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Influence of microscopic residual disease on survival for stage IB and IIA carcinoma of the cervix following intracavitary irradiation
Clinical Oncology (1990) 2:264-267 (~) 1990 The Royal College of Radiologists
Clinical Oncology
Original Article Influence of Microscopic Residual Disease on Survival for Stage IB and IIA Carcinoma of the Cervix Following Intracavitary Irradiation N. G. P. Davidson, J. H. LeVay and H. MacDonald Wessex Radiotherapy Centre, Royal South Hants Hospital, Southampton, UK
Abstract. From 1977 to 1982, 102 patients with Stage IB and IIA carcinoma of the cervix underwent preoperative intracavitary caesium irradiation followed by radical hysterectomy and pelvic lymphadenectomy at the Wessex Radiotherapy Centre. The actuarial 5-year survival rate for Stage IB is 80% and for Stage IIA is 62%. Patients who had microscopic residual disease in the hysterectomy specimen and negative nodes showed an actuarial 10-year survival rate of 62% as opposed to 82% in patients with no residual disease and negative nodes (P<0.05). Keywords: Carcinoma of the cervix; Intracavitary irradiation; Radical hysterectomy and pelvic lymphadenectomy
INTRODUCTION The optimal management of patients with Stage IB and IIA carcinoma of the uterine cervix is controversial. Surgery, irradiation or a combination of both have been advocated without definite statistical proof of the superiority of any of these methods, over the other in yielding higher cure rates and tumour control or less in the way of complications (Roddick and Greenlaw, 1971; Newton, 1975). Many radiotherapists agree that the therapeutic results obtained with radiation or surgery alone or combinations of both in patients with Stage IB and IIA carcinoma of the cervix are approximately the same and that the management should be based on the availability of the best therapy at the institution, the general condition of the patient, the gross and pathological characteristics of the tumour and the sexual function of the patient. This paper highlights the prognostic significance of residual disease in the Correspondence and offprint requests to:Dr N. G. P. Davidson, Senior Registrar, Leicester Royal Infirmary, Leicester LE1 5WW, UK.
hysterectomy specimen of early cervical cancer patients treated by intracavitary caesium and radical surgery.
PATIENTS AND METHODS From January 1977 until December 1982, 102 patients with Stage IB (n=66) and Stage IIA (n=36) carcinoma of the cervix were treated with a single intracavitary caesium insertion and radical surgery. The age of the patients ranged from 24 to 78 years (median 56 years). Histologically 84 patients had squamous carcinoma, 10 had adenocarcinoma and 8 had undifferentiated tumours. All patients were examined under a general anaesthetic and staged according to the International Federation of Gynaecology and Obstetrics (FIGO) system. A single intrauterine caesium source and a pair of small vaginal ovoid caesium sources were inserted in all patients and left in situ for 104 hours. In some patients a caesium barrel source was also left in the upper vagina. The dose at (based on the Manchester system) point A was 48 +_ 2 Gy. A radical hysterectomy (Wertheims) and bilateral pelvic lymphadenectomy (Meigs) was performed six weeks after the caesium insertion. Patients with positive nodes or incomplete/doubtful surgical excision margins received megavoltage external beam pelvic radiotherapy with midline shielding. A total dose of 30 Gy (midplane dose) in 12 fractions was given over a period of 3 weeks.
RESULTS One patient died postoperatively due to pulmonary embolism and three others were lost to follow-up. The remaining 98 patients have been followed-up
Microscopic Residual Disease and Survival for Stage IB and IIA Cervix Carcinoma
265
11o]
1(;0 gO' 80Stage IB
70"
Singe IIA
60" 50-
~
60-
~
50-
• o.
40-
-o-
Residualdisease, no nodes
30
--e-
No residual disease, no
40" 3020"
nodes
2O
10-
10
0o 1
2
3
0
4
1
I
I
I
I
I
I
I
I
i
I
1
2
3
4
5
6
7
8
9
10
11
1=2
Years
Fig. 1.5-year actuarial survival for Stage IB and IIA carcinoma of the cervix.
until death or for a minimum of 5 years. All 102 patients have been included in the analysis. A total of 29 patients have died from recurrent disease and three from unrelated causes. The actuarial 5-year survival for Stage IB is 80% and Stage IIA is 62% (Fig. 1). The three non-cancer deaths were excluded from the survival analysis, but the one death from pulmonary embolism was included. Table 1. Residual disease in the hysterectomy specimen and nodal status in 102 patients Number of patients
Alive Dead Total
Residual disease in the hysterectomy specimen
No residual disease in the hysterectomy specimen
Positive lymph nodes
Negative lymph nodes
Positive lymph nodes
Negative lymph nodes
2 7+la+l b 11
18 10 28
1 4 5
48 8+2 a 58
aNon-cancer death bDeaths from pulmonary embolism
Table 1 gives a breakdown of the data according to nodal status and the presence of residual disease in the hysterectomy specimen. Sixteen patients had positive lymph nodes and only three are alive at 5 years. Nine of these 16 patients also had residual disease in the hysterectomy specimen. A total of 28 patients had microscopic residual disease in the hysterectomy specimen and negative nodes. Ten of these patients have died. Of the 58 patients had no microscopic residual disease and negative nodes, eight have died due to recurrent disease and two of unrelated causes. Patients who had microscopic residual disease in the hysterectomy specimen and negative nodes showed an actuarial 10-year survival rate of 62% in contrast with 82% in those with negative specimens and negative nodes (Fig. 2). The log rank test shows a statistically significant difference between the two groups (X2 = 3.95, P<0.05).
Time (Years)
Fig. 2. 10-year actuarial survival for patients with no residual disease/negative nodes and residual disease/negative nodes.
Twenty of 84 patients and two of eight patients with squamous carcinoma and undifferentiated carcinoma respectively had residual disease in the hysterectomy specimens and negative nodes. Four of the 10 patients with adenocarcinoma had microscopic residual disease and negative nodes. Table 2 gives the relapse pattern in patients who died from recurrent disease. Of 28 patients four (14%) developed local recurrence in the group of patients who had microscopic residual disease in the hysterectomy specimen and negative nodes as opposed to 7/ 58 (12%) in the group with negative residual disease specimens and negative nodes. However, the incidence of distant metastasis .was higher 6/28 (21%) in the.former group as compared to 1/58 (2%) in the latter group. Three patients had incomplete/doubtful surgical excision margin. One is alive and well with no evidence of any recurrence. One patient died from local recurrence and the other from distant metastases. Three patients, developed urinary complications but none developed any serious radiotherapy-induceddamage (e.g. strictures, small Table 2. Relapse pattern in the 29 patients who died from recurrent disease Number of patients
Distant metastasis Distant metastasis and local recurrence Local recurrence only Total
Residual disease in the hysterectomy specimen
No residual disease in the hysterectomy specimen
Positive lymph nodes
Positive lymph nodes
Negative lymph nodes
Negative lymph nodes
4
6
3
1
2
1
1
1
1 7
3 10
0 4
6 8
266
bowel injury, or rectovaginal fistula). Urinary complications were minor. Two patients developed haematuria and one developed stress incontinence.
DISCUSSION
The influence of metastatic nodes found at the time of radical hysterectomy and survival has been documented in several studies and shows a 40%-50% reduction in 5-year survival (Hogan et al., 1982). The presence of microscopic residual disease in the hysterectomy specimen following intracavitary irradiation has been noted previously (Timmer et al., 1984), but the impact on survival has not been studied in detail. Wong et al. (1985) found 83% and 13% residual viable tumours in the hysterectomy specimens of adenocarcinoma and squamous carcinoma of the cervix respectively, following treatment with intracavitary irradiation, and suggested that adenocarcinoma may be more radioresistant. However, his patients had surgery 2 weeks after completion of radiation and many of the so-called viable tumour cells may have lost their proliferative capacity by 6 weeks. Timmer et al. (1983) compared the microscopic residual disease in the hysterectomy specimen after intracavitary irradiation at 4 and 6 weeks, and found greater increase in the percentage of morphologically intact tumour cells after 4 weeks as compared to 6 weeks. This indicated that some of the so-called viable tumour cells found at 4 weeks had lost their proliferative capacity by 6 weeks. In our study patients underwent surgery at 6 weeks and the presence of microscopic residual disease indicated viable radioresistant tumour cells. This is confirmed by the high 38% (10/26) failure rate in survival found in the group with microscopic residual disease as opposed to 17.5% (10/57) failure rate in the group where the specimens were clear. Histologically, adenocarcinoma patients had slightly higher incidence of residual disease, but due to the small numbers no conclusion can be reached. Tumour size was not recorded in a number of patients, therefore a correlation of tumour size with the presence of pelvic nodes was not possible. The actuarial 5-year survival for Stage IB and IIA shown in our study is similar to those produced at other centres (Timmer et al., 1984). Sixteen of our patients had positive nodes and nine of them also had microscopic residual disease in the hysterectomy specimens. Despite receiving further external beam radiotherapy to the pelvis only three of the 15 patients are alive at 5 years.
N . G . P . Davidson et al.
Recently adjuvant chemotherapy has shown some encouraging results in advanced carcinoma of the cervix. Initial results of locally advanced cervical cancer patients treated with chemotherapy followed by conventional radical therapy are encouraging (Kirsten et al., 1987; Symonds et al., 1987). However, identifying the subgroup of advanced cervical cancer patients who may benefit from adjuvant chemotherapy is difficult. Understandably many radiotherapists are reluctant to use chemotherapy initially in all patients with advanced carcinoma of the cervix. This is because the combined normal effects caused by chemotherapy and radiotherapy may necessitate reduction in the radiation dose delivered to the patient or delay the commencement of radiation therapy. However, in early carcinoma of the cervix treated by radiation followed by radical hysterectomy, microscopic residual tumour in the hysterectomy specimen might identify a subgroup of patients who may benefit from adjuvant chemotherapy. The radiotherapy doses used in our series (48 Gy to point A), preoperative radiotherapy followed if necessary by 30 Gy in 12 fractions in 3 weeks using midline shielding may be regarded as low in international standards. Therefore, alternatively it could be argued that an increase in the radiation dose may eliminate the survival disadvantage of the patients with microscopic residual tumour in the hysterectomy specimen. However, this may lead to an increase in the complication rate. The local failure rate was similar in the two groups, 14% and 12%. The group with microscopic residual disease had a higher distant metastasis (21%) than the group without any residual disease (2%). This suggests the occurrence of early systemic dissemination in this group. Therefore, adjuvant chemotherapy rather than an increase in radiation dose may be of more benefit in this subgroup of patients. Acknowledgements. We wish to thank Dr P. E. Bodkin for his permission to include patients under his care, and Mrs McLachlan for typing the manuscript, and Miss D. Bircumshaw for statistical help.
References Hogan, WM, Littman P, Griner L, Miller C, Mikuta, JJ (1982). Results of radiation therapy given after radical hysterectomy. Cancer, 49, 1278--1285. Kirsten F, Atkinson KH, Coppleson JVM, Elliot PM, Green D, Houghton R et al., (1987). Combination chemotherapy followed by surgery or radiotherapy in patients with locally advanced cervical cancer. British Journal of Obstetrics and Gynaecology, 94, 583--588. Newton M (1975). Radical hysterectomy or radiotherapy for stage I cervical cancer. A prospective comparison with 5 and 10 year follow-up. American Journal of Obstetrics and Gynaecology, 123, 535-542.
Microscopic Residual Disease and Survival for Stage IB and IIA Cervix Carcinoma Roddick JW, Greenlaw RW (1971). Treatment of cervical cancer. American Journal of Obstetrics and Gynaecology , 109, 754-764. Symonds RP, Habeshaw T, Watson ER, Kaye SB (1987). Combination chemotherapy prior to radical radiotherapy for stage III and IV carcinoma of the cervix. Clinical Radiology, 38, 273-274.
267
Timmer PR, Aalders JG, Bouma J (1984). Radical surgery after pre-operative intracavitary radiotherapy for stage IB and IIA carcinoma of the uterine cervix. Gynecologic Oncology, 18, 206--212. Wong LC, Hsu C, Choy D, Ma HK (1985). Combined treatment in adenocarcinoma of cervix. European Journal of Gynaecology and Oncology, 3, 186-192.
Received for publication September 1989 Accepted May 1990
Clinical Oncology
Original Article Influence of Microscopic Residual Disease on Survival for Stage IB and IIA Carcinoma of the Cervix Following Intracavitary Irradiation N. G. P. Davidson, J. H. LeVay and H. MacDonald Wessex Radiotherapy Centre, Royal South Hants Hospital, Southampton, UK
Abstract. From 1977 to 1982, 102 patients with Stage IB and IIA carcinoma of the cervix underwent preoperative intracavitary caesium irradiation followed by radical hysterectomy and pelvic lymphadenectomy at the Wessex Radiotherapy Centre. The actuarial 5-year survival rate for Stage IB is 80% and for Stage IIA is 62%. Patients who had microscopic residual disease in the hysterectomy specimen and negative nodes showed an actuarial 10-year survival rate of 62% as opposed to 82% in patients with no residual disease and negative nodes (P<0.05). Keywords: Carcinoma of the cervix; Intracavitary irradiation; Radical hysterectomy and pelvic lymphadenectomy
INTRODUCTION The optimal management of patients with Stage IB and IIA carcinoma of the uterine cervix is controversial. Surgery, irradiation or a combination of both have been advocated without definite statistical proof of the superiority of any of these methods, over the other in yielding higher cure rates and tumour control or less in the way of complications (Roddick and Greenlaw, 1971; Newton, 1975). Many radiotherapists agree that the therapeutic results obtained with radiation or surgery alone or combinations of both in patients with Stage IB and IIA carcinoma of the cervix are approximately the same and that the management should be based on the availability of the best therapy at the institution, the general condition of the patient, the gross and pathological characteristics of the tumour and the sexual function of the patient. This paper highlights the prognostic significance of residual disease in the Correspondence and offprint requests to:Dr N. G. P. Davidson, Senior Registrar, Leicester Royal Infirmary, Leicester LE1 5WW, UK.
hysterectomy specimen of early cervical cancer patients treated by intracavitary caesium and radical surgery.
PATIENTS AND METHODS From January 1977 until December 1982, 102 patients with Stage IB (n=66) and Stage IIA (n=36) carcinoma of the cervix were treated with a single intracavitary caesium insertion and radical surgery. The age of the patients ranged from 24 to 78 years (median 56 years). Histologically 84 patients had squamous carcinoma, 10 had adenocarcinoma and 8 had undifferentiated tumours. All patients were examined under a general anaesthetic and staged according to the International Federation of Gynaecology and Obstetrics (FIGO) system. A single intrauterine caesium source and a pair of small vaginal ovoid caesium sources were inserted in all patients and left in situ for 104 hours. In some patients a caesium barrel source was also left in the upper vagina. The dose at (based on the Manchester system) point A was 48 +_ 2 Gy. A radical hysterectomy (Wertheims) and bilateral pelvic lymphadenectomy (Meigs) was performed six weeks after the caesium insertion. Patients with positive nodes or incomplete/doubtful surgical excision margins received megavoltage external beam pelvic radiotherapy with midline shielding. A total dose of 30 Gy (midplane dose) in 12 fractions was given over a period of 3 weeks.
RESULTS One patient died postoperatively due to pulmonary embolism and three others were lost to follow-up. The remaining 98 patients have been followed-up
Microscopic Residual Disease and Survival for Stage IB and IIA Cervix Carcinoma
265
11o]
1(;0 gO' 80Stage IB
70"
Singe IIA
60" 50-
~
60-
~
50-
• o.
40-
-o-
Residualdisease, no nodes
30
--e-
No residual disease, no
40" 3020"
nodes
2O
10-
10
0o 1
2
3
0
4
1
I
I
I
I
I
I
I
I
i
I
1
2
3
4
5
6
7
8
9
10
11
1=2
Years
Fig. 1.5-year actuarial survival for Stage IB and IIA carcinoma of the cervix.
until death or for a minimum of 5 years. All 102 patients have been included in the analysis. A total of 29 patients have died from recurrent disease and three from unrelated causes. The actuarial 5-year survival for Stage IB is 80% and Stage IIA is 62% (Fig. 1). The three non-cancer deaths were excluded from the survival analysis, but the one death from pulmonary embolism was included. Table 1. Residual disease in the hysterectomy specimen and nodal status in 102 patients Number of patients
Alive Dead Total
Residual disease in the hysterectomy specimen
No residual disease in the hysterectomy specimen
Positive lymph nodes
Negative lymph nodes
Positive lymph nodes
Negative lymph nodes
2 7+la+l b 11
18 10 28
1 4 5
48 8+2 a 58
aNon-cancer death bDeaths from pulmonary embolism
Table 1 gives a breakdown of the data according to nodal status and the presence of residual disease in the hysterectomy specimen. Sixteen patients had positive lymph nodes and only three are alive at 5 years. Nine of these 16 patients also had residual disease in the hysterectomy specimen. A total of 28 patients had microscopic residual disease in the hysterectomy specimen and negative nodes. Ten of these patients have died. Of the 58 patients had no microscopic residual disease and negative nodes, eight have died due to recurrent disease and two of unrelated causes. Patients who had microscopic residual disease in the hysterectomy specimen and negative nodes showed an actuarial 10-year survival rate of 62% in contrast with 82% in those with negative specimens and negative nodes (Fig. 2). The log rank test shows a statistically significant difference between the two groups (X2 = 3.95, P<0.05).
Time (Years)
Fig. 2. 10-year actuarial survival for patients with no residual disease/negative nodes and residual disease/negative nodes.
Twenty of 84 patients and two of eight patients with squamous carcinoma and undifferentiated carcinoma respectively had residual disease in the hysterectomy specimens and negative nodes. Four of the 10 patients with adenocarcinoma had microscopic residual disease and negative nodes. Table 2 gives the relapse pattern in patients who died from recurrent disease. Of 28 patients four (14%) developed local recurrence in the group of patients who had microscopic residual disease in the hysterectomy specimen and negative nodes as opposed to 7/ 58 (12%) in the group with negative residual disease specimens and negative nodes. However, the incidence of distant metastasis .was higher 6/28 (21%) in the.former group as compared to 1/58 (2%) in the latter group. Three patients had incomplete/doubtful surgical excision margin. One is alive and well with no evidence of any recurrence. One patient died from local recurrence and the other from distant metastases. Three patients, developed urinary complications but none developed any serious radiotherapy-induceddamage (e.g. strictures, small Table 2. Relapse pattern in the 29 patients who died from recurrent disease Number of patients
Distant metastasis Distant metastasis and local recurrence Local recurrence only Total
Residual disease in the hysterectomy specimen
No residual disease in the hysterectomy specimen
Positive lymph nodes
Positive lymph nodes
Negative lymph nodes
Negative lymph nodes
4
6
3
1
2
1
1
1
1 7
3 10
0 4
6 8
266
bowel injury, or rectovaginal fistula). Urinary complications were minor. Two patients developed haematuria and one developed stress incontinence.
DISCUSSION
The influence of metastatic nodes found at the time of radical hysterectomy and survival has been documented in several studies and shows a 40%-50% reduction in 5-year survival (Hogan et al., 1982). The presence of microscopic residual disease in the hysterectomy specimen following intracavitary irradiation has been noted previously (Timmer et al., 1984), but the impact on survival has not been studied in detail. Wong et al. (1985) found 83% and 13% residual viable tumours in the hysterectomy specimens of adenocarcinoma and squamous carcinoma of the cervix respectively, following treatment with intracavitary irradiation, and suggested that adenocarcinoma may be more radioresistant. However, his patients had surgery 2 weeks after completion of radiation and many of the so-called viable tumour cells may have lost their proliferative capacity by 6 weeks. Timmer et al. (1983) compared the microscopic residual disease in the hysterectomy specimen after intracavitary irradiation at 4 and 6 weeks, and found greater increase in the percentage of morphologically intact tumour cells after 4 weeks as compared to 6 weeks. This indicated that some of the so-called viable tumour cells found at 4 weeks had lost their proliferative capacity by 6 weeks. In our study patients underwent surgery at 6 weeks and the presence of microscopic residual disease indicated viable radioresistant tumour cells. This is confirmed by the high 38% (10/26) failure rate in survival found in the group with microscopic residual disease as opposed to 17.5% (10/57) failure rate in the group where the specimens were clear. Histologically, adenocarcinoma patients had slightly higher incidence of residual disease, but due to the small numbers no conclusion can be reached. Tumour size was not recorded in a number of patients, therefore a correlation of tumour size with the presence of pelvic nodes was not possible. The actuarial 5-year survival for Stage IB and IIA shown in our study is similar to those produced at other centres (Timmer et al., 1984). Sixteen of our patients had positive nodes and nine of them also had microscopic residual disease in the hysterectomy specimens. Despite receiving further external beam radiotherapy to the pelvis only three of the 15 patients are alive at 5 years.
N . G . P . Davidson et al.
Recently adjuvant chemotherapy has shown some encouraging results in advanced carcinoma of the cervix. Initial results of locally advanced cervical cancer patients treated with chemotherapy followed by conventional radical therapy are encouraging (Kirsten et al., 1987; Symonds et al., 1987). However, identifying the subgroup of advanced cervical cancer patients who may benefit from adjuvant chemotherapy is difficult. Understandably many radiotherapists are reluctant to use chemotherapy initially in all patients with advanced carcinoma of the cervix. This is because the combined normal effects caused by chemotherapy and radiotherapy may necessitate reduction in the radiation dose delivered to the patient or delay the commencement of radiation therapy. However, in early carcinoma of the cervix treated by radiation followed by radical hysterectomy, microscopic residual tumour in the hysterectomy specimen might identify a subgroup of patients who may benefit from adjuvant chemotherapy. The radiotherapy doses used in our series (48 Gy to point A), preoperative radiotherapy followed if necessary by 30 Gy in 12 fractions in 3 weeks using midline shielding may be regarded as low in international standards. Therefore, alternatively it could be argued that an increase in the radiation dose may eliminate the survival disadvantage of the patients with microscopic residual tumour in the hysterectomy specimen. However, this may lead to an increase in the complication rate. The local failure rate was similar in the two groups, 14% and 12%. The group with microscopic residual disease had a higher distant metastasis (21%) than the group without any residual disease (2%). This suggests the occurrence of early systemic dissemination in this group. Therefore, adjuvant chemotherapy rather than an increase in radiation dose may be of more benefit in this subgroup of patients. Acknowledgements. We wish to thank Dr P. E. Bodkin for his permission to include patients under his care, and Mrs McLachlan for typing the manuscript, and Miss D. Bircumshaw for statistical help.
References Hogan, WM, Littman P, Griner L, Miller C, Mikuta, JJ (1982). Results of radiation therapy given after radical hysterectomy. Cancer, 49, 1278--1285. Kirsten F, Atkinson KH, Coppleson JVM, Elliot PM, Green D, Houghton R et al., (1987). Combination chemotherapy followed by surgery or radiotherapy in patients with locally advanced cervical cancer. British Journal of Obstetrics and Gynaecology, 94, 583--588. Newton M (1975). Radical hysterectomy or radiotherapy for stage I cervical cancer. A prospective comparison with 5 and 10 year follow-up. American Journal of Obstetrics and Gynaecology, 123, 535-542.
Microscopic Residual Disease and Survival for Stage IB and IIA Cervix Carcinoma Roddick JW, Greenlaw RW (1971). Treatment of cervical cancer. American Journal of Obstetrics and Gynaecology , 109, 754-764. Symonds RP, Habeshaw T, Watson ER, Kaye SB (1987). Combination chemotherapy prior to radical radiotherapy for stage III and IV carcinoma of the cervix. Clinical Radiology, 38, 273-274.
267
Timmer PR, Aalders JG, Bouma J (1984). Radical surgery after pre-operative intracavitary radiotherapy for stage IB and IIA carcinoma of the uterine cervix. Gynecologic Oncology, 18, 206--212. Wong LC, Hsu C, Choy D, Ma HK (1985). Combined treatment in adenocarcinoma of cervix. European Journal of Gynaecology and Oncology, 3, 186-192.
Received for publication September 1989 Accepted May 1990