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Para-aortic lymph node irradiation for carcinoma of the uterine cervix using split course technique
GYNECOLOGIC
ONCOLOGY
3, 168- 175 (1975)
PRELIMINARY
REPORT
Para-Aortic Lymph Node Irradiation for Carcinoma of the Uterine Cervix Using Split Course Technique’ M. STEVEN PIVER', M.D., FACOG, VITUNE VONGTAMA, M.D., AND
JOSEPH J. BARLOW, M.D.,FACOG Departments
of Gynecology
and Radiation Therapy, Roswell Buffalo, New York 14263
Park Memorial
Institute,
Received Twenty women with previously untreated cervical cancer received radical irradiation to the para-aortic lymph nodes and pelvis. Ninety percent received 6000 rads to the paraaortic nodes and pelvis in 8 weeks using split course technique. The mortality from complications of therapy, without evidence of recurrence, was 25%. Forty percent of the women were dead from recurrent cervical cancer (4-23M), and even with this short follow-up only 35% were surviving NED (6-29M). Methods for improving future trials of irradiation to the para-aortic nodes are discussed.
INTRODUCTION
Approximately 40% of women with Stage IIIB (pelvic wall) and IVA (bladder or rectum) cervical cancer have metastases to the para-aortic nodes [ 1,2,3]. Such para-aortic node metastases account, in part, for the failure to improve the five year cure rate by pelvic radiotherapy [4]. That sporadic cases with aortic node mestases can be cured by para-aortic node irradiation has been documented [5,6]. A recommended dose of 6000 rads in 6 wk to the aortic nodes [5] seemed excessive in view of the intolerance of the small intestine within the irradiated field. Using lower doses of external therapy (less than 6000 rads) by conventional anterior and posterior portals has not proven significantly efficacious. Support for this comes from a report by Castro, Issa and Fletcher who reported on the treatment of women with carcinoma of the cervix treated by external irradiation alone (without intracavitary radium). Of 30 women who received 5000 rads in 5 wk or less there were no women surviving without evidence of recurrence. Moreover, 10 of these 30 women also had para-aortic node metastases and received 5000 rads in five weeks by anterior and posterior ’ Presented at the Sixth Annual Meeting Society of Gynecologic Oncologists, January 7-9, 1975, Key Biscayne, FL. * Reprint requests to M. Steven Piver, M.D., Roswell Park Memorial Institute, 666 Elm Street, Buffalo, NY 14203. I68 Copyright @ 1975 by Academic Press, Inc. All rights of reproduction in any form reserved.
PARA-AORTIC
169
LYMPH NODE IRRADIATION
portals. All were dead of disease by 12 mo. Not until they reached dose rates of 6000 rads whole pelvis did they achieve cure rates (6 of 20 NED at 36 mo) [7]. We, therefore, started a prospective evaluation of 6000 rads to the para-aortic area in 8 wk by split course therapy with the first 3000 rads/3 wk given by anterior and posterior portals and a second 3000 rads/3 wk by 360” rotational therapy with a 2 wk rest period before resuming the second course. The theoretical basis for split course therapy is that the 2 wk rest would allow for repair of normal tissues, thus improving normal tissue tolerance, and also allow time for reoxygenation of tumor cells, thus increasing the cancericidal effects of the irradiation. This is a preliminary report of our first 20 patients with previously untreated carcinoma of the cervix who also have aortic node metastases. MATERIAL
AND METHODS
Twenty women with previously untreated carcinoma of the uterine cervix have received radical radiation to para-aortic nodes and pelvis. The plan of radiation was 6000 rads to pelvis and para-aortic nodes in 8 wk using split course technique with 2 wk rest after the first 3000 rads. Two-hundred rads were given per day using five fractions per week to the pat-a-aortic nodes, using a combination of opposed portals in the first course and a 360” rotational therapy on a 6MEV linear accelerator, 100 cm SSD in the second course. The average field size is 8 x 15 cm to the upper border of the 12th thoracic vertebrae. The pelvis was irradiated using an average field size 16 X 16 cm anteriorly and posteriorly and 10 x 15 cm bilateral pelvic portals. An average gap of 1 cm is allowed between the junction of the para-aortic and pelvic fields (Fig. 1). Table 1 shows the EXTENDED
FIELDS
( PELVIS
R PARA-AORTIC)
_..
Rotation
DOSE: 3000
-I-
-l-
IRods TD /
REST
3 Weeks
-l 3000
Rods TD / 3 Weeks
2 Weeks PARA-AORTIC: PELVIS
AtP :
PORTALS
BOX PELVIS
-
360°
Rotation
-
BOX PELVIS
FIG. 1. Plan of irradiation to pelvis and para-aortic nodes to deliver 6000 in 8 wk by split course
technique.
170
PIVER
ET AL.
TABLE PARA-AORTIC
NODE
1
IRRADIATION-CERVICAL
CARCINOMA
Dosage level in rads-20 Pelvis Para-Aortic Radium Number
patients
6000 6000 2500”
7000 6000 -
7000 5000
5200 4600 2500”
17
1
1
1
n Median dosage to point “A.”
dose of radiation to the para-aortic nodes and pelvis with 17 of the 20 patients receiving 6000 rads to the para-aortic nodes, 6000 rads to the pelvis plus an additional 2500 rads to point A by the use of intracavitary and vaginal radium. One patient received 5200 rads to the pelvis and 4600 rads to the para-aortic nodes when radiation therapy had to be discontinued because of severe radiation enteritis. Two additional patients received 7000 rads to the pelvis and 6000 and 5000 rads to the para-aortic nodes respectively, but did not receive intracavitary radium because of inability to place such a system. All patients were clinically staged and had the following work-up: SMA, CBC, chest X-ray, intravenous urogram and cytoscopy. Thirteen women had clinical State IIIB, five Stage IIB, one Stage IV and one Stage IB cervical cancer. The latter underwent laparotomy for radical hysterectomy and was found to have large aortic node metastases. Eighteen of the women had squamous carcinoma, and two had adenocarcinoma of the uterine cervix. Eighteen of the 20 women were surgically staged by exploratory laparotomy and para-aortic node biopsy or para-aortic lymphadenectomy. Two women who were poor surgical candidates had definitely positive para-aortic node metastases by lymphangiography. In two previous reports, our accuracy in the diagnosis of positive pelvic node metastases and aortic node metastases (confirmed histologically) by lymphangiography were 97.6 and 95.8% respectively [8,9]. With nearly 100% accuracy in diagnosing positive nodal metastases by lymphangiography, the inclusion of these two patients in the series seems warranted. If the aortic nodes were negative to palpation at the time of laparotomy, paraaortic lymphadenectomy was then carried out by removing the nodes anterior to the aorta and vena cava from the bifurcation of the aorta to just below the renal vessels. Retrocaval nodes and lymph nodes lateral to the aorta are not routinely removed. If the aortic nodes are clinically positive at the time of laparotomy, then biopsy of the nodes are performed and frozen section evaluation is carried out. The large positive nodes are not resected. Only one significant complication has resulted from this surgical staging and this was corrected by nonsurgical means [I]. Follow-up has ranged from six to 40 months with 80% being followed one yr. Complications were evaluated to those occurring in the pelvis or upper abdomen. The results of treatment were evaluated also as to (1) stage of disease, (2) findings of the aortic nodes at the time of surgical staging i.e., (a) microscopic
PARA-AORTIC
LYMPH
NODE
171
IRRADIATION
metastases in clinically negative aortic nodes and (b) aortic node metastases proven by biopsy with gross residual disease remaining. Ten patients had reexamination of the aortic nodes subsequent to radiation therapy, either by laparotomy or autopsy. RESULTS
Eighteen of the 20 women were surgically staged. Seven had para-aortic lymphadenectomy because of clinically negative aortic nodes. Microscopic metastases was found in all seven patients. Eleven women had grossly positive aortic nodes. These were biopsied and metastases confirmed by frozen section evaluation. Complicutions
Five (25%) of the 20 women developed six significant pelvic complications secondary to high dose radiation therapy: Sigmoid perforation (1), severe sigmoiditis requiring colostomy (2), rectovaginal fistula (2), and terminal ileum sigmoid fistula (1) (Table 2). All were NED at the time of development of these complications. Five (25%) of the 20 patients developed eight significant abdominal complications: Gastric ulcer (2), mid ileal obstruction (1), mid ileal perforation (1), descending colon perforation (1), radiation enteritis with electrolyte imbalance causing her death (1), and nonmalignant chylous ascites (2) (Table 3). Table 4 lists all the significant complications related to the area involved. Thus 45% (9 of 20) sustained significant complications. A 25% mortality from all complications was recorded with 15% mortality attributable to the para-aortic irradiation. Survival
and Eradication
of Aortic
Node Metastases
Ten women had re-examination of aortic nodes by laparotomy [5] or autopsy [5]. Eighty percent (8 of 10) had negative nodes-five clinically at the time of laparotomy and three histologically at the time of autopsy. Four women who initially had lymphadenectomy with the findings of microscopic aortic node metasPARA-AORTIC PELVIC
Time months
Complications 1. 2. 3. 4.
TABLE 2 IRRADIATION-CERVICAL CARCINOMA COMPLICATIONS IN 20 PATIENTS
Sigmoid perforation Severe sigmoiditis + colostomy Rectovaginal fistula Terminal ileum-colon fistula
6 5, 9 6, 14 14
Complications IlO.
Tumor status
1 2 2 1
NED NED” NED NED
Total: 6 Patients 5120 = 25% B One patient developed
metastases to t10 & 11 vertebrae
and mediastinum
at 18 months.
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PIVER
ET AL.
TABLE 3 PARA-AORTIC NODE IRRADIATION-CERVICAL CARCINOMA ABDOMINAL COMPLICATIONS IN 20 PATIENTS
1. 2. 3. 4. 5. 6.
Gastric ulcer Mid ileal obstruction Mid ileal perforation* Descending colon perforation Radiation enterocolitis + death Chylous ascites
Tumor
Complication no.
Time months
Complications
3, 5 10 18 10 36 7, 18
status
2 1 1 1 1 2
NED” NED NED NED NED NED
Total: 8 Patients 5120 = 25% (LOne patient developed * Not surgically staged.
metastases to tl0 and 11 vertebrae
and mediastinum
at 18 mo.
tases in clinically negative nodes had re-examination of aortic nodes and all were NED. Six women had gross residual tumor prior to radiation therapy, and four of these had negative aortic nodes at the time of re-examination (Table 5). Table 6 lists the survival to date in relationship to clinical stage. One patient with Stage IB cervical cancer and one patient with Stage IV are surviving NED at 29 and 14 months respectively. Of the women with Stage IIIB cervical cancer, only 23% (3 of 13) are alive NED, even with this short follow-up. This includes two women dying of complications at 13 and 40 mo respectively TABLE 4 PARA-AORTIC IRRADIATION-CERVICAL
Patients
6 7 8 9
Complications Mid ileal obstruction Mid ileal perforation” Descending colon perforationn Radiation enteritis + death gastric ulcer Sigmoiditis --, colostomy gastric ulcer Sigmoiditis -+ colostomy Rectovaginal fistula Rectovaginal fistula terminal ileum fistula Sigmoid perforation
9/20 = 45% a Also developed chylous ascites. b Developed metastases to tl0 and 11 vertebrae
CARCINOMA
Dead complications
Dead complications aortic irradiation
0 1 1
Tumor status NED NED NED NED NED” NED NED NED NED
5120 = 25%
and mediastinum
3120 = 15%
at 18 months.
8/9 = 88%
PARA-AORTIC
173
LYMPH NODE IRRADIATION TABLE 5
EXAMINATION
Number 1 2 3 4 5 6 7 8 9 10
OF PARA-AORTIC NODES SUBSEQUENT TO AORTIC NODE IRRADIATION
Stage
Method of diagnosis
Method of re-examination
Time months
Aortic nodes
2b 2b 3b 4 3b 3b 3b 3b 3b 2b
Lymphadenectomy Lymphadenectomy Lymphadenectomy Lymphadenectomy Biopsy Biopsy Biopsy Biopsy Biopsy Lymphangiography
Laparotomy Laparotomy Autopsy Laparotomy Laparotomy Autopsy Autopsy Autopsy Autopsy Laparotomy
18 9 13 13 5 4 5 40 23 23
NED NED NED NED NED” Positive Positive NED NED* NED
a Developed metastases to t 10 and 11 vertebrae and mediastinum at 18 months. B Recurrence in bladder and vagina only.
without evidence of recurrence. Of the five women with Stage IIB cervical cancer, none have died of recurrent cancer, but three are dead from complications without evidence of recurrence. Of the 20 patients, 40% are dead of disease from 4 to 13 mo after treatment, and 25% are dead of complications without evidence of recurrence from 11 to 40 mo. Only 35% are surviving without evidence of recurrence, and the follow-up in those surviving NED is too short to predict their eventual outcome. Table 7 evaluates the survival status in relationship to the findings of the aortic nodes at the time of surgical staging. Of those that had para-aortic lymphadenectomy because of clinically negative aortic nodes, none of the seven have TABLE 6 PARA-AORTIC NODE IRRADIATION-CERVICAL CARCINOMA SURVIVAL vs CLINICAL STAGE 20 PATIENTS
Stage
DOD”
Dead complications NED”
IB
-
-
IIB
8
(4,4,4,5,~,6,18,23) IV
-
8 40% u DOD = dead of disease b NED = no evidence of disease c ( ) = months surviving.
Survival NED
A
l/l
2 (l&23)
IIIB
Alive NED
6510) 3
(13240) -
@,9,W
5 25%
7 35%
1 (14)
21.5 3113 23% l/l
174
PIVER
ET AL.
TABLE PARA-AORTIC SURVIVAL
7
NODE IRRADIATION-CERVICAL vs SURGICAL FINDINGS IN
CARCINOMA
18 PATIENTS Survival
Laparotomy findings aortic nodes Nodes negative Nodes positive
Surgery Lymphadenectomy 7 Biopsy II 18
DOD” 7 (4,4,4,5,5.18,23) 7 39%
Dead complications NED” 3 (11,13,18)” 1 (40) 4 22%
Alive NED 4 (8,10,14,18) 3
Survival NED
(6,929)
417 57% 3/l 1 27%
1 39%
7118 39%
u DOD = dead of disease. ’ NED = no evidence of disease. C ( ) = months surviving.
died of recurrent cervical cancer. However, three of seven are dead of complications without evidence of recurrence at 11, 13 and 18 mo respectively. Of the 1 I patients that had only biopsy of aortic nodes, seven are dead of recurrent disease from 4 to 23 mo. Thus, even with this short follow-up, only 27% (3 of 11) were surviving NED in this group. DISCUSSION Twenty women with previously untreated cervical cancer received radical radiation therapy to the para-aortic nodes and pelvis. Ninety percent received 6000 rads to the para-aortic nodes and pelvis in 8 wk using split course technique. In addition, 18 of the 20 patients received intracavitary radium at a dose of 2500 rads to point A. The overall severe complication rate to the pelvis and abdomen has been high -45%. Twenty-five percent of the patients developed new complications attributable to the para-aortic irradiation, not normally seen in women receiving pelvic irradiation: Gastric ulcer, nonmalignant chylous ascites, mid ileal obstruction and perforation, and descending colon perforation. In addition, there was a 25% severe pelvic complication rate. Moreover, from this therapy there was a 25% mortality from all complications (5 of 20) and a 15% mortality from aortic node irradiation (3 of 20). All five women dying from complications of therapy were NED. That aortic node metastases can be eradicated is demonstrated in the 10 women who have had re-examination of aortic nodes after completing radiation therapy. Of the six women that did not have the positive aortic nodes resected, four were subsequently found to be NED on re-examination. Of the four patients that had para-aortic lymphadenectomy and were found to have microscopic metastases in the aortic nodes, all four were NED on re-examination of the aortic nodal area. However, this does not attest the efficacy of the irradiation since their only foci of metastases may have been resected.
PARA-AORTIC
LYMPH
NODE
IRRADIATION
175
With even this short follow-up, only 35% are surviving NED, or conversely, 65% are already dead either from complications of this therapy or recurrent cervical cancer. If, as is predictable, several of these 35% now surviving die from recurrent cervical cancer or complications of therapy, it will leave very few surviving by this treatment plan. The results of our therapy using 6000 rads in 8 wk by split course technique are not acceptable, because of the high mortality from complication and the poor survival rate. Silberstein et al. treated five women with aortic node metastases with 6000 rads in 6 wk with the entire treatment being given by 360” rotational therapy. Severe complications developed in only one case [5]. However, three of these women had recurrent tumor only to the para-aortic nodes and, therefore, did not have the large volume irradiated as did our patients who had the pelvis and aortic area treated simultaneously. This smaller volume irradiated may account, in part, for the low complication rate reported by Silberstein et al. because the tolerance to radiation is influenced not only by the total dose delivered and the duration of treatment but also by the volume of tissue irradiated. Our reservation with the delivery of the entire para-aortic node irradiation by 360” rotational therapy is the high dose to the kidneys (approximately 3000 rads) with the possible development of radiation nephritis. The necessity for an acceptable method of therapy for women with aortic node metastases from cervical cancer is certain. However, to date, the proper delivery of such therapy must await future trials. It is apparent, however, that women who are found to have only microscopic aortic node metastases, in clinically negative nodes, should not receive 6000 rads/6-8 wk, but should have a trial of approximately 4500 rads in 5 wk for control of subclinical disease [ IO]. Moreover, those women who are found to have large aortic node metastases should have an attempted resection of these nodes in order to reduce the amount of tumor, thus requiring less para-aortic nodal irradiation. Finally, it is hoped that future trials will demonstrate that radiosensitizing drugs, such as Hydroxyurea [ 111, in combination with lesser amounts of irradiation, (5000 rads/5 wk) will result in the eradication of large nonresectable aortic node metastases. REFERENCES I. 2. 3. 4. 5. 6. 7. 8. 9. IO. I I.
Piver, M. S., and Barlow, J. .I. Obstet., Gynecol. 43, 544 (1974). Buchsbaum, H. J., Amer. J. Obstrt. Gynecol. 113, 942 (1972). Nelson, J. H., Macasaet, M. A., Lu, T. et al. Amer. J. Obstet. Gynecol. 118, 749 (1974). Fletcher, G. H., and Rutledge, F. N. Clin. Obstet. Gynecol. 5, 958 (1968). Silberstein, A. B., Aron, B. S., and Alexander, L. L. Radiology 95, I8 I (1970). Fletcher, G. H., and Rutledge, F. N. Amer. J. Roentgen. Rad. Ther. Nut. Med. 114, 116 (1972). Castro, J. R., Issa, P., and Fletcher, G. H. Radiology 95, 163 (1970). Piver, M. S., Wallace, S., and Castro, J. R. Amer. J. Roentgen. Rad. Ther. Nut. Med. 111, 278 (1971). Piver, M. S., and Barlow, J. J. Cancer 32, 367 (I 973). Fletcher, G. H. Cancer 29, 545 (1972). Piver, M. S., Barlow, J. J., Vongtama, V., and Webster, J. Amer. J. Obstet. Gynecol. 120, 969 (I 974).
ONCOLOGY
3, 168- 175 (1975)
PRELIMINARY
REPORT
Para-Aortic Lymph Node Irradiation for Carcinoma of the Uterine Cervix Using Split Course Technique’ M. STEVEN PIVER', M.D., FACOG, VITUNE VONGTAMA, M.D., AND
JOSEPH J. BARLOW, M.D.,FACOG Departments
of Gynecology
and Radiation Therapy, Roswell Buffalo, New York 14263
Park Memorial
Institute,
Received Twenty women with previously untreated cervical cancer received radical irradiation to the para-aortic lymph nodes and pelvis. Ninety percent received 6000 rads to the paraaortic nodes and pelvis in 8 weeks using split course technique. The mortality from complications of therapy, without evidence of recurrence, was 25%. Forty percent of the women were dead from recurrent cervical cancer (4-23M), and even with this short follow-up only 35% were surviving NED (6-29M). Methods for improving future trials of irradiation to the para-aortic nodes are discussed.
INTRODUCTION
Approximately 40% of women with Stage IIIB (pelvic wall) and IVA (bladder or rectum) cervical cancer have metastases to the para-aortic nodes [ 1,2,3]. Such para-aortic node metastases account, in part, for the failure to improve the five year cure rate by pelvic radiotherapy [4]. That sporadic cases with aortic node mestases can be cured by para-aortic node irradiation has been documented [5,6]. A recommended dose of 6000 rads in 6 wk to the aortic nodes [5] seemed excessive in view of the intolerance of the small intestine within the irradiated field. Using lower doses of external therapy (less than 6000 rads) by conventional anterior and posterior portals has not proven significantly efficacious. Support for this comes from a report by Castro, Issa and Fletcher who reported on the treatment of women with carcinoma of the cervix treated by external irradiation alone (without intracavitary radium). Of 30 women who received 5000 rads in 5 wk or less there were no women surviving without evidence of recurrence. Moreover, 10 of these 30 women also had para-aortic node metastases and received 5000 rads in five weeks by anterior and posterior ’ Presented at the Sixth Annual Meeting Society of Gynecologic Oncologists, January 7-9, 1975, Key Biscayne, FL. * Reprint requests to M. Steven Piver, M.D., Roswell Park Memorial Institute, 666 Elm Street, Buffalo, NY 14203. I68 Copyright @ 1975 by Academic Press, Inc. All rights of reproduction in any form reserved.
PARA-AORTIC
169
LYMPH NODE IRRADIATION
portals. All were dead of disease by 12 mo. Not until they reached dose rates of 6000 rads whole pelvis did they achieve cure rates (6 of 20 NED at 36 mo) [7]. We, therefore, started a prospective evaluation of 6000 rads to the para-aortic area in 8 wk by split course therapy with the first 3000 rads/3 wk given by anterior and posterior portals and a second 3000 rads/3 wk by 360” rotational therapy with a 2 wk rest period before resuming the second course. The theoretical basis for split course therapy is that the 2 wk rest would allow for repair of normal tissues, thus improving normal tissue tolerance, and also allow time for reoxygenation of tumor cells, thus increasing the cancericidal effects of the irradiation. This is a preliminary report of our first 20 patients with previously untreated carcinoma of the cervix who also have aortic node metastases. MATERIAL
AND METHODS
Twenty women with previously untreated carcinoma of the uterine cervix have received radical radiation to para-aortic nodes and pelvis. The plan of radiation was 6000 rads to pelvis and para-aortic nodes in 8 wk using split course technique with 2 wk rest after the first 3000 rads. Two-hundred rads were given per day using five fractions per week to the pat-a-aortic nodes, using a combination of opposed portals in the first course and a 360” rotational therapy on a 6MEV linear accelerator, 100 cm SSD in the second course. The average field size is 8 x 15 cm to the upper border of the 12th thoracic vertebrae. The pelvis was irradiated using an average field size 16 X 16 cm anteriorly and posteriorly and 10 x 15 cm bilateral pelvic portals. An average gap of 1 cm is allowed between the junction of the para-aortic and pelvic fields (Fig. 1). Table 1 shows the EXTENDED
FIELDS
( PELVIS
R PARA-AORTIC)
_..
Rotation
DOSE: 3000
-I-
-l-
IRods TD /
REST
3 Weeks
-l 3000
Rods TD / 3 Weeks
2 Weeks PARA-AORTIC: PELVIS
AtP :
PORTALS
BOX PELVIS
-
360°
Rotation
-
BOX PELVIS
FIG. 1. Plan of irradiation to pelvis and para-aortic nodes to deliver 6000 in 8 wk by split course
technique.
170
PIVER
ET AL.
TABLE PARA-AORTIC
NODE
1
IRRADIATION-CERVICAL
CARCINOMA
Dosage level in rads-20 Pelvis Para-Aortic Radium Number
patients
6000 6000 2500”
7000 6000 -
7000 5000
5200 4600 2500”
17
1
1
1
n Median dosage to point “A.”
dose of radiation to the para-aortic nodes and pelvis with 17 of the 20 patients receiving 6000 rads to the para-aortic nodes, 6000 rads to the pelvis plus an additional 2500 rads to point A by the use of intracavitary and vaginal radium. One patient received 5200 rads to the pelvis and 4600 rads to the para-aortic nodes when radiation therapy had to be discontinued because of severe radiation enteritis. Two additional patients received 7000 rads to the pelvis and 6000 and 5000 rads to the para-aortic nodes respectively, but did not receive intracavitary radium because of inability to place such a system. All patients were clinically staged and had the following work-up: SMA, CBC, chest X-ray, intravenous urogram and cytoscopy. Thirteen women had clinical State IIIB, five Stage IIB, one Stage IV and one Stage IB cervical cancer. The latter underwent laparotomy for radical hysterectomy and was found to have large aortic node metastases. Eighteen of the women had squamous carcinoma, and two had adenocarcinoma of the uterine cervix. Eighteen of the 20 women were surgically staged by exploratory laparotomy and para-aortic node biopsy or para-aortic lymphadenectomy. Two women who were poor surgical candidates had definitely positive para-aortic node metastases by lymphangiography. In two previous reports, our accuracy in the diagnosis of positive pelvic node metastases and aortic node metastases (confirmed histologically) by lymphangiography were 97.6 and 95.8% respectively [8,9]. With nearly 100% accuracy in diagnosing positive nodal metastases by lymphangiography, the inclusion of these two patients in the series seems warranted. If the aortic nodes were negative to palpation at the time of laparotomy, paraaortic lymphadenectomy was then carried out by removing the nodes anterior to the aorta and vena cava from the bifurcation of the aorta to just below the renal vessels. Retrocaval nodes and lymph nodes lateral to the aorta are not routinely removed. If the aortic nodes are clinically positive at the time of laparotomy, then biopsy of the nodes are performed and frozen section evaluation is carried out. The large positive nodes are not resected. Only one significant complication has resulted from this surgical staging and this was corrected by nonsurgical means [I]. Follow-up has ranged from six to 40 months with 80% being followed one yr. Complications were evaluated to those occurring in the pelvis or upper abdomen. The results of treatment were evaluated also as to (1) stage of disease, (2) findings of the aortic nodes at the time of surgical staging i.e., (a) microscopic
PARA-AORTIC
LYMPH
NODE
171
IRRADIATION
metastases in clinically negative aortic nodes and (b) aortic node metastases proven by biopsy with gross residual disease remaining. Ten patients had reexamination of the aortic nodes subsequent to radiation therapy, either by laparotomy or autopsy. RESULTS
Eighteen of the 20 women were surgically staged. Seven had para-aortic lymphadenectomy because of clinically negative aortic nodes. Microscopic metastases was found in all seven patients. Eleven women had grossly positive aortic nodes. These were biopsied and metastases confirmed by frozen section evaluation. Complicutions
Five (25%) of the 20 women developed six significant pelvic complications secondary to high dose radiation therapy: Sigmoid perforation (1), severe sigmoiditis requiring colostomy (2), rectovaginal fistula (2), and terminal ileum sigmoid fistula (1) (Table 2). All were NED at the time of development of these complications. Five (25%) of the 20 patients developed eight significant abdominal complications: Gastric ulcer (2), mid ileal obstruction (1), mid ileal perforation (1), descending colon perforation (1), radiation enteritis with electrolyte imbalance causing her death (1), and nonmalignant chylous ascites (2) (Table 3). Table 4 lists all the significant complications related to the area involved. Thus 45% (9 of 20) sustained significant complications. A 25% mortality from all complications was recorded with 15% mortality attributable to the para-aortic irradiation. Survival
and Eradication
of Aortic
Node Metastases
Ten women had re-examination of aortic nodes by laparotomy [5] or autopsy [5]. Eighty percent (8 of 10) had negative nodes-five clinically at the time of laparotomy and three histologically at the time of autopsy. Four women who initially had lymphadenectomy with the findings of microscopic aortic node metasPARA-AORTIC PELVIC
Time months
Complications 1. 2. 3. 4.
TABLE 2 IRRADIATION-CERVICAL CARCINOMA COMPLICATIONS IN 20 PATIENTS
Sigmoid perforation Severe sigmoiditis + colostomy Rectovaginal fistula Terminal ileum-colon fistula
6 5, 9 6, 14 14
Complications IlO.
Tumor status
1 2 2 1
NED NED” NED NED
Total: 6 Patients 5120 = 25% B One patient developed
metastases to t10 & 11 vertebrae
and mediastinum
at 18 months.
172
PIVER
ET AL.
TABLE 3 PARA-AORTIC NODE IRRADIATION-CERVICAL CARCINOMA ABDOMINAL COMPLICATIONS IN 20 PATIENTS
1. 2. 3. 4. 5. 6.
Gastric ulcer Mid ileal obstruction Mid ileal perforation* Descending colon perforation Radiation enterocolitis + death Chylous ascites
Tumor
Complication no.
Time months
Complications
3, 5 10 18 10 36 7, 18
status
2 1 1 1 1 2
NED” NED NED NED NED NED
Total: 8 Patients 5120 = 25% (LOne patient developed * Not surgically staged.
metastases to tl0 and 11 vertebrae
and mediastinum
at 18 mo.
tases in clinically negative nodes had re-examination of aortic nodes and all were NED. Six women had gross residual tumor prior to radiation therapy, and four of these had negative aortic nodes at the time of re-examination (Table 5). Table 6 lists the survival to date in relationship to clinical stage. One patient with Stage IB cervical cancer and one patient with Stage IV are surviving NED at 29 and 14 months respectively. Of the women with Stage IIIB cervical cancer, only 23% (3 of 13) are alive NED, even with this short follow-up. This includes two women dying of complications at 13 and 40 mo respectively TABLE 4 PARA-AORTIC IRRADIATION-CERVICAL
Patients
6 7 8 9
Complications Mid ileal obstruction Mid ileal perforation” Descending colon perforationn Radiation enteritis + death gastric ulcer Sigmoiditis --, colostomy gastric ulcer Sigmoiditis -+ colostomy Rectovaginal fistula Rectovaginal fistula terminal ileum fistula Sigmoid perforation
9/20 = 45% a Also developed chylous ascites. b Developed metastases to tl0 and 11 vertebrae
CARCINOMA
Dead complications
Dead complications aortic irradiation
0 1 1
Tumor status NED NED NED NED NED” NED NED NED NED
5120 = 25%
and mediastinum
3120 = 15%
at 18 months.
8/9 = 88%
PARA-AORTIC
173
LYMPH NODE IRRADIATION TABLE 5
EXAMINATION
Number 1 2 3 4 5 6 7 8 9 10
OF PARA-AORTIC NODES SUBSEQUENT TO AORTIC NODE IRRADIATION
Stage
Method of diagnosis
Method of re-examination
Time months
Aortic nodes
2b 2b 3b 4 3b 3b 3b 3b 3b 2b
Lymphadenectomy Lymphadenectomy Lymphadenectomy Lymphadenectomy Biopsy Biopsy Biopsy Biopsy Biopsy Lymphangiography
Laparotomy Laparotomy Autopsy Laparotomy Laparotomy Autopsy Autopsy Autopsy Autopsy Laparotomy
18 9 13 13 5 4 5 40 23 23
NED NED NED NED NED” Positive Positive NED NED* NED
a Developed metastases to t 10 and 11 vertebrae and mediastinum at 18 months. B Recurrence in bladder and vagina only.
without evidence of recurrence. Of the five women with Stage IIB cervical cancer, none have died of recurrent cancer, but three are dead from complications without evidence of recurrence. Of the 20 patients, 40% are dead of disease from 4 to 13 mo after treatment, and 25% are dead of complications without evidence of recurrence from 11 to 40 mo. Only 35% are surviving without evidence of recurrence, and the follow-up in those surviving NED is too short to predict their eventual outcome. Table 7 evaluates the survival status in relationship to the findings of the aortic nodes at the time of surgical staging. Of those that had para-aortic lymphadenectomy because of clinically negative aortic nodes, none of the seven have TABLE 6 PARA-AORTIC NODE IRRADIATION-CERVICAL CARCINOMA SURVIVAL vs CLINICAL STAGE 20 PATIENTS
Stage
DOD”
Dead complications NED”
IB
-
-
IIB
8
(4,4,4,5,~,6,18,23) IV
-
8 40% u DOD = dead of disease b NED = no evidence of disease c ( ) = months surviving.
Survival NED
A
l/l
2 (l&23)
IIIB
Alive NED
6510) 3
(13240) -
@,9,W
5 25%
7 35%
1 (14)
21.5 3113 23% l/l
174
PIVER
ET AL.
TABLE PARA-AORTIC SURVIVAL
7
NODE IRRADIATION-CERVICAL vs SURGICAL FINDINGS IN
CARCINOMA
18 PATIENTS Survival
Laparotomy findings aortic nodes Nodes negative Nodes positive
Surgery Lymphadenectomy 7 Biopsy II 18
DOD” 7 (4,4,4,5,5.18,23) 7 39%
Dead complications NED” 3 (11,13,18)” 1 (40) 4 22%
Alive NED 4 (8,10,14,18) 3
Survival NED
(6,929)
417 57% 3/l 1 27%
1 39%
7118 39%
u DOD = dead of disease. ’ NED = no evidence of disease. C ( ) = months surviving.
died of recurrent cervical cancer. However, three of seven are dead of complications without evidence of recurrence at 11, 13 and 18 mo respectively. Of the 1 I patients that had only biopsy of aortic nodes, seven are dead of recurrent disease from 4 to 23 mo. Thus, even with this short follow-up, only 27% (3 of 11) were surviving NED in this group. DISCUSSION Twenty women with previously untreated cervical cancer received radical radiation therapy to the para-aortic nodes and pelvis. Ninety percent received 6000 rads to the para-aortic nodes and pelvis in 8 wk using split course technique. In addition, 18 of the 20 patients received intracavitary radium at a dose of 2500 rads to point A. The overall severe complication rate to the pelvis and abdomen has been high -45%. Twenty-five percent of the patients developed new complications attributable to the para-aortic irradiation, not normally seen in women receiving pelvic irradiation: Gastric ulcer, nonmalignant chylous ascites, mid ileal obstruction and perforation, and descending colon perforation. In addition, there was a 25% severe pelvic complication rate. Moreover, from this therapy there was a 25% mortality from all complications (5 of 20) and a 15% mortality from aortic node irradiation (3 of 20). All five women dying from complications of therapy were NED. That aortic node metastases can be eradicated is demonstrated in the 10 women who have had re-examination of aortic nodes after completing radiation therapy. Of the six women that did not have the positive aortic nodes resected, four were subsequently found to be NED on re-examination. Of the four patients that had para-aortic lymphadenectomy and were found to have microscopic metastases in the aortic nodes, all four were NED on re-examination of the aortic nodal area. However, this does not attest the efficacy of the irradiation since their only foci of metastases may have been resected.
PARA-AORTIC
LYMPH
NODE
IRRADIATION
175
With even this short follow-up, only 35% are surviving NED, or conversely, 65% are already dead either from complications of this therapy or recurrent cervical cancer. If, as is predictable, several of these 35% now surviving die from recurrent cervical cancer or complications of therapy, it will leave very few surviving by this treatment plan. The results of our therapy using 6000 rads in 8 wk by split course technique are not acceptable, because of the high mortality from complication and the poor survival rate. Silberstein et al. treated five women with aortic node metastases with 6000 rads in 6 wk with the entire treatment being given by 360” rotational therapy. Severe complications developed in only one case [5]. However, three of these women had recurrent tumor only to the para-aortic nodes and, therefore, did not have the large volume irradiated as did our patients who had the pelvis and aortic area treated simultaneously. This smaller volume irradiated may account, in part, for the low complication rate reported by Silberstein et al. because the tolerance to radiation is influenced not only by the total dose delivered and the duration of treatment but also by the volume of tissue irradiated. Our reservation with the delivery of the entire para-aortic node irradiation by 360” rotational therapy is the high dose to the kidneys (approximately 3000 rads) with the possible development of radiation nephritis. The necessity for an acceptable method of therapy for women with aortic node metastases from cervical cancer is certain. However, to date, the proper delivery of such therapy must await future trials. It is apparent, however, that women who are found to have only microscopic aortic node metastases, in clinically negative nodes, should not receive 6000 rads/6-8 wk, but should have a trial of approximately 4500 rads in 5 wk for control of subclinical disease [ IO]. Moreover, those women who are found to have large aortic node metastases should have an attempted resection of these nodes in order to reduce the amount of tumor, thus requiring less para-aortic nodal irradiation. Finally, it is hoped that future trials will demonstrate that radiosensitizing drugs, such as Hydroxyurea [ 111, in combination with lesser amounts of irradiation, (5000 rads/5 wk) will result in the eradication of large nonresectable aortic node metastases. REFERENCES I. 2. 3. 4. 5. 6. 7. 8. 9. IO. I I.
Piver, M. S., and Barlow, J. .I. Obstet., Gynecol. 43, 544 (1974). Buchsbaum, H. J., Amer. J. Obstrt. Gynecol. 113, 942 (1972). Nelson, J. H., Macasaet, M. A., Lu, T. et al. Amer. J. Obstet. Gynecol. 118, 749 (1974). Fletcher, G. H., and Rutledge, F. N. Clin. Obstet. Gynecol. 5, 958 (1968). Silberstein, A. B., Aron, B. S., and Alexander, L. L. Radiology 95, I8 I (1970). Fletcher, G. H., and Rutledge, F. N. Amer. J. Roentgen. Rad. Ther. Nut. Med. 114, 116 (1972). Castro, J. R., Issa, P., and Fletcher, G. H. Radiology 95, 163 (1970). Piver, M. S., Wallace, S., and Castro, J. R. Amer. J. Roentgen. Rad. Ther. Nut. Med. 111, 278 (1971). Piver, M. S., and Barlow, J. J. Cancer 32, 367 (I 973). Fletcher, G. H. Cancer 29, 545 (1972). Piver, M. S., Barlow, J. J., Vongtama, V., and Webster, J. Amer. J. Obstet. Gynecol. 120, 969 (I 974).