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The effect of postoperative external radiotherapy on cervical carcinoma stage IB and IIA
GYNECOLOGIC
ONCOLOGY
22, 73-84 (1985)
The Effect of Postoperative External Radiotherapy on Cervical Carcinoma Stage I6 and IIA A. HIMMELMANN, Department
of Oncology,
E. HOLMBERG, Gynecological University
I.
JANSSON,*
Section Hospital,
A. ODIN,
AND
and *Department of Obstetrics Gothenburg, Sweden
K.
SKOGSBERG and Gynecology,
Received August 20, 1984 Among 344 patients operated after intracavitary irradiation of cervical carcinoma stage IB and IIA, 55 had positive nodes in the operation specimen, 16 of these received no postoperative irradiation, 22 received pelvic irradiation without a boost dose to positive nodes, and 17 also received a boost. The crude 5-year survival was 52% for these 55 highrisk patients. All 3 patients with adenocarcinoma died. For squamous-cell carcinoma postoperative irradiation gave a later relapse and less distant metastases, but survival was not approved. Postoperative irradiation with a boost added, resulted in 3 recurrences among 16 patients, none in the treated volume, and only one complication. The numerically improved survival of this small group was not statistically significant, however. A randomized trial with and without postoperative irradiation with a boost dose, requiring 1100-1200 operated patients, would answer the question whether the observed improval is significant or not. 0 1985 Academic Press, Inc.
The effect of external irradiation on pelvic node control in the cervical carcinoma patient has been verified by operation after irradiation [ 1,2]. The rate of pelvic node control is also dose dependent [3]. However, postoperative external irradiation of the operated cervical carcinoma patient with pelvic node involvement has not improved survival [4]. Fuller et al. [5] reported a 5-year survival of 50% in 71 patients with stage IB and IIA. Survival was the same whether postoperative radiotherapy was given or not. This 5-year survival is in good agreement with a review of the literature by Delgado [6] comprising 179 node-positive patients with stage IB. It could be argued that a randomized trial should be performed to study the effects of postoperative irradiation in node-positive patients. A large number of patients would be needed, however. If the 5-year survival changed from 50 to 75%, which is optimistic, 80 node-positive patients would have to be irradiated postoperatively and 80 not, and then be observed for 5 years, to demonstrate a statistically significant difference (P < 0.05) with 90% probability. This investigation has been performed as a contribution to the discussion on the value of a randomized trial with and without postoperative irradiation. The results of our present postoperative irradiation regime including a boost dose have retrospectively been compared with those of other regimes of postoperative irradiation and no irradiation at all in the same clinic. 73
0090-8258185 $1 SO Copyright 0 1985 by Academic Press. Inc. All rights of reproduction in any form reserved.
HIMMELMANN
74
ET AL.
MATERIALS AND METHODS Patients. From January 1970 until May 1981, 691 women from our referral region with cervical carcinoma stage IB and IIA were treated. Staging was performed according to FIG0 [7]. Twenty-three of these patients were excluded from the analysis due to prior malignancies or prior pelvic irradiation. Three hundred and nineteen patients received intracavitary and external irradiation as the primary treatment. These patients, not subjected to surgery because of age or incurrent disease, are only analyzed in this paper for description of the total material (Table 1). Three hundred and forty-nine patients received intracavitary irradiation followed by operation. Five of these patients had to be excluded from the analysis due to lack of information on pelvic node status. Of the remaining operated patients 11% with stage IB showed tumor involvement of regional nodes at operation and 33% with stage IIA, altogether 55 patients (Table 2). Only 43% of the patients were operated upon at the beginning of the period while 62% were operated upon at the end of the period (Table 1). Patients with adenocarcinoma were operated upon to a larger extent throughout the period. Zntracavitary irradiation. For intracavitary irradiation, a modified Stockholm technique with radium was used [8]. Three manual insertions were given in 29 days. About 6500 mgh were used. A maximum dose of 50 Gy to the bladder and 45 Gy to the rectum was allowed. The dose rate was 0.025 Gy/min at point A. Since 1976 a 6oCo distant afterloading technique with high dose rates have been used as an alternative [9]. This method was planned to give the same cumulative radiation effect (CRE) for late effects at target surface points as the TABLE SELECTION
OF PATIENTS
1
FOR OPERATION RELATED TO AGE, AND TIME OF TREATMENT
STAGE,
MICROSCOPY,
No. of patients Op + non-op Total Age, years (z?) Stage IB IIA Microscopy Squamous-cell carcinoma Well/mod well diff Poorly diff/undiff Adenocarcinoma Time of treatment 1970-1972 1973-1976 1977-1981
OP
Non-op
663
344 (52%) 40 (SD = 9)
319 (48%) 59 (SD = 12)
404 259
265 (66%) 79 (31%)
139 (34%) 180 (69%)
237 356 70
122 (51%) 177 (50%) 45 (64%)
115 (49%) 179 (50%) 25 (36%)
200 225 238
86 (43%) 110 (49%) 148 (62%)
114 (57%) 115 (51%) 90 (38%)
EXTERNAL
RADIOTHERAPY
TABLE DISTRIBUTION
75
EFFECT
2
OF PELVIC NODE METASTASES AT OPERATION IN RELATION TO AGE, STAGE, MICROSCOPY, TIME OF TREATMENT, AND TUMOR REMNAN&
No. of patients All
Total Age, years (X) Stage IB IIA Microscopy Squamous-cell carcinoma Well/mod well diff Poorly diff/undiff Adenocarcinoma Time of treatment 1970-1972 1973-1976 1977-1981 Local tumor cells in the operation specimen, no. a One patient with adenocarcinoma
op
344 40 (SD = 9)
Pos nodes
Neg nodes
55 (16%) 41 (SD = 10)
289 (84%) 40 (SD = 9)
265 79
29 (11%) 26 (33%)
236 (89%) 53 (67%)
122 177 45
18 (15%) 34 (19%) 3 ( 7%)
104 (85%) 143 (81%) 42 (93%)
86 110 148 56/343” (16%)
16 (19%) 14 (12%) 25 (17%) 19/54” (35%)
70 (81%) 96 (88%) 123 (83%) 37/289 (13%)
excluded due to primary hysterectomy at diagnosis.
radium technique [ 101. Five insertions were given in 29 days with a total dose of 42.5 Gy to target surface points and with a dose rate of about 2 Gy/min at the same target surface. Operation. A Wertheim-Meigs radical hysterectomy with bilateral lymphadenectomy was performed 3-4 weeks after completion of intracavitary treatment. A vaginal cuff of about 3 cm was removed. Lymphography was not done preoperatively. The pelvic node stations were marked with silver clips to facilitate postoperative irradiation. Node involvement in the operation specimen was retrospectively graded according to an arbitrary scale (Table 3). Only routine pathology was performed. Postoperative irradiation. For the external irradiation 6oCo or 5 MV photons, with a SSD of 80-100 cm, were used, depending on the thickness of the patient. Patients with negative nodes in the operation specimen (N = 289), received no postoperative irradiation, except in five cases with residual tumor in the paracervical or paracolpic tissues. During 1970-1972 no postoperative irradiation was given to patients with positive nodes (N = 16). These patients will be referred to as the “No postop irrad” group among the node-positive patients. During 1973-1976 postoperative pelvic irradiation was used for I5 patients with positive nodes. A midline dose of 40 Gy was given in 20 fractions within 4 weeks. Two opposite fields and central shielding were used. The field size was 16-18 cm x 16-20 cm. In some cases 45 Gy was given to a smaller volume
76
HIMMELMANN
TABLE
ET
AL.
3
DISTRIBUTION OF GRADE OF NODE INVOLVEMENT IN THE OP SPECIMEN FOR 52 NODE-POSITIVE WOMEN WITH EPIDERMOID CARCINOMA RELATED TO POSTOP IRRADIATION AND TIME OF TREATMENT
Grade of node involvement 1. Microscopic findings in a single node; no periglandular involvement 2. Microscopic findings in several nodes; single moderately enlarged node with tumor involvement; no periglandular involvement 3. Large nodes with tumor involvement; periglandular growth
No postop irrad
Conv postop irrad
Boost dose added to postop irrad
1970-1972
1973-1976
1977-1981
2
2
0
8
10
5
3
6
4
6
4
2
only containing positive nodes with the same fractionation. These patients will be referred to as the “Conventional postop irrad” group. Since 1977, 17 patients with positive nodes received pelvic irradiation with central shielding postoperatively. Usually, 42.5 Gy, with 2.2 Gy per fraction, was given 4 times a week. A boost dose was then added to a smaller volume, containing positive node stations, to a total dose of 55-60 Gy (Fig. I). A cumulative radiation effect of 14 to the pelvic wall of the large field and 16 to the small field was delivered. These patients will be referred to as the “Boost dose added to postop irrad” group. Another seven patients with positive nodes received postoperative irradiation with 40 Gy in 4 weeks after 1976 and were referred to the “Conventional postop irrad” group. Follow-up and endpoints. After completion of treatment, the patients were seen every second to third month during the first year and later at longer intervals. Clinical examination, vaginal cytology, and renography or urography were performed regularly. Local recurrence was defined as cancer recurring in the uterus or the upper two thirds of the vagina. Pelvic recurrence was defined as recurrence in the pelvis or the lower third of the vagina, but outside the local region, defined above. Distant metastases were defined as cancer in distant nodes, lung, bone, or other organs outside the pelvis. Patients were regarded as dead from cancer if they died with recurrent disease or metastases, if the cause of death was uncertain, or due to a treatment complication.
EXTERNAL
FIG. 1. External irradiation nodes.
RADIOTHERAPY
EFFECT
77
with a boost dose. Silver clips indicate external iliac and obturator
In patients with recurrent disease or metastases, it is often uncertain whether a complication is due to cancer or to previous treatment. It was therefore decided to study the treatment complications until the date of relapse. Complications in the colon-rectum and the bladder were registered according to Kottmeier [ 1 I]. Complications in the small bowel and elsewhere were registered separately. Only two patients were lost to follow-up, both having moved to other countries. They were lost after 9 and 24 months of observation. Statistical analysis. The number of patients needed for a randomized trial was calculated on the assumption that Fisher’s exact test should be used for the comparison. Crude survival was used for evaluation of the operated patients. One intercurrent death occurred in the 55 node-positive patients. For comparison of the small node-positive subgroups, corrected survival was therefore used. Corrected survival was also used for the total material since old patients and those with other diseases were included. Observation time was taken into account by using lifetable technique for survival, recurrence, and metastasis [12]. Differences in age, stage, microscopy, and grade of node involvement between the different groups of patients, were tested by Pittman’s nonparametric twotailed method [ 131. Differences in survival and recurrence between the different groups, with and without elimination of the influence of unequal distribution of a background variable, were tested by a special nonparametric two-tailed method [14].
78
HIMMELMANN
ET
AL.
Mantel’s two-tailed test [15] was used for comparison of complication rates between operated patients with and without postoperative irradiation. The observation time had to be taken into account as node-positive patients with postoperative irradiation had a shorter observation time to relapse than most patients without postoperative irradiation. RESULTS Survival
Corrected actuarial survival for all operated and nonoperated patients in stage IB and IIA is shown in Fig. 2. As the nonoperated patients comprised a negatively selected group, no comparison of survival and recurrence rates was made between the two groups. The crude 5-year survival for the operated patients was 0.86 (Fig. 3). There was a statistically significant difference in crude 5-year survival (P < 0.001) between patients with positive nodes and negative nodes at operation (0.52 and 0.93, respectively).
ii01
,
0
60 Observations
FIG.
, 120
time, months
2. Cumulative corrected survival for operated and nonoperated patients (2 2 SD)
Op., neg. nodes All operated
Op., pos. nodes
0
120
60
0
Observations
time, months
FIG. 3. Cumulative crude survival for patients with positive and negative nodes in the operation specimen ( t 2 SD)
EXTERNAL
RADIOTHERAPY
79
EFFECT
The distribution of grade of node involvement in node-positive patients with epidermoid carcinomas is shown in Table 3. No statistically significant difference in this distribution was obtained between the different treatment groups or for different periods of treatment. The crude survival for nonoperated patients and operated node-negative patients showed no change due to the time of treatment. The different postoperative treatment regimes used for node-positive patients during different periods could therefore be compared. For squamous-cell carcinoma with positive nodes no difference in corrected 5-year survival was observed between the “No postop irrad” group and the “Conventional postop irrad.” group. “Boost dose added to postop irrad” gave a somewhat, but not significantly, better survival (Table 4). The observation time was taken into account individually in these small groups. There were no differences in age, stage, grade of differentiation, or local residual carcinoma between the node-positive subgroups. Only 3 of 45 operated patients with adenocarcinoma had positive nodes at operation (7%). All three died of cancer. Recurrence
and Metastasis
as the First
Sign of Relapse
Local and pelvic recurrence and distant metastasis in relation to time in nonoperated and operated patients with and without node involvement in the operation specimen are shown in Fig. 4. The incidences of recurrence and metastasis in the 52 node-positive patients with squamous-cell carcinoma in relation to postoperative treatment are shown in Table 4 and in relation to time in Fig. 5. Distant metastasis as the first sign of relaps occurred more frequently when no postoperative irradiation was used than for the other node-positive patients (P < 0.05). In the “boost dose added to postop in-ad” group, only three pelvic recurrences occurred and no local recurrences or distant metastases as the first sign of relapse. Two patients had TABLE THE OUTCOME
FOR
4
52 NODE-POSITIVE
WOMEN WITH SQUAMOS-CELL CARCINOMA IRRADIATION AND TIME OF TREATMENT
No postop irrad
Relapse within 5 years No. of pts Local recurrence Pelvic recurrence Metastases Corr Syear survival For postop irrad For treatm period
Boost dose added to postop irrad
Conv postop irrad
1970-1972
1973-1976
9 16 3 2 5
8 13 2 4 2
0.49 0.49
0.54
RELATED TO POSTOP
1977-1981 2 7 1 2 0
3 16 0 3 0
0.53
0.81 0.78
80
HIMMELMANN
ET AL.
non-op. op. neg. nodes 60 Observation
tine,
months
Observation
Gne,
months
120 ~-
op. pos. nodes
I 60
0 Observation
120 time,
months
FIG. 4. The primary sign of relapse (k 2 SD) for nonoperated patients and for patients with and without node involvement at operation. (a) Local and (b) pelvic recurrence, (c) distant metastasis.
their recurrences above the irradiated volume and one behind the central shielding between the sacrum and rectum. The P value obtained on testing the rate of relapse for the “boost dose added to postop irrad” group and the other treatment groups was 0.053. The observation times were taken into account individually. The grade of node involvement
No postop.
irrad.
z-f
211 0
p ..__ I 12 24 Observation
postop.
~i.~i~dedto 36 time,
48 months
60
FIG. 5. Time of relapse for node-positive squamous-cell carcinoma patients in relation to postoperative treatment.
EXTERNAL
RADIOTHERAPY
EFFECT
81
seemed to be lower in the “boost dose added to postop h-t-ad” group (Table 3), but the difference was not statistically significant (P = 0.14). When the grade of node involvement still was taken into account, the corresponding P value for the comparison of relapse rates for the boost dose group and the other treatment groups was 0.061. Complications
In this material, 8 out of 55 patients with positive nodes at operation (14%) had minor or major complications, none with a fatal outcome (Table 5). One woman had an uretervaginal fistula which healed after surgical repair. One woman had a temporary ureteric stasis and later an attack of subileus. No surgical intervention was needed. One more case of temporary ureteric stasis was recorded and one more case of subileus without surgical intervention. One bladder reaction grade 1 and two rectal reactions grade 1 were recorded. The eighth complication was a colovaginal fistula which healed on conservative treatment. This patient was treated with intracavitary radium application preoperatively and external irradiation with a boost dose added postoperatively. This was the only complication in the “boost dose added to postop irrad” group. Minor or major complications occured in 16% of 44 patients receiving postoperative external irradiation, while 8% complications occurred for 300 patients without postop irradiation (P < 0.05), see Table 5. There was no difference in incidence of complications indicating surgery for these two groups. There were significantly less major and minor complications (P < 0.05) among the 344 operated patients when the distant afterloading technique was used for intracavitary irradiation (387) than when manually handled radium was used (27/257). DISCUSSION
It has not been proved that operation improves survival in cervical carcinoma stage IB and IIA compared with external irradiation directly after intracavitary treatment [ 16,171. For women under 35 years of age, intracavitary irradiation followed by surgery might be advantageous, however [18]. One advantage of operation is that a distinct risk group can be selected, comprising patients with positive nodes at operation. This is only of importance if additional treatment which improves the outcome for this risk group can be offered. Postoperative irradiation has not improved the survival in these patients [5]. The dose may not have been sufficient but positive nodes may also be associated with systemic spread, not yet detected. The importance of primary tumor control for cervical carcinoma has been demonstrated by Anderson and Dische [19], however, leading to a lower incidence of distant metastasis in the subsequent years following treatment. In external irradiation, an additional boost to a smaller volume has been used for other carcinomas [20]. A similar technique for the advanced cervical carcinoma with single enlarged nodes has also been described [20]. In this retrospective material the crude 5-year survival of node-positive patients (0.52) is in agreement with that of Fuller et al. [51 and of Rampone et al. [21]. The incidence of distant metastasis was reduced for node-positive squamous-
82
HIMMELMANN
ET
AL.
000
:I’
-00
c-4000
000
OOOON
000
00-
U-l--
-
---m,a
0
0
0
0
-
-Iv
EXTERNAL
RADIOTHERAPY EFFECT
83
cell carcinoma patients by postoperative irradiation. Irradiation with 40-45 Gy without a boost did not improve survival, however, but recurrence and metastasis tended to occur later compared with no postoperative irradiation (Fig. 5). This delay of relapse is interesting as a similar delay can be seen for some pelvic recurrences and possibly distant metastases in nonoperated patients in Fig. 4. These delayed relapses could be due to persistent positive pelvic nodes, having received an insufficient dose, as the delay does not occur in patients with positive nodes without postoperative irradiation or patients receiving a boost. Only 16 out of 52 patients with squamous-cell carcinoma had postoperative irradiation to the pelvis with an additional boost to positive nodes. Of 16 patients, 3 relapsed and died of cancer. The corrected 5-year survival (0.81) was not significantly different from that of the other node-positive carcinomas (0.52). No recurrences occurred within the irradiated volume, however. The treatment was well tolerated, especially by patients who received distant afterloading with 6oCo preoperatively. Because of the higher dosimetric accuracy for this intracavitary treatment, better central shielding could be obtained during the external irradiation 191.
A randomized prospective study with and without postoperative irradiation including a boost could possibly signify the observed difference. A large number of patients would be demanded, however. One hundred and sixty node-positive patients correspond to 1001 operated patients with our rate of positive nodes. An additional number will be required if adenocarcinomas are excluded and if the benefit of the irradiation is less than stated. With our experience of postoperative irradiation, we hesitate to leave patients without this treatment. A cooperative study could possibly be performed by centers where a large number of patients with Stage IB and IIA are operated upon and postoperative irradiation of positive nodes has not been the rule. Einhom [22] reports a rate of 33% severe complications indicating surgery for patients with supplementary irradiation after surgery. This is not in agreement with our experience. In these studies, however, the definition of complications are different. To avoid reactions from the irradiation, the patients must either have intracavitary irradiation preoperatively with good precision or not at all. ACKNOWLEDGMENTS This work was supported by grants from the Swedish Cancer Society, and the Cancer Research Fund of Jubileumskliniken, Gothenburg.
REFERENCES 1. Rutledge, F. N., and Fletcher, G. H. Ttansperitoneal pelvic lymphadenectomy following supervoltage irradiation for squamous-cell carcinoma of the cervix, Amer. J. Obsret. Gynecol. 76, 321-334 (1958). 2. Lagasse, L. D., Smith, M. L., Moore, J. G., Morton, D. G., Jacobs, M., Johnson, G. H.,, and Watring, W. G. The effect of radiation therapy on pelvic lymph node involvement in Stage I carcinoma of the cervix, Amer. J. Obstet. Gynecol. 119, 330-334 (1974). 3. Awwad, H. K., Barsoum, M. S., Burgers, M. V., El Badawy, S. A., and Soliman, 0. M. The dose-time relationship in the radiotherapy of carcinoma of the cervix uteri: An application of the CRE formalism, Clin. radial. 30, 263-267 (1979).
84
HIMMELMANN
ET AL.
4. Panel report: Is Pelvic radiation beneficial in the postoperative management of stage IB squamouscell carcinoma of the cervix with pelvic node metastasis treated by radical hysterectomy and pelvic lymphadenectomy? Gynecol. Oncol. 10, 105-110 (1980). 5. Fuller, A. F., Elliott, N., Kosloff, C., and Lewis, J. L. Lymph node metastasis from carcinoma of the cervix, Stages IB and HA. Implications for prognosis and treatment, Gynecol. 0~01. 13, 165-177 (1982). 6. Delgado, G. Stage IB squamous cancer of the cervix: The choice of treatment, Obsref. Gynecol. Surv. 33, 174-183 (1978). 7. Kottmeier, H. L. Annual report on the results of treatment in gynecological cancer 1973-1975, p. 14, Radiumhemmet, Stockholm (1982). 8. Kjellgren, 0. Clinical invasive carcinoma of cervix: Place of radiotherapy as primary treatment, in Gynecological oncology (M. Coppleson, Ed.), pp. 482-503, Churchill Livingstone, Edinburgh (1981). 9. Himmelmann, A., and Ragnhult, I. High dose rate afterloading treatment of carcinoma of the uterine cervix using an individual planning and reconstruction system, Acta Radiol. Oncol. 22, 263-271 (1983). 10. Kirk, J., Gray, W., and Watson, E. R. Cumulative radiation effect. Part I. Fractionated treatment regimes, C/in. Radiol. 22, 145-155 (1971). 11. Kottmeier, H. L., and Gray, M. T. Rectal bladder injuries in relation to radiation dosage in carcinoma of the cervix, Amer. J. Obstet. Gynecol. 82, 74-82 (1961). 12. Cutler, S. J., and Ederer, F. Maximum utilization of the life table method in analysing survival, J. Chron. Dist. 8, 699-712 (1958). 13. Bradley, J. V. Distribution-free statistical tests, pp. 68-83, Printance-Hall, London, (1968). 14. Merck, C., Angervall, K., Kindblom, L. Cl., and Oden, A. Myxofibrosarcoma. A malignant soft tissue tumor of fibroblastic-histiocytic origin. A clinicopathologic and prognostic study of 110 cases using a multivariate analysis, Acta Pathol. Microbial. Stand. Suppl. 282, 91, l-40 (1983). 15. Mantel, N. Chi-square tests with one degree of freedom: Extension of the Mantel-Haenszel procedure, J. Amer. Statist. Assoc. 58, 690-700 (1963). 16. Iversen, T., Kjorstad, K. E., and Martimbeau, P. W. Treatment results in carcinoma of the cervix stage IB in a total population, Gynecol. Oncol. 14, 1-5 (1982). 17. Perez, C. A., Camel, H. M., Kao, M. S., and Askin, F. Randomized study of preoperative radiation and surgery or irradiation alone in the treatment of stage IB and IIA carcinoma of the uterine cervix: Preliminary analysis of failures and complications, Cancer 45, 2759-2768 (1980). 18. Gynning, I., Johnsson, J.-E., Alm, P., and Trope, C. Age and prognosis in stage IB squamouscell carcinoma of the uterine cervix, Gynecol. Oncol. 15, 18-26 (1983). 19. Anderson, P., and Dische, S. Local tumour control and the subsequent incidence of distant metastatic disease, Znt. J. Radiat. Oncol. Biol. Phys. 7, 1645-1648 (1981). 20. Fletcher, G. H. Textbook ofradiotherapy, 3rd edition, pp. 563-568 and 760-764 Lea and Febiger, Philadelphia (1980). 21. Rampone, J. F., Klem, V., and Kolstad, P. Combined treatment of Stage IB carcinoma of the cervix, Obstet. Gynecol. 41, 163-167 (1973). 22. Einhorn, N. Frequency of severe complications after radiation therapy for cervical carcinoma, Acta Radiol. Ther. Phys. Biol. 14, 42-48 (1975).
ONCOLOGY
22, 73-84 (1985)
The Effect of Postoperative External Radiotherapy on Cervical Carcinoma Stage I6 and IIA A. HIMMELMANN, Department
of Oncology,
E. HOLMBERG, Gynecological University
I.
JANSSON,*
Section Hospital,
A. ODIN,
AND
and *Department of Obstetrics Gothenburg, Sweden
K.
SKOGSBERG and Gynecology,
Received August 20, 1984 Among 344 patients operated after intracavitary irradiation of cervical carcinoma stage IB and IIA, 55 had positive nodes in the operation specimen, 16 of these received no postoperative irradiation, 22 received pelvic irradiation without a boost dose to positive nodes, and 17 also received a boost. The crude 5-year survival was 52% for these 55 highrisk patients. All 3 patients with adenocarcinoma died. For squamous-cell carcinoma postoperative irradiation gave a later relapse and less distant metastases, but survival was not approved. Postoperative irradiation with a boost added, resulted in 3 recurrences among 16 patients, none in the treated volume, and only one complication. The numerically improved survival of this small group was not statistically significant, however. A randomized trial with and without postoperative irradiation with a boost dose, requiring 1100-1200 operated patients, would answer the question whether the observed improval is significant or not. 0 1985 Academic Press, Inc.
The effect of external irradiation on pelvic node control in the cervical carcinoma patient has been verified by operation after irradiation [ 1,2]. The rate of pelvic node control is also dose dependent [3]. However, postoperative external irradiation of the operated cervical carcinoma patient with pelvic node involvement has not improved survival [4]. Fuller et al. [5] reported a 5-year survival of 50% in 71 patients with stage IB and IIA. Survival was the same whether postoperative radiotherapy was given or not. This 5-year survival is in good agreement with a review of the literature by Delgado [6] comprising 179 node-positive patients with stage IB. It could be argued that a randomized trial should be performed to study the effects of postoperative irradiation in node-positive patients. A large number of patients would be needed, however. If the 5-year survival changed from 50 to 75%, which is optimistic, 80 node-positive patients would have to be irradiated postoperatively and 80 not, and then be observed for 5 years, to demonstrate a statistically significant difference (P < 0.05) with 90% probability. This investigation has been performed as a contribution to the discussion on the value of a randomized trial with and without postoperative irradiation. The results of our present postoperative irradiation regime including a boost dose have retrospectively been compared with those of other regimes of postoperative irradiation and no irradiation at all in the same clinic. 73
0090-8258185 $1 SO Copyright 0 1985 by Academic Press. Inc. All rights of reproduction in any form reserved.
HIMMELMANN
74
ET AL.
MATERIALS AND METHODS Patients. From January 1970 until May 1981, 691 women from our referral region with cervical carcinoma stage IB and IIA were treated. Staging was performed according to FIG0 [7]. Twenty-three of these patients were excluded from the analysis due to prior malignancies or prior pelvic irradiation. Three hundred and nineteen patients received intracavitary and external irradiation as the primary treatment. These patients, not subjected to surgery because of age or incurrent disease, are only analyzed in this paper for description of the total material (Table 1). Three hundred and forty-nine patients received intracavitary irradiation followed by operation. Five of these patients had to be excluded from the analysis due to lack of information on pelvic node status. Of the remaining operated patients 11% with stage IB showed tumor involvement of regional nodes at operation and 33% with stage IIA, altogether 55 patients (Table 2). Only 43% of the patients were operated upon at the beginning of the period while 62% were operated upon at the end of the period (Table 1). Patients with adenocarcinoma were operated upon to a larger extent throughout the period. Zntracavitary irradiation. For intracavitary irradiation, a modified Stockholm technique with radium was used [8]. Three manual insertions were given in 29 days. About 6500 mgh were used. A maximum dose of 50 Gy to the bladder and 45 Gy to the rectum was allowed. The dose rate was 0.025 Gy/min at point A. Since 1976 a 6oCo distant afterloading technique with high dose rates have been used as an alternative [9]. This method was planned to give the same cumulative radiation effect (CRE) for late effects at target surface points as the TABLE SELECTION
OF PATIENTS
1
FOR OPERATION RELATED TO AGE, AND TIME OF TREATMENT
STAGE,
MICROSCOPY,
No. of patients Op + non-op Total Age, years (z?) Stage IB IIA Microscopy Squamous-cell carcinoma Well/mod well diff Poorly diff/undiff Adenocarcinoma Time of treatment 1970-1972 1973-1976 1977-1981
OP
Non-op
663
344 (52%) 40 (SD = 9)
319 (48%) 59 (SD = 12)
404 259
265 (66%) 79 (31%)
139 (34%) 180 (69%)
237 356 70
122 (51%) 177 (50%) 45 (64%)
115 (49%) 179 (50%) 25 (36%)
200 225 238
86 (43%) 110 (49%) 148 (62%)
114 (57%) 115 (51%) 90 (38%)
EXTERNAL
RADIOTHERAPY
TABLE DISTRIBUTION
75
EFFECT
2
OF PELVIC NODE METASTASES AT OPERATION IN RELATION TO AGE, STAGE, MICROSCOPY, TIME OF TREATMENT, AND TUMOR REMNAN&
No. of patients All
Total Age, years (X) Stage IB IIA Microscopy Squamous-cell carcinoma Well/mod well diff Poorly diff/undiff Adenocarcinoma Time of treatment 1970-1972 1973-1976 1977-1981 Local tumor cells in the operation specimen, no. a One patient with adenocarcinoma
op
344 40 (SD = 9)
Pos nodes
Neg nodes
55 (16%) 41 (SD = 10)
289 (84%) 40 (SD = 9)
265 79
29 (11%) 26 (33%)
236 (89%) 53 (67%)
122 177 45
18 (15%) 34 (19%) 3 ( 7%)
104 (85%) 143 (81%) 42 (93%)
86 110 148 56/343” (16%)
16 (19%) 14 (12%) 25 (17%) 19/54” (35%)
70 (81%) 96 (88%) 123 (83%) 37/289 (13%)
excluded due to primary hysterectomy at diagnosis.
radium technique [ 101. Five insertions were given in 29 days with a total dose of 42.5 Gy to target surface points and with a dose rate of about 2 Gy/min at the same target surface. Operation. A Wertheim-Meigs radical hysterectomy with bilateral lymphadenectomy was performed 3-4 weeks after completion of intracavitary treatment. A vaginal cuff of about 3 cm was removed. Lymphography was not done preoperatively. The pelvic node stations were marked with silver clips to facilitate postoperative irradiation. Node involvement in the operation specimen was retrospectively graded according to an arbitrary scale (Table 3). Only routine pathology was performed. Postoperative irradiation. For the external irradiation 6oCo or 5 MV photons, with a SSD of 80-100 cm, were used, depending on the thickness of the patient. Patients with negative nodes in the operation specimen (N = 289), received no postoperative irradiation, except in five cases with residual tumor in the paracervical or paracolpic tissues. During 1970-1972 no postoperative irradiation was given to patients with positive nodes (N = 16). These patients will be referred to as the “No postop irrad” group among the node-positive patients. During 1973-1976 postoperative pelvic irradiation was used for I5 patients with positive nodes. A midline dose of 40 Gy was given in 20 fractions within 4 weeks. Two opposite fields and central shielding were used. The field size was 16-18 cm x 16-20 cm. In some cases 45 Gy was given to a smaller volume
76
HIMMELMANN
TABLE
ET
AL.
3
DISTRIBUTION OF GRADE OF NODE INVOLVEMENT IN THE OP SPECIMEN FOR 52 NODE-POSITIVE WOMEN WITH EPIDERMOID CARCINOMA RELATED TO POSTOP IRRADIATION AND TIME OF TREATMENT
Grade of node involvement 1. Microscopic findings in a single node; no periglandular involvement 2. Microscopic findings in several nodes; single moderately enlarged node with tumor involvement; no periglandular involvement 3. Large nodes with tumor involvement; periglandular growth
No postop irrad
Conv postop irrad
Boost dose added to postop irrad
1970-1972
1973-1976
1977-1981
2
2
0
8
10
5
3
6
4
6
4
2
only containing positive nodes with the same fractionation. These patients will be referred to as the “Conventional postop irrad” group. Since 1977, 17 patients with positive nodes received pelvic irradiation with central shielding postoperatively. Usually, 42.5 Gy, with 2.2 Gy per fraction, was given 4 times a week. A boost dose was then added to a smaller volume, containing positive node stations, to a total dose of 55-60 Gy (Fig. I). A cumulative radiation effect of 14 to the pelvic wall of the large field and 16 to the small field was delivered. These patients will be referred to as the “Boost dose added to postop irrad” group. Another seven patients with positive nodes received postoperative irradiation with 40 Gy in 4 weeks after 1976 and were referred to the “Conventional postop irrad” group. Follow-up and endpoints. After completion of treatment, the patients were seen every second to third month during the first year and later at longer intervals. Clinical examination, vaginal cytology, and renography or urography were performed regularly. Local recurrence was defined as cancer recurring in the uterus or the upper two thirds of the vagina. Pelvic recurrence was defined as recurrence in the pelvis or the lower third of the vagina, but outside the local region, defined above. Distant metastases were defined as cancer in distant nodes, lung, bone, or other organs outside the pelvis. Patients were regarded as dead from cancer if they died with recurrent disease or metastases, if the cause of death was uncertain, or due to a treatment complication.
EXTERNAL
FIG. 1. External irradiation nodes.
RADIOTHERAPY
EFFECT
77
with a boost dose. Silver clips indicate external iliac and obturator
In patients with recurrent disease or metastases, it is often uncertain whether a complication is due to cancer or to previous treatment. It was therefore decided to study the treatment complications until the date of relapse. Complications in the colon-rectum and the bladder were registered according to Kottmeier [ 1 I]. Complications in the small bowel and elsewhere were registered separately. Only two patients were lost to follow-up, both having moved to other countries. They were lost after 9 and 24 months of observation. Statistical analysis. The number of patients needed for a randomized trial was calculated on the assumption that Fisher’s exact test should be used for the comparison. Crude survival was used for evaluation of the operated patients. One intercurrent death occurred in the 55 node-positive patients. For comparison of the small node-positive subgroups, corrected survival was therefore used. Corrected survival was also used for the total material since old patients and those with other diseases were included. Observation time was taken into account by using lifetable technique for survival, recurrence, and metastasis [12]. Differences in age, stage, microscopy, and grade of node involvement between the different groups of patients, were tested by Pittman’s nonparametric twotailed method [ 131. Differences in survival and recurrence between the different groups, with and without elimination of the influence of unequal distribution of a background variable, were tested by a special nonparametric two-tailed method [14].
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HIMMELMANN
ET
AL.
Mantel’s two-tailed test [15] was used for comparison of complication rates between operated patients with and without postoperative irradiation. The observation time had to be taken into account as node-positive patients with postoperative irradiation had a shorter observation time to relapse than most patients without postoperative irradiation. RESULTS Survival
Corrected actuarial survival for all operated and nonoperated patients in stage IB and IIA is shown in Fig. 2. As the nonoperated patients comprised a negatively selected group, no comparison of survival and recurrence rates was made between the two groups. The crude 5-year survival for the operated patients was 0.86 (Fig. 3). There was a statistically significant difference in crude 5-year survival (P < 0.001) between patients with positive nodes and negative nodes at operation (0.52 and 0.93, respectively).
ii01
,
0
60 Observations
FIG.
, 120
time, months
2. Cumulative corrected survival for operated and nonoperated patients (2 2 SD)
Op., neg. nodes All operated
Op., pos. nodes
0
120
60
0
Observations
time, months
FIG. 3. Cumulative crude survival for patients with positive and negative nodes in the operation specimen ( t 2 SD)
EXTERNAL
RADIOTHERAPY
79
EFFECT
The distribution of grade of node involvement in node-positive patients with epidermoid carcinomas is shown in Table 3. No statistically significant difference in this distribution was obtained between the different treatment groups or for different periods of treatment. The crude survival for nonoperated patients and operated node-negative patients showed no change due to the time of treatment. The different postoperative treatment regimes used for node-positive patients during different periods could therefore be compared. For squamous-cell carcinoma with positive nodes no difference in corrected 5-year survival was observed between the “No postop irrad” group and the “Conventional postop irrad.” group. “Boost dose added to postop irrad” gave a somewhat, but not significantly, better survival (Table 4). The observation time was taken into account individually in these small groups. There were no differences in age, stage, grade of differentiation, or local residual carcinoma between the node-positive subgroups. Only 3 of 45 operated patients with adenocarcinoma had positive nodes at operation (7%). All three died of cancer. Recurrence
and Metastasis
as the First
Sign of Relapse
Local and pelvic recurrence and distant metastasis in relation to time in nonoperated and operated patients with and without node involvement in the operation specimen are shown in Fig. 4. The incidences of recurrence and metastasis in the 52 node-positive patients with squamous-cell carcinoma in relation to postoperative treatment are shown in Table 4 and in relation to time in Fig. 5. Distant metastasis as the first sign of relaps occurred more frequently when no postoperative irradiation was used than for the other node-positive patients (P < 0.05). In the “boost dose added to postop in-ad” group, only three pelvic recurrences occurred and no local recurrences or distant metastases as the first sign of relapse. Two patients had TABLE THE OUTCOME
FOR
4
52 NODE-POSITIVE
WOMEN WITH SQUAMOS-CELL CARCINOMA IRRADIATION AND TIME OF TREATMENT
No postop irrad
Relapse within 5 years No. of pts Local recurrence Pelvic recurrence Metastases Corr Syear survival For postop irrad For treatm period
Boost dose added to postop irrad
Conv postop irrad
1970-1972
1973-1976
9 16 3 2 5
8 13 2 4 2
0.49 0.49
0.54
RELATED TO POSTOP
1977-1981 2 7 1 2 0
3 16 0 3 0
0.53
0.81 0.78
80
HIMMELMANN
ET AL.
non-op. op. neg. nodes 60 Observation
tine,
months
Observation
Gne,
months
120 ~-
op. pos. nodes
I 60
0 Observation
120 time,
months
FIG. 4. The primary sign of relapse (k 2 SD) for nonoperated patients and for patients with and without node involvement at operation. (a) Local and (b) pelvic recurrence, (c) distant metastasis.
their recurrences above the irradiated volume and one behind the central shielding between the sacrum and rectum. The P value obtained on testing the rate of relapse for the “boost dose added to postop irrad” group and the other treatment groups was 0.053. The observation times were taken into account individually. The grade of node involvement
No postop.
irrad.
z-f
211 0
p ..__ I 12 24 Observation
postop.
~i.~i~dedto 36 time,
48 months
60
FIG. 5. Time of relapse for node-positive squamous-cell carcinoma patients in relation to postoperative treatment.
EXTERNAL
RADIOTHERAPY
EFFECT
81
seemed to be lower in the “boost dose added to postop h-t-ad” group (Table 3), but the difference was not statistically significant (P = 0.14). When the grade of node involvement still was taken into account, the corresponding P value for the comparison of relapse rates for the boost dose group and the other treatment groups was 0.061. Complications
In this material, 8 out of 55 patients with positive nodes at operation (14%) had minor or major complications, none with a fatal outcome (Table 5). One woman had an uretervaginal fistula which healed after surgical repair. One woman had a temporary ureteric stasis and later an attack of subileus. No surgical intervention was needed. One more case of temporary ureteric stasis was recorded and one more case of subileus without surgical intervention. One bladder reaction grade 1 and two rectal reactions grade 1 were recorded. The eighth complication was a colovaginal fistula which healed on conservative treatment. This patient was treated with intracavitary radium application preoperatively and external irradiation with a boost dose added postoperatively. This was the only complication in the “boost dose added to postop irrad” group. Minor or major complications occured in 16% of 44 patients receiving postoperative external irradiation, while 8% complications occurred for 300 patients without postop irradiation (P < 0.05), see Table 5. There was no difference in incidence of complications indicating surgery for these two groups. There were significantly less major and minor complications (P < 0.05) among the 344 operated patients when the distant afterloading technique was used for intracavitary irradiation (387) than when manually handled radium was used (27/257). DISCUSSION
It has not been proved that operation improves survival in cervical carcinoma stage IB and IIA compared with external irradiation directly after intracavitary treatment [ 16,171. For women under 35 years of age, intracavitary irradiation followed by surgery might be advantageous, however [18]. One advantage of operation is that a distinct risk group can be selected, comprising patients with positive nodes at operation. This is only of importance if additional treatment which improves the outcome for this risk group can be offered. Postoperative irradiation has not improved the survival in these patients [5]. The dose may not have been sufficient but positive nodes may also be associated with systemic spread, not yet detected. The importance of primary tumor control for cervical carcinoma has been demonstrated by Anderson and Dische [19], however, leading to a lower incidence of distant metastasis in the subsequent years following treatment. In external irradiation, an additional boost to a smaller volume has been used for other carcinomas [20]. A similar technique for the advanced cervical carcinoma with single enlarged nodes has also been described [20]. In this retrospective material the crude 5-year survival of node-positive patients (0.52) is in agreement with that of Fuller et al. [51 and of Rampone et al. [21]. The incidence of distant metastasis was reduced for node-positive squamous-
82
HIMMELMANN
ET
AL.
000
:I’
-00
c-4000
000
OOOON
000
00-
U-l--
-
---m,a
0
0
0
0
-
-Iv
EXTERNAL
RADIOTHERAPY EFFECT
83
cell carcinoma patients by postoperative irradiation. Irradiation with 40-45 Gy without a boost did not improve survival, however, but recurrence and metastasis tended to occur later compared with no postoperative irradiation (Fig. 5). This delay of relapse is interesting as a similar delay can be seen for some pelvic recurrences and possibly distant metastases in nonoperated patients in Fig. 4. These delayed relapses could be due to persistent positive pelvic nodes, having received an insufficient dose, as the delay does not occur in patients with positive nodes without postoperative irradiation or patients receiving a boost. Only 16 out of 52 patients with squamous-cell carcinoma had postoperative irradiation to the pelvis with an additional boost to positive nodes. Of 16 patients, 3 relapsed and died of cancer. The corrected 5-year survival (0.81) was not significantly different from that of the other node-positive carcinomas (0.52). No recurrences occurred within the irradiated volume, however. The treatment was well tolerated, especially by patients who received distant afterloading with 6oCo preoperatively. Because of the higher dosimetric accuracy for this intracavitary treatment, better central shielding could be obtained during the external irradiation 191.
A randomized prospective study with and without postoperative irradiation including a boost could possibly signify the observed difference. A large number of patients would be demanded, however. One hundred and sixty node-positive patients correspond to 1001 operated patients with our rate of positive nodes. An additional number will be required if adenocarcinomas are excluded and if the benefit of the irradiation is less than stated. With our experience of postoperative irradiation, we hesitate to leave patients without this treatment. A cooperative study could possibly be performed by centers where a large number of patients with Stage IB and IIA are operated upon and postoperative irradiation of positive nodes has not been the rule. Einhom [22] reports a rate of 33% severe complications indicating surgery for patients with supplementary irradiation after surgery. This is not in agreement with our experience. In these studies, however, the definition of complications are different. To avoid reactions from the irradiation, the patients must either have intracavitary irradiation preoperatively with good precision or not at all. ACKNOWLEDGMENTS This work was supported by grants from the Swedish Cancer Society, and the Cancer Research Fund of Jubileumskliniken, Gothenburg.
REFERENCES 1. Rutledge, F. N., and Fletcher, G. H. Ttansperitoneal pelvic lymphadenectomy following supervoltage irradiation for squamous-cell carcinoma of the cervix, Amer. J. Obsret. Gynecol. 76, 321-334 (1958). 2. Lagasse, L. D., Smith, M. L., Moore, J. G., Morton, D. G., Jacobs, M., Johnson, G. H.,, and Watring, W. G. The effect of radiation therapy on pelvic lymph node involvement in Stage I carcinoma of the cervix, Amer. J. Obstet. Gynecol. 119, 330-334 (1974). 3. Awwad, H. K., Barsoum, M. S., Burgers, M. V., El Badawy, S. A., and Soliman, 0. M. The dose-time relationship in the radiotherapy of carcinoma of the cervix uteri: An application of the CRE formalism, Clin. radial. 30, 263-267 (1979).
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ET AL.
4. Panel report: Is Pelvic radiation beneficial in the postoperative management of stage IB squamouscell carcinoma of the cervix with pelvic node metastasis treated by radical hysterectomy and pelvic lymphadenectomy? Gynecol. Oncol. 10, 105-110 (1980). 5. Fuller, A. F., Elliott, N., Kosloff, C., and Lewis, J. L. Lymph node metastasis from carcinoma of the cervix, Stages IB and HA. Implications for prognosis and treatment, Gynecol. 0~01. 13, 165-177 (1982). 6. Delgado, G. Stage IB squamous cancer of the cervix: The choice of treatment, Obsref. Gynecol. Surv. 33, 174-183 (1978). 7. Kottmeier, H. L. Annual report on the results of treatment in gynecological cancer 1973-1975, p. 14, Radiumhemmet, Stockholm (1982). 8. Kjellgren, 0. Clinical invasive carcinoma of cervix: Place of radiotherapy as primary treatment, in Gynecological oncology (M. Coppleson, Ed.), pp. 482-503, Churchill Livingstone, Edinburgh (1981). 9. Himmelmann, A., and Ragnhult, I. High dose rate afterloading treatment of carcinoma of the uterine cervix using an individual planning and reconstruction system, Acta Radiol. Oncol. 22, 263-271 (1983). 10. Kirk, J., Gray, W., and Watson, E. R. Cumulative radiation effect. Part I. Fractionated treatment regimes, C/in. Radiol. 22, 145-155 (1971). 11. Kottmeier, H. L., and Gray, M. T. Rectal bladder injuries in relation to radiation dosage in carcinoma of the cervix, Amer. J. Obstet. Gynecol. 82, 74-82 (1961). 12. Cutler, S. J., and Ederer, F. Maximum utilization of the life table method in analysing survival, J. Chron. Dist. 8, 699-712 (1958). 13. Bradley, J. V. Distribution-free statistical tests, pp. 68-83, Printance-Hall, London, (1968). 14. Merck, C., Angervall, K., Kindblom, L. Cl., and Oden, A. Myxofibrosarcoma. A malignant soft tissue tumor of fibroblastic-histiocytic origin. A clinicopathologic and prognostic study of 110 cases using a multivariate analysis, Acta Pathol. Microbial. Stand. Suppl. 282, 91, l-40 (1983). 15. Mantel, N. Chi-square tests with one degree of freedom: Extension of the Mantel-Haenszel procedure, J. Amer. Statist. Assoc. 58, 690-700 (1963). 16. Iversen, T., Kjorstad, K. E., and Martimbeau, P. W. Treatment results in carcinoma of the cervix stage IB in a total population, Gynecol. Oncol. 14, 1-5 (1982). 17. Perez, C. A., Camel, H. M., Kao, M. S., and Askin, F. Randomized study of preoperative radiation and surgery or irradiation alone in the treatment of stage IB and IIA carcinoma of the uterine cervix: Preliminary analysis of failures and complications, Cancer 45, 2759-2768 (1980). 18. Gynning, I., Johnsson, J.-E., Alm, P., and Trope, C. Age and prognosis in stage IB squamouscell carcinoma of the uterine cervix, Gynecol. Oncol. 15, 18-26 (1983). 19. Anderson, P., and Dische, S. Local tumour control and the subsequent incidence of distant metastatic disease, Znt. J. Radiat. Oncol. Biol. Phys. 7, 1645-1648 (1981). 20. Fletcher, G. H. Textbook ofradiotherapy, 3rd edition, pp. 563-568 and 760-764 Lea and Febiger, Philadelphia (1980). 21. Rampone, J. F., Klem, V., and Kolstad, P. Combined treatment of Stage IB carcinoma of the cervix, Obstet. Gynecol. 41, 163-167 (1973). 22. Einhorn, N. Frequency of severe complications after radiation therapy for cervical carcinoma, Acta Radiol. Ther. Phys. Biol. 14, 42-48 (1975).