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Three cycles of chemotherapy followed by primary cytoreductive surgery for unresectable ovarian cancer
GYNECOLOGIC
ONCOLOGY
43, 313-316 (1991)
CASE REPORT Three Cycles of Chemotherapy Followed by Primary Cytoreductive Surgery for Unresectable Ovarian Cancer FRANCO GUIDOZZI, M.B.B.CH., Department
of Obstetrics
MRCOG,’ and Gynecology, Parktown,
AND ERNST W. W. SONNENDECKER, University of the Witwatersrand, 2193 Johannesburg, South Africa Received
May
Definitive primary cytoreductive surgery was achievedat setond laparotomy after three cycles of combinationchemotherapy (cisplatinand cyclophosphamide) in three patientswho presented with unresectable disease at our Ovarian Tumor Unit. The ovarian cancer was inoperableat the first laparotomy and no surgical procedurewas performedother than biopsy of malignanttumor to coniirm the diagnosis.Following interventional surgical cytoreduction the patientswere given a further six coursesof combination chemotherapyand then maintained for a further six cycleson oral chlorambucil.Two patients are diseasefree at 17 and 21 months, respectively, while the other patient has cytological evidenceof malignancybut no other clinically detectable tumor depositsat 27 months. o 191A=demic PI=, IK.
INTRODUCTION
Primary cytoreductive surgery that eliminates all tumor deposits having a diameter of greater than 1.5 cm followed by chemotherapy is still the cornerstone in the management of ovarian cancer. Radical resection of the tumor insult provides an initial exponential decrease in tumor bulk that will then allow ultimate irradication of remaining tumor deposits that are likely to be more sensitive to chemotherapy [l]. Although Chen and Bochner [2] have stated that optimal debulking can be achieved in 97.9% of cases by a gynecological oncologist, it is not always possible preoperatively to predict which patients have such extensive disease that the skill of the surgeon is not sufficient to ensure optimal primary cytoreduction of tumor deposits. It is policy in our Ovarian Tumor Clinic at the Johannesburg Hospital to subject all our patients to primary ’ To whom
reprint
requests
should
Medical
M.MED., FICS, FRCOG School,
7 York
Road,
2, 1991
cytoreductive surgery irrespective of staging and preoperative findings, as we firmly believe that determining the strategy of the radical debmking can take place only at the time of the laparotomy [3]. Optimal cytoreduction of all the tumors operated on in our unit has been achieved in 81% of 168 patients, and where it was not achieved it was because of large diaphragmatic, hepatic, anterior abdominal wall, or inaccessible tumor masses. In no patient was pelvic disease the reason for inadequate debulking. Against this background we present our management of three cases where at the time of laparotomy the extent of the disease precluded the benefits of optimal primary aggressive cytoreduction as it was adjudged that the morbidity and possible mortality would be unacceptable. These cases highlight the value of interval primary cytoreductive surgery following three courses of neoadjuvant chemotherapy in the management of unresectable ovarian cancer.
be addressed.
SUBJECTS AND METHODS
Since January 1979, 126 patients with FIG0 Stage III and IV primary ovarian cancer have been managed in our Ovarian Cancer Unit. Our fundamental management is primary cytoreductive surgery and then chemotherapy that is started within lo-14 days of the operation. Doses of 100 mg/m’ &-platinum and 750 mg/m’ cyclophosphamide are administered intravenously in sequence with intravenous hydration and diuresis on Day 1 of each 28day cycle. This combination is continued for six cycles and then two courses of 100 mg/m* c&platinum alone are given at 28-day cycles. Patients are then maintained on oral chlorambucil of 6 mg daily every 8 days of a 28day cycle for a further 6 months.
313 0090-82W91 $1.50 Copyright 0 1991 by Academic Press, Inc. All rights of reproduction in any form reserved.
314
GUIDOZZI
Despite all intentions to surgery at first operation been confronted with only first laparotomy, had truly
AND SONNENDECKER
perform optimal cytoreductive in the 126 patients, we have 3 patients who, at the time of unresectable tumor.
CASE 1 A 31-year-old female was admitted to our unit because of abdominal distension and a pelvic mass. Clinical examination, ultrasonography, and computed tomography confirmed not only the presence of a pelvic mass and ascites but extensive intra-abdominal metastatic disease. At the initial laparotomy, cytoreductive surgery was considered impossible because of an omental mass measuring 25 x 16 cm that was firmly adherent to stomach, anterior abdominal wall, and right lateral abdominal wall. This mass totally encased multiple loops of small bowel and would have required almost a total small bowel resection to attain bulk reduction. A biopsy only was taken and the ascitic fluid was drained and submitted for cytology. The presence of a poorly differentiated serous cystoadenocarcinoma with malignant cells in the ascitic fluid was confirmed. The patient was given our usual chemotherapy regime for three cycles only. Fourteen weeks after the first laparotomy, interval cytoreductive surgery to tumor masses less than 1.5 cm was achieved. The mass in the upper abdomen measured 15 x 7 cm. In order to resect the mass, approximately 8 cm of transverse colon, 20 cm of jejunum, and 3 x 3 cm of anterior abdominal wall rectus sheath and rectus muscle also had to be resected. A further six courses of chemotherapy (100 mg/m2 cisplatinum and 750 mg/m2 cyclophosphamide) at 2%day cycles was given and then the patient maintained on oral chlorambucil for six courses. She is alive and clinically free of disease 17 months after the first laparotomy. CASE 2 A 52-year-old female was referred to our unit because of marked ascites, a large pelvic mass, para-aortic lymphadenopathy, and two large abdominal masses. This had been confirmed on computed tomography. At the initial laparotomy, cytoreductive surgery was abandoned because of the two masses in the upper abdomen. One mass measuring 12 x 15 cm was firmly adherent to the anterior abdominal wall, liver capsule, and transverse colon. The other was an omental mass measuring 18 x 10 cm, fixed to the stomach, transverse colon, and spleen. A biopsy only was taken and the ascitic fluid was drained and sent for cytology. Histological and cytological examination confirmed the presence of a serous cystoadenocarcinoma with malignant cells in the ascites. She was given three courses of chemotherapy and read-
mitted and after a full bowel preparation interval primary cytoreductive surgery was performed. Both masses had decreased substantially. The mass in the right hypochondrium measured approximately 8 x 10 cm, but a tissue plane existed between it, the liver, and the anterior abdominal wall. The other mass measured approximately 12 x 6 cm and was fixed to transverse colon, although a tissue plane was present between it and the stomach. It was possible to strip it off the spleen without tearing the capsule. Fifteen centimeters of transverse colon and approximately twelve centimeters of rectosigmoid colon required resection to attain optimal cytoreduction. Six further courses of chemotherapy were given. This patient has survived 27 months, but has a 3 x 2-cm cystic accumulation of fluid on ultrasound in the left hypochondrium. Fine-needle aspiration has cytologically confirmed the presence of malignant cells consistent with the original pathology. Magnetic nuclear imaging failed to identify any evidence of recurrence. This patient is presently clinically well on single-agent maintenance chemotherapy.
CASE 3 A 64-year-old female was admitted to the medical unit of our hospital because of significant ascites. A pelvic examination revealed a large irregular mass, while a second mass was palpable in the left hypochrondrium. The patient was transferred to our unit. Our preoperative investigations and clinical examination confirmed the presence of very extensive metastatic disease, but in accordance with protocol, the patient was submitted to a laparotomy. Cytoreductive surgery was deemed impossible in view of a 22 x 15-cm mass in the left hypochondrium that was firmly adherent to the anterior and left lateral abdominal wall, stomach, transverse colon, and jejunum. The biopsy confirmed the presence of a serous cystoadenocarcinoma and cytological examination of the ascitic fluid revealed numerous malignant cells. Interval cytoreductive surgery followed three courses of chemotherapy. The mass had decreased in size and measured 14 x 9 cm. Resection of 4 x 4 cm of left lateral abdominal wall rectus sheath, 10 cm of transverse colon, and 8 cm of jejunum enabled us to successfully remove the mass. A tissue plane existed between the mass and the stomach. Six further courses of intravenous chemotherapy followed by six courses of oral chlorambucil were then given. This patient is alive and clinically free of disease 21 months since the first laparotomy. All three patients had as part of their cytoreductive surgery a total abdominal hysterectomy, bilateral salpingo-oophorectomy, appendectomy, and resection of any tumor with a diameter greater than 1.5 cm.
315
CASE REPORT
DISCUSSION Most of the literature that addresses the value of secondary surgery in the management of advanced ovarian cancer states that survival is not improved [4-lo]. The findings in these studies suggest that if a serious attempt at surgical cytoreduction has been made before initiation of chemotherapy, a second attempt by the surgeon during chemotherapy will not improve survival. Nevertheless Wiltshaw et al. [5] did show an apparent benefit in those patients who were subjected to secondary surgery who at the time of their primary surgery had less than a total abdominal hysterectomy and bilateral salpingo-oophorectomy but more than a biopsy. Einthorn et al. [ll] also showed that secondary surgery after chemotherapy or irradiation produced a survival similar to that of those patients in whom primary surgery satisfied the principles of cytoreductive surgery. It is well established that patients who begin first-line therapy with large tumor masses constitute a poor-prognosis group who have decreased response rates to chemotherapy, fewer complete clinical responses, and reduced survival compared to that of patients who begin treatment with small-volume disease [ 121. Skipper et al. [13] reported that, irrespective of the cell population initially present, the killing effect of the chemotherapeutic agents is a logarithmic function, and hence the larger the tumor volume prior to chemotherapy, the greater the number of cycles needed to irradicate the disease. A lengthy period of chemotherapy may accelerate the growth of a resistant population by stimulating the mutation rate [14]. Treatment failure is primarily the result of spontaneous mutation to drug-resistant cell lines; the larger the tumor mass, the more likely that it contains chemotherapy-resistant clones [15]. Furthermore, the Gruppo Interegionale Cooperativo Oncologico Ginecologia [16] have also shown that residual tumor size greater than 10 cm in diameter is associated with a low probability of overall response, while tumor deposits greater than 2 cm in diameter reduce the probability of complete response by three to eight times that achieved with a residual tumor deposit of less than 2 cm. It is not common in a gynecological oncology unit to be confronted with patients who have unresectable ovarian cancer. With special reference to our ovarian tumor unit, the majority of so-called inoperable cases have been due to lack of either diligence or experience on the part of the referring doctors. Sonnendecker and Beale [17] previously described the management of patients referred to our ovarian tumor unit with so-called inoperable cancer by gynecologists with no special interest in oncology. A 69% survival at 24 months was achieved in 13 patients who had second-attempt primary cytoreductive surgery followed by chemotherapy.
In the management of the three patients presented who were considered truly inoperable, we elected to give only three courses of chemotherapy to minimize the possible occurrence of drug resistance. Partial tumor regression was confirmed clinically prior to the second laparotomy and of paramount significance was the lack of recurrence of ascites during the first three courses of chemotherapy. The most striking features at laparotomy were tumor regression, mobility, and ability to identify tissue planes such that resection was possible. Neijt et al. [18] and Lawton et al. [19] have also suggested that this method of management may play a significant role in the management of these unfortunate patients, although in both of these studies the majority of the patients had been considered “inoperable” by referring gynecologists and not as in our case by the actual oncological surgeon. Our experience with this subset of patients supports the concept that initial debulking is not to be attempted at the first laparotomy in patients with unresectable ovarian cancer, but that successful interventional surgery can be instituted at the second laparotomy after three courses of aggressive combination chemotherapy, although we do not have a comparative cohort of patients in which only chemotherapy was given and the patients never subjected to cytoreductive surgery. However, in reference to the latter, despite the substantial regression of tumor in all three patients following the three courses of chemotherapy, significant disease, which in all three cases required radical surgery to attain optimal cytoreduction, was still present. In conclusion, we submit that three courses of neoadjuvant cisplatin-based chemotherapy followed by interventional definitive cytoreductive surgery is a modality of treatment that can be utilized in cases of truly unresectable ovarian cancer. REFERENCES Hoskins, W. J. The influence of cytoreductive surgery on progression-free interval and survival in epithelial ovarian cancer, Builliere’s Clin. Obstet. Gynaecol. 3, 1 59-69 (March 1989). Chen, S. S., and Bochner, R. Assessment of morbidity and mortality in primary cytoreductive surgery for advanced ovarian cancer, Gynecol. Oncol. 20, 190-195 (1985). Sonnendecker, E. W. W. Cancer of the ovary. The Johannesburg Hospital experience, South Afr. Med. J. 73, 713-715 (1988). Raju, K. S., McKinna, J. A., Barker, G. H., Wiltshaw, E., and Jones, J. M. Second-look operations in the planned management of advanced ovarian carcinoma, Am. J. Obstet. Gynecol. 144,650654 (1982). -. Wiltshaw, E., Raju, K. S., and Dawson, I. The role of cytoreductive surgery in advanced carcinoma of the ovary: An analysis of primary and secondary surgery, Br. J. Obstet. Gynaecol. 22,522-527 (1985). 6. Kottmeier, H. L. Radiotherapy in treatment of ovarian carcinoma, Clin. Obstet. Gynecol. 4, 865-868 (1961). 7. Philips, B. P., Buchsbaum, H. J., and Lifshiftz, S. Reexploration
316
GUIDOZZI
AND SONNENDECKER
after treatment for ovarian carcinoma, Gynecol. Oncol. 8,339-342 (1977). 8. Kjorstad, K. E., Welander, S., and Kolstad, P. Pre-operative irradiation in stage III carcinoma of the ovary, Actu Obsret. Gynecol. Scund. 56, 449 (1977). 9. Neijt, J. P., ten Bokkel-Huinink, W. W., van der Burg, M. E. L., van Oosterom, A. T., Willemse, P. H. B., Heintz, A. P. M., van Lent, M., Trimbos, J. B., Bouma, J., Vermoken, J. B., and Van Houwelingen, J. C. Randomized trial comparing two combination chemotherapy regimens (CHAP-5 vs CP) in advanced ovarian carcinoma, J. Clin. Oncol. 5, 1157-1168 (1987). 10. Come, P. F., Sertoli, M. R., Bruzzone, M., Rubagotti, A. M., Rosso, R., Bentivoglio, G., Conio, A., and Pescetto, G. Cisplatin, methotrexate and 5fluorouracil combination chemotherapy for advanced ovarian cancer, Gynecol. Oncol. 20, 290-297 (1985). 11. Einthom, N., Nilsson, B. O., and SjBvall, K. Factors influencing survival in carcinoma of the ovary, Cuncer 55, 2019-2025 (1985). 12. Ng, L. W., Rubin, S. C., Hoskins, W. J., Jones, W. B., Hakes, T. B., Markman, M., Reichman, B., Almadrones, L., and Lewis, J. L. Aggressive chemosurgical debulking in patients with advanced ovarian cancer, Gynecol. Oncol. 38, 358-363 (1990). 13. Skipper, H. E., Schabel, F. M., and Wilcox, W. S. Experimental evaluation of potential anticancer agents XII: On the criteria and
14. 15.
16.
17.
18.
19.
kinetics associated with “curability” of experimental leukemia, Cancer Chemother. Rep. 35, 1 (1964). De Vita, V. T. Cell kinetics and the chemotherapy of cancer, Cancer Chemother. Rep. 3, 23 (1971). Goldie, J. H., and Goldman, A. J. A mathematic model for relating the drug sensitivity of tumors to their spontaneous mutation rate, Cancer Treat. Rep. 63, 1727 (1979). Gruppo Interegionale Cooperativo Oncologico Ginecologia. Randomised comparison of cisplatin with cyclophosphamide/cisplatin and with cyclophosphamide/doxorubicin/cisplatin in advanced ovarian cancer, Lancet, 353-359 (August 1987). Sonnendecker, E. W. W., and Beale, P. Radical surgery in patients referred with a diagnosis of unresectable ovarian cancer, 5. Afr. Med. J. 71, 621-625 (1987). Neijt, J. P., ten Bokkel-Huinink, W. W., van der Burg, M. E. L., van Oosterom, A. T., Willemse, P. H. B., Heintz, A. P. M., van Lent, M., Trimbos, J. B., Bouma, J., Vermoken, J. B., and Van Houwelingen, J. C. Randomized trial comparing two combination chemotherapy regimens (Hexa-CAF vs CHAP-5) in advanced ovarian carcinoma, Lancet ii, 594-600 (1984). Lawton, F. G., Redman, C. W. E., Luesley, D. M., Chan, K. K., and Blackledge, G. Neoadjuvant (cytoreductive) chemotherapy combined with interventional debulking surgery in advanced, unresectable epithelial ovarian cancer, Obstet. Gynecof. 73, 61-65 (1989).
ONCOLOGY
43, 313-316 (1991)
CASE REPORT Three Cycles of Chemotherapy Followed by Primary Cytoreductive Surgery for Unresectable Ovarian Cancer FRANCO GUIDOZZI, M.B.B.CH., Department
of Obstetrics
MRCOG,’ and Gynecology, Parktown,
AND ERNST W. W. SONNENDECKER, University of the Witwatersrand, 2193 Johannesburg, South Africa Received
May
Definitive primary cytoreductive surgery was achievedat setond laparotomy after three cycles of combinationchemotherapy (cisplatinand cyclophosphamide) in three patientswho presented with unresectable disease at our Ovarian Tumor Unit. The ovarian cancer was inoperableat the first laparotomy and no surgical procedurewas performedother than biopsy of malignanttumor to coniirm the diagnosis.Following interventional surgical cytoreduction the patientswere given a further six coursesof combination chemotherapyand then maintained for a further six cycleson oral chlorambucil.Two patients are diseasefree at 17 and 21 months, respectively, while the other patient has cytological evidenceof malignancybut no other clinically detectable tumor depositsat 27 months. o 191A=demic PI=, IK.
INTRODUCTION
Primary cytoreductive surgery that eliminates all tumor deposits having a diameter of greater than 1.5 cm followed by chemotherapy is still the cornerstone in the management of ovarian cancer. Radical resection of the tumor insult provides an initial exponential decrease in tumor bulk that will then allow ultimate irradication of remaining tumor deposits that are likely to be more sensitive to chemotherapy [l]. Although Chen and Bochner [2] have stated that optimal debulking can be achieved in 97.9% of cases by a gynecological oncologist, it is not always possible preoperatively to predict which patients have such extensive disease that the skill of the surgeon is not sufficient to ensure optimal primary cytoreduction of tumor deposits. It is policy in our Ovarian Tumor Clinic at the Johannesburg Hospital to subject all our patients to primary ’ To whom
reprint
requests
should
Medical
M.MED., FICS, FRCOG School,
7 York
Road,
2, 1991
cytoreductive surgery irrespective of staging and preoperative findings, as we firmly believe that determining the strategy of the radical debmking can take place only at the time of the laparotomy [3]. Optimal cytoreduction of all the tumors operated on in our unit has been achieved in 81% of 168 patients, and where it was not achieved it was because of large diaphragmatic, hepatic, anterior abdominal wall, or inaccessible tumor masses. In no patient was pelvic disease the reason for inadequate debulking. Against this background we present our management of three cases where at the time of laparotomy the extent of the disease precluded the benefits of optimal primary aggressive cytoreduction as it was adjudged that the morbidity and possible mortality would be unacceptable. These cases highlight the value of interval primary cytoreductive surgery following three courses of neoadjuvant chemotherapy in the management of unresectable ovarian cancer.
be addressed.
SUBJECTS AND METHODS
Since January 1979, 126 patients with FIG0 Stage III and IV primary ovarian cancer have been managed in our Ovarian Cancer Unit. Our fundamental management is primary cytoreductive surgery and then chemotherapy that is started within lo-14 days of the operation. Doses of 100 mg/m’ &-platinum and 750 mg/m’ cyclophosphamide are administered intravenously in sequence with intravenous hydration and diuresis on Day 1 of each 28day cycle. This combination is continued for six cycles and then two courses of 100 mg/m* c&platinum alone are given at 28-day cycles. Patients are then maintained on oral chlorambucil of 6 mg daily every 8 days of a 28day cycle for a further 6 months.
313 0090-82W91 $1.50 Copyright 0 1991 by Academic Press, Inc. All rights of reproduction in any form reserved.
314
GUIDOZZI
Despite all intentions to surgery at first operation been confronted with only first laparotomy, had truly
AND SONNENDECKER
perform optimal cytoreductive in the 126 patients, we have 3 patients who, at the time of unresectable tumor.
CASE 1 A 31-year-old female was admitted to our unit because of abdominal distension and a pelvic mass. Clinical examination, ultrasonography, and computed tomography confirmed not only the presence of a pelvic mass and ascites but extensive intra-abdominal metastatic disease. At the initial laparotomy, cytoreductive surgery was considered impossible because of an omental mass measuring 25 x 16 cm that was firmly adherent to stomach, anterior abdominal wall, and right lateral abdominal wall. This mass totally encased multiple loops of small bowel and would have required almost a total small bowel resection to attain bulk reduction. A biopsy only was taken and the ascitic fluid was drained and submitted for cytology. The presence of a poorly differentiated serous cystoadenocarcinoma with malignant cells in the ascitic fluid was confirmed. The patient was given our usual chemotherapy regime for three cycles only. Fourteen weeks after the first laparotomy, interval cytoreductive surgery to tumor masses less than 1.5 cm was achieved. The mass in the upper abdomen measured 15 x 7 cm. In order to resect the mass, approximately 8 cm of transverse colon, 20 cm of jejunum, and 3 x 3 cm of anterior abdominal wall rectus sheath and rectus muscle also had to be resected. A further six courses of chemotherapy (100 mg/m2 cisplatinum and 750 mg/m2 cyclophosphamide) at 2%day cycles was given and then the patient maintained on oral chlorambucil for six courses. She is alive and clinically free of disease 17 months after the first laparotomy. CASE 2 A 52-year-old female was referred to our unit because of marked ascites, a large pelvic mass, para-aortic lymphadenopathy, and two large abdominal masses. This had been confirmed on computed tomography. At the initial laparotomy, cytoreductive surgery was abandoned because of the two masses in the upper abdomen. One mass measuring 12 x 15 cm was firmly adherent to the anterior abdominal wall, liver capsule, and transverse colon. The other was an omental mass measuring 18 x 10 cm, fixed to the stomach, transverse colon, and spleen. A biopsy only was taken and the ascitic fluid was drained and sent for cytology. Histological and cytological examination confirmed the presence of a serous cystoadenocarcinoma with malignant cells in the ascites. She was given three courses of chemotherapy and read-
mitted and after a full bowel preparation interval primary cytoreductive surgery was performed. Both masses had decreased substantially. The mass in the right hypochondrium measured approximately 8 x 10 cm, but a tissue plane existed between it, the liver, and the anterior abdominal wall. The other mass measured approximately 12 x 6 cm and was fixed to transverse colon, although a tissue plane was present between it and the stomach. It was possible to strip it off the spleen without tearing the capsule. Fifteen centimeters of transverse colon and approximately twelve centimeters of rectosigmoid colon required resection to attain optimal cytoreduction. Six further courses of chemotherapy were given. This patient has survived 27 months, but has a 3 x 2-cm cystic accumulation of fluid on ultrasound in the left hypochondrium. Fine-needle aspiration has cytologically confirmed the presence of malignant cells consistent with the original pathology. Magnetic nuclear imaging failed to identify any evidence of recurrence. This patient is presently clinically well on single-agent maintenance chemotherapy.
CASE 3 A 64-year-old female was admitted to the medical unit of our hospital because of significant ascites. A pelvic examination revealed a large irregular mass, while a second mass was palpable in the left hypochrondrium. The patient was transferred to our unit. Our preoperative investigations and clinical examination confirmed the presence of very extensive metastatic disease, but in accordance with protocol, the patient was submitted to a laparotomy. Cytoreductive surgery was deemed impossible in view of a 22 x 15-cm mass in the left hypochondrium that was firmly adherent to the anterior and left lateral abdominal wall, stomach, transverse colon, and jejunum. The biopsy confirmed the presence of a serous cystoadenocarcinoma and cytological examination of the ascitic fluid revealed numerous malignant cells. Interval cytoreductive surgery followed three courses of chemotherapy. The mass had decreased in size and measured 14 x 9 cm. Resection of 4 x 4 cm of left lateral abdominal wall rectus sheath, 10 cm of transverse colon, and 8 cm of jejunum enabled us to successfully remove the mass. A tissue plane existed between the mass and the stomach. Six further courses of intravenous chemotherapy followed by six courses of oral chlorambucil were then given. This patient is alive and clinically free of disease 21 months since the first laparotomy. All three patients had as part of their cytoreductive surgery a total abdominal hysterectomy, bilateral salpingo-oophorectomy, appendectomy, and resection of any tumor with a diameter greater than 1.5 cm.
315
CASE REPORT
DISCUSSION Most of the literature that addresses the value of secondary surgery in the management of advanced ovarian cancer states that survival is not improved [4-lo]. The findings in these studies suggest that if a serious attempt at surgical cytoreduction has been made before initiation of chemotherapy, a second attempt by the surgeon during chemotherapy will not improve survival. Nevertheless Wiltshaw et al. [5] did show an apparent benefit in those patients who were subjected to secondary surgery who at the time of their primary surgery had less than a total abdominal hysterectomy and bilateral salpingo-oophorectomy but more than a biopsy. Einthorn et al. [ll] also showed that secondary surgery after chemotherapy or irradiation produced a survival similar to that of those patients in whom primary surgery satisfied the principles of cytoreductive surgery. It is well established that patients who begin first-line therapy with large tumor masses constitute a poor-prognosis group who have decreased response rates to chemotherapy, fewer complete clinical responses, and reduced survival compared to that of patients who begin treatment with small-volume disease [ 121. Skipper et al. [13] reported that, irrespective of the cell population initially present, the killing effect of the chemotherapeutic agents is a logarithmic function, and hence the larger the tumor volume prior to chemotherapy, the greater the number of cycles needed to irradicate the disease. A lengthy period of chemotherapy may accelerate the growth of a resistant population by stimulating the mutation rate [14]. Treatment failure is primarily the result of spontaneous mutation to drug-resistant cell lines; the larger the tumor mass, the more likely that it contains chemotherapy-resistant clones [15]. Furthermore, the Gruppo Interegionale Cooperativo Oncologico Ginecologia [16] have also shown that residual tumor size greater than 10 cm in diameter is associated with a low probability of overall response, while tumor deposits greater than 2 cm in diameter reduce the probability of complete response by three to eight times that achieved with a residual tumor deposit of less than 2 cm. It is not common in a gynecological oncology unit to be confronted with patients who have unresectable ovarian cancer. With special reference to our ovarian tumor unit, the majority of so-called inoperable cases have been due to lack of either diligence or experience on the part of the referring doctors. Sonnendecker and Beale [17] previously described the management of patients referred to our ovarian tumor unit with so-called inoperable cancer by gynecologists with no special interest in oncology. A 69% survival at 24 months was achieved in 13 patients who had second-attempt primary cytoreductive surgery followed by chemotherapy.
In the management of the three patients presented who were considered truly inoperable, we elected to give only three courses of chemotherapy to minimize the possible occurrence of drug resistance. Partial tumor regression was confirmed clinically prior to the second laparotomy and of paramount significance was the lack of recurrence of ascites during the first three courses of chemotherapy. The most striking features at laparotomy were tumor regression, mobility, and ability to identify tissue planes such that resection was possible. Neijt et al. [18] and Lawton et al. [19] have also suggested that this method of management may play a significant role in the management of these unfortunate patients, although in both of these studies the majority of the patients had been considered “inoperable” by referring gynecologists and not as in our case by the actual oncological surgeon. Our experience with this subset of patients supports the concept that initial debulking is not to be attempted at the first laparotomy in patients with unresectable ovarian cancer, but that successful interventional surgery can be instituted at the second laparotomy after three courses of aggressive combination chemotherapy, although we do not have a comparative cohort of patients in which only chemotherapy was given and the patients never subjected to cytoreductive surgery. However, in reference to the latter, despite the substantial regression of tumor in all three patients following the three courses of chemotherapy, significant disease, which in all three cases required radical surgery to attain optimal cytoreduction, was still present. In conclusion, we submit that three courses of neoadjuvant cisplatin-based chemotherapy followed by interventional definitive cytoreductive surgery is a modality of treatment that can be utilized in cases of truly unresectable ovarian cancer. REFERENCES Hoskins, W. J. The influence of cytoreductive surgery on progression-free interval and survival in epithelial ovarian cancer, Builliere’s Clin. Obstet. Gynaecol. 3, 1 59-69 (March 1989). Chen, S. S., and Bochner, R. Assessment of morbidity and mortality in primary cytoreductive surgery for advanced ovarian cancer, Gynecol. Oncol. 20, 190-195 (1985). Sonnendecker, E. W. W. Cancer of the ovary. The Johannesburg Hospital experience, South Afr. Med. J. 73, 713-715 (1988). Raju, K. S., McKinna, J. A., Barker, G. H., Wiltshaw, E., and Jones, J. M. Second-look operations in the planned management of advanced ovarian carcinoma, Am. J. Obstet. Gynecol. 144,650654 (1982). -. Wiltshaw, E., Raju, K. S., and Dawson, I. The role of cytoreductive surgery in advanced carcinoma of the ovary: An analysis of primary and secondary surgery, Br. J. Obstet. Gynaecol. 22,522-527 (1985). 6. Kottmeier, H. L. Radiotherapy in treatment of ovarian carcinoma, Clin. Obstet. Gynecol. 4, 865-868 (1961). 7. Philips, B. P., Buchsbaum, H. J., and Lifshiftz, S. Reexploration
316
GUIDOZZI
AND SONNENDECKER
after treatment for ovarian carcinoma, Gynecol. Oncol. 8,339-342 (1977). 8. Kjorstad, K. E., Welander, S., and Kolstad, P. Pre-operative irradiation in stage III carcinoma of the ovary, Actu Obsret. Gynecol. Scund. 56, 449 (1977). 9. Neijt, J. P., ten Bokkel-Huinink, W. W., van der Burg, M. E. L., van Oosterom, A. T., Willemse, P. H. B., Heintz, A. P. M., van Lent, M., Trimbos, J. B., Bouma, J., Vermoken, J. B., and Van Houwelingen, J. C. Randomized trial comparing two combination chemotherapy regimens (CHAP-5 vs CP) in advanced ovarian carcinoma, J. Clin. Oncol. 5, 1157-1168 (1987). 10. Come, P. F., Sertoli, M. R., Bruzzone, M., Rubagotti, A. M., Rosso, R., Bentivoglio, G., Conio, A., and Pescetto, G. Cisplatin, methotrexate and 5fluorouracil combination chemotherapy for advanced ovarian cancer, Gynecol. Oncol. 20, 290-297 (1985). 11. Einthom, N., Nilsson, B. O., and SjBvall, K. Factors influencing survival in carcinoma of the ovary, Cuncer 55, 2019-2025 (1985). 12. Ng, L. W., Rubin, S. C., Hoskins, W. J., Jones, W. B., Hakes, T. B., Markman, M., Reichman, B., Almadrones, L., and Lewis, J. L. Aggressive chemosurgical debulking in patients with advanced ovarian cancer, Gynecol. Oncol. 38, 358-363 (1990). 13. Skipper, H. E., Schabel, F. M., and Wilcox, W. S. Experimental evaluation of potential anticancer agents XII: On the criteria and
14. 15.
16.
17.
18.
19.
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