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Adjuvant chemotherapy in early uterine sarcoma
GYNECOLOGIC
ONCOLOGY
15,
56-64 (1983)
Adjuvant Chemotherapy in Early Uterine Sarcoma EDWARD V. HANNIGAN, M.D. ,’ RALPH S. FREEDMAN, FELIX N. RUTLEDGE, M.D. Depurtmrnt
of
Gynecology. University and Tumor
Institute,
of‘ Texus M. D. Anderson Houston, Texas 77030
M.D.,
AND
Ho.cpitul
Received January 11, 1982 Nine years’ experience with early uterine sarcoma is reviewed. In addition to hysterectomy and radiotherapy, 34 patients received adjunctive chemotherapy; 67 patients received no adjunctive chemotherapy. Seventeen patients who received chemotherapy received combination vincristine, I.5 mgim’ weekly; actinomycin D, 0.5 mg intravenously on Days 1 to 5; and cyclophosphamide, 300 mg intravenously on Days 1 to 5. Seventeen other patients received adriamycin either alone at a dose of 50 mg/m’ BSAimonth or in combination with vincristine and cyclophosphamide. Neither the probability of survival nor the disease-free interval was improved by the addition of adjuvant chemotherapy.
Uterine sarcomas, even when they are confined to the uterus, will frequently recur or metastasize following hysterectomy. Adjunctive radiation therapy utilizing preoperative external beam and intracavitary radium has been utilized in the treatment of uterine sarcomas at The University of Texas M. D. Anderson Hospital and Tumor Institute at Houston for over 25 years. Edwards (3) and DiSaia et al. (2) noted that the addition of radiotherapy to surgery not only improves overall survival, but also helps control disease in the pelvis for those patients with early extrauterine spread. Clinical experience suggests, however, that many patients with apparently localized uterine sarcoma have widespread subclinical metastases. Despite local control of the uterine tumor by hysterectomy and radiotherapy, patients often develop evidence of metastases within a short time following completion of therapy. In an attempt to improve survival, adjunctive chemotherapy has been added to the initial therapy for sarcomas of various sites. The Southwest Oncology Group Adjuvant Osteosarcoma Study (8), using adriamycin, cyclophosphamide, vincristine, and dacarbazine (Cyvadic), suggests that adjuvant chemotherapy may increase the disease-free interval between the time of initial therapy and subsequent relapse. Jaffe et al. (7) demonstrated both improved survival rates and prolonged disease-free intervals utilizing adjunctive treatment with a combination of vincristine, actinomycin-D, and cyclophosphamide WAC) in patients with ’ To whom reprint requests should be addressed: Department of Gynecology, University of Texas Medical Branch, Galveston, Texas 77550. 56 0090-8258/83/010056-09$01.50/O Copyright All rights
0 1983 by Academic Press. Inc. of reproduction in any form reserved.
ADJUVANT
CHEMOTHERAPY
IN
UTERINE
57
SARCOMA
Ewing’s sarcoma. Buchsbaum (1) considered adjuvant VAC to improve survival in a group of 17 patients with uterine sarcoma when compared with a historical control. Piver et al. (9), in a randomized study involving 12 patients, however, could demonstrate no advantage by the addition of adriamycin to radiotherapy and hysterectomy. This retrospective review reports on the results of treatment of a relatively large group of patients who presented with early uterine sarcoma at the M. D. Anderson Hospital over a 9-year period. MATERIALS AND METHODS The clinical course of 109 patients treated at M. D. Anderson Hospital between 1970 and 1979 was reviewed. All of these patients were considered to have sarcoma confined to the uterus at the time of presentation. The frequencies of the different histologic types of uterine sarcomas encountered in this series are listed in Table I. The initial treatment plan for 102 of the patients included hysterectomy. At the time of laparotomy, clinically enlarged pelvic lymph nodes were removed. If there were no grossly enlarged nodes, lymph nodes were sampled from both pelvic sidewalls. A formal lymphadenectomy was not performed. One hundred one patients received radiotherapy. Thirty-four received adjunctive chemotherapy in addition to surgery and radiotherapy. Four patients received only palliative or supportive care because of a concurrent medical condition. Patients were not randomly assigned to any treatment arm, but rather, therapy decisions were based upon the clinical judgement of the patients’ primary physicians. Tables 2 and 3 compare characteristics and treatment plans of patients selected to receive adjunctive chemotherapy and those who were not offered adjunctive therapy. The age range, mean, and median for the two groups show no apparent difference. The patients who received adjunctive chemotherapy appeared more likely to have sarcomas involving the cervix as either a gross lesion or endocervical curettings containing sarcoma. This difference, however, was not statistically significant. Nor was there any difference between groups with regard to the frequency or sequence of irradiation and surgery. TREATMENT
TECHNIQUES
Radiotherapy was administered either pre- or postoperatively. Postoperative external irradiation consisted of 5000 rads of 22-MeV betatron photons delivered TABLE SARCOMAS CONFINED
Diagnosis Leiomyosarcoma Mixed mesodermal sarcoma Endometrial stromal sarcoma Other Total
I TO UTERUS
Total patients
Hysterectomy
21 77 9 2 109
21 70 9 2 102
Radiotherapy 16 74 9 2 101
Adjuvant chemotherapy 8 24 2 0 34
58
HANNIGAN,
FREEDMAN,
AND
TABLE CHARACTERISTICS
Total (n = 109)
Age
Mean Median Range Sarcomatous involvement of cervix
RUTLEDGE
2
OF PATIENT
Patients receiving adjuvant chemotherapy (n = 34)
GROUPS
Patients not receiving adjuvant chemotherapy (n
=
67)
59 59 28-72
58 60 20-79
13 (38.2%)
13 (19.4%)
Medically inoperable or failed to complete initial treatment (n
=
8)
71 68 57-94 2 (25%)
through 15 x 15cm parallel opposed pelvic portals. A vaginal applicator of radium provided an additional 3000-rad surface dose to the vagina1 mucosa. The majority of patients, however, received preoperative external irradiation and radium. Preoperative external irradiation consisted of 4000 rads from a 22-MeV photon beam delivered to a 15 x 15-cm pelvic field, followed by intracavitary radium delivered by afterloadable tandem and colpostats. The radium provided a dose of 2500 mg hr to the corpus and a surface dose to the vagina of 4000 to 6000 rads. Adjunctive chemotherapy consisted of a combination of vincristine, actinomycin D, and cyclophosphamide (VAC) in 17 patients. As currently administered, vincristine is given at a dose of 1.5 mg/m’ body surface area (m’ BSA) intravenously, weekly for 12 weeks. A single weekly dose should not exceed 2 mg. Both actinomycin D and cyclophosphamide are administered intravenously for 5 days every 4 weeks. During this time, actinomycin D is given at a dose of 0.5 mg daily and the cyclophosphamide 300 mg daily. Thirteen patients received adriamycin either as a single agent at a dose of 40 to 50 mgim* BSA monthly, or in combination with vincristine and/or cyclophosphamide. Survival and TABLE TREATMENT
Total (n = 109) Hysterectomy only Irradiation only Preop radium Postop radium Preop external irradiation Postop external irradiation
Patients receiving adjunctive chemotherapy (n = 34) 3 1 1s 6
3
PLANS OF PATIENT GROUPS
Patients not receiving adjunctive chemotherapy (n
=
67)
(8.8%) (2.9%) (44.1%) (17.6%)
5 (7.4%) 3 (4.5%) 39 (58.2%) 13 (19.4%)
16 (47.0%)
39 (58.2%)
13 (38.2%)
18 (26.9%)
Medically inoperable or failed to complete initial therapy (n
=
8)
5 (63.5%)
3 (37.5%)
ADJUVANT
CHEMOTHERAPY
IN
UTERINE
59
SARCOMA
disease-free interval curves were constructed by the Kaplan-Meier product limit life-table method (6) with intervals measured from the time of hysterectomy. RESULTS At the time of surgery, 25 patients were found to have previously unsuspected extrauterine sarcoma, either in pelvic lymph nodes or at the surgical margins. In addition, 4 patients developed obvious clinical signs of sarcoma spread while receiving preoperative radiotherapy and the planned surgical procedure was not performed. Therefore, 25 of 105 patients, 23.8%, were either initially understaged or had sarcoma which progressed rapidly during the phase of presurgical evaluation and irradiation. In the group of patients who are the subject of this report, no microscopically visible disease remained following hysterectomy, however, 8 of the 67 patients (1 I .9%), who received no chemotherapy, were found to have sarcoma in the surgical margins or the resected lymph nodes. Of those patients who did receive adjunctive chemotherapy, 13 of 34 (38.2%), were found to have a positive node or margins. The higher frequency (standard error of difference, 9.2%) of extrauterine sarcoma encountered in patients selected for adjunctive chemotherapy is undoubtedly due to selection bias. Patients who were considered for whatever reason to be at a higher risk for sarcoma spread or recurrence were more likely to be assigned to receive adjunctive chemotherapy. The probability of survival at 12, 24, 36, and 60 months of patients studied is given in Table 4. This data excludes the 8 patients with either clinically obvious disease progression prior to surgery or who were medically unsuitable for surgery. There is no significant difference in survival noted whether chemotherapy was given or withheld. The j-year cumulative probability of survival for the entire group was 47.8%: for those patients who received adjunctive chemotherapy, it was 46.8%; and for those who received no adjunctive therapy, it was 50.7%. The effect of microscopically positive surgical margins or lymph nodes on survival was significant. Patients with no microscopic evidence of disease in these areas had an improved probability of survival at all time periods studied (P = 0.003). The cumulative probability of survival at 60 months of a patient with no microscopic nodal disease was 54.9%. If the nodes or margins contained microscopic sarcoma, the probability of survival was 24.2%. As noted in Table 5, again no significant difference in the cumulative probability of survival existed between those groups of patients receiving chemotherapy and those from whom TABLE CUMULATIVE
Time in months: No adjunctive chemotherapy (n = 67) Adjunctive chemotherapy (n = 34) ” Standard error.
PROBABILITY
4 OF SURWAL.
12
24
36
60
0.924 (0.033)”
0.714 (0.057)
0.574 (0.064)
0.507 (0.067)
0.882 (0.055,
0.578 (0.092)
0.530 (0.096)
0.468 (0.103)
HANNIGAN,
60
FREEDMAN, AND RUTLEDGE TABLE
CUMULATIVE
PROBABILITY
Time in months: Nodes/margins chemotherapy Nodes/margins chemotherapy (?I = 59) Nodes/margins chemotherapy Nodes/margins chemotherapy (n = 8)
negative and given (n = 22) negative and not given positive and given (n = 12) positive and not given
5
OF SURVIVAL BY STATUS CHEMOTHERAPY
OF NODES
OR MARGINS,
AND
12
24
36
60
0.909 (0.061)
0.716 (0.099)
0.716 (0.099)
0.607 (0.131)
0.965 (0.024)
0.761 (0.058)
0.600 (0.068)
0.545 (0.072)
0.833 (0.108)
0.333 (0.151)
0.222 (0.135)
0.222 (0.135)
0.625 (0.171)
0.375 (0.171)
0.375 (0.171)
0.250 (0.153)
a Standard error.
chemotherapy was withheld when grouped by the status of nodes and margins. The survival at 5 years for patients with positive margins who received chemotherapy was 22.2%, while those in this group who received no adjunctive therapy was 25.0%. For patients whose surgical specimens demonstrated no microscopic sarcoma, the probability of survival at 5 years was 60.7% with adjunctive chemotherapy and 54.5% without chemotherapy. Table 6 lists the probability of survival of the patients who received adjunctive chemotherapy. Seventeen patients received the VAC regimen. The remaining 17 patients received adriamycin. In 4 patients it was the only drug used, while in 13 patients it was part of a combination regimen which included vincristine and cyclophosphamide. Of the 101 patients who completed therapy, those with leiomyosarcoma had a better probability of survival (P = 0.05) when compared to patients with other histologic types of sarcoma (Table 7). This improved survival is independent of whether chemotherapy was administered or withheld. Patients with leiomyosarcoma who received no adjunctive chemotherapy had an 83.1% survival rate at 60 months, compared to 38.2% survival probability for patients with mixed mesodermal sarcoma, and 50.8% for patients with stromal sarcomas. If adjuvant treatment was given, patients with leiomyosarcoma had a 75% survival rate at 60 months and patients with mixed mesodermal sarcoma, 36.6%. Only 2 patients with endometrial stromal sarcoma received adjurrctive VAC chemotherapy and both remained without evidence of disease at 36 months. TABLE CUMULATIVE
PROBABILITY
Time in months: VAC (n = 17) Adriamycin (n = 17) LI Standard error.
OF SURVIVAL
6 BY CHEMOTHERAPEUTIC
REGIMEN
12
24
36
60
0.882 (0.078)” 0.882 (0.078)
0.621 (0.125) 0.534 (0.133)
0.543 (0.131) 0.534 (0.133)
0.425 (0.137) 0.534 (0.133)
ADJUVANT
CHEMOTHERAPY
IN
TABLE CUMULATIVE
Leiomyosarcoma (n = 2 I ) Mixed mesodermal sarcoma (n = 71) Endometrial stromal sarcoma (n = 9)
61
SARCOMA
7 RY
HISTOI.OGICTYPE
I2
24
36
60
0.902 (0.066)”
0.849 (0.080)
0.796 (0.091)
0.796 (0.091)
0.889 (0.037)
0.71 (0.061)
0.424 (0.064)
0.358 (0.064)
0.889 (0.105)
0.889 (0.105)
0.762 (0.148)
0.508 (0.230)
PRORABILITY
Time in months:
UTERINE
OF SURVIVAL
” Standard error.
Tables 8 and 9 list data for the disease-free interval, as calculated from the time of hysterectomy until the first notation in the clinical record of objective evidence of recurrent sarcoma. At 12 months after hysterectomy, 76% of the entire group were free of evidence of recurrence; at 5 years, 53.3% remained free of disease. There was no difference in disease-free interval between those who received adjuvant therapy and those who did not. In those patients with microscopically positive nodes or margins, 36.5% had demonstrated objective evidence of recurrence in 1 year and only 31.5% were free of recurrence at 5 years. If there was no sarcoma in the surgical margins or resected nodes, 58.3% were free of recurrence at 5 years. Patients with leiomyosarcoma, had a prolonged TABLE C~MULATWE
Time in months:
PROBABILITY
8
OF BEING
FREE OF RECURRENCE
I2
24
36
60
0.740 (0.054)”
0.578 (0.062)
0.543 (0.063)
0.513 (0.066)
0.814 (0.069)
0.642 (0.088)
0.586 (0.096)
0.586 (0.096)
No adjunctive chemotherapy (n = 67)
Adjunctive chemotherapy (n = 34) ‘I Standard error.
TABLE CUMULATIVE
PROBABILITY OF BEING NODES AND MARGINS,
Time in months: Nodes/margins chemotherapy Nodes/margins chemotherapy (n = 59) Nodes/margins chemotherapy Nodes/margins chemotherapy (n = 8)
negative and given (n = 22) negative and not given positive and given (n = 12) positive and not given
” Standard error.
9
FREE OF RECURRENCE AND CHEMOTHERAPY
BY STATUS OF
I2
24
36
60
0.810 (0.086)”
0.762 (0.093)
0.682 (0.113)
0.682 (0.113)
0.790 (0.054)
0.605 (0.066)
0.587 (0.066)
0.552 (0.071)
0.375 (0.171)
0.375 (0.171)
0.250 (0.153)
0.250 (0.153)
0.825 (0.113)
0.374 (0.169)
0.374 (0.169)
0.374 (0.169)
62
HANNIGAN,
FREEDMAN,
AND
RUTLEDGE
disease-free interval (P = 0.02) when compared with patients with mixed mesodermal sarcomas, but this was independent of whether adjuvant chemotherapy was given or withheld. Manifestations of chemotherapy related toxicity observed in the two groups of patients are given in Table 10. Of the 17 patients receiving VAC chemotherapy, 7 patients were recorded as having vomiting of such a degree as to require intravenous rehydration. Alopecia to some degree occurred in all patients. All patients reported symptoms of vincristine-related neurotoxicity and 8 patients (48%) had vincristine therapy discontinued due to the appearance of toxicity. Severe neurotoxicity, defined as a motor disturbance of such degree that patients were confined to a wheelchair, occurred in 3 patients (17%). One patient developed a severe debilitating neurotoxicity after 5 weekly courses of 2 mg of vincristine. The other patients who manifested severe neurotoxicity received at least 10 weekly courses of the drug. Three patients (17%) were hospitalized for treatment of intestinal ileus. Severe myelosuppression was defined as any recorded leukocyte count of less than 1000 white cells/mm3 of blood. Four patients had severe leukopenia but rapidly recovered with outpatient observation. Three additional patients receiving VAC were hospitalized for neutropenia and sepsis. Of I7 patients receiving VAC therapy, 7 (41%) required hospitalization for treatment of drug toxicity, spending an average of 18 hospital days per admission. Eight of the seventeen patients (47%), however, had very little difficulty with tolerance of their therapy. These patients completed at least 5 months of VAC therapy with neither a delay in treatment nor a toxicity-mandated dose reduction. Of the patients treated with adriamycin, 4 received adriamycin as a single agent and 13 received a combination which included vincristine and cytoxan. Alopecia occurred in 13 patients. Severe vomiting requiring rehydration occurred in 4 patients, all of whom were on combination therapy. One patient was hospitalized 10 days for sepsis and agranulocytosis after receiving the three-drug combination. Of 13 patients receiving vincristine, 11 reported mild neurotoxicity and 2 were confined to wheelchairs as a result of severe toxicity. Two patients TABLE TOXIC MANIFESTATIONS
10
ASSOCIATED WITH ADJUNCTIVE
VAC (n = 17) Alopecia Nausea/vomiting (severe) Stomatitis Neurotoxicity Mild Severe Ileus Myelosuppression, severe Hospitalized for treatment of chemotherapy-induced toxicity Cardiac toxicity u Percentages given in parentheses.
17 (100)” 7 (41) 3 (18) 17 3 3 7
(100) (18) (18) (41)
7 (41)
CHEMOTHERAPY
Adriamycin (n = 17) 13 (76) 4 (24) 11/13 (85) 2113 (15)
6 (36) 1 (6) 2 (12)
ADJUVANT
CHEMOTHERAPY
IN
UTERINE
SARCOMA
63
developed possible adriamycin-associated cardiac toxicity. In both instances, the drug was administered as the only chemotherapeutic agent, with both patients receiving the drug at the rate of 60 mgim’ BSAimonth. One patient who received six monthly courses of adriamycin (total dose, 300 mgim’ BSA) developed overt congestive heart failure. The other patient developed electrocardiographic changes, characterized as significant voltage reductions in the limb leads. after six courses (300 mgim’ BSA). She had no symptoms 60 months after discontinuing therapy. No patient on any regimen died as a result of adjunctive chemotherapy. DISCUSSION Di Saia PI ~1. (2) have reported the experience at M. D. Anderson Hospital for a group of patients with mixed mesodermal sarcoma treated either by hysterectomy, radiotherapy, or both. In a group of patients with disease confined to the uterus, with negative surgical margins. 18 of 34 patients (53%) were free of disease at 2 years. However, if parametrial or vaginal margins contained sarcomas, only 3 of 35 (8.5%) patients were alive without evidence of disease at 2 years. In this high-risk group of patients, although the addition of radiation did provide local control of tumor in patients who developed progressive sarcoma. it had very little impact on survival rate. The disease status at 2 years in the group of patients comprising the current report is similar to this earlier group, regardless of whether adjuvant chemotherapy was given or withheld. The difference in the natural history of the various types of uterine sarcomas is apparent in this group of patients. Patients having leiomyosarcomas had both a prolonged disease-free interval and enhanced probability of survival when compared to patients with mixed mesodermal sarcoma. Eighty-three percent of patients with leiomyosarcoma confined to the uterus were disease free at 60 months without adjuvant chemotherapy. Combination chemotherapy consisting of vincristine, actinomycin D. and cyclophosphamide does, as noted by Smith and Rutledge (IO), have activity against metastatic sarcoma. A recent review (4) of a large series of patients with measurable disease lists a response rate to this combination of 29% (16% partial response added to 13% complete response). Combination therapy containing adriamycin demonstrated a response rate of 10.3% (10.3% partial response; no complete responses) (S). When using drugs for adjuvant therapy with these relatively low response rates, it requires a large number of patients in each assessment cell to demonstrate actual benefit. We conclude from the current experience that the effect of adjuvant chemotherapy, using currently available drug combinations, is not dramatic, and may have no effect. But the concept that adjuvant therapy may improve survival, especially when using more active therapy which may become available in the future, is neither proven nor disproven. Severe vincristine-associated neurotoxicity occurred in 15% of exposed patients and minor neurotoxicity occurred in every patient. Forty-one percent of the patients on the VAC regimen required hospitalization for treatment of VAC toxicity. Our experience with these and other patients treated with VAC chemotherapy has prompted us to reduce the intensity of vincristine therapy. No
64
HANNIGAN,
FREEDMAN,
AND
RUTLEDGE
single dose of vincristine currently exceeds 2 mg and weekly therapy is not used with the current drug combinations. Adriamycin-containing regimens seemed to be associated with a less severe degree of toxicity-only 1 patient was hospitalized for treatment related toxicity. Still, 4 of 17 patients (24%) required periodic intravenous rehydration, and 2 of 17 (12%) developed cardiac toxicity. In summary, we could demonstrate no discernible effect on either survival or disease-free interval after using combination chemotherapy in addition to hysterectomy and radiotherapy, in patients with sarcoma confined to the uterus. Clearly, we have not achieved a strong adjuvant effect by use of either VAC or adriamycin. However, because these patients have such a high risk of failure after initial treatment, we feel that trials with other systemic agents, administered in an adjuvant setting, are indicated. REFERENCES 1. Buchsbaum, H. J., Lifshitz, S., and Blyth, J. G. Prophylactic chemotherapy in Stages I and II uterine sarcoma, Gynecol. Oncol. 8, 346-348 (1979). 2. DiSaia, P. J., Castro, J. R., and Rutledge, F. N. Mixed mesodermal sarcoma of the uterus, Amer. .I. Roentgenol. Radium Ther. Nucl. Med. 3, 632-636 (1973). 3. Edwards, C. L. Undifferentiated tumors, in Cancer of the uterus and ovary, Year Book Med. Pub., Chicago, pp. 84-94 (1966). 4. Hannigan, E. V., Elder, K. W., Freedman, R. S., and Rutledge, F. N. Treatment of advanced uterine sarcoma with vincristine, actinomycin D, and cyclophosphamide, Gynecol. Oncol., in press. 5. Hannigan, E. V., Elder, K. W., Freedman, R. S., and Rutledge, F. N. Treatment of advanced uterine sarcoma with combination chemotherapy including adriamycin. Gyneco/. Oncol., in press. 6. Hull, C. H., and Nie, N. H. Survival, in SPSS update: New procedures andfacilitiesfor releases 7 and 8, McGraw-Hill, New York (1979). 7. Jaffe, N., Traggis, D., Salian, S., and Cassady, J. R. Improved outlook for Ewing’s sarcoma with combination chemotherapy (vincristine, actinomycin-D and cyclophosphamide) and radiation therapy, Cancer 38, 1925-1930 (1976). 8. Murphy, W. K., Benjamin, R. S., Eyre, H. J., Thigpen, T., Groppe, C., Uribe-Botero, G., Baker, L. J., Gehan, E. A., and Gottlieb, J. A. Update: Adjuvant chemotherapy in osteosarcoma of adults, in Adjuvant therapy of cancer II (S. E. Jones and S. E. Salmon, Eds.), Grune & Stratton, New York (1979). 9. Piver, M. D., Barlow, J. J., Lele, S. B., and Yazigi, R. Adriamycin in localized and metastatic uterine sarcomas, J. Surg. Oncol. 12, 263-265 (1979). 10. Smith, J. P., and Rutledge, F. N. Advances in chemotherapy for gynecologic cancer, Cancer 36, 669-674
(1975).
ONCOLOGY
15,
56-64 (1983)
Adjuvant Chemotherapy in Early Uterine Sarcoma EDWARD V. HANNIGAN, M.D. ,’ RALPH S. FREEDMAN, FELIX N. RUTLEDGE, M.D. Depurtmrnt
of
Gynecology. University and Tumor
Institute,
of‘ Texus M. D. Anderson Houston, Texas 77030
M.D.,
AND
Ho.cpitul
Received January 11, 1982 Nine years’ experience with early uterine sarcoma is reviewed. In addition to hysterectomy and radiotherapy, 34 patients received adjunctive chemotherapy; 67 patients received no adjunctive chemotherapy. Seventeen patients who received chemotherapy received combination vincristine, I.5 mgim’ weekly; actinomycin D, 0.5 mg intravenously on Days 1 to 5; and cyclophosphamide, 300 mg intravenously on Days 1 to 5. Seventeen other patients received adriamycin either alone at a dose of 50 mg/m’ BSAimonth or in combination with vincristine and cyclophosphamide. Neither the probability of survival nor the disease-free interval was improved by the addition of adjuvant chemotherapy.
Uterine sarcomas, even when they are confined to the uterus, will frequently recur or metastasize following hysterectomy. Adjunctive radiation therapy utilizing preoperative external beam and intracavitary radium has been utilized in the treatment of uterine sarcomas at The University of Texas M. D. Anderson Hospital and Tumor Institute at Houston for over 25 years. Edwards (3) and DiSaia et al. (2) noted that the addition of radiotherapy to surgery not only improves overall survival, but also helps control disease in the pelvis for those patients with early extrauterine spread. Clinical experience suggests, however, that many patients with apparently localized uterine sarcoma have widespread subclinical metastases. Despite local control of the uterine tumor by hysterectomy and radiotherapy, patients often develop evidence of metastases within a short time following completion of therapy. In an attempt to improve survival, adjunctive chemotherapy has been added to the initial therapy for sarcomas of various sites. The Southwest Oncology Group Adjuvant Osteosarcoma Study (8), using adriamycin, cyclophosphamide, vincristine, and dacarbazine (Cyvadic), suggests that adjuvant chemotherapy may increase the disease-free interval between the time of initial therapy and subsequent relapse. Jaffe et al. (7) demonstrated both improved survival rates and prolonged disease-free intervals utilizing adjunctive treatment with a combination of vincristine, actinomycin-D, and cyclophosphamide WAC) in patients with ’ To whom reprint requests should be addressed: Department of Gynecology, University of Texas Medical Branch, Galveston, Texas 77550. 56 0090-8258/83/010056-09$01.50/O Copyright All rights
0 1983 by Academic Press. Inc. of reproduction in any form reserved.
ADJUVANT
CHEMOTHERAPY
IN
UTERINE
57
SARCOMA
Ewing’s sarcoma. Buchsbaum (1) considered adjuvant VAC to improve survival in a group of 17 patients with uterine sarcoma when compared with a historical control. Piver et al. (9), in a randomized study involving 12 patients, however, could demonstrate no advantage by the addition of adriamycin to radiotherapy and hysterectomy. This retrospective review reports on the results of treatment of a relatively large group of patients who presented with early uterine sarcoma at the M. D. Anderson Hospital over a 9-year period. MATERIALS AND METHODS The clinical course of 109 patients treated at M. D. Anderson Hospital between 1970 and 1979 was reviewed. All of these patients were considered to have sarcoma confined to the uterus at the time of presentation. The frequencies of the different histologic types of uterine sarcomas encountered in this series are listed in Table I. The initial treatment plan for 102 of the patients included hysterectomy. At the time of laparotomy, clinically enlarged pelvic lymph nodes were removed. If there were no grossly enlarged nodes, lymph nodes were sampled from both pelvic sidewalls. A formal lymphadenectomy was not performed. One hundred one patients received radiotherapy. Thirty-four received adjunctive chemotherapy in addition to surgery and radiotherapy. Four patients received only palliative or supportive care because of a concurrent medical condition. Patients were not randomly assigned to any treatment arm, but rather, therapy decisions were based upon the clinical judgement of the patients’ primary physicians. Tables 2 and 3 compare characteristics and treatment plans of patients selected to receive adjunctive chemotherapy and those who were not offered adjunctive therapy. The age range, mean, and median for the two groups show no apparent difference. The patients who received adjunctive chemotherapy appeared more likely to have sarcomas involving the cervix as either a gross lesion or endocervical curettings containing sarcoma. This difference, however, was not statistically significant. Nor was there any difference between groups with regard to the frequency or sequence of irradiation and surgery. TREATMENT
TECHNIQUES
Radiotherapy was administered either pre- or postoperatively. Postoperative external irradiation consisted of 5000 rads of 22-MeV betatron photons delivered TABLE SARCOMAS CONFINED
Diagnosis Leiomyosarcoma Mixed mesodermal sarcoma Endometrial stromal sarcoma Other Total
I TO UTERUS
Total patients
Hysterectomy
21 77 9 2 109
21 70 9 2 102
Radiotherapy 16 74 9 2 101
Adjuvant chemotherapy 8 24 2 0 34
58
HANNIGAN,
FREEDMAN,
AND
TABLE CHARACTERISTICS
Total (n = 109)
Age
Mean Median Range Sarcomatous involvement of cervix
RUTLEDGE
2
OF PATIENT
Patients receiving adjuvant chemotherapy (n = 34)
GROUPS
Patients not receiving adjuvant chemotherapy (n
=
67)
59 59 28-72
58 60 20-79
13 (38.2%)
13 (19.4%)
Medically inoperable or failed to complete initial treatment (n
=
8)
71 68 57-94 2 (25%)
through 15 x 15cm parallel opposed pelvic portals. A vaginal applicator of radium provided an additional 3000-rad surface dose to the vagina1 mucosa. The majority of patients, however, received preoperative external irradiation and radium. Preoperative external irradiation consisted of 4000 rads from a 22-MeV photon beam delivered to a 15 x 15-cm pelvic field, followed by intracavitary radium delivered by afterloadable tandem and colpostats. The radium provided a dose of 2500 mg hr to the corpus and a surface dose to the vagina of 4000 to 6000 rads. Adjunctive chemotherapy consisted of a combination of vincristine, actinomycin D, and cyclophosphamide (VAC) in 17 patients. As currently administered, vincristine is given at a dose of 1.5 mg/m’ body surface area (m’ BSA) intravenously, weekly for 12 weeks. A single weekly dose should not exceed 2 mg. Both actinomycin D and cyclophosphamide are administered intravenously for 5 days every 4 weeks. During this time, actinomycin D is given at a dose of 0.5 mg daily and the cyclophosphamide 300 mg daily. Thirteen patients received adriamycin either as a single agent at a dose of 40 to 50 mgim* BSA monthly, or in combination with vincristine and/or cyclophosphamide. Survival and TABLE TREATMENT
Total (n = 109) Hysterectomy only Irradiation only Preop radium Postop radium Preop external irradiation Postop external irradiation
Patients receiving adjunctive chemotherapy (n = 34) 3 1 1s 6
3
PLANS OF PATIENT GROUPS
Patients not receiving adjunctive chemotherapy (n
=
67)
(8.8%) (2.9%) (44.1%) (17.6%)
5 (7.4%) 3 (4.5%) 39 (58.2%) 13 (19.4%)
16 (47.0%)
39 (58.2%)
13 (38.2%)
18 (26.9%)
Medically inoperable or failed to complete initial therapy (n
=
8)
5 (63.5%)
3 (37.5%)
ADJUVANT
CHEMOTHERAPY
IN
UTERINE
59
SARCOMA
disease-free interval curves were constructed by the Kaplan-Meier product limit life-table method (6) with intervals measured from the time of hysterectomy. RESULTS At the time of surgery, 25 patients were found to have previously unsuspected extrauterine sarcoma, either in pelvic lymph nodes or at the surgical margins. In addition, 4 patients developed obvious clinical signs of sarcoma spread while receiving preoperative radiotherapy and the planned surgical procedure was not performed. Therefore, 25 of 105 patients, 23.8%, were either initially understaged or had sarcoma which progressed rapidly during the phase of presurgical evaluation and irradiation. In the group of patients who are the subject of this report, no microscopically visible disease remained following hysterectomy, however, 8 of the 67 patients (1 I .9%), who received no chemotherapy, were found to have sarcoma in the surgical margins or the resected lymph nodes. Of those patients who did receive adjunctive chemotherapy, 13 of 34 (38.2%), were found to have a positive node or margins. The higher frequency (standard error of difference, 9.2%) of extrauterine sarcoma encountered in patients selected for adjunctive chemotherapy is undoubtedly due to selection bias. Patients who were considered for whatever reason to be at a higher risk for sarcoma spread or recurrence were more likely to be assigned to receive adjunctive chemotherapy. The probability of survival at 12, 24, 36, and 60 months of patients studied is given in Table 4. This data excludes the 8 patients with either clinically obvious disease progression prior to surgery or who were medically unsuitable for surgery. There is no significant difference in survival noted whether chemotherapy was given or withheld. The j-year cumulative probability of survival for the entire group was 47.8%: for those patients who received adjunctive chemotherapy, it was 46.8%; and for those who received no adjunctive therapy, it was 50.7%. The effect of microscopically positive surgical margins or lymph nodes on survival was significant. Patients with no microscopic evidence of disease in these areas had an improved probability of survival at all time periods studied (P = 0.003). The cumulative probability of survival at 60 months of a patient with no microscopic nodal disease was 54.9%. If the nodes or margins contained microscopic sarcoma, the probability of survival was 24.2%. As noted in Table 5, again no significant difference in the cumulative probability of survival existed between those groups of patients receiving chemotherapy and those from whom TABLE CUMULATIVE
Time in months: No adjunctive chemotherapy (n = 67) Adjunctive chemotherapy (n = 34) ” Standard error.
PROBABILITY
4 OF SURWAL.
12
24
36
60
0.924 (0.033)”
0.714 (0.057)
0.574 (0.064)
0.507 (0.067)
0.882 (0.055,
0.578 (0.092)
0.530 (0.096)
0.468 (0.103)
HANNIGAN,
60
FREEDMAN, AND RUTLEDGE TABLE
CUMULATIVE
PROBABILITY
Time in months: Nodes/margins chemotherapy Nodes/margins chemotherapy (?I = 59) Nodes/margins chemotherapy Nodes/margins chemotherapy (n = 8)
negative and given (n = 22) negative and not given positive and given (n = 12) positive and not given
5
OF SURVIVAL BY STATUS CHEMOTHERAPY
OF NODES
OR MARGINS,
AND
12
24
36
60
0.909 (0.061)
0.716 (0.099)
0.716 (0.099)
0.607 (0.131)
0.965 (0.024)
0.761 (0.058)
0.600 (0.068)
0.545 (0.072)
0.833 (0.108)
0.333 (0.151)
0.222 (0.135)
0.222 (0.135)
0.625 (0.171)
0.375 (0.171)
0.375 (0.171)
0.250 (0.153)
a Standard error.
chemotherapy was withheld when grouped by the status of nodes and margins. The survival at 5 years for patients with positive margins who received chemotherapy was 22.2%, while those in this group who received no adjunctive therapy was 25.0%. For patients whose surgical specimens demonstrated no microscopic sarcoma, the probability of survival at 5 years was 60.7% with adjunctive chemotherapy and 54.5% without chemotherapy. Table 6 lists the probability of survival of the patients who received adjunctive chemotherapy. Seventeen patients received the VAC regimen. The remaining 17 patients received adriamycin. In 4 patients it was the only drug used, while in 13 patients it was part of a combination regimen which included vincristine and cyclophosphamide. Of the 101 patients who completed therapy, those with leiomyosarcoma had a better probability of survival (P = 0.05) when compared to patients with other histologic types of sarcoma (Table 7). This improved survival is independent of whether chemotherapy was administered or withheld. Patients with leiomyosarcoma who received no adjunctive chemotherapy had an 83.1% survival rate at 60 months, compared to 38.2% survival probability for patients with mixed mesodermal sarcoma, and 50.8% for patients with stromal sarcomas. If adjuvant treatment was given, patients with leiomyosarcoma had a 75% survival rate at 60 months and patients with mixed mesodermal sarcoma, 36.6%. Only 2 patients with endometrial stromal sarcoma received adjurrctive VAC chemotherapy and both remained without evidence of disease at 36 months. TABLE CUMULATIVE
PROBABILITY
Time in months: VAC (n = 17) Adriamycin (n = 17) LI Standard error.
OF SURVIVAL
6 BY CHEMOTHERAPEUTIC
REGIMEN
12
24
36
60
0.882 (0.078)” 0.882 (0.078)
0.621 (0.125) 0.534 (0.133)
0.543 (0.131) 0.534 (0.133)
0.425 (0.137) 0.534 (0.133)
ADJUVANT
CHEMOTHERAPY
IN
TABLE CUMULATIVE
Leiomyosarcoma (n = 2 I ) Mixed mesodermal sarcoma (n = 71) Endometrial stromal sarcoma (n = 9)
61
SARCOMA
7 RY
HISTOI.OGICTYPE
I2
24
36
60
0.902 (0.066)”
0.849 (0.080)
0.796 (0.091)
0.796 (0.091)
0.889 (0.037)
0.71 (0.061)
0.424 (0.064)
0.358 (0.064)
0.889 (0.105)
0.889 (0.105)
0.762 (0.148)
0.508 (0.230)
PRORABILITY
Time in months:
UTERINE
OF SURVIVAL
” Standard error.
Tables 8 and 9 list data for the disease-free interval, as calculated from the time of hysterectomy until the first notation in the clinical record of objective evidence of recurrent sarcoma. At 12 months after hysterectomy, 76% of the entire group were free of evidence of recurrence; at 5 years, 53.3% remained free of disease. There was no difference in disease-free interval between those who received adjuvant therapy and those who did not. In those patients with microscopically positive nodes or margins, 36.5% had demonstrated objective evidence of recurrence in 1 year and only 31.5% were free of recurrence at 5 years. If there was no sarcoma in the surgical margins or resected nodes, 58.3% were free of recurrence at 5 years. Patients with leiomyosarcoma, had a prolonged TABLE C~MULATWE
Time in months:
PROBABILITY
8
OF BEING
FREE OF RECURRENCE
I2
24
36
60
0.740 (0.054)”
0.578 (0.062)
0.543 (0.063)
0.513 (0.066)
0.814 (0.069)
0.642 (0.088)
0.586 (0.096)
0.586 (0.096)
No adjunctive chemotherapy (n = 67)
Adjunctive chemotherapy (n = 34) ‘I Standard error.
TABLE CUMULATIVE
PROBABILITY OF BEING NODES AND MARGINS,
Time in months: Nodes/margins chemotherapy Nodes/margins chemotherapy (n = 59) Nodes/margins chemotherapy Nodes/margins chemotherapy (n = 8)
negative and given (n = 22) negative and not given positive and given (n = 12) positive and not given
” Standard error.
9
FREE OF RECURRENCE AND CHEMOTHERAPY
BY STATUS OF
I2
24
36
60
0.810 (0.086)”
0.762 (0.093)
0.682 (0.113)
0.682 (0.113)
0.790 (0.054)
0.605 (0.066)
0.587 (0.066)
0.552 (0.071)
0.375 (0.171)
0.375 (0.171)
0.250 (0.153)
0.250 (0.153)
0.825 (0.113)
0.374 (0.169)
0.374 (0.169)
0.374 (0.169)
62
HANNIGAN,
FREEDMAN,
AND
RUTLEDGE
disease-free interval (P = 0.02) when compared with patients with mixed mesodermal sarcomas, but this was independent of whether adjuvant chemotherapy was given or withheld. Manifestations of chemotherapy related toxicity observed in the two groups of patients are given in Table 10. Of the 17 patients receiving VAC chemotherapy, 7 patients were recorded as having vomiting of such a degree as to require intravenous rehydration. Alopecia to some degree occurred in all patients. All patients reported symptoms of vincristine-related neurotoxicity and 8 patients (48%) had vincristine therapy discontinued due to the appearance of toxicity. Severe neurotoxicity, defined as a motor disturbance of such degree that patients were confined to a wheelchair, occurred in 3 patients (17%). One patient developed a severe debilitating neurotoxicity after 5 weekly courses of 2 mg of vincristine. The other patients who manifested severe neurotoxicity received at least 10 weekly courses of the drug. Three patients (17%) were hospitalized for treatment of intestinal ileus. Severe myelosuppression was defined as any recorded leukocyte count of less than 1000 white cells/mm3 of blood. Four patients had severe leukopenia but rapidly recovered with outpatient observation. Three additional patients receiving VAC were hospitalized for neutropenia and sepsis. Of I7 patients receiving VAC therapy, 7 (41%) required hospitalization for treatment of drug toxicity, spending an average of 18 hospital days per admission. Eight of the seventeen patients (47%), however, had very little difficulty with tolerance of their therapy. These patients completed at least 5 months of VAC therapy with neither a delay in treatment nor a toxicity-mandated dose reduction. Of the patients treated with adriamycin, 4 received adriamycin as a single agent and 13 received a combination which included vincristine and cytoxan. Alopecia occurred in 13 patients. Severe vomiting requiring rehydration occurred in 4 patients, all of whom were on combination therapy. One patient was hospitalized 10 days for sepsis and agranulocytosis after receiving the three-drug combination. Of 13 patients receiving vincristine, 11 reported mild neurotoxicity and 2 were confined to wheelchairs as a result of severe toxicity. Two patients TABLE TOXIC MANIFESTATIONS
10
ASSOCIATED WITH ADJUNCTIVE
VAC (n = 17) Alopecia Nausea/vomiting (severe) Stomatitis Neurotoxicity Mild Severe Ileus Myelosuppression, severe Hospitalized for treatment of chemotherapy-induced toxicity Cardiac toxicity u Percentages given in parentheses.
17 (100)” 7 (41) 3 (18) 17 3 3 7
(100) (18) (18) (41)
7 (41)
CHEMOTHERAPY
Adriamycin (n = 17) 13 (76) 4 (24) 11/13 (85) 2113 (15)
6 (36) 1 (6) 2 (12)
ADJUVANT
CHEMOTHERAPY
IN
UTERINE
SARCOMA
63
developed possible adriamycin-associated cardiac toxicity. In both instances, the drug was administered as the only chemotherapeutic agent, with both patients receiving the drug at the rate of 60 mgim’ BSAimonth. One patient who received six monthly courses of adriamycin (total dose, 300 mgim’ BSA) developed overt congestive heart failure. The other patient developed electrocardiographic changes, characterized as significant voltage reductions in the limb leads. after six courses (300 mgim’ BSA). She had no symptoms 60 months after discontinuing therapy. No patient on any regimen died as a result of adjunctive chemotherapy. DISCUSSION Di Saia PI ~1. (2) have reported the experience at M. D. Anderson Hospital for a group of patients with mixed mesodermal sarcoma treated either by hysterectomy, radiotherapy, or both. In a group of patients with disease confined to the uterus, with negative surgical margins. 18 of 34 patients (53%) were free of disease at 2 years. However, if parametrial or vaginal margins contained sarcomas, only 3 of 35 (8.5%) patients were alive without evidence of disease at 2 years. In this high-risk group of patients, although the addition of radiation did provide local control of tumor in patients who developed progressive sarcoma. it had very little impact on survival rate. The disease status at 2 years in the group of patients comprising the current report is similar to this earlier group, regardless of whether adjuvant chemotherapy was given or withheld. The difference in the natural history of the various types of uterine sarcomas is apparent in this group of patients. Patients having leiomyosarcomas had both a prolonged disease-free interval and enhanced probability of survival when compared to patients with mixed mesodermal sarcoma. Eighty-three percent of patients with leiomyosarcoma confined to the uterus were disease free at 60 months without adjuvant chemotherapy. Combination chemotherapy consisting of vincristine, actinomycin D. and cyclophosphamide does, as noted by Smith and Rutledge (IO), have activity against metastatic sarcoma. A recent review (4) of a large series of patients with measurable disease lists a response rate to this combination of 29% (16% partial response added to 13% complete response). Combination therapy containing adriamycin demonstrated a response rate of 10.3% (10.3% partial response; no complete responses) (S). When using drugs for adjuvant therapy with these relatively low response rates, it requires a large number of patients in each assessment cell to demonstrate actual benefit. We conclude from the current experience that the effect of adjuvant chemotherapy, using currently available drug combinations, is not dramatic, and may have no effect. But the concept that adjuvant therapy may improve survival, especially when using more active therapy which may become available in the future, is neither proven nor disproven. Severe vincristine-associated neurotoxicity occurred in 15% of exposed patients and minor neurotoxicity occurred in every patient. Forty-one percent of the patients on the VAC regimen required hospitalization for treatment of VAC toxicity. Our experience with these and other patients treated with VAC chemotherapy has prompted us to reduce the intensity of vincristine therapy. No
64
HANNIGAN,
FREEDMAN,
AND
RUTLEDGE
single dose of vincristine currently exceeds 2 mg and weekly therapy is not used with the current drug combinations. Adriamycin-containing regimens seemed to be associated with a less severe degree of toxicity-only 1 patient was hospitalized for treatment related toxicity. Still, 4 of 17 patients (24%) required periodic intravenous rehydration, and 2 of 17 (12%) developed cardiac toxicity. In summary, we could demonstrate no discernible effect on either survival or disease-free interval after using combination chemotherapy in addition to hysterectomy and radiotherapy, in patients with sarcoma confined to the uterus. Clearly, we have not achieved a strong adjuvant effect by use of either VAC or adriamycin. However, because these patients have such a high risk of failure after initial treatment, we feel that trials with other systemic agents, administered in an adjuvant setting, are indicated. REFERENCES 1. Buchsbaum, H. J., Lifshitz, S., and Blyth, J. G. Prophylactic chemotherapy in Stages I and II uterine sarcoma, Gynecol. Oncol. 8, 346-348 (1979). 2. DiSaia, P. J., Castro, J. R., and Rutledge, F. N. Mixed mesodermal sarcoma of the uterus, Amer. .I. Roentgenol. Radium Ther. Nucl. Med. 3, 632-636 (1973). 3. Edwards, C. L. Undifferentiated tumors, in Cancer of the uterus and ovary, Year Book Med. Pub., Chicago, pp. 84-94 (1966). 4. Hannigan, E. V., Elder, K. W., Freedman, R. S., and Rutledge, F. N. Treatment of advanced uterine sarcoma with vincristine, actinomycin D, and cyclophosphamide, Gynecol. Oncol., in press. 5. Hannigan, E. V., Elder, K. W., Freedman, R. S., and Rutledge, F. N. Treatment of advanced uterine sarcoma with combination chemotherapy including adriamycin. Gyneco/. Oncol., in press. 6. Hull, C. H., and Nie, N. H. Survival, in SPSS update: New procedures andfacilitiesfor releases 7 and 8, McGraw-Hill, New York (1979). 7. Jaffe, N., Traggis, D., Salian, S., and Cassady, J. R. Improved outlook for Ewing’s sarcoma with combination chemotherapy (vincristine, actinomycin-D and cyclophosphamide) and radiation therapy, Cancer 38, 1925-1930 (1976). 8. Murphy, W. K., Benjamin, R. S., Eyre, H. J., Thigpen, T., Groppe, C., Uribe-Botero, G., Baker, L. J., Gehan, E. A., and Gottlieb, J. A. Update: Adjuvant chemotherapy in osteosarcoma of adults, in Adjuvant therapy of cancer II (S. E. Jones and S. E. Salmon, Eds.), Grune & Stratton, New York (1979). 9. Piver, M. D., Barlow, J. J., Lele, S. B., and Yazigi, R. Adriamycin in localized and metastatic uterine sarcomas, J. Surg. Oncol. 12, 263-265 (1979). 10. Smith, J. P., and Rutledge, F. N. Advances in chemotherapy for gynecologic cancer, Cancer 36, 669-674
(1975).