objective improvement, and 5- and IO-year survival has been reported.jgz 6o Therapy should be administered for a minimum of 12 weeks since delayed responses to progestational agents are reported.jg When a patient does not respond to progestational agents, a combination of chemotherapeutic agents including Adriamycin, cyclophosphamide, 5-fluorouracil, and others are occasionally of benefit.62 Although controlled investigation of cytotoxic drugs in managing recurrent endometrial cancer has not been reported, a recent study evaluated Adriamycin and cyclophosphamide in eight patients with metastases refractory to progestational drugs. Objective responses were seen in six patients including three complete responses lasting up to one year. 63 Horton and associates64 reported a 19% response rate to Adriamycin in 21 patients unresponsive to progestins. Responses occurred from 21 to 200 days after treatment with a duration of 21 to 524

days. Cyclophosphamide administered as a single agent was ineffective in a similar group of patients. Survival was not improved in those patients who responded to Adriamycin when compared with those who failed to respond. Cohen and co-worker@s treated seven patients with a combination of melphalan, 5-fluorouracil and megestrol acetate and noted response in six patients. Bruckner and Deppe@ reported seven responders to a combination of cyclophosphamide, Adriamytin, 5-fluorouracil, and megestrol acetate and Omura and associate@’ reported two responses in six patients treated with methyl CCNU.67 Pelvic exenteration for recurrent pelvic tumor has only rarely been of value because of the high association with occult extrapelvic metastases. Of 36 patients who underwent exenteration for recurrent corpus cancer, 31 died within 18 months. The 5-year survival rate in this series was 14%.6s

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