Phase 2 trial of intraperitoneal carboplatin and etoposide as salvage treatment of advanced epithelial ovarian cancer

To evaluate the efficacy of intraperitoneal (IP) carboplatin-based therapy as salvage treatment of ovarian cancer, 46 patients with persistent or recurrent ovarian cancer following initial systemic chemotherapy were treated with a regimen of carboplatin (200-300 mg/m2) and etoposide (100 mg/m2) administered on a monthly schedule. A maximum of six courses of therapy was delivered, followed by a response laparotomy. The treatment program was well tolerated, except for bone marrow suppression, with one-quarter of patients developing platelet count depressions to < or = 50,000/mm3, and one-third experiencing hemoglobin levels of < or = 8 g/dl during treatment. Twelve (38%) of 32 patients evaluable for efficacy of the treatment program achieved a surgically documented response, including 8 (25%) complete responses. Of 25 patients whose largest tumor mass at the initiation of therapy measured < or = 0.5 cm, 11 (44%) responded, including 8 (32%) complete responses. We conclude that the IP administration of carboplatin can result in surgically documented responses when used in the salvage setting in patients with advanced ovarian cancer. The relative efficacy of carboplatin versus cisplatin when administered by the IP route to patients with ovarian cancer previously treated with platinum-based systemic therapy remains to be defined.     

Ifosfamide/mesna plus adriamycin as salvage therapy of advanced epithelial ovarian cancer

Linasmita V, Wilailak S, Srisupundit S, Tangtrakul S, Bullangpoti S,Israngura N. Ifosfamide/mesna plus adriamycin as salvage therapy of advancedepithelial ovarian cancer. Int J Gynecol Cancer 1997; 7:388–391.
The objective of this study was to determine the efficacy and toxicity ofifosfamide/mesna plus adriamycin as salvage therapy for epithelial ovariancancer (EOC). From October1992 to September 1995, patients with advanced EOC who had their recurrentdisease after platinum and cyclophosphamide received ifosfamide(IFX)/mesna andadriamycin (ADR). IFX wasadministered as a 24-hour infusion at a dose of 1.2 g/m² daily forthree days and 1.2 g/m² of mesna were added to the infusion solutionand run for the subsequent 24 hours after completion of the IFX. ADR was given as a singleintravenous bolus at a dose of 50 mg/m² on day 1. Measurementsinclude objective response,duration of response and toxicities to the therapy regimen. There were 20patients who received the therapy regimen, a total of 54 cycles: their medianage was 50 years, range25–71. Of the 17 evaluable patients, two achieved clinical response (1CR,1PR) for an objective response rate of 11.8%. However, among 14 patientswith platinum-refractorydisease, the response rate was only 7.1% (95% CI 0.2%,33.9%) (1CR, 0PR). At the time of the report, the patient is alivewithout evidence of disease. Eightpatients (47.0%) had stable disease. Median time to progression was fivemonths, range two to six. Alopecia and microscopic hematuria were the commontoxicities. In conclusion,the combination of ifosfamide/mesna and adriamycin has tolerable toxicities,but its efficacy as salvage therapy in platinum-refractory epithelial ovariancancer is modest.     

Clinical trial of etoposide and cisplatin as salvage therapy in advanced ovarian carcinoma

The combination of etoposide and cis-platinum was evaluated in the treatment of advanced ovarian cancer. Of 13 treated patients, 4 demonstrated complete clinical responses and 3 demonstrated partial clinical responses. The mean progression free interval was 14 months+ for the complete responders and 8.3+ months for the partial responders. The 100 mg/m2 dose of etoposide appears to be critical in attaining response. This etoposide and cisplatinum combination appears to be effective as a salvage regimen in ovarian carcinoma.     

Etoposide (VP-16-213) plus cis-diamminedichloroplatinum as salvage therapy in advanced epithelial ovarian cancer

Twenty-two patients with advanced epithelial ovarian cancer were treated with etoposide and cis-platinum. Each had failed one to three regimens of combination chemotherapy including cis-platinum-based combinations. Prior total cis-platinum doses ranged from 50 to 1600 mg/m2 with a median of 440 mg/m2. One of 18 evaluable patients had a complete response lasting 8 months, 1 had a partial response lasting 3 months, 8 had stable disease for a mean of 5.6 months, and 8 had progressive disease. The 4 unevaluable patients had undetectable clinical disease for a mean of 6.7 months. Bone marrow suppression was seen in 4 of 22 patients; two of whom had serious sequelae. The poor objective response rate (9.1%) seen with this combination in patients heavily pretreated with cis-platinum is similar to that seen for single agent etoposide in patients pretreated with alkylating agents. The difficulty of obtaining a good objective response in the face of prior cis-platinum-based combination chemotherapy failure is again verified.     

Oral altretamine used as salvage therapy in recurrent ovarian cancer

BACKGROUND: Altretamine has reported efficacy in the treatment of recurrent ovarian cancer following platinum-based therapy. This report presents the cases of two long-term survivors with recurrent ovarian cancer given oral altretamine. CASES: Two patients diagnosed with stage IIIC ovarian cancer underwent optimal cytoreductive surgery. Both women were subsequently treated with platinum-based chemotherapy. One had persistent cancer documented 2 months post therapy, while the other was disease-free for 22 months before recurring. Both received altretamine in a salvage setting. Each of these women achieved a prolonged response to third-line altretamine therapy, and one of whom was disease-free for 4 years and the other remains disease-free over 7 years following initiation of salvage therapy. CONCLUSION: Outpatient-administered oral altretamine can provide a prolonged disease-free interval with minimal toxicity.     

Continuous infusion fluoropyrimidines as salvage therapy for patients with advanced ovarian carcinoma

A major challenge facing those caring for patients with ovarian carcinoma is inducing remission following the failure of first-line treatment. Toward this end, we have examined the efficacy of continuous infusion fluoropyrimidines. During a 2-year period, nine patients with recurrent ovarian carcinoma received treatment with continuous infusion 5-fluorouracil (5-FU) or 5-fluorouracil-deoxyribose as single agents or in combination with other drugs. Eight patients were evaluable, with responses obtained with each treatment regimen. Myelotoxicity was mild, with only 3 episodes of grade 4 toxicity out of 70 total cycles of chemotherapy. Mucositis was moderate to severe, tending to be the dose-limiting adverse effect. Continuous infusion 5-FU in these combinations appears to be active with very acceptable toxicity in heavily pretreated patients.     

Whole abdominal radiation as salvage therapy for epithelial ovarian cancer

Thirty patients found to have residual epithelial ovarian cancer at second-look laparotomy were treated with whole abdominal radiation as salvage therapy. Dosage fractions were 120 rad per day until 3000 rad were delivered, then the pelvis was boosted to 5000 rad at 180 rad per day. Fourteen patients (47%) completed therapy without interruption and seven (23%) completed therapy with interruptions due to myelosuppression ranging from one to four weeks. Therapy was not completed in nine patients (30%). Four of 16 patients (25%) with microscopic residual disease before radiation remain alive and free of disease at 22 to 41 months. Two of six (33%) patients with minimal (less than or equal to 5 mm) residual disease remain alive and free of disease 19 to 40 months after radiation treatment. Patients with residual nodules greater than 5 mm uniformly did poorly. Patients who progressed on primary chemotherapy had a median survival of seven months, compared with more than 38 months for chemotherapy responders. Chronic bowel morbidity was a significant problem, with 30% of patients surviving at least four months from completion of radiation requiring laparotomy for small bowel obstruction. These preliminary results suggest that whole abdominal radiation may be useful in the management of patients who have responded to primary chemotherapy, but the benefit is confined to those patients who have minimal or microscopic disease at second-look laparotomy.     

Intraperitoneal cis-platinum as salvage therapy for refractory epithelial ovarian cancer

Eighteen patients with residual epithelial ovarian cancer at second-look laparotomy were treated with a combined total of 210 cycles of intraperitoneal cis-platinum. Sixteen patients had previously received cis-platinum containing combination chemotherapy systemically. Seven patients had microscopic residual disease at the start of intraperitoneal therapy, eight had macroscopic disease of 5 mm in diameter or less, and three had disease of 6-10 mm in diameter. The drug was administered weekly in 2 L of Ringer's lactate solution via an indwelling Tenckhoff catheter, and the dose ranged from 30-270 mg per cycle (median 120 mg). The dwell time was 20 minutes. After 12 cycles, response was assessed by open laparoscopy (six patients), laparotomy (eight patients), or peritoneal cytology (three patients). One patient developed distant metastases. Local and systemic toxicity was mild. Delays of therapy were necessary for eight of the 210 cycles because of hematologic toxicity. Of the 15 patients available for pathologic evaluation, four (26.6%) had a complete response and two (13.3%) had a partial response. Results of this pilot study suggest a possible role for intraperitoneal cis-platinum in the management of carefully selected patients with epithelial ovarian cancer.     

Unusual presentation of cervical cancer as advanced ovarian cancer

Background Ovarian metastases from cervical cancers are uncommon. In most cases, the primary site of cervix is known before the occurrence of metastasis. We report a case of cervical adenocarcinoma presenting primarily as advanced ovarian cancer with the primary site totally silent. Case report A 47-year old multiparous patient presented to her local hospital with vague abdominal pain for 2 months. Initial investigations with abdominal ultrasound and computerized tomography scan suggested right ovarian dermoid cyst. Her CA125 was 12 μ/ml (0–35). Right salpingo-oophorectomy was performed with the histologic diagnosis of dermoid cyst. Follow-up after 5 months showed a higher level of serum CA 125 (1,594 μ/ml) and a negative cervical smear. Exploratory laparotomy was done with the intent to progress to total abdominal hysterectomy, left salpingo-oophorectomy and omentectomy with staging. Surprisingly, the histologic features of the specimen obtained at laparotomy were consistent with a moderately differentiated cervical adenocarcinoma with metastases to corpus uterus, ovaries, left fallopian tube, omentum and pleural cavity. The final stage was stage IV cervical cancer. Following this, the patient was referred to medical oncologist for chemotherapy. Conclusion Cervical carcinoma should be suspected in any patient presented with bilateral ovarian tumors and positive ascitic fluid cytology. Negative cervical smears do not exclude the possibility of primary cervical carcinoma.     

Retrospective analysis of weekly topotecan as salvage therapy in relapsed ovarian cancer

OBJECTIVE: To retrospectively investigate the safety and efficacy of weekly topotecan in heavily pretreated patients with ovarian cancer. METHODS: Data were collected by retrospective review of patient records. Eligible patients had received > or =2 prior regimens for ovarian cancer before treatment with weekly topotecan. Efficacy was determined by measurable disease or CA 125 levels. Adverse event and growth factor support data were also collected. RESULTS: Fifty patients (median age, 61 years) were evaluable for safety and received a total of 244 4-week cycles of therapy (median, 3; range, 1-21 cycles). Most patients (84%) had measurable disease, and 30% had performance status of > or =2. Patients had received two to six prior treatments for ovarian cancer. Median weekly dose per patient was topotecan 3.7 mg/m(2). Grade 4 hematologic toxicities (generally manageable) occurred in 4% of patients. One patient had febrile neutropenia. Grade 3/4 nonhematologic toxicities were fatigue in two (4%) patients. Forty-two patients were evaluable for response. Of 35 evaluable patients with measurable disease, 11 (31%) had a partial response (median duration, 3 months), and 15 (43%) patients had stable disease (median duration, 3.5 months). Of 41 evaluable patients with elevated CA 125 (median, 154 U/l; range, 47-7200 U/l), 11 (27%) had > or =50% decreases or normalization of CA 125 levels. Median time to progression in all patients with stable disease has not been reached (follow-up range, 1.5-17.3 months). CONCLUSIONS: Weekly topotecan is active and well tolerated in heavily pretreated patients with relapsed ovarian cancer. Prospective studies of this regimen are warranted.     

Carboplatin and etoposide as first-line chemotherapy in advanced epithelial ovarian cancer

Carboplatin and etoposide are chemotherapeutic agents active in ovarian cancer, previously proved to have a synergistic activity in animal models. The objective of this phase II study was to determine the feasibility and the efficacy of the combination of carboplatin and etoposide in previously untreated patients with advanced epithelial ovarian cancer.
Carboplatin, 400 mg m⁻² day 1, and etoposide, 100 mg m⁻² days 1–3 every 4 weeks were administered to 28 patients with advanced stage (III–IV) ovarian cancer and a performance status 0–2 (ECOG scale), as a firstline chemotherapy.
Twenty-three patients were evaluable for response; 15 (65%) (95% CI: 45–81%) responded, 10 (43%) (95% CI: 25–63%) with clinical complete response. Pathologic complete response demonstrated during postchemotherapy laparotomy was noted in 5/23 (22%) (95% CI: 9–42%) patients. The median progression-free interval was 8.5 months, and median survival was 19.5 months. Toxicity, mainly hematologic, was severe. Nine (32%) patients experienced at least one episode of leucopenic fever, which consequently led to toxic deaths in two (7%) patients.
The relatively low response and survival rates with increased toxicity rate are disappointing.     

晚期卵巢癌外科治疗中的过度与不足

国内卵巢癌循证医学研究非常少,特别是在卵巢癌手术方面,国际学术领域很少有我国学者的研究报道,因而对卵巢癌手术度的把握,观念上和实践上都非常匮乏。文章分别从卵巢癌外科治疗观念的变更、外科治疗中存在的过度与不足等方面进行讨论。     

Mini-laparotomy in advanced ovarian cancer

Optimal cytoreduction (OCR) remains the gold standard treatment of ovarian cancer. Current radiological imaging has limited sensitivity and specificity in prediction of achieving OCR prior to surgery. This prospective pilot study included 50 patients with advanced ovarian carcinoma. Prior to the main laparotomy, a mini-laparotomy—just large enough to allow a hand in—was performed. A decision was then made as to whether achieving OCR is “possible”, “not possible” or lastly “unsure”. Formal laparotomy then followed. At the end of the formal laparotomy, cytoreduction was regarded as either “optimal” or “suboptimal” based on residual disease. Out of 45 cases where results were deemed suitable for analysis, 27 were regarded as “OCR possible”, out of which OCR was achieved in 24 cases following full laparotomy. Ten were commented upon as “unsure” and only in three cases OCR was feasible. Eight were classed as “OCR not possible” and in none of these OCR was obtained. The only noted complication associated with mini-laparotomy was bleeding in just three cases (6%). The sensitivity, specificity, PPV and NPV of mini-laparotomy were 100%, 73%, 89% and 100%, respectively. However, when “unsure”, only in 30% OCR was achieved. We concluded that mini-laparotomy is a safe, simple and effective technique for predicting feasibility of OCR. This simple technique could obviate the need for full laparotomy in patients who may benefit from neo-adjuvant chemotherapy.     

New approaches to the treatment of advanced ovarian cancer

With this research work our aim is to summarise the bulgarian and the experience of foreign /western/ authors in the field of treatment of the advanced ovarian cancer. We summerised the experience from the treatment of 250 patients for 5 years period /from 2000 till 2006/. On the basis from the results of treatment we tried to produce algorrhythm, which can be used from the oncogynaecologists in their everyday practice. We are convinced that with the development of the oncogynaecological science and practice this algorrhythm can be bettered. The main therapeutical approaches for the treatment of the advanced ovarian cancer include: primary cytoreductive surgery, neoadjuvant and adjuvant chemotherapy, interval debulking, second look laparotomy, intestinal resections and anastomosis. Very often is made resection of the bladder and reanastomosis of the ureters. The use of new chemotherapeutics, radiotherapy, hormonal medicaments and immunotherapy will better the fight against the advanced ovarian cancer.     

Topotecan and liposomal doxorubicin in recurrent ovarian cancer: is sequence important?

Abstract.   Dupont J, Aghajanian C, Andrea G, Lovegren M, Chuai S, Venkatraman E, Hensley M, Anderson S, Spriggs D, Sabbatini P. Topotecan and liposomal doxorubicin in recurrent ovarian cancer: is sequence important? Int J Gynecol Cancer 2006; 16(Suppl. 1): 68–73.
A variety of agents have emerged to treat patients with recurrent epithelial ovarian cancer (EOC). Most patients receive both topotecan (T) and liposomal doxorubicin (D); however, there are no data regarding the benefit of a sequence—D followed by T (DT) or T followed by D (TD). We identified 89 consecutive patients with recurrent EOC, who received both D and T from January 1994 to January 2004 at Memorial Hospital. We compared the duration of treatment, toxicity, and overall survival (OS) for patients who received either DT or TD. Sixty-four patients received DT, and 25 patients received TD. The groups were balanced regarding age, stage, surgical debulking, platinum sensitivity, prior therapy, and intervening drugs between D and T. Median numbers of cycles on DT and TD were seven and six, respectively ( P = 0.61); there was no difference in duration based on platinum sensitivity. Removal from therapy for toxicity was similar, DT (22%) and TD (36%) ( P = 0.18). Finally, there was no difference in median OS based on sequence, DT (18.28 months) and TD (17.75 months) ( P = NS). Platinum sensitivity did not affect median OS based on sequence. Based on duration, toxicity, and OS there is no advantage of one sequence of D and T when treating patients with recurrent EOC.     

Topotecan as a second-line therapy in patients with ovarian and primary peritoneal cancer: initial response and long-term follow-up

The purpose of this study was to evaluate the role of topotecan at a dose of 5-day standard 1.5 mg/m2/day in patients with relapsed ovarian cancer. Two different groups of patients were included. In group 1, 23 patients who had bidemensionally measurable disease were examined, and in group 2, 11 patients were given topotecan after positive second-look laparotomy (SLL) were analyzed. Total number of cycles was 190 with a median value of six cycles. In group 1, three (13%) patients had complete response (CR) and seven (30%) had partial response (PR) with a total response rate of 43%. Six patients (27%) had stable disease (SD), and seven (30%) had progressive disease (PD). Median survival durations for patients with CR, PR, SD, and PD were 35, 14, 15, and two months, respectively. In group 2, two patients had PD during treatment. The remaining nine patients had no measurable disase or marker relapse at the end of treatment period. Median survival duration was 27 months. In conclusion, topotecan had significant antitumor activity as a second-line therapy in relapsed ovarian cancer patients with measurable disease. In a subgroup of patients with positive second-look laparotomy topotecan was also associated with long median survival duration.     

First-line intraperitoneal cisplatin-paclitaxel and intravenous ifosfamide in Stage IIIc ovarian epithelial cancer

OBJECTIVES: To determine the feasibility, toxicity and efficacy of a first-line combination of intraperitoneal (i.p.) paclitaxel and cisplatin and intravenous (i.v.) ifosfamide in untreated patients with Stage IIIc ovarian cancer after cytoreduction or biopsies only. METHODS: Twenty-six patients entered the trial from 1995 to 1999. Twenty underwent initial cytoreduction which was complete, with residual nodules < 0.5 cm or = 0.5 cm in six, five and nine patients, respectively. Six patients underwent biopsies only at initial surgery. Ten cycles of chemotherapy were planned by both routes. Second-look surgery was planned for all patients. RESULTS: Twenty-one (81%) of the 26 patients were in complete clinical remission (CCR) at the time of second-look surgery. Of the 15 patients who underwent second-look surgery, ten were in CCR including seven in complete remission (CR) confirmed pathologically. Median overall-survival had not been reached at 53 months (range 16-87), and median disease-free survival was 40 months (range 8-85), for a median follow-up of 53 months (range 16-87). Local toxicity consisted mainly of mild abdominal pain. Systemic toxicity was essentially haematological, with eight (31%) grade 3-4 leukopenia. CONCLUSION: This study has demonstrated the feasibility, moderate toxicity and efficacy of first-line intraperitoneal paclitaxel-cisplatin chemotherapy.