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Systematic review on the efficacy of cytoreductive surgery combined with perioperative intraperitoneal chemotherapy for peritoneal carcinomatosis from colorectal carcinoma. A systematic review on the efficacy of cytoreductive surgery and perioperative intraperitoneal chemotherapy for pseudomyxoma peritonei. A systematic review on the efficacy of cytoreductive surgery combined with perioperative intraperitoneal chemotherapy for diffuse malignancy peritoneal mesothelioma.
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Intraperitoneal Therapy of Ovarian Cancer
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In addition, a recently reported phase III trial comparing initial treatment of small-volume residual advanced ovarian cancer with either intravenous or intraperitoneal cisplatin concluded that the intraperitoneal route of drug administration was associated with a longer survival and less toxicity. Patients with cancers resistant to initial systemic chemotherapy or with larger tumor bulk should probably be treated by alternative strategies.
Initial treatment of ovarian cancer with cisplatin delivered by the intraperitoneal route is a reasonable therapeutic option, based on currently available data. The intraperitoneal delivery of antineoplastic agents remains an interesting and potentially important management strategy for a select group of individuals small-volume residual disease with advanced ovarian cancer. Further exploration of a more defined role for this therapeutic approach in ovarian cancer is indicated.
The concept of the intraperitoneal administration of antineoplastic agents in the management of ovarian cancer has attracted the interest of numerous investigators. In fact, alkylating agents, the first cytotoxic drugs to be introduced into clinical practice, were initially examined for intraperitoneal delivery in the early s [ 1 ]. However, it was not until the late s that both the problems and potential of regional drug administration in the treatment of ovarian cancer began to be thoroughly explored [ 1 , 2 ].
An important event in the development of a rational strategy for the examination of intraperitoneal drug delivery was the publication of a now-classic paper by Dedrick et al. A number of both practical and theoretical concerns have been raised regarding intraperitoneal therapy of ovarian cancer and other malignancies [ 1 , 2 , 4 — 6 ].
Practical concerns associated with intraperitoneal therapy of ovarian cancer. Theoretical concerns associated with intraperitoneal therapy of ovarian cancer. In this analysis performed at MSKCC, a second important feature was found to strongly predict response to salvage intraperitoneal cisplatin. These data provide strong evidence that the to fold higher concentrations of cisplatin achievable within the peritoneal cavity following intraperitoneal drug administration are able to overcome some degree of drug resistance associated with tumors shown to be at least partially sensitive to the cytotoxic agent.
However, these drug levels cannot achieve this goal in tumors with a high degree of inherent resistance, which is characterized at the clinical level by a failure of the cancer to exhibit at least a partial response to initial intravenous treatment. In addition to cisplatin, a number of other cytotoxic and biological agents have been examined for safety and potential efficacy when delivered by the intraperitoneal route as salvage treatment of ovarian cancer.
Combination regimens have also been explored. The interested reader is referred to the original publications for details of each trial. Surgically defined responses, including complete responses, have been observed with a number of agents and drug combinations delivered by the intraperitoneal route. Unfortunately, no randomized trial of intraperitoneal versus intravenous therapy in the salvage setting in patients with ovarian cancer has been reported.
Therefore, it is reasonable to conclude that the ultimate impact of these responses on progression-free survival, overall survival, or quality of life in the patients with persistent disease, or developing recurrent ovarian cancer following initial intravenous therapy remains to be defined. In the absence of randomized controlled trial data, and despite the evidence of clinical activity of intraperitoneal therapy particularly cisplatin-based in patients with ovarian cancer, there remained and continues to remain considerable skepticism as to the value of this strategy in the management of this malignancy.
Criticisms of the use of intraperitoneal therapy in the management of ovarian cancer.
The recent preliminary report of a large intergroup randomized trial examining intraperitoneal cisplatin as initial treatment of ovarian cancer has muted much of this criticism and has renewed considerable interest in the intraperitoneal approach to the management of ovarian cancer [ 13 ]. All patients also received intravenous cyclophosphamide.
Toxicity, Technical Challenges
With a median patient follow up of approximately four years from study entry, patients treated by the intraperitoneal route experienced a statistically significant improvement in survival median: In addition, women treated with intraperitoneal cisplatin experienced significantly less neutropenia and clinically relevant hearing loss. These findings are presumably due to lower peak levels of cisplatin achieved within the systemic compartment following intraperitoneal delivery, compared to intravenous administration. This large, well-designed and well-conducted randomized study has provided strong support for the argument that high peritoneal cavity concentrations of an active cytotoxic agent can increase the effectiveness of treatment of women with small-volume residual advanced ovarian cancer.
In addition, it demonstrates that this therapeutic strategy can be employed outside the tertiary research center with an acceptable degree of catheter-related side effects e. However, it is important to note that the local toxicity of regional treatment will be dependent on the specific drug or drugs employed, and the favorable side-effect profile documented in this landmark study may not be observed with other cytotoxic drugs. Unfortunately, this intergroup study was initiated 10 years ago, prior to the introduction of paclitaxel into the clinic and the demonstration of the impact of this agent on survival in advanced ovarian cancer.
Thus, while this study has clearly shown the superiority of intraperitoneal cisplatin and intravenous cyclophosphamide compared to intravenous cisplatin and cyclophosphamide in small-volume residual advanced ovarian cancer, the impact of intraperitoneal cisplatin when combined with paclitaxel is unknown.
This important question has been partially addressed by another recently completed intergroup study, but the results of this trial will not be available for several years. With the demonstrated activity of paclitaxel in ovarian cancer, it was natural to examine this agent for intraperitoneal delivery [ 14 ]. Several additional factors suggested that paclitaxel might be a good candidate for regional therapy, including its large size and hepatic metabolism increasing cavity exposure compared to the systemic compartment. In addition, potentially cytotoxic concentrations of the agent were found to persist within the cavity for more than a week following intraperitoneal treatment.
These data suggest that with a weekly intraperitoneal paclitaxel dosing schedule it may be possible to continuously expose thin layers of tumor on the surface of the cavity to paclitaxel for the duration of treatment. In a phase II trial, the Gynecologic Oncology Group is currently examining a weekly intraperitoneal paclitaxel regimen as salvage treatment of women with small-volume persistent or recurrent ovarian cancer following initial systemic therapy.
The results of this interesting trial should be available within the next year. On the basis of what is currently known about the limitations and potential benefits of intraperitoneal therapy of ovarian cancer, in what clinical settings might investigators continue to explore potential roles for this unique therapeutic approach?
Reasonable clinical settings in which to explore a role for intraperitoneal therapy in the management of ovarian cancer.