Small-volume Residual Ovarian Cancer Research Articles

Gynecological malignancies

A large study of tumors of low malignant potential confirmed the favorable survival in this group of patients compared to invasive epithelial ovarian tumors. Only 8% of patients died with recurrent disease after surgery. Patients with stage IA borderline tumors with mucinous histology tended to recur later and carried a poorer prognosis than patients with serous histology and similar stage. The group at highest risk for relapse were age greater than 70, stage II or III tumors, and histology other than serous. Long-term survival in this group was less than 75%. This high-risk group of patients should be targeted for innovative adjuvant treatment strategies. This year several well-designed studies with large sample sizes showed DNA ploidy to be an important new independent prognostic factor in stage I ovarian carcinoma. In patients with well-differentiated early stage ovarian cancer, DNA flow cytometric analysis may indicate subgroups with less favorable prognostic characteristics. This method of analysis may be beneficial in determining the need for additional treatments after surgery for early stage ovarian carcinoma. Recommendations for the definitive management of early stage ovarian cancer awaits completion of current GOG and European randomized prospective studies. Paclitaxel given in combination with platinum-containing agents is an intense area of research for treatment of advanced stage disease. Early data from a prospective randomized trial of patients with advanced ovarian cancer showed a higher response rate and longer disease-free survival in patients treated with paclitaxel and cisplatin compared to a standard regimen of cyclophosphamide and cisplatin. The impact of this treatment on long-term survival awaits maturation of data. Preliminary results evaluating G-CSF in combination with paclitaxel and cisplatin for dose escalation was reported. Paclitaxel, 250 mg/m2, and cisplatin, 75 mg/m2, were the maximally tolerated doses, with peripheral neuropathy or myalgias the dose limiting toxicities. Further studies are now underway to test the effect of dose-response with escalation therapies and to determine the optimal dose and schedule for the management of patients with advanced ovarian cancer. IL-3 significantly ameliorated neutropenia but did not prevent cumulative platelet toxicity in a regimen utilizing high-dose carboplatin. This mild improvement in myelosuppression was obtained at the cost of significant toxicity. Nausea, vomiting, malaise, bone pain, headache, fever, chills and facial flushing were frequent. Intraperitoneal chemotherapy was tested as a means of consolidation treatment for patients after having a negative second-look laparotomy. These treatments were shown to be feasible; however, prospective randomized trials will be necessary to determine a benefit over operative therapy alone. Several studies addressed to problem of residual disease after primary surgery and adjuvant chemotherapy. A large phase II study conducted by the GOG confirmed the activity of salvage cisplatin-based intraperitoneal chemotherapy in patients with small-volume residual ovarian cancer with favorable pretreatment characteristics. Whether intraperitoneal platinum-based therapy represents an advantage over systemic platinum therapy is being addressed in a prospective SWOG study. The use of six additional cycles of CAP for treatment of residual disease after primary treatment of surgery and adjuvant chemotherapy did not significantly improve complete pathological response and survival. Prolonged duration of chemotherapy above six cycles is not likely to impact treatment for residual disease. A regimen of high dose carboplatin was compared to whole abdominal radiotherapy for treatment of residual disease after initial chemotherapy. There was no difference in survival or disease-free survival between treatments.(ABSTRACT TRUNCATED)

Toxicities, complications, and clinical encounters during intraperitoneal chemotherapy in 17 women with ovarian cancer

Purpose of the researchIntraperitoneal (IP) chemotherapy is a viable and superior treatment to standard intravenous (IV) chemotherapy in women with small volume residual ovarian cancer following optimal debulking. Despite this clinical advantage, widespread adoption of the treatment regimen has been hampered by concerns related to toxicities and complications. The purpose of this descriptive study was to describe nursing implications related to toxicities, complications and clinical encounters in 17 women with ovarian cancer who received IP chemotherapy. Methods and sampleWomen with ovarian cancer who received IP chemotherapy at one NCI-designated comprehensive cancer center were accrued. Data related to IP chemotherapy summary, clinical encounters and admissions were obtained through comprehensive chart audits. Key resultsCommon treatment-related toxicities included nausea and vomiting, fatigue, hypomagnesia, pain, neuropathy, anemia, and constipation. Reasons for dose-modifications were multi-factorial, and were primarily related to catheter complications and chemotherapy toxicities. The number of clinical encounters was high, and they were primarily related to admissions for inpatient IP chemotherapy and follow-up clinic visits. ConclusionsTreatment-related toxicities and complications were common in women with ovarian cancer who received IP chemotherapy. Use of IP chemotherapy results in multiple clinical encounters, such as outpatient clinic visits and inpatient admissions. Nursing is a critical part of the interdisciplinary approach in caring for women treated with IP chemotherapy. Interdisciplinary teams with high levels of knowledge and skills related to IP chemotherapy administration are needed to manage treatment-related toxicities and complications, and support multiple clinical encounters during treatment.

Intraperitoneal chemotherapy in the management of ovarian cancer: focus on carboplatin

Both pre-clinical studies and phase 1-2 clinical trials have provided strong support for the potential role of regional drug delivery in the management of epithelial ovarian cancer, a disease process whose major manifestations remain largely localized to the peritoneal cavity in the majority of individuals with this malignancy. The results of 3 phase 3 randomized trials have revealed the favorable impact of primary cisplatin-based intraperitoneal chemotherapy in women who initiate drug treatment with small-volume residual ovarian cancer following an attempt at optimal surgical cytoreduction. Concerns have been raised regarding the toxicity of regional treatment, particularly the side-effect profile associated with cisplatin. One rational approach to improving the tolerability of intraperitoneal chemotherapy is to substitute carboplatin for cisplatin. This review discusses the rationale for and data supporting regional treatment of epithelial ovarian cancer, and highlights the potential role for intraperitoneal carboplatin in this clinical setting.

What is the optimal approach to the administration of intraperitoneal chemotherapy in ovarian cancer?

Three well-designed and conducted randomized phase 3 trials have revealed that the intraperitoneal administration of cisplatin-based chemotherapy as primary treatment of small-volume residual advanced ovarian cancer improves both progression-free and overall survivals compared to an all intravenous cisplatin-based regimen. Based on very reasonable extrapolations from existing evidence-based data, a number of possible "options" can be proposed that use the intraperitoneal route for delivery of chemotherapy in this clinical setting.

Intraperitoneal Chemotherapy as First-Line Treatment in the Management of Epithelial Ovarian Cancer

Recent evidence has suggested improved outcomes following incorporation of intraperitoneal chemotherapy administration with intravenous systemic chemotherapy as first-line treatment of small volume residual epithelial ovarian cancer. This review focuses on the mechanism of actions of the chemotherapeutic drugs and reviews the possible reasons for the superior outcomes of intraperitoneal chemotherapy.

A Phase II Study of Intraperitoneal Cisplatin and Thiotepa in Residual Ovarian Carcinoma: A Gynecologic Oncology Group Study

Objective.Patients with advanced epithelial ovarian cancer treated with salvage therapy using new combinations of systemic chemotherapy, radiation therapy, and systemic immunotherapy have had limited success. Since the most common site of relapse or failure to conventional systemic chemotherapy has been the peritoneal cavity, intraperitoneal (IP) chemotherapy was selected to treat small-volume residual disease.Methods.Sixty-five patients were entered on a protocol using intraperitoneal cisplatin and thiotepa following a response to intravenous cisplatin-based chemotherapy. Patients had surgically documented residual disease (0.5 cm or less maximum tumor diameter) at completion of preprotocol surgery and had no clinical, radiologic, or histologic evidence of extraperitoneal disease. Cisplatin (100 mg/m2) and thiotepa 30 mg/m2was delivered intraperitoneally every 4 weeks for a maximum of six cycles. The dose of thiotepa was reduced to 12 mg/m2due to unexpected severe myelosuppression.Results.Of the 52 evaluable patients, grade 4 neutropenia, thrombocytopenia, neurotoxicity, and nephrotoxicity were observed in 31, 19, 13, and 6% of patients, respectively. For all evaluable patients, the complete response rate was 19% and the partial response rate was 2% for a total response rate of 21%. Of 16 patients who had a reassessment laparotomy, 10 patients achieved a surgically documented complete response and 1 patient had a partial response. Four patients are still in response for 67+, 70+, 70+, and 73+ months after third-look surgery. Three patients who did not undergo third-look surgery after chemotherapy are alive and clinically free of disease at 49+, 69+, and 85+ months.Conclusion.Thiotepa, when used with cisplatin for IP salvage therapy in patients with advanced or recurrent ovarian cancer, may produce significant myelosuppression and doses must be adjusted accordingly. In cisplatin-sensitive patients with small-volume residual ovarian cancer, IP cisplatin and thiotepa appears to have activity. Determining the utility of this approach will require a randomized trial.

Intraperitoneal chemotherapy in the treatment of ovarian cancer.

Over the past decade the intraperitoneal administration of chemotherapeutic agents has evolved from a pharmacokinetic concept into a rational treatment strategy for a selected group of women with advanced ovarian cancer. A recently reported large randomized controlled clinical trial has confirmed that the intraperitoneal administration of cisplatin is associated with superior efficacy and less toxicity than intravenous cisplatin in patients receiving initial chemotherapy for advanced small-volume residual ovarian cancer. Intraperitoneal chemotherapy is also a reasonable therapeutic option in women with very-small-volume residual disease following an initial response to a platinum-paclitaxel systemic chemotherapy programme. On the basis of the data available to date, further exploration of a role for intraperitoneal chemotherapy in the management of ovarian cancer is indicated.

Phase II study of intraperitoneal cisplatin plus systemic etoposide as second-line treatment in patients with small volume residual ovarian cancer

The efficacy and toxicity of intraperitoneal (i.p.) cisplatin plus systemic etoposide were studied in 36 patients with small (< 2 cm) residual i.p. ovarian cancer after achieving a partial response to platinum-based, first-line chemotherapy. Treatment comprised 90 mg/m2 i.p. cisplatin with intravenous (i.v.) sodium thiosulphate (day 1) and 600-800 mg/m2 i.v. etoposide (days 1 and 2), every 4 weeks for four to six cycles. 7 patients achieved a pathological complete response (pCR), one a pathological partial response and 16 were clinically stable without evidence of disease. After a median follow-up of 13 months, the median progression-free survival (PFS) was 11 months (95% confidence interval 7-16 months). The actuarial PFS at 24 months is 22% (95% confidence interval 8-36%). Three of six relapses after achieving a pCR (50%) were sited i.p., and 9 of 14 other patients with disease progression (64%) had an i.p. relapse, indicating insufficient local efficacy. There was no renal toxicity, but grade 3-4 leucopenia occurred in 63% and grade 3-4 thrombocytopenia in 8% of cycles, while nausea, vomiting and complete alopecia were common. Although side-effects were acceptable, the efficacy of treatment with i.p. cisplatin plus i.v. etoposide is limited.

Second-line chemotherapy for refractory cancer: intraperitoneal chemotherapy.

Over the past decade intraperitoneal therapy in the management of ovarian cancer has evolved from a pharmacokinetic concept into a rationale treatment strategy for a specific subset of patients with this disease. Patients with small-volume residual ovarian cancer (microscopic disease only or macroscopic tumor with largest tumor nodule < or = 0.5 cm in maximum diameter) when treatment is initiated are reasonable candidates to be considered for this therapeutic strategy. At least for salvage platinum-based intraperitoneal therapy, a documented prior response to systemic cisplatin or carboplatin helps to define a patient population who would be anticipated to have the greatest opportunity to respond to a regional treatment approach.

Salvage intraperitoneal therapy of ovarian cancer employing cisplatin and etoposide: A gynecologic oncology group study

Abstract Background . To further explore the potential of salvage intraperitoneal cisplatin-based therapy in patients with small-volume residual ovarian cancer a Phase II trial was conducted by the Gynecologic Oncology Group. Methods . Ninety-two patients entered into this trial were treated with a regimen of cisplatin (100 mg/m 2 ) and etoposide (200 mg/m 2 ) delivered intraperitoneally every 4 weeks for a maximum of six cycles. Results . Of the 84 patients evaluable for toxicity, grades 3-4 neutropenia, thrombocytopenia, neurotoxicity, and nephrotoxicity were observed in 25, 12, 6, and 9% of patients, respectively. A total of 41 patients were evaluable for response to the treatment program. Of the 25 evaluable patients with favorable pretreatment characteristics (prior response to systemic cisplatin or relapse >6 months after completing initial chemotherapy), 10 (40%) achieved a surgically documented response (S-R), including 6 (24%) who achieved a surgically documented complete response (S-CR). Of the 16 patients with unfavorable pretreatment characteristics (less than a partial response to systemic cisplatin or a response of Conclusions . In this large multi-institutional cooperative group study, we have confirmed the activity of salvage cisplatin-based intraperitoneal chemotherapy in patients with small-volume residual ovarian cancer who have favorable pretreatment characteristics. The overall impact of these responses on disease-free and overall survival remains to be defined.

Salvage Intraperitoneal Therapy of Ovarian Cancer Employing Cisplatin and Etoposide: A Gynecologic Oncology Group Study

Background. To further explore the potential of salvage intraperitoneal cisplatin-based therapy in patients with small-volume residual ovarian cancer a Phase II trial was conducted by the Gynecologic Oncology Group. Methods. Ninety-two patients entered into this trial were treated with a regimen of cisplatin (100 mg/m 2) and etoposide (200 mg/m 2) delivered intraperitoneally every 4 weeks for a maximum of six cycles. Results. Of the 84 patients evaluable for toxicity, grades 3-4 neutropenia, thrombocytopenia, neurotoxicity, and nephrotoxicity were observed in 25, 12, 6, and 9% of patients, respectively. A total of 41 patients were evaluable for response to the treatment program. Of the 25 evaluable patients with favorable pretreatment characteristics (prior response to systemic cisplatin or relapse >6 months after completing initial chemotherapy), 10 (40%) achieved a surgically documented response (S-R), including 6 (24%) who achieved a surgically documented complete response (S-CR). Of the 16 patients with unfavorable pretreatment characteristics (less than a partial response to systemic cisplatin or a response of <6 months duration) the S-R rate was only 12% (S-CR: 6%). Conclusions. In this large multi-institutional cooperative group study, we have confirmed the activity of salvage cisplatin-based intraperitoneal chemotherapy in patients with small-volume residual ovarian cancer who have favorable pretreatment characteristics. The overall impact of these responses on disease-free and overall survival remains to be defined.

Evidence Supporting the Superiority of Intraperitoneal Cisplatin Compared to Intraperitoneal Carboplatin for Salvage Therapy of Small-Volume Residual Ovarian Cancer

Purpose: To examine the relative efficacy of cisplatin-based intraperitoneal (IP) therapy versus carboplatin-based IP therapy as salvage treatment of small-volume residual ovarian cancer. Patients and methods: We retrospectively examined the surgically defined response rates of patients with ovarian cancer treated at the Memorial SIoan-Kettering Cancer Center on four organoplatinum-based salvage IP trials (cisplatin/etoposide, cisplatin/cytarabine, carboplatin/etoposide, carboplatin/etoposide + recombinant human erythropoietin). Additional criteria for inclusion in this analysis were: (a) small-volume residual disease (microscopic disease only or largest residual tumor mass ⩽ 0.5 cm) when IP therapy was initiated; (b) prior response to organoplatinum-based systemic therapy; (c) laparotomy evaluation for response to the IP salvage program. Results: The surgically documented complete response rate for patients with microscopic disease treated with cisplatin-based or carboplatin-based therapy was 46% (6/13) versus 38% (6/16), respectively ( P > 0.25). In contrast, the surgically documented overall and complete response rates for patients with small-volume macroscopic disease treated with cisplatin or carboplatin were 71% (12/17) versus 32% (6/19) ( P < 0.05, χ 2 test with Yates' correction), and 41% (6/17) versus 11% (2/19) (p < 0.1), respectively. Conclusion: In agreement with experimental data demonstrating that the concentration of platinum within tumor is higher following equimolar doses of cisplatin, compared to carboplatin, we have observed, in this retrospective analysis, a higher surgically documented response rate for patients with small-volume residual macroscopic ovarian cancer receiving salvage cisplatin-based IP therapy. While a randomized trial will be required to definitively address the question of the relative effectiveness of the two commercially available organoplatinum agents for IP treatment of ovarian cancer, our data suggest that cisplatin is the superior agent for regional therapy in this disease.

Intraperitoneal chemotherapy in the management of ovarian cancer

During the past decade, intraperitoneal therapy of ovarian cancer has evolved from a pharmacologic model into an established treatment technique for women with this malignancy. Approximately 40% of patients with small-volume residual ovarian cancer (microscopic disease or macroscopic tumor, < or = 0.5 cm in maximum tumor diameter), after an objective response to initial organoplatinum-based systemic chemotherapy, may have a surgically documented complete response to platinum-based intraperitoneal chemotherapy. Patients who have not responded to systemic platinum administration rarely will respond to the drug given intraperitoneally, despite the presence of only small-volume residual disease when this regional treatment strategy is used. Other agents with antineoplastic activity after intraperitoneal administration in women with ovarian cancer include mitoxantrone, taxol, alpha-interferon and gamma-interferon, and interleukin-2. Although intraperitoneal therapy currently is being examined as a component of the initial chemotherapeutic program for patients with ovarian cancer, a precise role for regional drug delivery in this clinical setting remains to be defined.

Evidence for Persistence of Mitoxantrone within the Peritoneal Cavity Following Intraperitoneal Delivery

In clinical trials examining the intraperitoneal (ip) administration of mitoxantrone as therapy of platinum-refractory small-volume residual ovarian cancer, the characteristic "blue color" of the agent has been demonstrated to stain the surface of the peritoneal cavity and to persist for ⩾1 month following the last course of therapy. To determine if this blue staining material contains potentially cytotoxic concentrations of mitoxantrone, we analyzed tissue obtained at exploratory laparotomy in six women who had last received the agent administered ip from 6-22 weeks prior to surgery. Concentrations of mitoxantrone ranged from <0.1 to 13.8 μg/g of tissue examined. Since any mitoxantrone present on the peritoneal surface will be highly protein bound, any residual drug may not have cytotoxic potential. The dose-response curves of mitoxantrone in a human clonogenic cytotoxicity assay against the RPMI 2780/S human ovarian cell line were virtually identical when the cells were incubated in either 5 or 50% fetal bovine serum, suggesting that protein binding will not significantly impair mitoxantrone-induced tumor cell killing. We conclude that the ip administration of mitoxantrone may lead to prolonged exposure of surface tumor to the high local concentrations of the active cytotoxic agent. This effect may contribute significantly to the antineoplastic potential of ip mitoxantrone in patients with small-volume residual ovarian cancer.

Characteristics of Patients With Small-Volume Residual Ovarian Cancer Unresponsive to Cisplatin-Based Intraperitoneal Chemotherapy

MARKMAN, MAURIE; BEREK, JONATHAN S.; BLESSING, JOHN A.; McGUIRE, WILLIAM P.; BELL, JEFFREY; HOMESLEY, HOWARD Author Information

Association between pretreatment CA-125 levels and surgically documented complete responses in patients with ovarian cancer treated with second-line intraperitoneal therapy.

Approximately 20%-40% of patients with small-volume residual ovarian cancer, following systemically administered platinum-based chemotherapy, will respond to a second-line intraperitoneal treatment regimen. In an effort to improve the selection criteria for patients being considered for this regional therapeutic approach, we retrospectively evaluated the influence of pretreatment CA-125 levels on the ability of a group of 70 patients with small-volume residual ovarian cancer (no tumor mass greater than 1 cm in diameter) to achieve a surgically defined complete response (S-CR) following treatment on one of three phase-2 intraperitoneal chemotherapy trials conducted at the Memorial Sloan-Kettering Cancer Center. Overall, 18/46 (39%) patients with normal pretreatment CA-125 levels (less than or equal to units/ml) achieved a S-CR, compared to only 4/24 patients (17%) with an elevated pretreatment value (chi 2 = 3.7, P greater than 0.5). Despite the lower S-CR rate in patients with elevated CA-125 levels, the duration of response and survival were similar in the two patient populations achieving a S-CR. Thus, we conclude that an elevated pretreatment CA-125 level in a patient with small-volume residual ovarian cancer should not be used by itself to disqualify an individual from consideration for a second-line intraperitoneal treatment regimen, although the finding suggests a reduced likelihood of achieving a S-CR with this therapeutic approach.

Characteristics of patients with small-volume residual ovarian cancer unresponsive to cisplatin-based ip chemotherapy: Lessons learned from a gynecologic oncology group phase II trial of ip cisplatin and recombinant α-interferon

The Gynecologic Oncology Group conducted a phase II trial of intraperitoneal (ip) cisplatin plus recombinant human α-interferon in patients with small-volume persistent/recurrent ovarian cancer. This study was based on the known single agent activity of the drugs administered by the ip route and experimental evidence of cytotoxic synergy between the agents. In 18 evaluable patients, only 1 partial response was observed (5.5% response rate). In an effort to explain these disappointing findings, patients were retrospectively divided into two groups; those with favorable disease (documented response to systemic platinum and absence of surgical findings of diffuse carcinomatosis at laparotomy prior to initiation of ip therapy) or unfavorable disease (no evidence of response to systemic platinum and/or laparotomy findings of diffuse carcinomatosis before ip treatment). The favorable patient population would be predicted to have a far greater chance of responding to local therapy, but only 3 of the evaluable patients fell into this category. In the 15 unfavorable patients, only 1 partial response was observed (7% response rate). We conclude that patients who have failed to demonstrate a response to systemic cisplatin or carboplatin or who have diffuse carcinomatosis at second-look laparotomy are poor candidates for second-line ip cisplatin-based therapy, even if they are considered to have small-volume residual disease (each individual tumor nodules <0.5–1 cm). Such patients should be considered for alternative therapeutic strategies.

Salvage intraperitoneal therapy of small-volume residual ovarian cancer: impact of pretreatment finding of peritoneal carcinomatosis on the surgical complete response rate.

Second-line intraperitoneal (i.p.) therapy has been demonstrated to result in surgically defined complete responses (S-CR) in 25%-40% of patients with small-volume residual ovarian cancer (microscopic disease or largest tumor mass less than 1 cm in diameter). To evaluate the influence of the surgical finding of diffuse peritoneal carcinomatosis on the S-CR rate to salvage i.p. therapy in this patient population, we retrospectively reviewed the operative reports of 70 patients with small-volume residual ovarian cancer treated on one of three phase-2 second-line i.p. trials at the Memorial Sloan-Kettering Cancer Center. Of the 11 patients with diffuse carcinomatosis, none achieved a S-CR compared to a S-CR rate of 37% (22/59) in patients without this surgical finding (chi 2 = 6.0; P less than 0.025). However, of the 7 patients with diffuse carcinomatosis treated on a cisplatin-based i.p. program, the only 2 who had previously responded to systemic platinum also experienced a response (partial) to the i.p. cisplatin regimen. In conclusion, while the surgical finding of diffuse peritoneal carcinomatosis indicates a poor prognosis in patients with small-volume residual ovarian cancer for response to i.p. chemotherapy, patients in this clinical setting with prior evidence of platinum sensitivity may experience some benefit from an i.p. cisplatin-based treatment strategy.

Impact of laparotomy finding of significant intraabdominal adhesions on the surgically defined complete response rate to subsequent salvage intraperitoneal chemotherapy

One possible explanation for the failure of the high concentrations of cytotoxic agents achieved following intraperitoneal (i.p.) drug delivery to produce a favorable response in patients with ovarian cancer is the inability of the drug-containing fluid to be adequately distributed throughout the peritoneal cavity, usually because of intraabdominal adhesion formation. To evaluate the influence of the severity of adhesions, observed at the time of laparotomy performed immediately preceding the initiation of i.p. therapy, on the ability to achieve a surgically defined complete response (S-CR), we retrospectively reviewed the operative reports of 70 patients with small-volume residual ovarian cancer treated on one of three phase-2 salvage i.p. trials at the Memorial Sloan-Kettering Cancer Center. The S-CR rate in the 36 patients with limited adhesion formation observed upon entering the peritoneal cavity was 28%, compared to 35% in the 34 patients with extensive adhesions (P greater than 0.05). In 33 patients treated with a phase-2 cisplatin-based i.p. program, who had previously responded to systemic platinum, 47% (8/17) and 44% (7/16) of those with limited and extensive adhesions, respectively, achieved a S-CR (P greater than 0.05). We conclude that the presence of extensive adhesions observed within the peritoneal cavity at the time of a laparotomy performed immediately prior to the initiation of i.p. therapy does not have a negative impact on the potential to achieve an S-CR, assuming it is technically feasible to lyse all significant adhesions prior to the completion of the operative procedure.