- Email: [email protected]
Indications, advantages, and limits of laparoscopy in ovarian cancer
GYNECOLOGIC
ONCOLOGY
Indications,
7,
41-55 (1979)
Advantages, and Limits of Laparoscopy Ovarian Cancer
in
COSTANTINO MANGIONI, M.D., GIORGIO BOLIS, M.D., PIERO MOLTENI, M.D. AND CARLO BELLONI, M.D. I Clinica Ostetrica Ginecologica, University of Milan, Via Commenda 12, Milan 20122, Italy Received January 3, 1978 Ninety-two patients with ovarian cancer (72 epithelial and 20 special) underwent 123 laparoscopies for restaging (23 patients), follow-up (46 patients), and second look (28 patients), All cases are analyzed according to the indications, characteristics of procedure, and morbidity. The results are discussed. Isolated diaphragmatic metastases were absent in the restaging of referred localized cancer (O/17);the number of positive peritoneal washings in the same patients, on the contrary, was significant (j/17). Laparoscopy seems to be a very useful procedure in the follow-up of patients without clinically followable disease or showing questionable response to chemotherapy. Combined laparoscopyilaparotomy procedures show the limits of sole laparoscopy: All this notwithstanding, the present 2-year study emphasizes the great value of this “minor” surgery in the surveillance of ovarian cancer.
The first to report the value of laparoscopy in ovarian cancer was Bagley and coauthors in 1973 [I]. The experience of the National Cancer Institute was subsequently published by Rosenoff and coauthors in 1975 [2-41. These authors described their use of laparoscopy both for initial staging and as second look in ovarian patients. Diaphragmatic metastases were detected in patients referred with localized tumor after laparotomy staging. A conspicuous number of patients showing “no clinical evidence of disease” (NED) after definitive therapy were found at second-look laparoscopy to have residual unsuspected tumor and were thus spared further major surgery. In 1976 Spinelli and coauthors [5] reported on a large series of laparoscopies in ovarian cancer. In these cases at the Istituto Nazionale Tumori of Milan, isolated diaphragmatic metastases were uncommon and usually associated with peritoneal involvement. The value of laparoscopy for the second-look procedure was not questioned. Piver and coauthors [6] described their laparoscopy findings in 14 women with alleged localized ovarian cancer. None was found to have diaphragmatic metastases, but five were found to have positive peritoneal washings. These authors emphasize the utility of laparoscopy in all ovarian patients who have not undergone either peritoneal cytology examination or diaphragm inspection at the time of laparotomy. This paper presents our experience of 123 laparoscopies in 92 ovarian patients 47 0090-8258/79/010047-09$01.00/O Copyright @ 1979 by Academic F’ress, Inc. All tights of reproduction in any form reserved.
48
MANGIONI
ET AL.
and discusses: (i) the frequency of laparoscopy upstaging in patients with alleged localized tumor by laparotomy, with particular respect to diaphragmatic metastases and positive peritoneal cytology; (ii) the value of laparoscopy in the followup both during and after therapy; (iii) the accuracy of laparoscopy, independently of the indications, when combined with laparotomy. MATERIALS
AND METHODS
Patients, From September 1975up to June 1977,92 patients with ovarian cancer (72 with epithelial and 20 with special tumors) underwent laparoscopy at the Gynecologic Oncologic Unit of the I” Clink Ostetrica Ginecologica of Milan University. Nineteen patients had two and six patients had three laparoscopies. Zndications. The indications are shown in Table 1. Laparoscopy “staging” was not performed as a routine in all patients. In eight poor surgical risk patients, it was done in order to spare major surgical procedures. Laparoscopy “restaging” was performed in 23 consecutive patients referred to our unit within 1 month of laparotomy. Pretherapy laparoscopy was performed to complete the evaluation regarding peritoneal cytology as well as diaphragm and liver capsule metastases. Even in advanced ovarian cancer, primary surgery sometimes leaves either undetectable tumor or scarce findings of the disease. Thirty-seven “laparoscopic follow-ups” for 26 patienti provided the best means of assessing therapeutic response during chemotherapy, after adequate exposure to therapy. In another 20 patients with relapse of tumor after apparently complete clinical remission, 21 laparoscopies gave a picture of the extent of the disease in the pelvis and abdomen. Twenty-eight laparoscopies were performed as “second-look”” procedures in patients with apparently complete clinical remission. About a quarter of the patients showing NED at second look had subsequent relapses [7]. We repeated laparoscopy as a “third-looF’ procedure in six patients 1 year after negative second-look Iaparotom y . Laparoscopy. Laparoscopy was used in all procedures, applying the technique previously described 14, s]. Particular attention was given to testing and confirmTABLE
1
LAPABXXXWY IN OVARIAN CANCER
Epi?helial Indication
Sta%iag Restagqim Follow-up During therapy For recurrence
Tumor 6)
6
Special 2
22.3 16 31 14 21 6 94
Tumor (So) 31.1
7 49.0 28.7
6 7 7 29
44.8 24.2
LAPAROSCOPY
IN
OVARIAN
CANCER
49
ing a clear entry tract, especially in patients with previous abdominal surgery (92.4%) and radiotherapy (9.7%), in order to avoid frequent adhesions. Premedication is believed to be important in preventing cardiac change. We use Phenergan 1 hr before the procedure or diazepam with atropine just before surgery. General anesthesia was used in 95 laparoscopies with intubation to assure adequate ventilation and to avoid aspiration during surgery. Another 28 laparoscopies were performed with local lignocaine hydrochloride (Xylocaine) anesthesia. There is no evidence to support that laparoscopy needs to be routinely performed as an in-patient procedure. The two different anesthetic techniques were utilized according to the anesthetist’s opinion and to each patient’s characteristics (poor surgical risk) and patient’s wishes (especially in patients with repeated laparoscopies). The incidence of cardiac complications was related to different causes: abdominal distension and consequent pain, cardiac compression, Trendelenburg position, relative immobilization of the diaphragm and consequent hypoventilation. With local anesthesia we had two cases of cardiac instability requiring both general anesthesia and intubation. The age of these patients ranged from 14 to 82 years; 25 of the 92 patients were at poor surgical risk. In 19 patients (20.6%), there were some problems in adequate visualization of intraperitoneal spaces; in almost all of these cases, the causes of inadequacy were adhesions following previous surgery. The pelvis was the site most frequently obstructed (70%), followed by the omentum and iieal loops (45%) and the liver surface and diaphragm (27%). This incidence of an inadequate procedure is acceptable if it is related to the high percentage of previously repeated surgery in these patients (23.9%). In six patients major surgery corrected the inadequacy of laparoscopy in detecting residual disease in the pelvis. Postoperative complications. The morbidity was unremarkable (4%). One patient had lesions to the tunica serosa and the muscular wall of the transverse colon was partially injured by the trocar at the site of abdominal wall adhesions; diagnosis was made at laparotomy and the wall was closed with silk. Another patient had omental emphysema, but the course was uneventful The other three patients had fever on Day 1 of laparoscopy. There were no fatalities. Patients not awaiting major surgery were discharged within 48 hr. RESULTS
Restaging. Twenty-three patients were submitted to laparoscopy for restaging (Table 2); 17 were stage I, 3 were stage II, and 3 were stage III. These three latter laparoscopies were performed because the amount of residual tumor was not known and there was no evidence of assessable disease. In 20 patients the laparoscopy was adequate, with a clear visualization of the pelvis, abdomen, and diaphragm. In only three patients adhesions created some problems, which, however, did not interfere in the final staging. Two patients presented diaphragmatic metastases associated with other metastatic implants on the abdominal and pelvic peritoneum and, in one case, on the liver capsule, too. In both patients described at laparotomy as stage IIB, the stage was modified to stage III. In a third patient, microscopic metastases were found on biopsy in the posterior pelvic
50
MANGIONI
ET AL.
TABLE
2
LAPAROSCOPY IN THE RESTAGING OF OVARIAN CANCER”
Laparoscopy Laparotomy Stage
Not confirmed
Confirmed
Epithelial
Special
Epithelial
Special
A B
4 6
7
2 5
5
A B
I 2
I
Early Late
I 2
I 2
Epithelial
I
Special
2 UC) 2 UC)
WB)
1 W)
II 2 (III)*
III
a Patients upstaged: epithelial, 31.2% (5/16); special, 28.5% (217). * Both with positive cytology.
peritoneum: The stage of this patient (IA at surgery) was modified to stage IIB. Nineteen patients had unknown abdominal cytology; at the time of laparoscopy, four had some amount of free peritoneal fluid (positive in two cases) and all others had peritoneal washings (positive in four cases). These six patients were upstaged for positive cytology: five to stage IC and one to stage IIC. Follow-up. In 26 patients, 37 laparoscopies were performed to assess the response to treatment, in 21 in the absence of evaluable disease and in 5 for questionable clinical response (Table 3). Laparoscopy was carried out after adequate exposure to the drugs prescribed (in patients with clinically nonevaluable disease after 3-4 months of chemotherapy). In 4 of the 21 patients (9 of 30 laparoscopies) with no clinical evidence of disease, the tumor showed progression, TABLE 3 LAPAROSCOPY IN THE FOLLOW-UP OF OVARIAN CANCER
Laparoscopic findings Clinical findings” Indication Follow-up During therapy Negative Response > 50% For recurrence Only distant metastases Intraperitoneal tumor
Confirmed
Not confirmed
Epithelial
Special
Epithelial
Special
Epithelial
Special
24 7
6
19 5
2
5 2
4
5
1
5
1
9
6
6
2
3
4
’ Clinical findings not confirmed: epithelial, 22.2% (10/45); special, 61.5% (8/13).
LAPAROSCOPY
LAPAROSCOPY
IN
IN THE SECOND
OVARIAN
TABLE 4 AND THIRD
LOOKS OF OVARIAN
Second look Stage I II III Total
Negative + Cytology 10 I 14 25
2 2
51
CANCER
CANCER
Third look
+ Histology
1 1
Cases 10 1 17 28
Negative + Cytology 2 2 4
I 1
+ Histology Cases
1 I
2 4 6
and likewise in 2 of the 5 patients (2 of 7 laparoscopies) with partial clinical response. Laparoscopy follow-up was performed in 6 patients with distant relapse of tumor (one vagina, three distant lymph nodes, one lung, one abdominal wall) but a clinically negative pelvis and abdomen; laparoscopy was negative in all of them. In another 15 patients with clinical evidence of relapsed tumor in the peritoneal cavity, laparoscopy was used to determine the exact extent of tumor. In five patients laparoscopy was falsely negative because of retro- and extraperitoneal tumor growth (three pelvic lymph nodes, two pelvic cellular tissue). In 5 of 21 patients with no clinical evidence of disease, peritoneal cytology was positive (2 free fluid and 3 washings). Three of these showed tumor progression, one residual tumor, and one no histologic evidence of tumor. In three patients (11.5%), adhesions rendered follow-up laparoscopy unsatisfactory. Second and third looks. Second-look laparoscopy was performed in 28 patients (Table 4). Twenty-three of 24 patients with NED had negative laparoscopy. Laparoscopy was also negative in the last four patients with clinical evidence of residual tumor in the pelvis, because of adhesions (two cases) and of retroperitoneal residual tumor (two cases). No ascites was found. Washings were positive in three cases, initially at stage III; one had histologic evidence of tumor at laparoscopy and laparotomy, a second with negative laparoscopy had positive laparotomy for residual microscopic omental metastases, and a third only positive washing. In six patients without any evidence of tumor, laparoscopic third look was performed 12 or more months from the end of therapy; it was negative in two patients initially at stage IIC and in two patients at stage III with previous negative laparoscopic second look. There were two positive third looks: The first patient at stage III had disseminated isolated neoplastic cells in the washing and the second patient had microscopic foci of residual tumor in the pelvic peritoneum showing questionable viability. Comparison of laparoscopy and laparotomy explorations. In order to check the accuracy of laparoscopic findings, 34 patients underwent exploratory laparotomy immediately after or within 10 days of laparoscopy (Table 5). The purpose of this combined exploration was staging in seven patients and restaging in three patients. Microscopic tumor foci were detected histologically at the laparotomic restaging in the omentum of one patient and in the omentum and sigmoid epiploon in the second case. These two patients, initially at stage IB and with negative laparoscopic restaging, were upstaged to stage III. In the third patient, initially at stage IA with laparoscopic upstaging for positive washings, lymphography re-
52
MANGIONI
ET AL.
TABLE 5 COMBINED
LAPAROSCOPY
AND LAPAROTOMY
IN OVARIAN
CANCER
Laparotomy Indication
Not confirmed Epithelial
Special
2
I
Special
Epithelial
Special
5 2
2 1
5
2
3
I I
I
I I
2
14
4
9
3
5
Epithelial Staging Restaging Follow-up During therapy For recurrence Second look Negative or positive cytology Positive histology
Confirmed
Laparoscopy”
I
I
I
a Laparoscopic findings not confirmed: epithelial, 36% (9/25); special, 22.2% (2/9).
vealed lumboaortic lymph node metastases, confirmed at laparotomy; the patient was upstaged to stage III. In one of the five patients undergoing laparoscopic and laparotomic follow-up, the negative laparoscopic finding was not confirmed because of residual tumor in the right parametrial lymph node. In 6 of 11 patients initially at stage III, second-look laparotomy gave positive findings after negative second-look laparoscopy; two of these patients had clinical evidence of pelvic residual tumor, but laparoscopy was inadequate because of abdominal and pelvic adhesions. Three patients with unremarkable laparoscopic findings were found to have microfoci of residual tumor in the omentum, sigmoid epiploon, and infundibulum pelvic ligament at the site of previous resection in the salpinx and in the residual ovary. The last patient with positive lymphangiogram was found at second-look laparotomy to have metastatic cancer in one of the left external iliac lymph nodes. The last eight patients at stages I and II had laparoscopic negative findings confirmed by laparotomy. DISCUSSION
Our purpose is to discuss some aspects of laparoscopy arising from this experience. Diaphragmatic metastases were demonstrated in 9 of 92 patients with ovarian cancer (9.70/o),5 of them with concomitant implants on the liver capsule. Two of these patients were at stage IIB, four were at stage III, and three had pelvic and abdominal relapsed tumor. According to Piver’s findings, diaphragmatic involvement seems not to be frequent in localized ovarian cancer. In fact, the two patients referred to us at stage IIB had been inadequately staged in another hospital and were found to have a considerable amount of unreported tumor all around the peritoneal cavity. The prognostic value of cytologic washings is not well known. In the experience
LAPAROSCOPY
IN
OVARIAN
CANCER
53
of M. D. Anderson, a poorer prognosis is predicted in ovarian patients with free-floating cancer cells [8]. There is also little agreement about how to collect samples for cytological diagnosis [9, 101.In our series, we found five positive washings in the 17 restaged patients at stages IA and B (29.4%). This high incidence of positive washings suggests that this check should be considered essential because of different treatment required at stages IC and IIC as compared to stages IA and IB. In 19 negative second-look laparoscopies carried out in patients initially at stage III, there were two positive washings (7.1%), and in six third-look laparoscopies (16.6%) 1 year after second-look laparotomy in patients without clinical evidence of disease, there was one. In one of these cases laparotomy showed microfoci of residual tumor, while in the other two patients floating cancer cells were the only signs of residual disease. We performed 27 follow-up laparoscopies in 19 patients with epithelial ovarian cancer initially at stage III. In seven cases the peritoneal washings became negative; these patients have shown partial or complete response. Another seven patients gave positive washings in 11 follow-up laparoscopies. All but one had progression of the disease; three of these were clinically NED. In contrast, no particular agreement between washings, response, and relapse of tumor was found in two patients with endodermal sinus tumor. Our preliminary experience and that of MacGowan suggest that the presence of free-floating cancer cells may be of some prognostic value in the follow-up during chemotherapy. Accuracy in staging ovarian cancer is generally emphasized as being vital. Full, intensive staging is mandatory, and laparoscopy, like lymphangiography, should be performed routinely in patients referred at stages 1 and II after inadequate laparotomy staging [ 111. The problem of diaphragmatic metastases, which are so difficult to demonstrate and to biopsy at laparotomy, can be usefully approached by the laparoscope before closure of the abdomen at the end of laparotomy staging, with a careful look at any diaphragmatic vault histologically proved or suspected as being affected by cancer. In our experience, follow-up laparoscopy has been of great value as a whole during chemotherapy in patients without followable tumor, in patients with localized cancer who have undergone precautional chemotherapy 6 months after surgery in patients with disseminated cancer with clinically questionable response, and in patients with localized cancer who have undergone conservative surgery (dysgerminoma, mutinous adenocarcinoma) 4-6 and 12- 18 months after initial surgery. In the latter cases, follow-up laparoscopy allows an early diagnosis of tumor relapse. Follow-up laparoscopy also demonstrated its value in patients with relapsed tumor outside the peritoneal cavity, in checking for pelvic or abdominal metastases, and in patients with clinically relapsed peritoneal tumor in whom it is not possible clinically to ascertain the extent of the disease. The use of laparoscopy as second look needs no further discussion, as it is well known that it can spare major surgery in patients with disseminated cancer and in patients with localized tumor after adequate periods of precautional chemo-
54
MANGIONI
ET AL.
therapy or clinical follow-up. In previous reports [3-51 laparoscopy, used as second look in NED patients after a dramatic response to therapy, showed a worthwhile incidence of clinically undetectable residual tumor and eventually spared major surgery in one-third of the patients. In our experience before we started using follow-up laparoscopy, 70% of the NED patients initially at stage III showed residual micro- or macroscopic tumor in the peritoneal cavity [12, 131. Since October 1975, routine laparoscopy has reduced the number of positive laparotomies, and in fact residual tumors at laparotomy have generally been in retroperitoneal sites or microscopic foci. The value of laparoscopy as a second-look procedure is still much debated. Laparoscopy may be used as the only second-look procedure in patients at stages IC, IIB, and IIC-and obviously where clinical evaluation at stages IA, IB, and IIA leaves doubt-if in these patients a previous laparoscopy, done as a follow-up from 3 to 6 months after primary surgery, was negative. At stage III, positive laparoscopy as second look can only avoid major surgery, while if it is negative, laparotomy is mandatory. In our experience, 6 of 18 patients with adequate negative laparoscopies showed residual disease at major surgery. One possible application of laparoscopy could be as “third look” in stage III 1 year after negative laparotomy second look. The possible relapse of tumor in these patients is well demonstrated. Our series of combined laparoscopy/laparotomy procedures confirms the limits of laparoscopy [4, 5, 151, which is known to be a valuable means of checking clinically nonfollowable intraperitoneal disease, but is of little use in endoscopitally unexplorable abdominal spaces and in showing up almost all retroperitoneal metastases. In conclusion, laparoscopy-in the absence of really effective markers [ 15]-is of great help in the surveillance of the ovarian cancer patient as long as the clinician bears its limits in mind. Note added in proof. Up to October 31, 1978,306 laparoscopies have been performed on 214 patients with ovarian cancer; 64 of these patients were referred for restaging (30% upstaged); another group of 70 patients had 95 laparoscopic follow-ups during therapy (25% clinical misevaluation). This wider body of evidence confirms the clinical value of the above-mentioned considerations.
REFERENCES I. Bagley, C. M., Jr., Young, R. C., Schein, P. S., et nl. Ovarian carcinoma metastatic to the diaphragm frequently undiagnosed at laparotomy. A preliminary report, Amer. J. Obstet. Gynecol. 116, 397-400 (1973). 2. Rosenoff, S. H., Young, R. C., Anderson, T., et al. Peritoneoscopy; A valuable staging tool in ovarian carcinoma, Ann. Intern. Med. 83, 37-41 (1975). 3. Rosenoff, S. H., De Vita, V. T., Hubbard, S., and Young, R. C. Peritoneoscopy in the staging and follow-up of ovarian cancer, Semin. Oncol. 2, 223-228 (1975). 4. Rosenoff, S. H., Young, R. C., Chabner, B., et al. Use of peritoneoscopy for initial staging and posttherapy evaluation of patients with ovarian carcinoma, Symposium on Ovarian Carcinoma, NC1 Monograph 42, pp. 81-84 (1975). 5. Spinelli, P., Luini, A., Pizzetti, P., and De Palo, G. M. Laparoscopy in staging and restaging of 95 patients with ovarian carcinoma, Tumori 62, 493-502 (1976). 6. Piver, M. S., Lopez, R. G., Xynos, F., and Barlow, J. J. The value ofpretherapyperitoneoscopy in localized ovarian cancer, Amer. J. Obstet. Gynecol. 127, 288-290 (1977).
LAPAROSCOPY IN OVARIAN
CANCER
55
7. Smith, J. P., Delgado, G., and Rutledge, F. Second look operation in ovarian carcinoma. Postchemotherapy, Cancer 38, 143% 1442 (1976). 8. Creasman, W. T., and Rutledge, F. The prognostic value of peritoneal cytology in gynecologic malignant disease, Amer. J. Obstet. Gynecol. 110, 773-785 (1971). 9. McGowan, L., and Davis, R. H. Peritoneal fluid cellular patterns in obstetrics and gynecology, Amer. J. Obstet. Gynecol. 106, 979-995 (1970). 10. McGowan, L. Peritoneal fluid profiles, Symposium on Ovarian Carcinoma, NC1 Monograph 42, pp. 75-79 (1975). I I. Mattioli, G., De Palo, G. M., Di Re, F., et al. Classification anatomoradiochirurgicale dans les tumeurs du revetement ovarien, Gynecologie 26, 347-349 (1975). 12. Mangioni, C., Bolis, G., and Natale, N. Terapia sequenziale dei tumori epiteliali dell’ovaio: I’utilita de1 second-look, Ann. Ostet. Ginecol. 97, 205-214 (1976). 13. Mangioni, C., Bolis G., Bortolozzi G., et al. I’ second-look laparotomico nella clinica de1 tumori maligni dell’ovaio. Le neoplasie dell’apparato genitale femminile. Ed. ambrosiana milano. pp. 279-287, (1978). 14. Poulhes, J., Becau, J., and Hoff, J. Le traitement des tumeurs du revetement ovarien. Tumeurs de I’ovaire, XXVII Assoc. Franc. Gynecol., Masson, Paris, pp. 189-220 (1975). 15. Samaan, N. A., Smith, J. P., Rutledge, F. N., and Schultz, P. N. The significance of measurement of human placental lactogen, human chorionic gonadotropin, and carcinoembryonic antigen in patients with ovarian carcinoma, Amer. J. Obstet. Gynecol. 126, 186-189 (1976).
ONCOLOGY
Indications,
7,
41-55 (1979)
Advantages, and Limits of Laparoscopy Ovarian Cancer
in
COSTANTINO MANGIONI, M.D., GIORGIO BOLIS, M.D., PIERO MOLTENI, M.D. AND CARLO BELLONI, M.D. I Clinica Ostetrica Ginecologica, University of Milan, Via Commenda 12, Milan 20122, Italy Received January 3, 1978 Ninety-two patients with ovarian cancer (72 epithelial and 20 special) underwent 123 laparoscopies for restaging (23 patients), follow-up (46 patients), and second look (28 patients), All cases are analyzed according to the indications, characteristics of procedure, and morbidity. The results are discussed. Isolated diaphragmatic metastases were absent in the restaging of referred localized cancer (O/17);the number of positive peritoneal washings in the same patients, on the contrary, was significant (j/17). Laparoscopy seems to be a very useful procedure in the follow-up of patients without clinically followable disease or showing questionable response to chemotherapy. Combined laparoscopyilaparotomy procedures show the limits of sole laparoscopy: All this notwithstanding, the present 2-year study emphasizes the great value of this “minor” surgery in the surveillance of ovarian cancer.
The first to report the value of laparoscopy in ovarian cancer was Bagley and coauthors in 1973 [I]. The experience of the National Cancer Institute was subsequently published by Rosenoff and coauthors in 1975 [2-41. These authors described their use of laparoscopy both for initial staging and as second look in ovarian patients. Diaphragmatic metastases were detected in patients referred with localized tumor after laparotomy staging. A conspicuous number of patients showing “no clinical evidence of disease” (NED) after definitive therapy were found at second-look laparoscopy to have residual unsuspected tumor and were thus spared further major surgery. In 1976 Spinelli and coauthors [5] reported on a large series of laparoscopies in ovarian cancer. In these cases at the Istituto Nazionale Tumori of Milan, isolated diaphragmatic metastases were uncommon and usually associated with peritoneal involvement. The value of laparoscopy for the second-look procedure was not questioned. Piver and coauthors [6] described their laparoscopy findings in 14 women with alleged localized ovarian cancer. None was found to have diaphragmatic metastases, but five were found to have positive peritoneal washings. These authors emphasize the utility of laparoscopy in all ovarian patients who have not undergone either peritoneal cytology examination or diaphragm inspection at the time of laparotomy. This paper presents our experience of 123 laparoscopies in 92 ovarian patients 47 0090-8258/79/010047-09$01.00/O Copyright @ 1979 by Academic F’ress, Inc. All tights of reproduction in any form reserved.
48
MANGIONI
ET AL.
and discusses: (i) the frequency of laparoscopy upstaging in patients with alleged localized tumor by laparotomy, with particular respect to diaphragmatic metastases and positive peritoneal cytology; (ii) the value of laparoscopy in the followup both during and after therapy; (iii) the accuracy of laparoscopy, independently of the indications, when combined with laparotomy. MATERIALS
AND METHODS
Patients, From September 1975up to June 1977,92 patients with ovarian cancer (72 with epithelial and 20 with special tumors) underwent laparoscopy at the Gynecologic Oncologic Unit of the I” Clink Ostetrica Ginecologica of Milan University. Nineteen patients had two and six patients had three laparoscopies. Zndications. The indications are shown in Table 1. Laparoscopy “staging” was not performed as a routine in all patients. In eight poor surgical risk patients, it was done in order to spare major surgical procedures. Laparoscopy “restaging” was performed in 23 consecutive patients referred to our unit within 1 month of laparotomy. Pretherapy laparoscopy was performed to complete the evaluation regarding peritoneal cytology as well as diaphragm and liver capsule metastases. Even in advanced ovarian cancer, primary surgery sometimes leaves either undetectable tumor or scarce findings of the disease. Thirty-seven “laparoscopic follow-ups” for 26 patienti provided the best means of assessing therapeutic response during chemotherapy, after adequate exposure to therapy. In another 20 patients with relapse of tumor after apparently complete clinical remission, 21 laparoscopies gave a picture of the extent of the disease in the pelvis and abdomen. Twenty-eight laparoscopies were performed as “second-look”” procedures in patients with apparently complete clinical remission. About a quarter of the patients showing NED at second look had subsequent relapses [7]. We repeated laparoscopy as a “third-looF’ procedure in six patients 1 year after negative second-look Iaparotom y . Laparoscopy. Laparoscopy was used in all procedures, applying the technique previously described 14, s]. Particular attention was given to testing and confirmTABLE
1
LAPABXXXWY IN OVARIAN CANCER
Epi?helial Indication
Sta%iag Restagqim Follow-up During therapy For recurrence
Tumor 6)
6
Special 2
22.3 16 31 14 21 6 94
Tumor (So) 31.1
7 49.0 28.7
6 7 7 29
44.8 24.2
LAPAROSCOPY
IN
OVARIAN
CANCER
49
ing a clear entry tract, especially in patients with previous abdominal surgery (92.4%) and radiotherapy (9.7%), in order to avoid frequent adhesions. Premedication is believed to be important in preventing cardiac change. We use Phenergan 1 hr before the procedure or diazepam with atropine just before surgery. General anesthesia was used in 95 laparoscopies with intubation to assure adequate ventilation and to avoid aspiration during surgery. Another 28 laparoscopies were performed with local lignocaine hydrochloride (Xylocaine) anesthesia. There is no evidence to support that laparoscopy needs to be routinely performed as an in-patient procedure. The two different anesthetic techniques were utilized according to the anesthetist’s opinion and to each patient’s characteristics (poor surgical risk) and patient’s wishes (especially in patients with repeated laparoscopies). The incidence of cardiac complications was related to different causes: abdominal distension and consequent pain, cardiac compression, Trendelenburg position, relative immobilization of the diaphragm and consequent hypoventilation. With local anesthesia we had two cases of cardiac instability requiring both general anesthesia and intubation. The age of these patients ranged from 14 to 82 years; 25 of the 92 patients were at poor surgical risk. In 19 patients (20.6%), there were some problems in adequate visualization of intraperitoneal spaces; in almost all of these cases, the causes of inadequacy were adhesions following previous surgery. The pelvis was the site most frequently obstructed (70%), followed by the omentum and iieal loops (45%) and the liver surface and diaphragm (27%). This incidence of an inadequate procedure is acceptable if it is related to the high percentage of previously repeated surgery in these patients (23.9%). In six patients major surgery corrected the inadequacy of laparoscopy in detecting residual disease in the pelvis. Postoperative complications. The morbidity was unremarkable (4%). One patient had lesions to the tunica serosa and the muscular wall of the transverse colon was partially injured by the trocar at the site of abdominal wall adhesions; diagnosis was made at laparotomy and the wall was closed with silk. Another patient had omental emphysema, but the course was uneventful The other three patients had fever on Day 1 of laparoscopy. There were no fatalities. Patients not awaiting major surgery were discharged within 48 hr. RESULTS
Restaging. Twenty-three patients were submitted to laparoscopy for restaging (Table 2); 17 were stage I, 3 were stage II, and 3 were stage III. These three latter laparoscopies were performed because the amount of residual tumor was not known and there was no evidence of assessable disease. In 20 patients the laparoscopy was adequate, with a clear visualization of the pelvis, abdomen, and diaphragm. In only three patients adhesions created some problems, which, however, did not interfere in the final staging. Two patients presented diaphragmatic metastases associated with other metastatic implants on the abdominal and pelvic peritoneum and, in one case, on the liver capsule, too. In both patients described at laparotomy as stage IIB, the stage was modified to stage III. In a third patient, microscopic metastases were found on biopsy in the posterior pelvic
50
MANGIONI
ET AL.
TABLE
2
LAPAROSCOPY IN THE RESTAGING OF OVARIAN CANCER”
Laparoscopy Laparotomy Stage
Not confirmed
Confirmed
Epithelial
Special
Epithelial
Special
A B
4 6
7
2 5
5
A B
I 2
I
Early Late
I 2
I 2
Epithelial
I
Special
2 UC) 2 UC)
WB)
1 W)
II 2 (III)*
III
a Patients upstaged: epithelial, 31.2% (5/16); special, 28.5% (217). * Both with positive cytology.
peritoneum: The stage of this patient (IA at surgery) was modified to stage IIB. Nineteen patients had unknown abdominal cytology; at the time of laparoscopy, four had some amount of free peritoneal fluid (positive in two cases) and all others had peritoneal washings (positive in four cases). These six patients were upstaged for positive cytology: five to stage IC and one to stage IIC. Follow-up. In 26 patients, 37 laparoscopies were performed to assess the response to treatment, in 21 in the absence of evaluable disease and in 5 for questionable clinical response (Table 3). Laparoscopy was carried out after adequate exposure to the drugs prescribed (in patients with clinically nonevaluable disease after 3-4 months of chemotherapy). In 4 of the 21 patients (9 of 30 laparoscopies) with no clinical evidence of disease, the tumor showed progression, TABLE 3 LAPAROSCOPY IN THE FOLLOW-UP OF OVARIAN CANCER
Laparoscopic findings Clinical findings” Indication Follow-up During therapy Negative Response > 50% For recurrence Only distant metastases Intraperitoneal tumor
Confirmed
Not confirmed
Epithelial
Special
Epithelial
Special
Epithelial
Special
24 7
6
19 5
2
5 2
4
5
1
5
1
9
6
6
2
3
4
’ Clinical findings not confirmed: epithelial, 22.2% (10/45); special, 61.5% (8/13).
LAPAROSCOPY
LAPAROSCOPY
IN
IN THE SECOND
OVARIAN
TABLE 4 AND THIRD
LOOKS OF OVARIAN
Second look Stage I II III Total
Negative + Cytology 10 I 14 25
2 2
51
CANCER
CANCER
Third look
+ Histology
1 1
Cases 10 1 17 28
Negative + Cytology 2 2 4
I 1
+ Histology Cases
1 I
2 4 6
and likewise in 2 of the 5 patients (2 of 7 laparoscopies) with partial clinical response. Laparoscopy follow-up was performed in 6 patients with distant relapse of tumor (one vagina, three distant lymph nodes, one lung, one abdominal wall) but a clinically negative pelvis and abdomen; laparoscopy was negative in all of them. In another 15 patients with clinical evidence of relapsed tumor in the peritoneal cavity, laparoscopy was used to determine the exact extent of tumor. In five patients laparoscopy was falsely negative because of retro- and extraperitoneal tumor growth (three pelvic lymph nodes, two pelvic cellular tissue). In 5 of 21 patients with no clinical evidence of disease, peritoneal cytology was positive (2 free fluid and 3 washings). Three of these showed tumor progression, one residual tumor, and one no histologic evidence of tumor. In three patients (11.5%), adhesions rendered follow-up laparoscopy unsatisfactory. Second and third looks. Second-look laparoscopy was performed in 28 patients (Table 4). Twenty-three of 24 patients with NED had negative laparoscopy. Laparoscopy was also negative in the last four patients with clinical evidence of residual tumor in the pelvis, because of adhesions (two cases) and of retroperitoneal residual tumor (two cases). No ascites was found. Washings were positive in three cases, initially at stage III; one had histologic evidence of tumor at laparoscopy and laparotomy, a second with negative laparoscopy had positive laparotomy for residual microscopic omental metastases, and a third only positive washing. In six patients without any evidence of tumor, laparoscopic third look was performed 12 or more months from the end of therapy; it was negative in two patients initially at stage IIC and in two patients at stage III with previous negative laparoscopic second look. There were two positive third looks: The first patient at stage III had disseminated isolated neoplastic cells in the washing and the second patient had microscopic foci of residual tumor in the pelvic peritoneum showing questionable viability. Comparison of laparoscopy and laparotomy explorations. In order to check the accuracy of laparoscopic findings, 34 patients underwent exploratory laparotomy immediately after or within 10 days of laparoscopy (Table 5). The purpose of this combined exploration was staging in seven patients and restaging in three patients. Microscopic tumor foci were detected histologically at the laparotomic restaging in the omentum of one patient and in the omentum and sigmoid epiploon in the second case. These two patients, initially at stage IB and with negative laparoscopic restaging, were upstaged to stage III. In the third patient, initially at stage IA with laparoscopic upstaging for positive washings, lymphography re-
52
MANGIONI
ET AL.
TABLE 5 COMBINED
LAPAROSCOPY
AND LAPAROTOMY
IN OVARIAN
CANCER
Laparotomy Indication
Not confirmed Epithelial
Special
2
I
Special
Epithelial
Special
5 2
2 1
5
2
3
I I
I
I I
2
14
4
9
3
5
Epithelial Staging Restaging Follow-up During therapy For recurrence Second look Negative or positive cytology Positive histology
Confirmed
Laparoscopy”
I
I
I
a Laparoscopic findings not confirmed: epithelial, 36% (9/25); special, 22.2% (2/9).
vealed lumboaortic lymph node metastases, confirmed at laparotomy; the patient was upstaged to stage III. In one of the five patients undergoing laparoscopic and laparotomic follow-up, the negative laparoscopic finding was not confirmed because of residual tumor in the right parametrial lymph node. In 6 of 11 patients initially at stage III, second-look laparotomy gave positive findings after negative second-look laparoscopy; two of these patients had clinical evidence of pelvic residual tumor, but laparoscopy was inadequate because of abdominal and pelvic adhesions. Three patients with unremarkable laparoscopic findings were found to have microfoci of residual tumor in the omentum, sigmoid epiploon, and infundibulum pelvic ligament at the site of previous resection in the salpinx and in the residual ovary. The last patient with positive lymphangiogram was found at second-look laparotomy to have metastatic cancer in one of the left external iliac lymph nodes. The last eight patients at stages I and II had laparoscopic negative findings confirmed by laparotomy. DISCUSSION
Our purpose is to discuss some aspects of laparoscopy arising from this experience. Diaphragmatic metastases were demonstrated in 9 of 92 patients with ovarian cancer (9.70/o),5 of them with concomitant implants on the liver capsule. Two of these patients were at stage IIB, four were at stage III, and three had pelvic and abdominal relapsed tumor. According to Piver’s findings, diaphragmatic involvement seems not to be frequent in localized ovarian cancer. In fact, the two patients referred to us at stage IIB had been inadequately staged in another hospital and were found to have a considerable amount of unreported tumor all around the peritoneal cavity. The prognostic value of cytologic washings is not well known. In the experience
LAPAROSCOPY
IN
OVARIAN
CANCER
53
of M. D. Anderson, a poorer prognosis is predicted in ovarian patients with free-floating cancer cells [8]. There is also little agreement about how to collect samples for cytological diagnosis [9, 101.In our series, we found five positive washings in the 17 restaged patients at stages IA and B (29.4%). This high incidence of positive washings suggests that this check should be considered essential because of different treatment required at stages IC and IIC as compared to stages IA and IB. In 19 negative second-look laparoscopies carried out in patients initially at stage III, there were two positive washings (7.1%), and in six third-look laparoscopies (16.6%) 1 year after second-look laparotomy in patients without clinical evidence of disease, there was one. In one of these cases laparotomy showed microfoci of residual tumor, while in the other two patients floating cancer cells were the only signs of residual disease. We performed 27 follow-up laparoscopies in 19 patients with epithelial ovarian cancer initially at stage III. In seven cases the peritoneal washings became negative; these patients have shown partial or complete response. Another seven patients gave positive washings in 11 follow-up laparoscopies. All but one had progression of the disease; three of these were clinically NED. In contrast, no particular agreement between washings, response, and relapse of tumor was found in two patients with endodermal sinus tumor. Our preliminary experience and that of MacGowan suggest that the presence of free-floating cancer cells may be of some prognostic value in the follow-up during chemotherapy. Accuracy in staging ovarian cancer is generally emphasized as being vital. Full, intensive staging is mandatory, and laparoscopy, like lymphangiography, should be performed routinely in patients referred at stages 1 and II after inadequate laparotomy staging [ 111. The problem of diaphragmatic metastases, which are so difficult to demonstrate and to biopsy at laparotomy, can be usefully approached by the laparoscope before closure of the abdomen at the end of laparotomy staging, with a careful look at any diaphragmatic vault histologically proved or suspected as being affected by cancer. In our experience, follow-up laparoscopy has been of great value as a whole during chemotherapy in patients without followable tumor, in patients with localized cancer who have undergone precautional chemotherapy 6 months after surgery in patients with disseminated cancer with clinically questionable response, and in patients with localized cancer who have undergone conservative surgery (dysgerminoma, mutinous adenocarcinoma) 4-6 and 12- 18 months after initial surgery. In the latter cases, follow-up laparoscopy allows an early diagnosis of tumor relapse. Follow-up laparoscopy also demonstrated its value in patients with relapsed tumor outside the peritoneal cavity, in checking for pelvic or abdominal metastases, and in patients with clinically relapsed peritoneal tumor in whom it is not possible clinically to ascertain the extent of the disease. The use of laparoscopy as second look needs no further discussion, as it is well known that it can spare major surgery in patients with disseminated cancer and in patients with localized tumor after adequate periods of precautional chemo-
54
MANGIONI
ET AL.
therapy or clinical follow-up. In previous reports [3-51 laparoscopy, used as second look in NED patients after a dramatic response to therapy, showed a worthwhile incidence of clinically undetectable residual tumor and eventually spared major surgery in one-third of the patients. In our experience before we started using follow-up laparoscopy, 70% of the NED patients initially at stage III showed residual micro- or macroscopic tumor in the peritoneal cavity [12, 131. Since October 1975, routine laparoscopy has reduced the number of positive laparotomies, and in fact residual tumors at laparotomy have generally been in retroperitoneal sites or microscopic foci. The value of laparoscopy as a second-look procedure is still much debated. Laparoscopy may be used as the only second-look procedure in patients at stages IC, IIB, and IIC-and obviously where clinical evaluation at stages IA, IB, and IIA leaves doubt-if in these patients a previous laparoscopy, done as a follow-up from 3 to 6 months after primary surgery, was negative. At stage III, positive laparoscopy as second look can only avoid major surgery, while if it is negative, laparotomy is mandatory. In our experience, 6 of 18 patients with adequate negative laparoscopies showed residual disease at major surgery. One possible application of laparoscopy could be as “third look” in stage III 1 year after negative laparotomy second look. The possible relapse of tumor in these patients is well demonstrated. Our series of combined laparoscopy/laparotomy procedures confirms the limits of laparoscopy [4, 5, 151, which is known to be a valuable means of checking clinically nonfollowable intraperitoneal disease, but is of little use in endoscopitally unexplorable abdominal spaces and in showing up almost all retroperitoneal metastases. In conclusion, laparoscopy-in the absence of really effective markers [ 15]-is of great help in the surveillance of the ovarian cancer patient as long as the clinician bears its limits in mind. Note added in proof. Up to October 31, 1978,306 laparoscopies have been performed on 214 patients with ovarian cancer; 64 of these patients were referred for restaging (30% upstaged); another group of 70 patients had 95 laparoscopic follow-ups during therapy (25% clinical misevaluation). This wider body of evidence confirms the clinical value of the above-mentioned considerations.
REFERENCES I. Bagley, C. M., Jr., Young, R. C., Schein, P. S., et nl. Ovarian carcinoma metastatic to the diaphragm frequently undiagnosed at laparotomy. A preliminary report, Amer. J. Obstet. Gynecol. 116, 397-400 (1973). 2. Rosenoff, S. H., Young, R. C., Anderson, T., et al. Peritoneoscopy; A valuable staging tool in ovarian carcinoma, Ann. Intern. Med. 83, 37-41 (1975). 3. Rosenoff, S. H., De Vita, V. T., Hubbard, S., and Young, R. C. Peritoneoscopy in the staging and follow-up of ovarian cancer, Semin. Oncol. 2, 223-228 (1975). 4. Rosenoff, S. H., Young, R. C., Chabner, B., et al. Use of peritoneoscopy for initial staging and posttherapy evaluation of patients with ovarian carcinoma, Symposium on Ovarian Carcinoma, NC1 Monograph 42, pp. 81-84 (1975). 5. Spinelli, P., Luini, A., Pizzetti, P., and De Palo, G. M. Laparoscopy in staging and restaging of 95 patients with ovarian carcinoma, Tumori 62, 493-502 (1976). 6. Piver, M. S., Lopez, R. G., Xynos, F., and Barlow, J. J. The value ofpretherapyperitoneoscopy in localized ovarian cancer, Amer. J. Obstet. Gynecol. 127, 288-290 (1977).
LAPAROSCOPY IN OVARIAN
CANCER
55
7. Smith, J. P., Delgado, G., and Rutledge, F. Second look operation in ovarian carcinoma. Postchemotherapy, Cancer 38, 143% 1442 (1976). 8. Creasman, W. T., and Rutledge, F. The prognostic value of peritoneal cytology in gynecologic malignant disease, Amer. J. Obstet. Gynecol. 110, 773-785 (1971). 9. McGowan, L., and Davis, R. H. Peritoneal fluid cellular patterns in obstetrics and gynecology, Amer. J. Obstet. Gynecol. 106, 979-995 (1970). 10. McGowan, L. Peritoneal fluid profiles, Symposium on Ovarian Carcinoma, NC1 Monograph 42, pp. 75-79 (1975). I I. Mattioli, G., De Palo, G. M., Di Re, F., et al. Classification anatomoradiochirurgicale dans les tumeurs du revetement ovarien, Gynecologie 26, 347-349 (1975). 12. Mangioni, C., Bolis, G., and Natale, N. Terapia sequenziale dei tumori epiteliali dell’ovaio: I’utilita de1 second-look, Ann. Ostet. Ginecol. 97, 205-214 (1976). 13. Mangioni, C., Bolis G., Bortolozzi G., et al. I’ second-look laparotomico nella clinica de1 tumori maligni dell’ovaio. Le neoplasie dell’apparato genitale femminile. Ed. ambrosiana milano. pp. 279-287, (1978). 14. Poulhes, J., Becau, J., and Hoff, J. Le traitement des tumeurs du revetement ovarien. Tumeurs de I’ovaire, XXVII Assoc. Franc. Gynecol., Masson, Paris, pp. 189-220 (1975). 15. Samaan, N. A., Smith, J. P., Rutledge, F. N., and Schultz, P. N. The significance of measurement of human placental lactogen, human chorionic gonadotropin, and carcinoembryonic antigen in patients with ovarian carcinoma, Amer. J. Obstet. Gynecol. 126, 186-189 (1976).