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doi:10.1111/jog.12460
J. Obstet. Gynaecol. Res. Vol. 40, No. 9: 2066–2075, September 2014
Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for management of recurrent/relapsed ovarian granulosa cell tumor: A single-center experience Ismail A. Al-Badawi1,2, Ahmed Abu-Zaid1,2, Ayman Azzam3,4, Osama AlOmar1, Hamed AlHusaini3 and Tarek Amin3 1
Department of Obstetrics and Gynecology, 3Oncology Center, King Faisal Specialist Hospital and Research Center, 2College of Medicine, Alfaisal University, Riyadh, Saudi Arabia; and 4Faculty of Medicine, Alexandria University, Alexandria, Egypt
Abstract Aim: The aim of this study was to retrospectively report our experience (efficacy/morbidity) with cytoreductive surgery+hyperthermic intraperitoneal chemotherapy (CRS+HIPEC) for the management of recurrent/relapsed ovarian granulosa cell tumors (OGCT). Material and Methods: From 2010 to 2013, six patients underwent CRS+HIPEC. CRS was performed with standard peritonectomy procedures and visceral resections directed towards complete elimination of tumors from the abdominopelvic cavity. HIPEC was performed with cisplatin (50 mg/m2) and doxorubicin (15 mg/ m2) and allowed to circulate in the abdominopelvic cavity for 90 min at 41.0–42.2°C. Results: Cytoreduction completeness (CC-0) was achieved in all except one patient (CC-1). Five patients had OGCT recurrences in abdomen+pelvis and one patient in abdomen only. No grade V morbidity (Clavien– Dindo classification) occurred. Two patients developed lung atelectasis, which was managed by mere chest physiotherapy (grade I). One patient developed urinary tract infection (grade II) and another patient developed pneumonia (grade II) – both of which were managed by antibiotics. One patient developed splenic bed and anterior abdominal wall collections requiring ultrasound-guided aspiration without general anesthesia (grade III). One patient developed pulmonary embolism requiring intensive care-unit management (grade IV). Four chemo-naïve patients received adjuvant chemotherapy whereas the remaining two previously chemoexposed patients received no adjuvant therapy. All patients were alive and disease-free without proof of recurrence/relapse at 40, 32, 27, 24, 20 and 16 months. The average interval of follow-up after CRS+HIPEC was roughly 27 months (range: 16–40 months). Conclusion: CRS+HIPEC appears to be an efficacious and morbidly well-tolerated therapeutic modality for recurrent/relapsed OGCT. Long-term follow-up data and further research are needed. Key words: cytoreductive surgery, hyperthermic intraperitoneal chemotherapy, ovarian granulosa cell tumor.
Introduction Ovarian granulosa cell tumors (OGCT) are quite infrequent neoplasms accounting for roughly 70% of ovarian sex cord-stromal tumors and 2–5% of all
ovarian neoplasms.1 The natural biological behavior of OGCT is unique. OGCT are characterized by clinically indolent course, slow-paced tumor growth and increased propensity for late recurrence.2–4 Recurrences of OGCT most commonly happen between 5 and 30
Received: January 28 2014. Accepted: March 31 2014. Reprint request to: Dr Ismail A. Al-Badawi, Gynecologic Oncology, Department of Obstetrics and Gynecology, MBC-52, King Faisal Specialist Hospital and Research Centre, P.O. Box 3354, Riyadh 11211, Saudi Arabia. Email: [email protected]
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years following the initial management.5 To date, the longest time to recurrence of an OGCT documented in the published work is 40 years following initial treatment.6 Prognosis of patients with recurrent OGCT largely signifies unfavorable outcomes.7 There are no universally approved guidelines for the management of recurrent OGCT.7,8 Complete surgical debulking – with or without adjuvant chemotherapy – is the standard of care management, and has been shown to yield longer survival rates.9 The benefit of adjuvant chemotherapy is still questionable, and the bleomycin, etoposide and cisplatin (BEP) combination has emerged as the best active chemotherapeutic regimen.10 Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) have revealed fortunate, favorable and promising outcomes in the management of advanced and recurrent epithelial ovarian cancers.11,12 Use of CRS and HIPEC for the management of recurrent OGCT is very limited. The objective of this study was to report our experience (efficacy and morbidity) with CRS and HIPEC for the management of recurrent/relapsed OGCT.
Methods The study took place at King Faisal Specialist Hospital and Research Center (KFSH&RC), Riyadh, Saudi Arabia – a tertiary health care institute. From November 2010 to September 2013, all patients with recurrent OGCT managed by CRS and HIPEC were retrospectively analyzed. Approval of the Research Advisory Council was obtained to publish this research work. In our institute, intraoperative administration of HIPEC is optional. Patients were informed in detail about the current literature, benefits and risks of undergoing the standard treatment (CRS plus/minus postoperative chemotherapy) or the optional treatment (CRS plus HIPEC plus/minus postoperative chemotherapy). Afterwards, patients were requested to sign a written consent regarding the desired treatment option. Inclusion criteria for considering CRS and HIPEC included: (i) age below 75 years; (ii) Karnofsky performance status more than 50%; (iii) satisfactory hematological, hepatic, coagulation, renal and electrolyte profiles; (iv) proven diagnosis of recurrent OGCT confirmed by imaging modality and/or intraoperative biopsy; (v) no evidence of distant OGCT metastatic foci to brain, lungs or bones; and (vi) signed written informed consent by patients.
All operations were carried out by the same surgeons from the departments of surgical oncology and gynecologic oncology at KFSH&RC. Under general anesthesia, a midline incision extending from the xiphoid process to the pubic tubercle was performed to completely explore the abdominopelvic cavity for peritoneal carcinomatosis (PC). Foci of recurrent OGCT were confirmed intraoperatively by analysis of frozen section biopsies. Extent of PC was evaluated intraoperatively by utilizing the Peritoneal Cancer Index (PCI).13 CRS was performed as previously portrayed by Sugarbaker14 and included multiple visceral resections directed towards optimal eradication of neoplastic foci from the abdominopelvic cavity. After completion of CRS, assessment of residual tumors was determined intraoperatively using the cytoreduction completeness (CC) scores.13 Only CC-0 scores were regarded as complete cytoreduction. HIPEC was performed at the end of CRS. Abdominopelvic cavity was lavaged 15 times with 1 L of normal saline prior to HIPEC. Two inflow drains were positioned below hemidiaphragms whereas two outflow drains were positioned in the pouch of Douglas. All drains were connected to an extracorporeal closed sterile circuit in which a 2-L perfusate was circulated by means of two peristaltic rollup pumps (one inflow and one outflow) at a flow rate of 2 L/min. Cisplatin (50 mg/m2) and doxorubicin (15 mg/m2) were supplemented to the perfusate and allowed to circulate in the abdominopelvic cavity for 90 min at 41.0–42.2°C. The heated perfusate plus chemotherapy (41.0–42.2°C) was achieved by means of a heat exchanger connected to the sterile circuit. Intraperitoneal temperature was continuously checked by thermometers situated in the abdominopelvic cavity to ensure maintenance of 41.0–42.2°C. During the HIPEC procedure, hemodynamic and cardiopulmonary parameters were continuously and carefully monitored. At the end of the HIPEC procedure, the abdominopelvic cavity was again lavaged 15 times with 1 L of normal saline. Moreover, the left hemidiaphragmatic drain was kept for a couple of days to facilitate draining of the residual perfusate. All other drains were taken out intraoperatively. All patients were moved to the intensive care unit for 1–3 days, and afterwards transferred to wards for recovery. Postoperative morbidity and mortality following CRS and HIPEC were evaluated according to the Clavien–Dindo classification system for postoperative complications.15
© 2014 The Authors Journal of Obstetrics and Gynaecology Research © 2014 Japan Society of Obstetrics and Gynecology
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71 119 84 46 150 120 28 17 50 25 2 62 26 53 62 43 55 64 1 2 3 4 5 6
FIGO, International Federation of Gynecology and Obstetrics; HIPEC, hyperthermic intraperitoneal chemotherapy.
2 — — 1 — — 2 1 2 1 4 3 2 1 2 1 4 3 Yes No No No No No No No No No No No Yes No No Yes No No Yes Yes Yes Yes Yes Yes IB IB IC IB IC IB
Surgery Initial FIGO staging Histology Age (years) Patient
Table 1 Characteristics of patients
A total of six patients (n = 6) with recurrent/relapsed OGCT had undergone CRS and HIPEC. The characteristics of the patients are demonstrated in Table 1. All patients (100%) had adult OGCT histology. At initial presentation, four patients and two patients had International Federation of Gynecology and Obstetrics stage IB and IC, respectively. Moreover, at initial presentation, four patients (66.7%) were managed with surgery alone, whereas one patient (16.7%) was managed with surgery plus the BEP regimen. One patient (33.3%) was managed with hormonal therapy (leuprolide), which failed and was replaced with single-agent paclitaxel chemotherapy and failed, too. No patient had previously received radiation therapy at initial treatment. The average age at time of CRS and HIPEC was 51 years (range: 26–64 years). CRS and HIPEC were performed for the first OGCT recurrence in two patients (33.3%), second recurrence in two patients (33.3%), third recurrence in one patient (16.7%) and fourth recurrence in one patient (16.7%). The average period from initial surgery to first recurrence was roughly 31 months (range: 2–62 months). The average period from initial diagnosis to CRS and HIPEC was roughly 101 months (range: 46–150 months). Prior to HIPEC, the
Initial management Chemo Radio Hormonal
Results
Adult Adult Adult Adult Adult Adult
Number of relapses before HIPEC
Number of debulking before HIPEC
Number of chemo lines before HIPEC
Time from initial diagnosis to first recurrence (months)
Time from initial diagnosis to HIPEC (months)
Karnofsky performance status scoring (%)
Following CRS and HIPEC, selected patients underwent adjuvant systemic chemotherapy. Such chemotherapeutic drugs included the BEP regimen and the carboplatin and paclitaxel (CP) regimen. The BEP chemotherapy regimen was administered at 4-week intervals for a total of three cycles. Conversely, the CP chemotherapy regimen was administered at 3-week intervals for a total of four cycles. All patients were followed up regularly. No patient was lost during follow-up visits. During the first year following HIPEC, patients were followed up every 4 months. During the second year and afterwards, patients were followed up every 6 months. The follow-up work-up included: routine physical examination, hematological profiles (complete blood count), biochemical profiles (electrolyte, renal, bone, hepatic and coagulation), serum tumor markers (cancer antigen [CA]-125, inhibin, lactate dehydrogenase, α-fetoprotein, β-human chorionic gonadotrophin), chest X-ray, whole-body computed tomography (CT) scan or positron emission tomography (PET)–CT scan (whenever deemed necessary).
90 80 70 80 70 70
I. A. Al-Badawi et al.
© 2014 The Authors Journal of Obstetrics and Gynaecology Research © 2014 Japan Society of Obstetrics and Gynecology
32 8 0
© 2014 The Authors Journal of Obstetrics and Gynaecology Research © 2014 Japan Society of Obstetrics and Gynecology
CRS, cytoreductive surgery; HIPEC, hyperthermic intraperitoneal chemotherapy.
Abdomen + pelvis 6
7
16 10 1 Abdomen + pelvis 5
11
14 8 0 Abdomen + pelvis 4
9
20 9 0 Abdomen alone 3
9
14 12 0 Abdomen + pelvis 2
5
12 9 0
Omentectomy, umbilical resection, small bowel resection, low anterior resection Cholecystectomy, omentectomy, rectosigmoid resection, small bowel resection Cholecystectomy, splenectomy, omentectomy, right diaphragmatic stripping Omentectomy, partial peritonectomy, rectosigmoid resection, total abdominal hysterectomy with left salpingo-oophorectomy Cholecystectomy, appendectomy, omentectomy, partial peritonectomy, total abdominal hysterectomy, pelvic dissection Cholecystectomy, appendectomy, splenectomy, omentectomy, partial peritonectomy, perihepatic dissection, pelvic dissection Abdomen + pelvis 1
12
Duration of CRS and HIPEC (h) Cytoreduction completeness score Peritoneal cancer index score Surgical resections (procedures) Site of recurrence Patient
Table 2 Details of CRS and HIPEC
Karnofsky performance status scores were as follows: three patients with 70%, two patients with 80%, and one patient with 90%. Details of CRS and HIPEC are shown in Table 2. One patient (16.7%) had restricted recurrence in the abdomen whereas the remaining five patients (83.3%) had recurrences in both the abdomen and the pelvis. Multifocal involvement of recurrence was noted in all patients. Further, all patients (100%) underwent peritonectomy and omentectomy surgical procedures. Three patients (50%) had anterior low resections and one patient (16.7%) had diaphragmatic stripping. The average PCI, examined intraoperatively, was 9 (range: 5–12). Five patients (83.3%) achieved complete cytoreduction (CC-0). The remaining patient (16.7%) achieved near complete cytoreduction (CC-1). The average duration of CRS and HIPEC was 9 h (range: 8–12 h). The average postoperative hospital stay was 18 days (range: 12–32 days). Details and grading of postoperative complications according to the Clavien–Dindo classification system are shown in Table 3. No intraoperative or grade V morbidity occurred. Two patients (33.3%) developed lung atelectasis, which was managed by mere chest physiotherapy (grade I). One patient (16.7%) developed urinary tract infection (grade II) and another patient (16.7%) developed pneumonia (grade II) – both of which were managed only by antibiotics. One patient developed splenic bed and anterior abdominal wall collections requiring ultrasound-guided aspiration without the need for general anesthesia (grade III). One patient (16.7%) developed pulmonary embolism requiring intensive care unit (ICU) management (grade IV). Details of myelosuppression (immediately) and blood product transfusion (during hospital stay) post-HIPEC are presented in Table 4. The average white blood cell count was 6.02 × 109/L (range: 3.45–11.31 × 109/L), red blood cell (RBC) count was 3.56 × 1012/L (range: 2.22–4.17 × 1012/L), platelet count was 141 × 109/L (range: 105–173 × 109/L) and hemoglobin was 105 g/L (range: 85–121 g/L). During hospital stay, no patient experienced severe chemotherapyinduced myelosuppression requiring administration of granulocyte colony-stimulating factor to promote recovery of bone marrow granulocytes. Only two patients required 1 unit of packed RBC transfusion to correct anemia. No patient required platelet transfusion. Overall, myelosuppression was well tolerated. Moreover, with respect to chemotherapy-related toxicity, no patient developed doxorubicin-induced cardiotoxicity or cisplatin-induced nephrotoxicity.
Hospital stay (days)
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Table 3 Postoperative complications following cytoreductive surgery+hyperthermic intraperitoneal chemotherapy (according to Clavien–Dindo classification) Patient
Postoperative complication, grade
Management
1 2 3
Lung atelectasis, grade I Lung atelectasis, grade I Splenic bed collection, grade III Anterior abdominal wall collection, grade III Urinary tract infection, grade II Pneumonia, grade II Pulmonary embolism, grade IV
Chest physiotherapy Chest physiotherapy Ultrasound-guided aspiration without general anesthesia Ultrasound-guided aspiration without general anesthesia Antibiotics Antibiotics Intensive care unit management
4 5 6
Table 4 Myelosuppression (immediately) and blood product transfusion (during hospital stay) post HIPEC Patient
White blood count 109/L
Red blood count 1012/L
Hemoglobin g/L
Platelet 109/L
Blood transfusion during hospital stay post HIPEC
Platelet transfusion during hospital stay post HIPEC
Granulocyte colonystimulating factor administration during hospital stay post HIPEC
1 2 3 4 5 6
4.75 6.62 11.31 4.76 5.23 3.45
4.15 4.17 4.00 2.22 3.73 3.09
115 107 121 85 114 86
145 169 139 105 115 173
— — — 1 unit — 1 unit
— — — — — —
— — — — — —
HIPEC, hyperthermic intraperitoneal chemotherapy.
Table 5 Postoperative therapy, follow-up and outcome following CRS+HIPEC Patient
Adjuvant therapy
Recurrence after CRS+HIPEC
Period from CRS+HIPEC to last follow-up (months)
Current status
1 2 3 4 5 6
— BEP CP — BEP BEP
No No No No No No
40 32 27 24 20 16
Alive and disease-free Alive and disease-free Alive and disease-free Alive and disease-free Alive and disease-free Alive and disease-free
BEP, bleomycin, etoposide, cisplatin; CP, carboplatin and paclitaxel; CRS, cytoreductive surgery; HIPEC, hyperthermic intraperitoneal chemotherapy.
Details of postoperative therapy, follow-up and outcome following CRS and HIPEC are presented in Table 5. Four patients (66.67%) received adjuvant chemotherapy, whereas the remaining two patients (33.33%) received no modality of adjuvant therapy. All patients are alive and disease-free without proof of recurrence/relapse at 40, 32, 27, 24, 20 and 16 months. The average interval of follow-up after CRS and HIPEC is approximately 27 months (range: 16–40 months).
Discussion There are no universally approved guidelines for the management of recurrent OGCT.7,8 As a consequence,
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various therapeutic approaches, such as surgical debulking, chemotherapy, radiotherapy, hormonal therapy, targeted therapy and novel therapy, have been suggested. Some of these are associated with prolonged disease-free survival rates in isolated numbers of case reports and small-sized retrospective series, and owing to relative rarity of OGCT, it has largely been impossible to conduct prospective clinical randomized trials and draw concrete conclusions.16,17 The aim of this study was to explore the feasibility, efficacy and morbidity of CRS and HIPEC for the management of a retrospective series of six patients with recurrent OGCT.
© 2014 The Authors Journal of Obstetrics and Gynaecology Research © 2014 Japan Society of Obstetrics and Gynecology
CRS+HIPEC for recurrent/relapsed OGCT
There is a general consensus that complete surgical debulking of recurrent OGCT masses – whenever technically possible and regardless of the number of recurrences – should be carried out.8,9 In our study, complete cytoreduction (CC-0) was achieved in 83.3% of patients with recurrent OGCT. Our findings mirrored another study in which CC-0 was achieved in more than 80% of patients with recurrent OGCT.18 At present, complete surgical resection remains the standard of care for primary and recurrent OGCT settings,8,9 as residual tumor disease considerably influences disease-free survival and accelerates recurrence rate.4,9,19,20 In the Multicenter Italian Trials in Ovarian Cancer 9 retrospective study about recurrent OGCT,8 35 patients with recurrent OGCT were identified. At the time of the first recurrence, the median disease-free survival was 64.5 months in patients receiving complete cytoreduction and 47 months in patients receiving incomplete cytoreduction. Moreover, at the time of the first recurrence, although CC-0 was achieved in 30 patients, 11 patients developed a second relapse after a median period of 38 months, and four patients developed a third relapse after a median period of 41 months from the time of the second recurrence. The 5-year survival from the time of first recurrence was roughly 60% and 87% for patients with and without residual tumor foci at successive debulking surgery, respectively. In another study by Fotopoulou et al.,18 45 patients with OGCT were analyzed. Eighteen patients had primary OGCT and CC-0 was achieved in all patients. Alternatively, 27 patients had recurrent OGCT, and CC-0 was achieved in only 23 patients (85.2%). For all patients, during a median follow-up period of 69 months (range: 4–120 months), the median disease-free survival and overall survival were 58 months and 63 months, respectively. Optimal surgical debulking remains the standard of care for primary and recurrent OGCT settings,8,9 and cytoreduction completeness of residual disease significantly influences recurrence-free survival and overall survival.4,9,19,20 However, with subsequent relapses, optimal (complete) surgical debulking using multivisceral resections may be more challenging and unfeasible, and hence one should look for other effective intraoperative therapeutic modalities, one of which is intraoperative HIPEC. The justification for using HIPEC is primarily based on the thermal-improved efficacious penetration, cytotoxicity and synergism of chemotherapeutic drugs on
the malignant cells.21,22 Moreover, administration of perioperative intraperitoneal chemotherapy offers higher local drug concentrations, lower unwanted systemic side-effects23 and effectively bathes the surgical fields7 for microscopic/macroscopic residual tumor implants, which are the most significant factors influencing the recurrence rates. The above-mentioned benefits of HIPEC allow combination of CRS and HIPEC to emerge as a therapeutic modality that is potentially worth testing for the management of recurrent OGCT. Moreover, in line with the promising outcomes of HIPEC in management of PC arising from recurrent gynecological11,12,24–26 and nongynecological27 malignancies, we highly anticipate that utilization of optimal CRS and HIPEC will also be effective in: (i) managing recurrent OGCT with PC; (ii) reducing the risk of future repetitive recurrences; and (iii) decreasing the need for subsequent debulking surgeries. The selection of chemotherapeutic drugs for HIPEC should be rationalized according to proven scientific research-based improved heat-enhancing effects on the chemotherapeutic drugs. Chemotherapeutic drugs of such nature include cisplatin,28 doxorubicin (adriamycin),29 and mitomycin C.30 The combined platinum- and doxorubicin-based chemotherapy regimen is widely used as a common HIPEC cytotoxic regimen in the management of widespread PC arising from gynecological (epithelial ovarian and endometrial)24–26 and non-gynecological (mesothelioma)27 malignancies with acceptable efficacy and morbidity results. Canbay et al.31 and Gouy et al.7 have previously used platinum-based HIPEC cytotoxic agents in the management of recurrent OGCT with PC. Therefore, the use of cisplatin in our study is well rationalized based on the two previous studies. Conversely, doxorubicin-based HIPEC cytotoxic agents have not been previously used for management of recurrent OGCT with PC. However, in our study, we decided to use doxorubicin for two reasons: (i) doxorubicin is commonly used as a standard HIPEC cytotoxic drug in the management of PC arising from many gynecological and non-gynecological malignancies with very acceptable morbidity and promising results; and (ii) this HIPEC chemotherapy combination of cisplatin plus doxorubicin is expected to maximize the cytotoxic effects with tolerable toxicity and morbidity. However, further research is needed. The morbidity of platinum-based versus doxorubicin-based chemotherapy has been studied and shown to be insignificant. A recent study by
© 2014 The Authors Journal of Obstetrics and Gynaecology Research © 2014 Japan Society of Obstetrics and Gynecology
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Glockzin et al.32 compared the treatment-related morbidity in patients receiving oxaliplatin versus doxorubicin plus mitomycin C as HIPEC cytotoxic agents for management of PC. A total of 307 patients were retrospectively analyzed. Forty patients received oxaliplatin whereas the remaining patients received doxorubicin plus mitomycin C. According to Common Terminology Criteria for Adverse Events (version 3.0), grade III/IV (severe adverse events) morbidity was relatively lower in the doxorubicin plus mitomycin C treated groups (37.5%) as compared to the oxaliplatin treated groups (42.5%) without significant statistical difference (P = 0.648). This study suggests that doxorubicin toxicity is generally well tolerated in selected patients and fairly comparable to oxaliplatin. Multifocal pattern of recurrence is very common among OGCT. The most frequently reported regions of recurrence (descending order of frequency) are the pelvis, liver and bowel.18,20 In our study, recurrence multifocality was present in all patients (100%) and reflected by the number of various surgical resections performed (peritonectomy, omentectomy, splenectomy, low anterior resections, etc.). Furthermore, abdominopelvic recurrences occurred in five patients (83.3%) whereas only recurrences confined to the abdomen occurred in one patient (6.7%). Interestingly, no patient developed hepatic recurrences in our study, as opposed to the reported 14% (n = 4/27) and 10% (n = 9/82) of patients in other studies by Fotopoulou et al.18 and Lee et al.,4 respectively. Dissection of paraaortic or pelvic lymph nodes was not performed owing to the quite low rate of retroperitoneal disease involvement in recurrent OGCT settings (less than 6%).33 In our study, all patients are alive and disease-free without proof of recurrence/relapse at 40, 32, 27, 24, 20 and 16 months. The average interval of follow-up after CRS and HIPEC is 27 months (range: 16–40 months). Our study suggests that CRS and HIPEC seem to be a feasible modality for management of recurrent OGCT. Morbidity of CRS and HIPEC was very tolerable and acceptable. Four patients developed grade I/II morbidities without the need for surgical, endoscopic or radiological interventions. One patient developed splenic bed and anterior abdominal wall collections requiring ultrasound-guided aspiration without the need for general anesthesia (grade III). One patient (16.7%) developed pulmonary embolism requiring ICU management (grade IV). All complications were managed successfully without problematic events. No intraoperative mortality or grade V morbidity occurred. There is a learning curve associated with this
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procedure; with accumulated experience in this procedure, an acceptable morbidity rate can be achieved. In our tertiary care center, up to this moment, a total of 161 HIPEC cases (over the past 5 years) were treated by surgeons from the departments of surgical oncology and gynecologic oncology. In particular, a total of 48 HIPEC cases were treated for various malignant ovarian tumors, six cases of which were OGCT with PC – presented here in this study as a sub-group analysis. Complete surgical debulking – despite repetitive recurrences – with or without adjuvant chemotherapy is the standard of care management and has been shown to yield longer survival rates.8,9 Currently, there is no powerful proof that postoperative adjuvant chemotherapy prevents further recurrences of OGCT.9,34,35 However, adjuvant chemotherapy should be employed in the management of widespread disease, inoperable/unresectable metastatic disease or disease with suboptimal cytoreduction.36,37 The BEP combination emerges as the best active chemotherapeutic regimen.10 Other chemotherapeutic regimens with documented usefulness include doxorubicin38 and the cisplatin, vinblastine and bleomycin protocol.37 Earlier studies showed promising results for taxane-based chemotherapy in management of GCT and with less toxicity and fewer adverse side-effects when compared to the BEP regimen.39–41 At present, the Gynecologic Oncology Group is carrying out a randomized phase II clinical trial exploring efficacy of BEP regimen versus the combination of carboplatin and paclitaxel for management of patients with newly diagnosed and chemonaïve recurrent metastatic ovarian sex-cord stromal tumors.42 The outcomes of this important trial are anticipated to provide high-quality and powerful evidences regarding the best active regimens for management of the uncommon recurrent OGCT. In our study, all patients who received prior chemotherapy did not receive adjuvant chemotherapy following CRS and HIPEC. We anticipated they would be unlikely to benefit from further adjuvant chemotherapeutic schedules and we did not want to expose them to additional unnecessary chemotherapy-related toxicities. For chemo-naïve patients (n = 4), we elected to employ adjuvant BEP regimen in three patients and CP regimen in one patient. A genuine question arises: in chemo-naïve patients with recurrent OGCT, is HIPEC needed? No studies have been carried out to explore this question, and this is indeed an interesting area for future research. However, the natural clinical behavior of OGCT is commonly featured by slow growth and increased
© 2014 The Authors Journal of Obstetrics and Gynaecology Research © 2014 Japan Society of Obstetrics and Gynecology
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predisposition for late recurrences, despite complete debulking.2–4 Complete surgical cytoreduction – regardless of multiple recurrences – with or without postoperative chemotherapy remains the standard of care and has been demonstrated to result in prolonged overall survival rates.9 At present, there is no strong evidence supporting that postoperative adjuvant chemotherapy in chemo-naïve patients prevents further recurrences of OGCT.9,34,35 Considering the abovementioned advantages of HIPEC, we anticipated chemo-naïve patients with multiple OGCT recurrences would greatly benefit from a combination therapy of intraoperative HIPEC (optional) plus postoperative chemotherapy. No studies have been conducted on this matter and further research is needed – a study worthy of exploration. Postoperative radiotherapy43,44 and hormonal therapy45,46 – despite limited efficacy and variable disease-free survival – can be offered to patients with refractory high-risk recurrent OGCT, localized or inoperable metastatic disease, or patients who are not candidates for surgical debulking or chemotherapeutic intervention. To our best knowledge, use of CRS and HIPEC for management of recurrent/relapsed OGCT is very limited to two studies only.7,31 Canbay et al.31 employed CRS and HIPEC for five patients with recurrent OGCT. HIPEC was performed with 100 mg cisplatin and allowed to circulate in the abdominopelvic cavity for 40 min at 43.0°C. Median follow-up of patients was 4 years (range: 1–6 years). Among the five patients, one patient died and another three patients were alive with no disease progression. Recently, Gouy et al.7 explored the feasibility of CRS and HIPEC for management of seven patients with recurrent OGCT. Complete cytoreduction was achieved in all patients. HIPEC was performed with oxaliplatin (460 mg/m2) or oxaliplatin (360 mg/m2) plus irinotecan (360 mg/m2) and allowed to circulate in the abdominopelvic cavity for 30 min at 41.0–43.0°C. Median follow-up of patients was 32 months (range: 25–56 months). Among the seven patients, two were disease-free, three had relapsed with PC and two had relapsed with liver metastases. As opposed to our study, all patients were alive and disease-free without proof of recurrence/relapse at 40, 32, 27, 24, 20 and 16 months. The average interval of follow-up after CRS and HIPEC is approximately 27 months (range: 16–40 months). Limitations to this study include the retrospective study design, comparatively small sample size (case series of six patients), relatively short period of follow-
up, and lack of consistent therapy and control group. Such limitations make it fairly uncertain to draw concrete and definitive conclusions. In summary, our study suggests that CRS and HIPEC appear to be a well-tolerated and feasible treatment modality in management of recurrent OGCT. However, long-term follow-up of patients is mandatory to verify efficacy of CRS and HIEPC in reducing the risk of further recurrences of OGCT. Moreover, a larger series of patients and possibly prospective randomized clinical trials, along with prolonged follow-up data and control groups, are needed to draw definitive conclusions regarding CRS and HIPEC for the management of patients with recurrent OGCT.
Acknowledgment The authors sincerely acknowledge the editorial assistance of Ms Evelyn Dinio.
Disclosure None declared.
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10. Pautier P, Gutierrez-Bonnaire M, Rey A et al. Combination of bleomycin, etoposide, and cisplatin for the treatment of advanced ovarian granulosa cell tumors. Int J Gynecol Cancer 2008; 18: 446–452. 11. Cotte E, Glehen O, Mohamed F et al. Cytoreductive surgery and intraperitoneal chemo-hyperthermia for chemo-resistant and recurrent advanced epithelial ovarian cancer: Prospective study of 81 patients. World J Surg 2007; 31: 1813–1820. 12. Jaaback K, Johnson N. Intraperitoneal chemotherapy for the initial management of primary epithelial ovarian cancer. Cochrane Database Syst Rev 2006; (1): CD005340. 13. Sugarbaker PH. Management of peritoneal-surface malignancy: The surgeon’s role. Langenbecks Arch Surg 1999; 384: 576–587. 14. Sugarbaker PH. Peritonectomy procedures. Ann Surg 1995; 221: 29–42. 15. Dindo D, Demartines N, Clavien PA. Classification of surgical complications: A new proposal with evaluation in a cohort of 6336 patients and results of a survey. Ann Surg 2004; 240: 205–213. 16. Colombo N, Parma G, Zanagnolo V, Insinga A. Management of ovarian stromal cell tumors. J Clin Oncol 2007; 25: 2944– 2951. 17. Schumer ST, Cannistra SA. Granulosa cell tumor of the ovary. J Clin Oncol 2003; 21: 1180–1189. 18. Fotopoulou C, Savvatis K, Braicu EI et al. Adult granulosa cell tumors of the ovary: Tumor dissemination pattern at primary and recurrent situation, surgical outcome. Gynecol Oncol 2010; 119: 285–290. 19. Sehouli J, Drescher FS, Mustea A et al. Granulosa cell tumor of the ovary: 10 years follow-up data of 65 patients. Anticancer Res 2004; 24: 1223–1229. 20. Sun HD, Lin H, Jao MS et al. A long-term follow-up study of 176 cases with adult-type ovarian granulosa cell tumors. Gynecol Oncol 2012; 124: 244–249. 21. Witkamp AJ, de Bree E, Van Goethem R, Zoetmulder FA. Rationale and techniques of intra-operative hyperthermic intraperitoneal chemotherapy. Cancer Treat Rev 2001; 27: 365– 374. 22. Mohamed F, Marchettini P, Stuart OA, Urano M, Sugarbaker PH. Thermal enhancement of new chemotherapeutic agents at moderate hyperthermia. Ann Surg Oncol 2003; 10: 463– 468. 23. Glehen O, Beaujard AC, Arvieux C, Huber O, Gilly FN. Peritoneal carcinomatosis. Surgical treatment, peritonectomy and intraperitoneal chemohyperthermia. Gastroenterol Clin Biol 2002; 26: 210–215. (In French). 24. Ansaloni L, Agnoletti V, Amadori A et al. Evaluation of extensive cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC) in patients with advanced epithelial ovarian cancer. Int J Gynecol Cancer 2012; 22: 778–785. 25. Deraco M, Kusamura S, Virzì S et al. Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy as upfront therapy for advanced epithelial ovarian cancer: Multiinstitutional phase-II trial. Gynecol Oncol 2011; 122: 215–220. 26. Jérôme D, Mariangela D, Mélanie F et al. Cytoreductive surgery with hyperthermic intraperitoneal chemotherapy for the treatment of endometrial cancer with peritoneal carcinomatosis. Eur J Obstet Gynecol Reprod Biol 2014; 172: 111–114. 27. Baratti D, Kusamura S, Cabras AD, Bertulli R, Hutanu I, Deraco M. Diffuse malignant peritoneal mesothelioma: Long-
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term survival with complete cytoreductive surgery followed by hyperthermic intraperitoneal chemotherapy (HIPEC). Eur J Cancer 2013; 49: 3140–3148. Rietbroek RC, van de Vaart PJ, Haveman J et al. Hyperthermia enhances the cytotoxicity and platinum-DNA adduct formation of lobaplatin and oxaliplatin in cultured SW 1573 cells. J Cancer Res Clin Oncol 1997; 123: 6–12. Herman TS, Henle KJ, Nagle WA, Moss AJ, Monson TP. Effect of step-down heating on the cytotoxicity of adriamycin, bleomycin, and cis-diamminedichloroplatinum. Cancer Res 1984; 44: 1823–1826. Teicher BA, Kowal CD, Kennedy KA, Sartorelli AC. Enhancement by hyperthermia of the in vitro cytotoxicity of mitomycin C toward hypoxic tumor cells. Cancer Res 1981; 41: 1096–1099. Canbay E, Ishibashi H, Sako S, Miyata R, Nishino E, Yonemura Y. Management of peritoneal dissemination of recurrences granulosa cell tumor of the ovary. Gan To Kagaku Ryoho 2012; 39: 2435–2437. Glockzin G, von Breitenbuch P, Schlitt HJ, Piso P. Treatmentrelated morbidity and toxicity of CRS and oxaliplatin-based HIPEC compared to a mitomycin and doxorubicin-based HIPEC protocol in patients with peritoneal carcinomatosis: A matched-pair analysis. J Surg Oncol 2013; 107: 574–578. Abu-Rustum NR, Restivo A, Ivy J et al. Retroperitoneal nodal metastasis in primary and recurrent granulosa cell tumors of the ovary. Gynecol Oncol 2006; 103: 31–34. Gershenson DM, Copeland LJ, Kavanagh JJ, Stringer CA, Saul PB, Wharton JT. Treatment of metastatic stromal tumors of the ovary with cisplatin, doxorubicin, and cyclophosphamide. Obstet Gynecol 1987; 70: 765–769. Uygun K, Aydiner A, Saip P et al. Clinical parameters and treatment results in recurrent granulosa cell tumor of the ovary. Gynecol Oncol 2003; 88: 400–403. Gershenson DM, Morris M, Burke TW, Levenback C, Matthews CM, Wharton JT. Treatment of poor-prognosis sex cord-stromal tumors of the ovary with the combination of bleomycin, etoposide, and cisplatin. Obstet Gynecol 1996; 87: 527–531. Zambetti M, Escobedo A, Pilotti S, De Palo G. Cis-platinum/ vinblastine/bleomycin combination chemotherapy in advanced or recurrent granulosa cell tumors of the ovary. Gynecol Oncol 1990; 36: 317–320. Disaia P, Saltz A, Kagan AR, Rich W. A temporary response of recurrent granulosa cell tumor to adriamycin. Obstet Gynecol 1978; 52: 355–358. Brown J, Shvartsman HS, Deavers MT et al. The activity of taxanes compared with bleomycin, etoposide, and cisplatin in the treatment of sex cord-stromal ovarian tumors. Gynecol Oncol 2005; 97: 489–496. Shavit T, Bruchim I, Ben-Harim Z, Fishman A. Successful response to docetaxel treatment in recurrent ovarian granulosa cell tumor: A case report. Eur J Gynaecol Oncol 2012; 33: 419–420. Tresukosol D, Kudelka AP, Edwards CL, Charnsangavej C, Narboni N, Kavanagh JJ. Recurrent ovarian granulosa cell tumor: A case report of a dramatic response to Taxol. Int J Gynecol Cancer 1995; 5: 156–159. Gershenson DM. Current advances in the management of malignant germ cell and sex cord-stromal tumors of the ovary. Gynecol Oncol 2012; 125: 515–517.
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43. Wolf JK, Mullen J, Eifel PJ, Burke TW, Levenback C, Gershenson DM. Radiation treatment of advanced or recurrent granulosa cell tumor of the ovary. Gynecol Oncol 1999; 73: 35–41. 44. Hauspy J, Beiner ME, Harley I et al. Role of adjuvant radiotherapy in granulosa cell tumors of the ovary. Int J Radiat Oncol Biol Phys 2011; 79: 770–774.
45. Kim HJ, Lee SC, Bae SB et al. GnRH agonist therapy in a patient with recurrent ovarian granulosa cell tumors. J Korean Med Sci 2009; 24: 535–538. 46. Ameryckx L, Fatemi HM, De Sutter P, Amy JJ. GnRH antagonist in the adjuvant treatment of a recurrent ovarian granulosa cell tumor: A case report. Gynecol Oncol 2005; 99: 764–766.
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doi:10.1111/jog.12460
J. Obstet. Gynaecol. Res. Vol. 40, No. 9: 2066–2075, September 2014
Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for management of recurrent/relapsed ovarian granulosa cell tumor: A single-center experience Ismail A. Al-Badawi1,2, Ahmed Abu-Zaid1,2, Ayman Azzam3,4, Osama AlOmar1, Hamed AlHusaini3 and Tarek Amin3 1
Department of Obstetrics and Gynecology, 3Oncology Center, King Faisal Specialist Hospital and Research Center, 2College of Medicine, Alfaisal University, Riyadh, Saudi Arabia; and 4Faculty of Medicine, Alexandria University, Alexandria, Egypt
Abstract Aim: The aim of this study was to retrospectively report our experience (efficacy/morbidity) with cytoreductive surgery+hyperthermic intraperitoneal chemotherapy (CRS+HIPEC) for the management of recurrent/relapsed ovarian granulosa cell tumors (OGCT). Material and Methods: From 2010 to 2013, six patients underwent CRS+HIPEC. CRS was performed with standard peritonectomy procedures and visceral resections directed towards complete elimination of tumors from the abdominopelvic cavity. HIPEC was performed with cisplatin (50 mg/m2) and doxorubicin (15 mg/ m2) and allowed to circulate in the abdominopelvic cavity for 90 min at 41.0–42.2°C. Results: Cytoreduction completeness (CC-0) was achieved in all except one patient (CC-1). Five patients had OGCT recurrences in abdomen+pelvis and one patient in abdomen only. No grade V morbidity (Clavien– Dindo classification) occurred. Two patients developed lung atelectasis, which was managed by mere chest physiotherapy (grade I). One patient developed urinary tract infection (grade II) and another patient developed pneumonia (grade II) – both of which were managed by antibiotics. One patient developed splenic bed and anterior abdominal wall collections requiring ultrasound-guided aspiration without general anesthesia (grade III). One patient developed pulmonary embolism requiring intensive care-unit management (grade IV). Four chemo-naïve patients received adjuvant chemotherapy whereas the remaining two previously chemoexposed patients received no adjuvant therapy. All patients were alive and disease-free without proof of recurrence/relapse at 40, 32, 27, 24, 20 and 16 months. The average interval of follow-up after CRS+HIPEC was roughly 27 months (range: 16–40 months). Conclusion: CRS+HIPEC appears to be an efficacious and morbidly well-tolerated therapeutic modality for recurrent/relapsed OGCT. Long-term follow-up data and further research are needed. Key words: cytoreductive surgery, hyperthermic intraperitoneal chemotherapy, ovarian granulosa cell tumor.
Introduction Ovarian granulosa cell tumors (OGCT) are quite infrequent neoplasms accounting for roughly 70% of ovarian sex cord-stromal tumors and 2–5% of all
ovarian neoplasms.1 The natural biological behavior of OGCT is unique. OGCT are characterized by clinically indolent course, slow-paced tumor growth and increased propensity for late recurrence.2–4 Recurrences of OGCT most commonly happen between 5 and 30
Received: January 28 2014. Accepted: March 31 2014. Reprint request to: Dr Ismail A. Al-Badawi, Gynecologic Oncology, Department of Obstetrics and Gynecology, MBC-52, King Faisal Specialist Hospital and Research Centre, P.O. Box 3354, Riyadh 11211, Saudi Arabia. Email: [email protected]
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years following the initial management.5 To date, the longest time to recurrence of an OGCT documented in the published work is 40 years following initial treatment.6 Prognosis of patients with recurrent OGCT largely signifies unfavorable outcomes.7 There are no universally approved guidelines for the management of recurrent OGCT.7,8 Complete surgical debulking – with or without adjuvant chemotherapy – is the standard of care management, and has been shown to yield longer survival rates.9 The benefit of adjuvant chemotherapy is still questionable, and the bleomycin, etoposide and cisplatin (BEP) combination has emerged as the best active chemotherapeutic regimen.10 Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) have revealed fortunate, favorable and promising outcomes in the management of advanced and recurrent epithelial ovarian cancers.11,12 Use of CRS and HIPEC for the management of recurrent OGCT is very limited. The objective of this study was to report our experience (efficacy and morbidity) with CRS and HIPEC for the management of recurrent/relapsed OGCT.
Methods The study took place at King Faisal Specialist Hospital and Research Center (KFSH&RC), Riyadh, Saudi Arabia – a tertiary health care institute. From November 2010 to September 2013, all patients with recurrent OGCT managed by CRS and HIPEC were retrospectively analyzed. Approval of the Research Advisory Council was obtained to publish this research work. In our institute, intraoperative administration of HIPEC is optional. Patients were informed in detail about the current literature, benefits and risks of undergoing the standard treatment (CRS plus/minus postoperative chemotherapy) or the optional treatment (CRS plus HIPEC plus/minus postoperative chemotherapy). Afterwards, patients were requested to sign a written consent regarding the desired treatment option. Inclusion criteria for considering CRS and HIPEC included: (i) age below 75 years; (ii) Karnofsky performance status more than 50%; (iii) satisfactory hematological, hepatic, coagulation, renal and electrolyte profiles; (iv) proven diagnosis of recurrent OGCT confirmed by imaging modality and/or intraoperative biopsy; (v) no evidence of distant OGCT metastatic foci to brain, lungs or bones; and (vi) signed written informed consent by patients.
All operations were carried out by the same surgeons from the departments of surgical oncology and gynecologic oncology at KFSH&RC. Under general anesthesia, a midline incision extending from the xiphoid process to the pubic tubercle was performed to completely explore the abdominopelvic cavity for peritoneal carcinomatosis (PC). Foci of recurrent OGCT were confirmed intraoperatively by analysis of frozen section biopsies. Extent of PC was evaluated intraoperatively by utilizing the Peritoneal Cancer Index (PCI).13 CRS was performed as previously portrayed by Sugarbaker14 and included multiple visceral resections directed towards optimal eradication of neoplastic foci from the abdominopelvic cavity. After completion of CRS, assessment of residual tumors was determined intraoperatively using the cytoreduction completeness (CC) scores.13 Only CC-0 scores were regarded as complete cytoreduction. HIPEC was performed at the end of CRS. Abdominopelvic cavity was lavaged 15 times with 1 L of normal saline prior to HIPEC. Two inflow drains were positioned below hemidiaphragms whereas two outflow drains were positioned in the pouch of Douglas. All drains were connected to an extracorporeal closed sterile circuit in which a 2-L perfusate was circulated by means of two peristaltic rollup pumps (one inflow and one outflow) at a flow rate of 2 L/min. Cisplatin (50 mg/m2) and doxorubicin (15 mg/m2) were supplemented to the perfusate and allowed to circulate in the abdominopelvic cavity for 90 min at 41.0–42.2°C. The heated perfusate plus chemotherapy (41.0–42.2°C) was achieved by means of a heat exchanger connected to the sterile circuit. Intraperitoneal temperature was continuously checked by thermometers situated in the abdominopelvic cavity to ensure maintenance of 41.0–42.2°C. During the HIPEC procedure, hemodynamic and cardiopulmonary parameters were continuously and carefully monitored. At the end of the HIPEC procedure, the abdominopelvic cavity was again lavaged 15 times with 1 L of normal saline. Moreover, the left hemidiaphragmatic drain was kept for a couple of days to facilitate draining of the residual perfusate. All other drains were taken out intraoperatively. All patients were moved to the intensive care unit for 1–3 days, and afterwards transferred to wards for recovery. Postoperative morbidity and mortality following CRS and HIPEC were evaluated according to the Clavien–Dindo classification system for postoperative complications.15
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71 119 84 46 150 120 28 17 50 25 2 62 26 53 62 43 55 64 1 2 3 4 5 6
FIGO, International Federation of Gynecology and Obstetrics; HIPEC, hyperthermic intraperitoneal chemotherapy.
2 — — 1 — — 2 1 2 1 4 3 2 1 2 1 4 3 Yes No No No No No No No No No No No Yes No No Yes No No Yes Yes Yes Yes Yes Yes IB IB IC IB IC IB
Surgery Initial FIGO staging Histology Age (years) Patient
Table 1 Characteristics of patients
A total of six patients (n = 6) with recurrent/relapsed OGCT had undergone CRS and HIPEC. The characteristics of the patients are demonstrated in Table 1. All patients (100%) had adult OGCT histology. At initial presentation, four patients and two patients had International Federation of Gynecology and Obstetrics stage IB and IC, respectively. Moreover, at initial presentation, four patients (66.7%) were managed with surgery alone, whereas one patient (16.7%) was managed with surgery plus the BEP regimen. One patient (33.3%) was managed with hormonal therapy (leuprolide), which failed and was replaced with single-agent paclitaxel chemotherapy and failed, too. No patient had previously received radiation therapy at initial treatment. The average age at time of CRS and HIPEC was 51 years (range: 26–64 years). CRS and HIPEC were performed for the first OGCT recurrence in two patients (33.3%), second recurrence in two patients (33.3%), third recurrence in one patient (16.7%) and fourth recurrence in one patient (16.7%). The average period from initial surgery to first recurrence was roughly 31 months (range: 2–62 months). The average period from initial diagnosis to CRS and HIPEC was roughly 101 months (range: 46–150 months). Prior to HIPEC, the
Initial management Chemo Radio Hormonal
Results
Adult Adult Adult Adult Adult Adult
Number of relapses before HIPEC
Number of debulking before HIPEC
Number of chemo lines before HIPEC
Time from initial diagnosis to first recurrence (months)
Time from initial diagnosis to HIPEC (months)
Karnofsky performance status scoring (%)
Following CRS and HIPEC, selected patients underwent adjuvant systemic chemotherapy. Such chemotherapeutic drugs included the BEP regimen and the carboplatin and paclitaxel (CP) regimen. The BEP chemotherapy regimen was administered at 4-week intervals for a total of three cycles. Conversely, the CP chemotherapy regimen was administered at 3-week intervals for a total of four cycles. All patients were followed up regularly. No patient was lost during follow-up visits. During the first year following HIPEC, patients were followed up every 4 months. During the second year and afterwards, patients were followed up every 6 months. The follow-up work-up included: routine physical examination, hematological profiles (complete blood count), biochemical profiles (electrolyte, renal, bone, hepatic and coagulation), serum tumor markers (cancer antigen [CA]-125, inhibin, lactate dehydrogenase, α-fetoprotein, β-human chorionic gonadotrophin), chest X-ray, whole-body computed tomography (CT) scan or positron emission tomography (PET)–CT scan (whenever deemed necessary).
90 80 70 80 70 70
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32 8 0
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CRS, cytoreductive surgery; HIPEC, hyperthermic intraperitoneal chemotherapy.
Abdomen + pelvis 6
7
16 10 1 Abdomen + pelvis 5
11
14 8 0 Abdomen + pelvis 4
9
20 9 0 Abdomen alone 3
9
14 12 0 Abdomen + pelvis 2
5
12 9 0
Omentectomy, umbilical resection, small bowel resection, low anterior resection Cholecystectomy, omentectomy, rectosigmoid resection, small bowel resection Cholecystectomy, splenectomy, omentectomy, right diaphragmatic stripping Omentectomy, partial peritonectomy, rectosigmoid resection, total abdominal hysterectomy with left salpingo-oophorectomy Cholecystectomy, appendectomy, omentectomy, partial peritonectomy, total abdominal hysterectomy, pelvic dissection Cholecystectomy, appendectomy, splenectomy, omentectomy, partial peritonectomy, perihepatic dissection, pelvic dissection Abdomen + pelvis 1
12
Duration of CRS and HIPEC (h) Cytoreduction completeness score Peritoneal cancer index score Surgical resections (procedures) Site of recurrence Patient
Table 2 Details of CRS and HIPEC
Karnofsky performance status scores were as follows: three patients with 70%, two patients with 80%, and one patient with 90%. Details of CRS and HIPEC are shown in Table 2. One patient (16.7%) had restricted recurrence in the abdomen whereas the remaining five patients (83.3%) had recurrences in both the abdomen and the pelvis. Multifocal involvement of recurrence was noted in all patients. Further, all patients (100%) underwent peritonectomy and omentectomy surgical procedures. Three patients (50%) had anterior low resections and one patient (16.7%) had diaphragmatic stripping. The average PCI, examined intraoperatively, was 9 (range: 5–12). Five patients (83.3%) achieved complete cytoreduction (CC-0). The remaining patient (16.7%) achieved near complete cytoreduction (CC-1). The average duration of CRS and HIPEC was 9 h (range: 8–12 h). The average postoperative hospital stay was 18 days (range: 12–32 days). Details and grading of postoperative complications according to the Clavien–Dindo classification system are shown in Table 3. No intraoperative or grade V morbidity occurred. Two patients (33.3%) developed lung atelectasis, which was managed by mere chest physiotherapy (grade I). One patient (16.7%) developed urinary tract infection (grade II) and another patient (16.7%) developed pneumonia (grade II) – both of which were managed only by antibiotics. One patient developed splenic bed and anterior abdominal wall collections requiring ultrasound-guided aspiration without the need for general anesthesia (grade III). One patient (16.7%) developed pulmonary embolism requiring intensive care unit (ICU) management (grade IV). Details of myelosuppression (immediately) and blood product transfusion (during hospital stay) post-HIPEC are presented in Table 4. The average white blood cell count was 6.02 × 109/L (range: 3.45–11.31 × 109/L), red blood cell (RBC) count was 3.56 × 1012/L (range: 2.22–4.17 × 1012/L), platelet count was 141 × 109/L (range: 105–173 × 109/L) and hemoglobin was 105 g/L (range: 85–121 g/L). During hospital stay, no patient experienced severe chemotherapyinduced myelosuppression requiring administration of granulocyte colony-stimulating factor to promote recovery of bone marrow granulocytes. Only two patients required 1 unit of packed RBC transfusion to correct anemia. No patient required platelet transfusion. Overall, myelosuppression was well tolerated. Moreover, with respect to chemotherapy-related toxicity, no patient developed doxorubicin-induced cardiotoxicity or cisplatin-induced nephrotoxicity.
Hospital stay (days)
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Table 3 Postoperative complications following cytoreductive surgery+hyperthermic intraperitoneal chemotherapy (according to Clavien–Dindo classification) Patient
Postoperative complication, grade
Management
1 2 3
Lung atelectasis, grade I Lung atelectasis, grade I Splenic bed collection, grade III Anterior abdominal wall collection, grade III Urinary tract infection, grade II Pneumonia, grade II Pulmonary embolism, grade IV
Chest physiotherapy Chest physiotherapy Ultrasound-guided aspiration without general anesthesia Ultrasound-guided aspiration without general anesthesia Antibiotics Antibiotics Intensive care unit management
4 5 6
Table 4 Myelosuppression (immediately) and blood product transfusion (during hospital stay) post HIPEC Patient
White blood count 109/L
Red blood count 1012/L
Hemoglobin g/L
Platelet 109/L
Blood transfusion during hospital stay post HIPEC
Platelet transfusion during hospital stay post HIPEC
Granulocyte colonystimulating factor administration during hospital stay post HIPEC
1 2 3 4 5 6
4.75 6.62 11.31 4.76 5.23 3.45
4.15 4.17 4.00 2.22 3.73 3.09
115 107 121 85 114 86
145 169 139 105 115 173
— — — 1 unit — 1 unit
— — — — — —
— — — — — —
HIPEC, hyperthermic intraperitoneal chemotherapy.
Table 5 Postoperative therapy, follow-up and outcome following CRS+HIPEC Patient
Adjuvant therapy
Recurrence after CRS+HIPEC
Period from CRS+HIPEC to last follow-up (months)
Current status
1 2 3 4 5 6
— BEP CP — BEP BEP
No No No No No No
40 32 27 24 20 16
Alive and disease-free Alive and disease-free Alive and disease-free Alive and disease-free Alive and disease-free Alive and disease-free
BEP, bleomycin, etoposide, cisplatin; CP, carboplatin and paclitaxel; CRS, cytoreductive surgery; HIPEC, hyperthermic intraperitoneal chemotherapy.
Details of postoperative therapy, follow-up and outcome following CRS and HIPEC are presented in Table 5. Four patients (66.67%) received adjuvant chemotherapy, whereas the remaining two patients (33.33%) received no modality of adjuvant therapy. All patients are alive and disease-free without proof of recurrence/relapse at 40, 32, 27, 24, 20 and 16 months. The average interval of follow-up after CRS and HIPEC is approximately 27 months (range: 16–40 months).
Discussion There are no universally approved guidelines for the management of recurrent OGCT.7,8 As a consequence,
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various therapeutic approaches, such as surgical debulking, chemotherapy, radiotherapy, hormonal therapy, targeted therapy and novel therapy, have been suggested. Some of these are associated with prolonged disease-free survival rates in isolated numbers of case reports and small-sized retrospective series, and owing to relative rarity of OGCT, it has largely been impossible to conduct prospective clinical randomized trials and draw concrete conclusions.16,17 The aim of this study was to explore the feasibility, efficacy and morbidity of CRS and HIPEC for the management of a retrospective series of six patients with recurrent OGCT.
© 2014 The Authors Journal of Obstetrics and Gynaecology Research © 2014 Japan Society of Obstetrics and Gynecology
CRS+HIPEC for recurrent/relapsed OGCT
There is a general consensus that complete surgical debulking of recurrent OGCT masses – whenever technically possible and regardless of the number of recurrences – should be carried out.8,9 In our study, complete cytoreduction (CC-0) was achieved in 83.3% of patients with recurrent OGCT. Our findings mirrored another study in which CC-0 was achieved in more than 80% of patients with recurrent OGCT.18 At present, complete surgical resection remains the standard of care for primary and recurrent OGCT settings,8,9 as residual tumor disease considerably influences disease-free survival and accelerates recurrence rate.4,9,19,20 In the Multicenter Italian Trials in Ovarian Cancer 9 retrospective study about recurrent OGCT,8 35 patients with recurrent OGCT were identified. At the time of the first recurrence, the median disease-free survival was 64.5 months in patients receiving complete cytoreduction and 47 months in patients receiving incomplete cytoreduction. Moreover, at the time of the first recurrence, although CC-0 was achieved in 30 patients, 11 patients developed a second relapse after a median period of 38 months, and four patients developed a third relapse after a median period of 41 months from the time of the second recurrence. The 5-year survival from the time of first recurrence was roughly 60% and 87% for patients with and without residual tumor foci at successive debulking surgery, respectively. In another study by Fotopoulou et al.,18 45 patients with OGCT were analyzed. Eighteen patients had primary OGCT and CC-0 was achieved in all patients. Alternatively, 27 patients had recurrent OGCT, and CC-0 was achieved in only 23 patients (85.2%). For all patients, during a median follow-up period of 69 months (range: 4–120 months), the median disease-free survival and overall survival were 58 months and 63 months, respectively. Optimal surgical debulking remains the standard of care for primary and recurrent OGCT settings,8,9 and cytoreduction completeness of residual disease significantly influences recurrence-free survival and overall survival.4,9,19,20 However, with subsequent relapses, optimal (complete) surgical debulking using multivisceral resections may be more challenging and unfeasible, and hence one should look for other effective intraoperative therapeutic modalities, one of which is intraoperative HIPEC. The justification for using HIPEC is primarily based on the thermal-improved efficacious penetration, cytotoxicity and synergism of chemotherapeutic drugs on
the malignant cells.21,22 Moreover, administration of perioperative intraperitoneal chemotherapy offers higher local drug concentrations, lower unwanted systemic side-effects23 and effectively bathes the surgical fields7 for microscopic/macroscopic residual tumor implants, which are the most significant factors influencing the recurrence rates. The above-mentioned benefits of HIPEC allow combination of CRS and HIPEC to emerge as a therapeutic modality that is potentially worth testing for the management of recurrent OGCT. Moreover, in line with the promising outcomes of HIPEC in management of PC arising from recurrent gynecological11,12,24–26 and nongynecological27 malignancies, we highly anticipate that utilization of optimal CRS and HIPEC will also be effective in: (i) managing recurrent OGCT with PC; (ii) reducing the risk of future repetitive recurrences; and (iii) decreasing the need for subsequent debulking surgeries. The selection of chemotherapeutic drugs for HIPEC should be rationalized according to proven scientific research-based improved heat-enhancing effects on the chemotherapeutic drugs. Chemotherapeutic drugs of such nature include cisplatin,28 doxorubicin (adriamycin),29 and mitomycin C.30 The combined platinum- and doxorubicin-based chemotherapy regimen is widely used as a common HIPEC cytotoxic regimen in the management of widespread PC arising from gynecological (epithelial ovarian and endometrial)24–26 and non-gynecological (mesothelioma)27 malignancies with acceptable efficacy and morbidity results. Canbay et al.31 and Gouy et al.7 have previously used platinum-based HIPEC cytotoxic agents in the management of recurrent OGCT with PC. Therefore, the use of cisplatin in our study is well rationalized based on the two previous studies. Conversely, doxorubicin-based HIPEC cytotoxic agents have not been previously used for management of recurrent OGCT with PC. However, in our study, we decided to use doxorubicin for two reasons: (i) doxorubicin is commonly used as a standard HIPEC cytotoxic drug in the management of PC arising from many gynecological and non-gynecological malignancies with very acceptable morbidity and promising results; and (ii) this HIPEC chemotherapy combination of cisplatin plus doxorubicin is expected to maximize the cytotoxic effects with tolerable toxicity and morbidity. However, further research is needed. The morbidity of platinum-based versus doxorubicin-based chemotherapy has been studied and shown to be insignificant. A recent study by
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Glockzin et al.32 compared the treatment-related morbidity in patients receiving oxaliplatin versus doxorubicin plus mitomycin C as HIPEC cytotoxic agents for management of PC. A total of 307 patients were retrospectively analyzed. Forty patients received oxaliplatin whereas the remaining patients received doxorubicin plus mitomycin C. According to Common Terminology Criteria for Adverse Events (version 3.0), grade III/IV (severe adverse events) morbidity was relatively lower in the doxorubicin plus mitomycin C treated groups (37.5%) as compared to the oxaliplatin treated groups (42.5%) without significant statistical difference (P = 0.648). This study suggests that doxorubicin toxicity is generally well tolerated in selected patients and fairly comparable to oxaliplatin. Multifocal pattern of recurrence is very common among OGCT. The most frequently reported regions of recurrence (descending order of frequency) are the pelvis, liver and bowel.18,20 In our study, recurrence multifocality was present in all patients (100%) and reflected by the number of various surgical resections performed (peritonectomy, omentectomy, splenectomy, low anterior resections, etc.). Furthermore, abdominopelvic recurrences occurred in five patients (83.3%) whereas only recurrences confined to the abdomen occurred in one patient (6.7%). Interestingly, no patient developed hepatic recurrences in our study, as opposed to the reported 14% (n = 4/27) and 10% (n = 9/82) of patients in other studies by Fotopoulou et al.18 and Lee et al.,4 respectively. Dissection of paraaortic or pelvic lymph nodes was not performed owing to the quite low rate of retroperitoneal disease involvement in recurrent OGCT settings (less than 6%).33 In our study, all patients are alive and disease-free without proof of recurrence/relapse at 40, 32, 27, 24, 20 and 16 months. The average interval of follow-up after CRS and HIPEC is 27 months (range: 16–40 months). Our study suggests that CRS and HIPEC seem to be a feasible modality for management of recurrent OGCT. Morbidity of CRS and HIPEC was very tolerable and acceptable. Four patients developed grade I/II morbidities without the need for surgical, endoscopic or radiological interventions. One patient developed splenic bed and anterior abdominal wall collections requiring ultrasound-guided aspiration without the need for general anesthesia (grade III). One patient (16.7%) developed pulmonary embolism requiring ICU management (grade IV). All complications were managed successfully without problematic events. No intraoperative mortality or grade V morbidity occurred. There is a learning curve associated with this
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procedure; with accumulated experience in this procedure, an acceptable morbidity rate can be achieved. In our tertiary care center, up to this moment, a total of 161 HIPEC cases (over the past 5 years) were treated by surgeons from the departments of surgical oncology and gynecologic oncology. In particular, a total of 48 HIPEC cases were treated for various malignant ovarian tumors, six cases of which were OGCT with PC – presented here in this study as a sub-group analysis. Complete surgical debulking – despite repetitive recurrences – with or without adjuvant chemotherapy is the standard of care management and has been shown to yield longer survival rates.8,9 Currently, there is no powerful proof that postoperative adjuvant chemotherapy prevents further recurrences of OGCT.9,34,35 However, adjuvant chemotherapy should be employed in the management of widespread disease, inoperable/unresectable metastatic disease or disease with suboptimal cytoreduction.36,37 The BEP combination emerges as the best active chemotherapeutic regimen.10 Other chemotherapeutic regimens with documented usefulness include doxorubicin38 and the cisplatin, vinblastine and bleomycin protocol.37 Earlier studies showed promising results for taxane-based chemotherapy in management of GCT and with less toxicity and fewer adverse side-effects when compared to the BEP regimen.39–41 At present, the Gynecologic Oncology Group is carrying out a randomized phase II clinical trial exploring efficacy of BEP regimen versus the combination of carboplatin and paclitaxel for management of patients with newly diagnosed and chemonaïve recurrent metastatic ovarian sex-cord stromal tumors.42 The outcomes of this important trial are anticipated to provide high-quality and powerful evidences regarding the best active regimens for management of the uncommon recurrent OGCT. In our study, all patients who received prior chemotherapy did not receive adjuvant chemotherapy following CRS and HIPEC. We anticipated they would be unlikely to benefit from further adjuvant chemotherapeutic schedules and we did not want to expose them to additional unnecessary chemotherapy-related toxicities. For chemo-naïve patients (n = 4), we elected to employ adjuvant BEP regimen in three patients and CP regimen in one patient. A genuine question arises: in chemo-naïve patients with recurrent OGCT, is HIPEC needed? No studies have been carried out to explore this question, and this is indeed an interesting area for future research. However, the natural clinical behavior of OGCT is commonly featured by slow growth and increased
© 2014 The Authors Journal of Obstetrics and Gynaecology Research © 2014 Japan Society of Obstetrics and Gynecology
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predisposition for late recurrences, despite complete debulking.2–4 Complete surgical cytoreduction – regardless of multiple recurrences – with or without postoperative chemotherapy remains the standard of care and has been demonstrated to result in prolonged overall survival rates.9 At present, there is no strong evidence supporting that postoperative adjuvant chemotherapy in chemo-naïve patients prevents further recurrences of OGCT.9,34,35 Considering the abovementioned advantages of HIPEC, we anticipated chemo-naïve patients with multiple OGCT recurrences would greatly benefit from a combination therapy of intraoperative HIPEC (optional) plus postoperative chemotherapy. No studies have been conducted on this matter and further research is needed – a study worthy of exploration. Postoperative radiotherapy43,44 and hormonal therapy45,46 – despite limited efficacy and variable disease-free survival – can be offered to patients with refractory high-risk recurrent OGCT, localized or inoperable metastatic disease, or patients who are not candidates for surgical debulking or chemotherapeutic intervention. To our best knowledge, use of CRS and HIPEC for management of recurrent/relapsed OGCT is very limited to two studies only.7,31 Canbay et al.31 employed CRS and HIPEC for five patients with recurrent OGCT. HIPEC was performed with 100 mg cisplatin and allowed to circulate in the abdominopelvic cavity for 40 min at 43.0°C. Median follow-up of patients was 4 years (range: 1–6 years). Among the five patients, one patient died and another three patients were alive with no disease progression. Recently, Gouy et al.7 explored the feasibility of CRS and HIPEC for management of seven patients with recurrent OGCT. Complete cytoreduction was achieved in all patients. HIPEC was performed with oxaliplatin (460 mg/m2) or oxaliplatin (360 mg/m2) plus irinotecan (360 mg/m2) and allowed to circulate in the abdominopelvic cavity for 30 min at 41.0–43.0°C. Median follow-up of patients was 32 months (range: 25–56 months). Among the seven patients, two were disease-free, three had relapsed with PC and two had relapsed with liver metastases. As opposed to our study, all patients were alive and disease-free without proof of recurrence/relapse at 40, 32, 27, 24, 20 and 16 months. The average interval of follow-up after CRS and HIPEC is approximately 27 months (range: 16–40 months). Limitations to this study include the retrospective study design, comparatively small sample size (case series of six patients), relatively short period of follow-
up, and lack of consistent therapy and control group. Such limitations make it fairly uncertain to draw concrete and definitive conclusions. In summary, our study suggests that CRS and HIPEC appear to be a well-tolerated and feasible treatment modality in management of recurrent OGCT. However, long-term follow-up of patients is mandatory to verify efficacy of CRS and HIEPC in reducing the risk of further recurrences of OGCT. Moreover, a larger series of patients and possibly prospective randomized clinical trials, along with prolonged follow-up data and control groups, are needed to draw definitive conclusions regarding CRS and HIPEC for the management of patients with recurrent OGCT.
Acknowledgment The authors sincerely acknowledge the editorial assistance of Ms Evelyn Dinio.
Disclosure None declared.
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