Laparotomy for post chemotherapy residue in ovarian germ cell tumorsGK Mathew, SS Singh, RG Swaminathan, SG Tenali
Departments of Medical Oncology and Pathology, Cancer Institute (WIA), 18, Sardar Patel Road, Chennai - 600 036, India
Correspondence Address: Source of Support: None, Conflict of Interest: None PMID: 17102543
Source of Support: None, Conflict of Interest: None
Background : Primary conservative surgery and cisplatin-based chemotherapy have resulted in high cure ratesin malignant ovarian germ cell tumors. A significant proportion of advanced tumors may have post-chemotherapyresidue and it is important to distinguish necrosis or fibrosis without viable tumor from persistent viable tumorand teratoma. Aims : To evaluate the role of laparotomy in assessing the nature of post-chemotherapy residue in ovariangerm cell tumors. Materials and Methods : Eighty-three patients with malignant ovarian germ cell tumors seen at Cancer Institute,Chennai between 1992 and 2002 were studied. Sixty-eight patients completed combination chemotherapywith cisplatin regimes, of whom 35 had radiological residual masses. Twenty-nine out of these 35 patientsunderwent laparotomy to assess the nature of the residue. Results : On laparotomy, three patients had viable tumor, seven immature teratoma, three mature teratomaand 16 only necrosis or fibrosis. None of our patients with dysgerminoma, embryonal carcinoma, absence ofteratoma element in the primary tumor and radiological residue of <5 cm had viable tumor whereas all patientswith tumors containing teratoma component initially had residual tumor. Absence of viable disease was higherin patients who had normalization of serum markers by two cycles of chemotherapy. Conclusion : Our study suggests that patients with absence of teratoma element initially, radiological residue of<5 cm and normalization of serum markers after two cycles of chemotherapy do not require surgery to assessthe nature of post-chemotherapy residue. However, laparotomy should be performed in patients with tumorsthat initially contain teratoma element and in those with sluggish tumor marker response after two cycles ofchemotherapy since they have a high chance of having viable postchemotherapy residue.
Keywords: Laparotomy, ovarian germ cell tumor, post-chemotherapy residue
Ovarian germ cell tumors though less common than their epithelial counterparts, are highly curable malignancies which affect young women of childbearing potential. They usually present in early stages and fertility-preserving surgery followed by adjuvant chemotherapy is considered standard of care.,
Surgical principles in the management of ovarian germ cell tumors have been extrapolated from experiences gathered from epithelial ovarian malignancies, while the principles of chemotherapy have evolved from numerous trials conducted in testicular germ cell tumors. Chemotherapy with cisplatin-based combination regimes are used, with the bleomycin, etoposide, cisplatin (BEP) regime producing high response rates in advanced and metastatic disease and cure rates of above 90% when used as adjuvant. Postchemotherapy residual disease is a common scenario in testicular germ cell tumors and definite recommendations regarding their management exist. From the experience gained from testicular germ cell tumors, laparotomy may be required to assess the nature of the residual masses. These masses may be only necrosis or fibrosis, mature teratoma, immature teratoma or viable tumor and their status is crucial in planning further management .
Primary chemotherapy is not widely practiced in ovarian germ cell tumors as most patients have early stage disease amenable to optimal surgery, while the approach to postchemotherapy residual masses is still to be defined. The impact of laparotomy for postchemotherapy residue on patient management is still unclear.,,, Though there has been a study on the role of aggressive cytoreductive surgery for nondysgerminomatous tumors, this is the first Indian study to our knowledge on the role of laparotomy for postchemotherapy residue in ovarian germ cell tumors.
All patients with histologically proven germ cell tumor of the ovary who reported to the Cancer Institute (W.I.A.), Adyar, Chennai from January 1992 to December 2002 were included in this study.
An attempt at a pathologic diagnosis was made for all patients. All patients underwent primary conservative surgery, if feasible. After a complete staging workup, either by laparotomy or by CT scan and serum tumor markers, the tumors were staged according to the FIGO classification system for ovarian malignancies. A complete staging laparotomy similar to that described for epithelial ovarian cancer was done for most patients, with preservation of opposite ovary and uterus whenever possible. A complete resection of the pelvic residue was attempted with bilateral pelvic and paraaortic nodal sampling. Ascitic fluid or peritoneal washings were collected for cytology and multiple peritoneal biopsies were taken. If there was a retroperitoneal residue, bilateral pelvic lymph node sampling and infrahilar retroperitoneal lymphnode dissection was done. If a grossly enlarged contralateral ovary was present, ovarian cystectomy was done.
All patients had the levels of alfa feto protein (AFP) and beta human chorionic gonadotropin assessed serially throughout treatment and during follow-up.
Some patients with early stage dysgerminoma after initial optimal surgery were kept on surveillance. All patients with nondysgerminomatous tumors and advanced stage dysgerminoma received combination chemotherapy with cisplatin-based regimes- bleomycin, etoposide, cisplatin (BEP) / etoposide, cisplatin (EP) or vinblastine, ifosfamide, cisplatin (VeIP) for three to four cycles. Bleomycin was omitted after the third cycle to minimize the chance of pulmonary toxicity. All patients who received cisplatin-based chemotherapy had clinical, radiological and biochemical response assessment after every two cycles and at the end of chemotherapy. Those with residual radiological masses were taken up for laparotomy to determine the nature of residue.
Chemotherapy with cisplatin-based regime, either EP or VeIP was given for two or three cycles if viable disease or immature teratoma was detected on laparotomy. After completion of therapy, patients were followed up every two months for two years and at gradually increasing intervals thereafter. Relapses were documented and survival was measured from time of diagnosis to time of death or on May 31, 2005.
Eighty-three patients with histology proven ovarian germ cell tumors were treated at the institute in the 11-year period. Thirty patients had dysgerminoma, 16 patients had immature teratoma, 2 had embyonal carcinoma, 12 had yolk sac tumor and 23 patients had mixed germ cell tumors. AFP was elevated in 37 patients while BHCG was elevated in 23 patients initially. Thirty-four patients had no documented marker elevation at presentation [Table - 1]. Thirteen patients underwent primary optimal surgery (cytoreduction of all visible disease to < 2cm residue). The remaining 70 patients who had either suboptimal surgery or had advanced disease which precluded primary surgery were taken up for chemotherapy. Five out of the 13 patients who had undergone primary surgery were also taken up for chemotherapy.
Out of the 75 who were taken up for chemotherapy, seven patients defaulted and only 68 completed chemotherapy. Thirty-five out of the 68 patients who completed chemotherapy had radiological residual intraabdominal masses. Of these, 30 patients had Stage III or IV disease initially. Eleven of them had teratoma, eight each had dysgerminoma, yolk sac tumor and mixed germ cell tumor [Table - 2]. Only 29 patients with radiological residue underwent laparotomy for assessing the nature of postchemotherapy residuum. Out of the six patients who did not undergo laparotomy two had refused surgery, two had extensive disease not amenable to surgery, one patient with dysgerminoma (1.3 cm residue) was advised close observation and one patient (3 cm residue) received radiotherapy as she was not keen on surgery. All are alive except two patients with immature teratomatous element who defaulted chemotherapy, progressed on treatment hence were not suitable for laparotomy and died later.
Histopathological examination of the residual masses in the 29 patients who underwent laparotomy revealed only necrosis or fibrosis in 16 patients, immature teratoma in 7 patients, mature teratoma in 3 and viable tumor in 3 patients [Table - 3]. All the three patients with viable tumor had Stage III disease initially, while six of the patients with immature teratoma had Stage III and one of them had IIB disease. Fourteen out of 17 patients with teratomatous elements who had completed chemotherapy had residual masses. Of these, 11 patients underwent laparotomy out of which 8 had immature teratoma or viable disease. None of the 7 patients with dysgerminoma had viable tumor on laparotomy. Only one out of 7 patients with endodermal sinus tumor who had elevated marker before surgery was found to have viable residue.
None of the 17 patients who had normalization of serum tumor markers after two cycles of chemotherapy had residual viable tumor. Eight out of 12 patients who continued to have raised serum markers after two cycles of chemotherapy had viable residue at surgery. Of the 10 patients who had elevated markers after two cycles of chemotherapy which normalized by four cycles, two had viable disease and five had immature teratoma. Five patients had raised markers before laparotomy out of which three had viable disease and one had immature teratoma [Table - 4].
Size of the residual tumor by radiological assessment was significant in that, none of the residual tumors less than 5 cm in largest diameter had viable tumor. Of the five tumor masses more than 10 cm in size, two had viable tumor, two had immature teratoma and one had mature teratoma [Table - 5]. The three patients who had viable residual disease and six of the seven patients with immature teratoma at laparotomy received salvage chemotherapy, which consisted of VeIP or EP for two to three cycles. All of them are alive with no evidence of disease at present. The patient with immature teratoma who did not receive postoperative chemotherapy expired within one year due to progressive disease. All patients with mature teratoma or necrosis in postchemotherapy residue are alive with no documented relapse.
Out of the 68 patients who completed chemotherapy, 33 had a complete response and did not undergo laparotomy. Only one patient had a late relapse. She had immature teratoma, relapsed with skeletal metastasis, received salvage chemotherapy and radiation and continues to be free of disease.
Malignant ovarian germ cell tumors in most series present in early stages of disease. Primary conservative surgery with comprehensive staging laparotomy and surgical cytoreduction of advanced disease, followed by prompt institution of adjuvant cisplatin-based combination chemotherapy have resulted in high cure rates in this disease.,, The role of laparotomy for postchemotherapy residue in ovarian germ cell tumors is in a state of evolution. The type of operative procedure in this setting is dictated by initial disease status, histology and operative findings, with fertility preservation always considered a desirable end point. In the studies about second look laparotomy for ovarian germ cell tumors, the patients who had initial complete resection of the tumor, with no teratomatous element and clinically no postchemotherapy residue with normal tumor markers were not found to benefit from the procedure.,,,,
In contrast to published data, 65.8% of patients in our series reported with Stage III or IV disease. As the majority of our patients had advanced disease at presentation, it was considered desirable to start chemotherapy initially so as to avoid major organ resection and also to facilitate preservation of fertility. Exploratory laparotomy has been reported to have a definite role in the management of all patients with postchemotherapy residue (who did not have an optimal surgery initially). In our study, laparotomy was not found to be beneficial in tumors without teratomatous component, <5 cm size of postchemotherapy residue and normalization of tumor markers after two cycles of chemotherapy.
Dysgerminomas are exquisitely chemosensitive and the persistence of residual viable tumor after completion of optimal chemotherapy is a rarity., None of the patients in our series with dysgerminoma or embryonal carcinoma had residual viable disease. It can be said with reasonable degree of certainty that if the initial disease is dysgerminoma or embryonal carcinoma the possibility of existing viable tumor is extremely rare after complete surgery and adequate combination chemotherapy and if markers are normal after two cycles chemotherapy.
In teratomas, residual immature teratoma or retroconversion to mature teratoma are possible. Residual mature teratoma should be resected as they may produce 'growing teratoma syndrome' with obstructive features as happened in one of our patients. The dedifferentiation of any of the elements of teratoma to malignancy, though rare, is to be expected if they are not resected completely. In most series, benefit of second look laparotomy was in the subgroup of patients with incompletely resected teratoma.,,, Some of the studies in testicular germ cell tumors also suggest that completely resected immature teratoma may not warrant any adjuvant chemotherapy as the chance of relapse is 5-10%. Little information regarding the biology of postchemotherapy ovarian immature teratoma is available., However, the presence of immature teratomatous elements, size of residue, initial marker elevation, especially that of AFP and marker level before surgery seemed to have a bearing on the presence of viable tumor or immature teratoma in the postchemotherapy residue.
In testicular germ cell tumors the value of LDH in staging has been proven. It indicates the burden of disease. It has no role to play in predicting the presence or absence of residual disease. This information is presently being extrapolated to ovarian germ cell tumors and hence it is not mandatory to do LDH for presence or absence of residue.
Earlier studies have shown that patients who underwent complete resection prior to treatment may have a better five-year survival of 94% than patients whose tumors had been incompletely resected with a survival of 50%. In advanced ovarian germ cell tumors treated with cisplatin, vinblastine, bleomycin (PVB) regime the disease-free survival improved in patients who were started on chemotherapy with nonmeasurable disease compared to patients with measurable disease. This observation has not been seen in our series, where most patients could not undergo a complete surgery initially due to the advanced nature of the disease and this was not reflected by a decrease in survival after optimal chemotherapy followed by surgery. It may be that the inherent nature and stage of the disease which had precluded complete surgery initially, may have contributed to the poorer survival rather than incompleteness of primary surgery itself. With the advent of effective combination chemotherapeutic schedules, the prognostic impact of initial optimal surgery may have lost its significance.
Presence of postchemotherapy viable tumor or immature teratoma did not affect survival in our patients, probably due to the aggressive salvage chemotherapy given. But the sole patient who did not receive second line chemotherapy for immature teratoma relapsed and died.
Ovarian germ cell tumors have high cure rates with conservative surgery if feasible or with cisplatin chemotherapy and resection of residual masses if present followed by salvage chemotherapy when viable tumor or immature teratoma is present. Unlike the western world most of our patients presented with advanced tumors probably due to the late presentation. Due to the rarity of germ cell tumors the number of patients in our study is small to have statistical significance. However, it can be inferred with reasonable confidence that the presence of viable postchemotherapy residue in patients with dysgerminoma and embryonal carcinoma and those with radiological size of < 5 cm is rare. We recommend that patients in the above subgroup be followed up instead of laparotomy. If teratomatous elements are present in the initial tumor, then surgery is indicated to diagnose the nature of postchemotherapy residue and plan further treatment.
[Table - 1], [Table - 2], [Table - 3], [Table - 4], [Table - 5]