Recurrent Endometrial Adenocarcinoma EDWARD H. COPENHAVER, M.D. WILLIAM A. NAHHAS, M.D.
How frequent is recurrent endometrial adenocarcinoma after apparently complete removal of the tumor? When and where does it recur? How do we treat it? Can it be prevented? An analysis is presented of recurrent malignant disease after hysterectomy for adenocarcinoma confined to the uterine fundus.
PRESENT STUDY From 1926 through 1962, 194 patients were confirmed to have adenocarcinoma of the endometrium limited to the fundus after total hysterectomy with salpingo-oophorectomy at the Lahey Clinic. The pre therapy classification was as follows: Stage I, 185; Stage II, 2; and unknown, 7. Concentration on this series of cases is believed to be important for two reasons: the majority of patients with endometrial adenocarcinoma fall into this category, and recurrent malignant disease in this group is a medical pitfall to the surgeon and the patient who have been inclined to an optimistic viewpoint owing to the surgical and laboratory findings. Table 1 presents a summary of the follow-up status of all patients. The courses of patients who are alive have been followed a minimum of five years; many have been followed much longer. Note that 29 of the 194 patients have a history of recurrent malignant disease, yet only 16 are known to have died from recurrent disease before reaching the magic classification of a "five-year cure." Table 2 presents an analysis of the 29 patients with confirmed or suspected recurrent adenocarcinoma of the endometrium. We have included one patient with remote recurrence without tissue confirmation (Case 7) and several cases at the end of the table with a reasonable clinical implication of recurrent malignant disease. Of the 17 patients with vaginal involvement, 6 are living, 2 of whom are receiving treatment. Of the 6 patients with focal vaginal tumor, 5 are living. Our results indicate that patients with focal vaginal involveSurgical Clinics of North America- VoL 48, No.3, June, 1968
Summary of 194 Cases of Endometrial Adenocarcinoma Limited to Uterine Fundus (1926-1962)
Alive No recurrent malignant disease Following apparent cure of recurrent malignant disease With recurrent malignant disease
146 140 4
Recurrent malignant disease (before 5 years) Recurrent malignant disease (after 5 years) Postoperative period Intercurrent disease Unknown cause
16 5 5 12 2
With recurrent malignant disease Without recurrent malignant disease
ment have a good prognosis with irradiation, and that patients with both vaginal and deep pelvic tumors may obtain good palliation with irradiation. For the 12 patients without vaginal disease, the prognosis was poor, but only 1 patient had a fair trial of progestin therapy. The timetable for the manifestation of the 29 recurrences was as follows: first year, 7 (24.1 per cent); second year, 7 (24.1 per cent); third year, 3 (10.4 per cent); fourth year, 4 (13.8 per cent); fifth year, 3 (10.4 per cent); and from the sixth to the sixteenth year, 5 (17.2 per cent). The disease recurred in 24 of the 29 patients (82.8 per cent) within the first five years after initial treatment. While all the living patients had Inicroscopically well-differentiated tumors, no relation was apparent between the degree of Inicroscopic differentiation and the survival pattern for the patients who had died. No correlation could be obtained between the age of the patients and the ability to survive after recurrence.
PREVENTION Glancing at Table 2, we may conjecture that the focal vaginal recurrences could have been prevented. However, when deeper or remote tissues are involved, we wonder whether the vaginal involvement was primary or secondary. Indeed, when surveying the records of those with involvement of the deep pelvic tissues or with remote spread of the tumor, we wonder if such recurrence can be prevented or if the patient's fate is sealed even before the physician sees the patient. At this point we shall continue from an optiInistic point of view. There are three logical considerations for the prevention of recurrent adenocarcinoma of the endometrium: the effect of surgical technique, the role of irradiation, and the possible benefit of hormone therapy. What changes can be made in surgical technique? First, there should be a minimum of manipulation in making the diagnosis, including the bimanual exaInination. Cole and associates 5 have demon-
RECURRENT ENDOMETRIAL ADENOCARCINOMA
strated the potential dissemination of tumor cells through curettage and operative handling of the uterus. Hurtigl1 has expressed concern about the hazards of dilatation of the cervix, emphasizing the merit of a suction dilator. It has been our experience that tissue may be obtained in most instances of malignant disease of the uterus with little or no dilatation. In short, we should not be driven to overzealous diagnostic or therapeutic techniques because of a routine but should be flexible in the best interest of the patient. Before hysterectomy, various surgical techniques have been tried. The cervix, upper vagina, or both have been packed. The external Table 2. Analysis of Recurrences Among 194 Cases of Endometrial Adenocarcinoma Limited to Uterine Fundus at Hysterectomy (1926-1962 ) FOLLOW-UP CASE
1 2 3 4
Vagina, Vagina, Vagina, Vagina,
apex apex apex apex
Vagina, middle third Vagina, middle third
7 8 9 10 11
Vagina, Vagina, Vagina, Vagina, Vagina,
12 13 14 15 16 17
Vagina, apex; pelvis Vagina, apex; pelvis Vagina, middle third; pelvis Vagina, apex; pelvis; abdomen Vagina, apex; abdomen Vagina, apex; pelvis; bladder; lungs Pelvis; abdomen Pelvis; abdomen; omentum Pelvis; lungs Abdomen Lungs Lungs; brain Lungs; supraclavicular node Bones; supraclavicular node Unknown Unknown Unknown Unknown
18 19 20 21 22 23 24 25 26 27 28 29
lower third; vulva apex; pelvis apex; pelvis apex; pelvis apex; pelvis
TIME (months*) 12 24 40 62 132 166 13 54 83 189 3 10 13 16 41 85 4 36 13 82 59 126 8 26 48 56 30 15 8 11 20 45
Irradiation; radium Irradiation Radium Irradiation Cautery; irradiation Progestins Irradiation Irradiation Radium Irradiation; radium Unknown Irradiation Unknown Irradiation; progestins Irradiation Radium Irradiation Radium None
Alive Dead Alive Alive
92 8 106 104
Progestins Progestins None Irradiation Unknown None None Progestins , Progestins None Unknown None None
Lost Dead Dead Lost Dead
Dead Dead Dead Dead Dead
64 62 5 26 2
Alive Dead Dead Dead Dead Dead Dead Dead Dead Dead Dead Dead Dead
59 8 13 7 1 5 1 1 1 1 21 5 9
"Number of months between initial treatment and discovery of recurrence. tNumber of months between diagnosis of recurrence and death or last contact. NOTE: Initial treatment included irradiation or radium in addition to hysterectomy and salpingo-oophorectomy (Cases 16, 19,23, 24, 25, and 28).
cervical os has been sutured; no benefit was demonstrated among 67 of our patients with this technique. 7 Adequate blocking of the cervix with the solid metal Spratt 30 obturator has been used in 33 patients at the Lahey Clinic from 1960 through 1966; to date no vaginal recurrences have been noted. However, one patient has manifested metastasis to the bone and another, metastasis to the lungs. Pratt and co-workers22 observed no recurrences in 100 patients managed by a combination of a dry pack, suture closure of the cervix and vagina, and rescrubbing of the operative field before proceeding with a hysterectomy. Can recurrence be prevented by extending the scope of surgery? In 1952, J avert 12 pointed out that benign and malignant disease of the endometrium was capable of spreading to the pelvic lymph nodes and found a 28 per cent incidence of such metastasis among 50 patients with endometrial adenocarcinoma. Thus began a short period of enthusiasm for radical hysterectomy and pelvic lymphadenectomy. Schwartz and Brunschwig's,26 Winterton's,34 and Parsons and Cesare's21 five-year survival rates of 73 per cent, 79 per cent (with preoperative irradiation in many cases), and 81 per cent respectively do not, in our judgment, justify the routine use of radical surgical procedures. It is of interest that J avert and Renning13 concluded that such procedures should be considered only for selected patients and that only 2 per cent of patients may be benefited because of coexisting hematogenous spread in the presence of positive pelvic nodes. The merit of supplementary irradiation has been debatable for many years. Extended survival with irradiation has not been proved to everyone's satisfaction. We have abandoned irradiation when a microscopically well-differentiated tumor is confined to a normal-sized uterus. For initial treatment, we have replaced radium with total pelvic 2 Mev. irradiation. Boutselis et al.,3 Price et al.,23 Rutledge et al.,25 and Dobbie 8 have presented good evidence that vaginal recurrences are reduced by irradiation, especially in the form of vaginal radium. Perhaps some selection can be used in judging the need for irradiation to reduce the incidence of recurrent tumor in the vagina. Carmichael and Bean4 have shown that vaginal recurrence is more likely when the tumor penetrates deeply into the myometrium and when the lower uterus is involved. Since such involvement cannot be determined before operation, this would serve only as a guide for postoperative irradiation. As noted in the preceding paragraphs, it is possible that the disseInination of cancer may be reduced by mechanical means, thereby obviating the need for irradiation. Three questions should be raised in regard to both the prophylactic and definitive use of radiotherapy for adenocarcinoma of the endometrium: (1) Does multiple source intra-uterine radium provide an accurate and uniform source of irradiation for the endometrium and myometrium? We think not. (2) When high voltage x-ray therapy is given, are its margins accurately defined? Smedal 28 believes that a common universal fault is the failure to check the inferior margin, thereby having the field of irradiation too high and consequently missing
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the lower vagina and obturator nodes. (3) Is the radium in a vaginal applicator aligned to provide uniform, effective irradiation to the vagina? Several years ago our applicators had to be revised to achieve this result. In the future what will be the role of hormone therapy in preventing recurrence of endometrial adenocarcinoma? A large, cooperative, controlled study is now in progress to assess the addition of progestins as an adjunct to primary treatment. Lewis and co-workers 18 have cited the problems of this type of research and stress the need for more material and time to research any conclusions. McDuff and Barrall 19 noted that only 3 of 24 patients had residual carcinoma at hysterectomy following intracavitary radium and progestin therapy. Sherman 27 reported the effect of progestin therapy before definitive treatment, noting that the size of the uterus decreased, bleeding decreased, and the histologic appearance of the cancer was altered in 75 per cent of patients with 18 per cent of them showing no identifiable cancer after treatment. Also, it is noteworthy that Wall and associates 32 were able to produce regression of a well-differentiated tumor with prolonged use of clomiphene citrate. In conclusion, it is conceivable that hormone therapy could be useful either in preventing or reversing the formation of endometrial cancer or in altering the cancer so that our standard treatment is more effective.
TREATMENT Therapy is, of course, dependent upon the location of the recurrence, its size and mobility, and the previous treatment rendered to the patient. For focal vaginal recurrence, Greentree 9 reported deep electrocoagulation of a lesion, 3 cm. in diameter, in a patient whose four-year follow-up course was negative for cancer. The senior author (E.H.C.) has treated two patients in this manner but later had to resort to irradiation. Bateman et aU have used local submucosal injections of thio-tepa every two to three weeks directly into the vaginal tumor with little growth noted through 39 months of observation. We believe radium, high voltage x-ray therapy, or both, to be the treatments of choice, as attested by the results outlined in Table 2. Rubin et al. 24 summarized eight reports regarding recurrent vaginal tumor; five-year survival rates varied from 7 to 40 per cent. For pelvic recurrence with or without vaginal involvement the choice lies between irradiation and radical surgery. Since adenocarcinoma of the endometrium may be amenable to x-ray therapy, it would seem logical to subInit the patient to definitive, total pelvic irradiation, provided this is not prohibited because of previous similar treatment. For the resectable tumor, for which a tumoricidal dose of irradiation cannot be given, radical surgical excision is the only hope for cure. Unfortunately, the opportunity for surgical resection is rare in the patient with recurrent endometrial carcinoma. In the past eight years the senior author (E.H.C.) has seen only two: the first patient is alive four
years after pelvic exenteration as reported elsewhere;6 and the second died two months after exenteration. Recurrent involvement of the intestine is rarely amenable to resection; we have seen two instances of prolonged survival after surgical treatment. For recurrent tumor not amenable to definitive irradiation or operation the treatment of choice is administration of a long-acting progestin with or without complementary irradiation. In 1961, Kelley and Baker15 reported favorable results in 7 of 22 patients with faradvanced adenocarcinoma of the endometrium treated with a large dose of 17-alpha-hydroxyprogesterone caproate (Delalutin). Kelley 14 recently suggested an initial loading dose of 1,500 mg. intramuscularly each week when treating pulmonary metastases and a higher dose of 2,500 mg. in other instances, such as pelvic recurrence, when the blood supply may be reduced from previous irradiation. Varga and Henriksen 31 noted significant tumor alteration in 14 of 28 patients treated with 17-alpha-hydroxyprogester.one caproate. They were able to ascertain the response with a dosage of 2,500 mg. in each of four weeks. They noted that anaplastic tumors were refractory. Kennedy16 noted improvement in 9 of 27 patients with a dose of 750 to 1,500 mg. per week, observing that patients with slow-growing lesions had a better chance of responding and that those who did respond survived about one year longer than those who did not. Mussey and Malkasian,20 using a dose of 1,000 to 2,000 mg. per week, noted objective improvement in 5 of 20 patients and questionable improvement in 4. Kistner, Griffiths, and Craig 17 noted objective remission in 35 per cent of patients and subjective reInission in 70 per cent, using either 17-alpha-hydroxyprogesterone caproate or medroxyprogesterone acetate (Depo-Provera). Griffiths 10 indicated current successful palliation in approximately 50 per cent of his patients, using medroxyprogesterone acetate in an initial loading dose of 4 gm. intramuscularly in six weeks with a subsequent maintenance dose of from 100 mg. to 400 mg. once monthly. For investigation, medroxyprogesterone acetate is available in a concentration of 400 mg. per cubic centimeter, whereas the presently available strength of 50 mg. per cubic centimeter naturally requires larger injections at more frequent intervals. Smith, Rutledge, and Soff'ar29 noted a 40 per cent objective response in a group of 42 patients, most of whom were treated with intramuscular medroxyprogesterone acetate. They believed that the younger patients, who had recently received estrogens, responded more often. Prescribing oral medroxyprogesterone acetate (Provera) in a dosage of 100 mg. three times a day, Anderson 1 obtained an objective reInission in 8 of 20 patients. Waterman and Benson 33 also used an experimental oral progestin, medrogestone (Colprone), with a good response noted in 8 of 16 patients; they concluded that the long-term dosage for most patients would be 500 mg. or two tablets a day. Fourteen of our patients (six in Table 2) have received progestin therapy. Nine received an adequate trial, usually consisting of 1,500 mg. to 3,000 mg. of 17-alphahydroxyprogesterone caproate a week for one or two months followed by a maintenance dose of 1,000 mg. every one to
RECURRENT ENDOMETRIAL ADENOCARCINOMA
four weeks. An excellent response was noted in three and a questionable short-term response in four. SUMMARY The records of 29 patients with recurrent adenocarcinoma of the endometrium among 194 patients with tumor limited to the uterine fundus at the time of total hysterectomy are analyzed. Only 16 of 29 patients died from recurrent disease in the five years after initial treatment. In 17 patients the vagina was involved; 5 of the 6 with focal involvement are living, whereas only 1 of the remaining 11 with multiple sites of recurrent malignant disease is alive. For prevention of recurrent malignant disease, refinements in surgical technique may reduce dissemination of cancer cells at the time of curettage and hysterectomy. Supplementary irradiation certainly reduces the incidence of focal recurrence of vaginal tumor, but two questions are raised: Can better surgical technique accomplish the same result? Does such treatment improve the survival rate? In the broader consideration of irradiation, other questions arise: Does intrauterine radium provide accurate irradiation? When high voltage x-ray therapy is employed, is its inferior margin accurately defined in relation to the patient? Is the radium in a vaginal applicator properly positioned to provide a uniform dose? The role of progestins in reducing recurrent tumor by treatment of the initial lesion is under investigation. Since irradiation has the proved capacity to destroy this tumor, we believe it to be the treatment of choice when recurrence is limited to the vagina, pelvis, or both. Our results indicate that patients with a recurrent tumor localized in the vagina have a good prognosis with irradiation. Even when the recurrent tumor involves the vagina and the deep pelvis, irradiation would seem to have definite merit from a palliative standpoint. However, when a tumoricidal dose of irradiation cannot be applied by virtue of tumor location or previous treatment, then the progestins offer the main hope of palliation, except for the rare instance amenable to radical surgery. Finally, the physician must be flexible in the use of surgery, irradiation, hormones, or a combination of these modes of therapy. REFERENCES 1. Anderson, D. G.: Management of advanced endometrial adenocarcinoma with medroxyprogesterone acetate. Amer. J. Obstet. Gynec. 92:87-99 (May 1) 1965. 2. Bateman, J. C., Carlton, H. M., and Thibeault, J. P.: Chemotherapy for carcinoma of the uterus. Obstet. Gynec. 15:35-42 (Jan.) 1960. 3. Boutselis, J. G., Ullery, J. C., and Bair, 1.: Vaginal metastases following treatment of endometrial carcinoma. Obstet. Gynec. 21 :622-626 (May) 1963. 4. Carmichael, J. A., and Bean, H. A.: Carcinoma of the endometrium in Saskatchewan. A review of 603 cases with a suggested scheme of management for patients with Stage I disease and regarded as good surgical risks. Amer. J. Obstet. Gynec. 97:294307 (Feb. 1) 1967. 5. Cole, W. H., McDonald, G. 0., Roberts, S. S., and Southwick, H. W.: Dissemination of Cancer: Prevention and Therapy. New York, Appleton-Century-Crofts, Inc., 1961, 462pp.
6. Copenhaver, E. H., and Barsamian, M.: Management of adenocarcinoma of the endometrium. SURG. CLIN. N. AMER. 47:723-735 (June) 1967. 7. Copenhaver, E. H., and Barsamian, M.: Management of Stage I adenocarcinoma of the endometrium. Amer. J. Obstet. Gynec. 99:864-868 (Nov. 15) 1967. 8. Dobbie, B. N. W.: Vaginal recurrences in carcinoma of the body of the uterus and their prevention by radium therapy. J. Obstet. Gynaec. Brit. Emp. 60:702-705 (Oct.) 1953. 9. Greentree, L. B.: Electrocoagulation of vaginal metastases following treatment of endometrial carcinoma Amer. J. Obstet. Gynec. 90:833-834 (Nov. 15) 1964. 10. Griffiths, C. T.: Personal communication. 11. Hurtig, A.: Dilatation of cervix uteri; a modified technique. J. Obstet. Gynaec. Brit. Emp. 63:725-727 (Oct.) 1956. 12. Javert, C. T.: Spread of benign and malignant endometrium in lymphatic system with note on coexisting vascular involvement. Amer. J. Obstet. Gynec. 64:780-806 (Oct.) 1952. 13. Javert, C. T., and Renning, E. L.: Endometrial cancer. A chronologic review of therapy at Women's Hospital. South. Med. J. 57:1185-1190 (Oct.) 1964. 14. Kelley, R M.: Adenocarcinoma of the endometrium. Panel discussion, District I Annual Meeting, American College of Obstetrics & Gynecology, October 1967 (unpublished data). 15. Kelley, R. M., and Baker, W. H.: Progestational agents in the treatment of carcinoma of the endometrium. New Eng. J. Med. 264:216-222 (Feb. 2) 1961. 16. Kennedy, B. J.: A progestogen for treatment of advanced endometrial cancer. J.A.M.A. 184:758-761 (June 8) 1963. 17. Kistner, R W., Griffiths, C. T., and Craig, J. M.: Use of progestational agents in the management of endometrial cancer. Cancer 18:1563-1579 (Dec.) 1965. 18. Lewis, G. C., Jr., Nadler, S. H., Bross, I. D. J., and Slack, N. H.: Adjuvant chemotherapy for cancer of the corpus uteri: preliminary report. Obstet. Gynec. 29:797-876 (June) 1967. 19. McDuff, H. C., Jr., and Barrall, J. H.: The use of progestational agents in the treatment of carcinoma of the endometrium. Trans. New Eng. Obstet. Gynec. Soc. 19:75-89, 1965. 20. Mussey, E., and Malkasian, G. D., Jr.: Progestogen treatment of recurrent carcinoma of the endometrium. Amer. J. Obstet. Gynec. 94:78-85 (Jan. 1) 1966. 21. Parsons, L., and Cesare, F.: Wertheim hysterectomy in the treatment of endometrial carcinoma. Surg. Gynec. Obstet. 108:582-590 (May) 1959. 22. Pratt, J. H., Symmonds, R. E., and Welch, J. S.: Vaginal hysterectomy for carcinoma of the fundus. Amer. J. Obstet. Gynec. 88:1063-1072 (April 15) 1964. 23. Price, J. J., Hahn, G. A., and Rominger, C. J.: Vaginal involvement in endometrial carcinoma Amer. J. Obstet. Gynec. 91 :1060-1065 (April 15) 1965. 24. Rubin, P., Gerle, R. D., Quick, R S., and Greenlaw, R. H.: Significance of vaginal recurrence in endometrial carcinoma Amer. J. Roentgen. 89:91-100 (Jan.) 1963. 25. Rutledge, F. N., Tan, S. K., and Fletcher, G. H.: Vaginal metastases from adenocarcinoma of the corpus uteri. Amer. J. Obstet. Gynec. 75:167-174 (Jan.) 1958. 26. Schwartz, A. E., and Brunschwig, A.: Radical panhysterectomy and pelvic node excision for carcinoma of the corpus uteri. Surg. Gynec. Obstet. 105:675-680 (Dec.) 1957. 27. Sherman, A. I.: Progesterone caproate in the treatment of endometrial cancer. Obstet. Gynec. 28:309-314 (Sept.) 1966. 28. Smedal, M. 1.: Personal communication. 29. Smith, J. P., Rutledge, F., and Soffar, S. W.: Progestins in the treatment of patients with endometrial adenocarcinoma. Amer. J. Obstet. Gynec. 94:977-984 (April 1) 1966. 30. Spratt, D. W.: The cervical obturator. New instrument for occlusion of the cervix. Obstet. Gynec. 15:526-527 (April) 1960. 31. Varga, A., and Henriksen, E.: Histologic observations on the effect of 17-alpha-hydroxyprogesterone-17-n-caproate on endometrial carcinoma Obstet. Gynec. 26:656-664 (Nov.) 1965. 32. Wall, J. A., Franklin, R R, and Kaufman, R H.: Reversal of benign and malignant endometrial changes with Clomiphene. Amer. J. Obstet. Gynec. 88:1072-1085 (April 15) 1964. 33. Waterman, E. A., and Benson, R. C.: Medrogestone therapy in advanced endometrial adenocarcinoma Obstet. Gynec. 30:626-634 (Nov.) 1967. 34. Winterton, W. R: Discussion of Hawksworth, W.: The treatment of carcinoma of the body of the uterus. Proc. Roy. Soc. Med. 57:471-473 (June) 1964.