Intraperitoneal chemotherapy with taxanes for ovarian cancer with peritoneal dissemination
Introduction
Before 1993 the chemotherapy of choice for advanced ovarian cancer was cisplatin or carboplatin in combination with a classic alkylating agent like cyclophosphamide. Since the mid-1990s cytoreductive surgery and systemic combination chemotherapy with a platinum compound and a taxane have become the standard of care for this disease. Paclitaxel (Taxol®, Bristol-Myers Squibb) and docetaxel (Taxotere®, Sanofi-Aventis) are currently the two clinically available taxanes. Systemic treatment with taxanes has shown impressive activity in advanced and platinum-resistant ovarian cancer. Randomised trials have demonstrated the superiority of paclitaxel in combination with platinum compounds over more classic drug regimens both in primary and recurrent ovarian cancer.1 The combination of paclitaxel and carboplatin was found to be less toxic and equally effective in comparison with the combination of paclitaxel and cisplatin, making it for many physicians the chemotherapy of choice for ovarian cancer.1 In a large randomised trial,2 the combination of docetaxel and carboplatin appeared to be similar to a regimen with paclitaxel and carboplatin as first-line chemotherapy for ovarian cancer in terms of survival (2-year overall survival rate: 64% vs. 69%) and response rates (76% vs. 77%). The toxicity profile, however, seems to be slightly more favourable for the docetaxel–carboplatin combination.#
Patients with ovarian cancer who relapse after initial systemic chemotherapy with paclitaxel and platinum often have disease that is still responsive to re-treatment with paclitaxel, especially in case of late recurrence.34 An alternative treatment option in such cases is intravenous administration of docetaxel. In experimental and clinical phase II studies, docetaxel has demonstrated definite activity not only in platinum-resistant but also in paclitaxel-resistant gynaecological malignancies, because of the lack of complete cross-resistance with paclitaxel.5–7#
Despite this progress of systemic chemotherapy, most patients with advanced disease experience relapse and ultimately die of drug-resistant disease. Overall treatment results remain unsatisfactory, since the median survival is still 2–3years and the 5-year survival rate 30% for patients with advanced ovarian cancer.8 Therefore, more effective systemic chemotherapy regimens or alternative treatment modalities are warranted. Intraperitoneal chemotherapy with taxanes is such an alternative treatment option.#
Intraperitoneal chemotherapy
Ovarian cancer, a tumour that remains largely confined to the peritoneal cavity, may be amenable to intraperitoneal chemotherapy. Patients with no gross or very small volume residual disease seem suitable for this approach. Intraperitoneal chemotherapy is unlikely to be beneficial in bulky disease since drug penetration into larger tumour nodules is limited.9–11 Recently, two large randomised trials demonstrated an 8–9-month survival benefit for patients with chemotherapy native small residual volume stage III ovarian cancer after intraperitoneal instillation chemotherapy with cisplatin and systemic chemotherapy compared to only systemic chemotherapy following cytoreductive surgery.1213 Progression-free survival was significantly increased from 22 to 28months.13 In a large retrospective series of patients with persistent disease, prolonged survival was observed in selected patients receiving intraperitoneal chemotherapy.13 In recurrent ovarian cancer, several phase II studies of second-line intraperitoneal chemotherapy reported a moderate survival improvement. Patients with response to prior chemotherapy are most likely to benefit.10#
In early intraperitoneal chemotherapy trials, patients who failed to respond to systemic chemotherapy did not respond to intraperitoneal platinum.14 Taxanes have a high efficacy after systemic administration in primary and recurrent ovarian cancer and favourable pharmacokinetics after intraperitoneal administration. Because paclitaxel and docetaxel have a high molecular weight and hepatic metabolism, high intraperitoneal to systemic drug concentration and exposure ratios might be achievable after intraperitoneal delivery. Since the response to taxanes seems to be dose-dependent in clinical studies,15–17 increased efficacy is to be awaited during intraperitoneal chemotherapy.#
Pharmacokinetics of taxanes after intraperitoneal administration
The favourable pharmacokinetics of taxanes during intraperitoneal instillation chemotherapy and intraoperative hyperthermic intraperitoneal perfusion chemotherapy have been confirmed in several animal and clinical studies (Table 1).18–23 After intraperitoneal administration of taxanes, highly cytotoxic concentration of the agents persists within the peritoneal cavity for several days. Generally, for all cytotoxic drugs maximal concentration and AUC ratios are reported to be much higher after instillation chemotherapy than those observed after intraoperative hyperthermic intraperitoneal chemotherapy. These significant differences may be explained by the short duration of intraoperative hyperthermic intraperitoneal chemotherapy compared to the longer treatment duration for instillation intraperitoneal chemotherapy and increased drug absorption due to better exposure of the agent to the seroperitoneal surface during intraoperative hyperthermic intraperitoneal chemotherapy.#
Taxanes and hyperthermia
Although the taxanes paclitaxel and docetaxel are heat stable and hyperthermia seems to increase intracellular taxane accumulation, conflicting results have been reported in experimental studies regarding the interaction of heat and taxanes. It seems that high local taxane concentrations and prolonged periods of hyperthermia are associated with considerable thermal enhancement,24–27 conditions that are met during intraoperative hyperthermic intraperitoneal chemotherapy.#
Clinical studies on intraperitoneal chemotherapy with paclitaxel for ovarian cancer
Instillation intraperitoneal chemotherapy with paclitaxel
Markman et al.18 evaluated the feasibility of intraperitoneal administration of paclitaxel every 3–4weeks in ovarian cancer patients. The dose-limiting toxicity on this schedule was the development of severe abdominal pain at paclitaxel doses of more than 175mg/m2. Systemic toxicity was mild at doses less than 175mg/m2. The same Gynecologic Oncology Group performed a second study to define the maximum-tolerated dose of paclitaxel administered by the intraperitoneal route on a weekly schedule.19 Multiple grade 2 toxicities, including abdominal pain, nausea, vomiting, leukopenia and fatigue, were observed at the 75mg/m2 per week dose level. The absence of severe toxicity and the favourable pharmacokinetics at dose levels of 60 and 65mg/m2 made this the recommended dose for weekly intraperitoneal chemotherapy treatment with paclitaxel.#
After its phase I studies, the Gynecologic Oncology Group performed a phase II trial to evaluate the efficacy of intraperitoneal administration of paclitaxel in cancer of the ovary, tube and peritoneum with microscopic or small volume residual peritoneal disease after second-look surgery.28 Patients were enrolled in this study to receive 60mg/m2 intraperitoneally weekly. Treatment was well tolerated. Seventeen of the 28 (61%) assessable patients with microscopic residual disease were free of disease at surgical re-evaluation. However in sharp contrast to the experience with microscopic residual disease, only one of the 31 (3%) patients with macroscopic disease at the start of intraperitoneal chemotherapy achieved a complete response at surgical evaluation. The authors concluded that salvage intraperitoneal chemotherapy with paclitaxel is tolerable and effective in patients with microscopic residual disease.#
Combination of intraperitoneal chemotherapy with paclitaxel with systemic chemotherapy
Markman et al.29 provided the rationale for second-line therapy of ovarian cancer with paclitaxel administered by both the intravenous and intraperitoneal routes in carefully selected patients. Simultaneous intraperitoneal and intravenous administration of paclitaxel attempts to provide increased concentration and exposure duration of this agent within the peritoneal cavity compartment by regional chemotherapy and to optimize drug delivery to the tumour by capillary flow (systemic chemotherapy). This management strategy was associated with reasonable tolerance.#
Various phase II studies examined the efficacy of the combination of intraperitoneal and intravenous chemotherapy for ovarian cancer. Hofstra et al.20 demonstrated the efficacy of intraperitoneal administration of 75mg/m2 paclitaxel combined with intravenous chemotherapy with carboplatin and cyclophosphamide following cytoreductive surgery as first-line treatment in 25 patients with ovarian cancer. The regimen was well tolerated. At a median follow-up of 30months, the 10 patients with residual disease after primary surgical cytoreduction had a median progression-free survival of 13months. For the 15 patients who underwent optimal cytoreductive surgery an actuarial progression-free survival of 60% was noted at 48months.#
Zylberberg et al.30 determined the feasibility, toxicity and efficacy of a first-line treatment combination of intraperitoneal chemotherapy with paclitaxel and cisplatin and intravenous administration of ifosfamide in 26 untreated patients with stage IIIc ovarian cancer after cytoreductive surgery or biopsies only. Grade 3/4 leukopenia was noted in 31% of the cases. At surgical evaluation after 10 cycles of chemotherapy by both routes, complete clinical remission was observed in 81% of the cases. At a median follow-up of 53months the median disease-free survival was 40months, while the median overall-survival had not been reached.#
An Intergroup phase II trial evaluated the efficacy of intraperitoneal administration of cisplatin and paclitaxel and intravenous chemotherapy with paclitaxel for women with optimally debulked stage III ovarian cancer.31 At least one grade 3/4 adverse effect was experienced by 96% of all patients. The survival rates were very promising. The 2-year survival rate was 91% and the median survival time 51months. The 2-year disease-free survival rate was 66% and the median disease-free survival time 33months.#
Recently, the Gynecologic Oncology Group conducted a multicentric randomised trial (GOG 172) that compared an experimental regimen of intravenous administration of paclitaxel followed by intraperitoneal instillation chemotherapy with paclitaxel and cisplatin with a standard intravenous chemotherapy regimen of cisplatin and paclitaxel in 417 ovarian cancer patients with residual tumour smaller than 1cm.32 The experimental regimen was associated with significantly increased grade 3 and 4 toxicity. Preliminary analysis of this study showed an improvement in progression-free survival associated with intraperitoneal chemotherapy with a relative risk of recurrence of 0.73 in favour of intraperitoneal treatment. Although yet very immature, survival data follow a similar trend favouring intraperitoneal chemotherapy. A final report of this study, which includes regional treatment with the most active class of agents in ovarian cancer (cisplatin) and a drug that takes maximum advantage of the pharmacology associated with intraperitoneal cavity delivery (paclitaxel), is anticipated with considerable interest.#
Intraoperative hyperthermic intraperitoneal chemotherapy with paclitaxel
Only one small study addressing the feasibility of paclitaxel as cytotoxic agent in intraoperative hyperthermic intraperitoneal chemotherapy has been reported by Orlando et al.33 Mild toxicity was observed in a small number of patients. After a median follow-up period of 28months, 6 patients relapsed, but only 2 of them intraperitoneally. Evidence of activity was suggested by the low incidence of peritoneal recurrence (11%).#
Clinical studies on intraperitoneal chemotherapy with docetaxel
Instillation intraperitoneal chemotherapy with docetaxel
A dose-finding study of intraperitoneal delivery of docetaxel in treatment of 21 patients with advanced malignancies primarily confined to the peritoneal cavity, among them 4 with ovarian cancer, demonstrated that 100mg/m2 docetaxel can be safely administered every 3weeks.23 The development of ileus, grade 4 neutropenic sepsis and stomatitis were the dose-limiting toxicity. Other common treatment-related toxicities included thrombocytopenia, renal toxicity, emesis, dehydration and abdominal pain. Seven of 18 assessable patients demonstrated stable disease for a median of 5 cycles. Eleven patients progressed by the first evaluation after a median of 2 cycles.#
Intraoperative hyperthermic intraperitoneal chemotherapy with docetaxel for ovarian cancer
Only one study with intraoperative hyperthermic intraperitoneal chemotherapy with docetaxel has been reported.34 Nineteen patients with early recurrent or persistent peritoneal carcinomatosis mainly of ovarian origin were treated 20 times with 75mg/m2 docetaxel at an intraperitoneal temperature of 41–43°C. Seventeen patients received systemic chemotherapy postoperatively. Treatment-related death was noted in two elderly patients with a high tumour load, accounting for a 10% mortality rate. One patient died after postoperative intra-abdominal bleeding and leakage of a colorectal anastomosis, while a second patient died of gram-negative sepsis of unknown origin in the absence of leukopenia. Overall regional treatment-related morbidity was mainly minor. The most commonly observed haematological disorder was thrombopenia, which was probably caused by major surgery with extensive blood loss rather than drug toxicity. Median overall and disease-free survival were 54 (±17) and 26 (±11)months, respectively. These results seem to be superior to that of phase II HIPEC studies using other chemotherapeutic agents for the same indication.34#
Conclusions
Paclitaxel and docetaxel are attractive agents for intraperitoneal chemotherapy in advanced ovarian cancer for several reasons. They demonstrate significant cytotoxic activity in ovarian cancer and exhibit highly advantageous pharmacokinetics after intraperitoneal administration. They show a dose-dependent response and hence the resulting high locoregional drug concentrations should theoretically lead to increased cytotoxicity. Intraperitoneal chemotherapy may be combined with mild or moderate hyperthermia, which enhances tissue penetration and cytotoxic activity of many drugs. The data concerning thermal enhancement of taxanes are inconsistent, but it seems that at the high locoregional concentrations provided by intraperitoneal drug administration considerable thermal enhancement exists.#
Clinical phase I and II studies have demonstrated clearly the feasibility and efficacy of intraperitoneal instillation chemotherapy with paclitaxel with or without concurrent systemic chemotherapy in patients with ovarian cancer. Concurrent intravenous chemotherapy may be beneficial to achieve residual peritoneal tumour penetration not only from the side of the peritoneal cavity, but also from that of the capillary blood supply. Preliminary results of a phase III study demonstrated improved outcome with the addition of intraperitoneal instillation chemotherapy to systemic chemotherapy in such cases. From the very limited data that are available, it seems that the use of paclitaxel is feasible in intraoperative hyperthermic intraperitoneal chemotherapy. The intraperitoneal administration of docetaxel has been less extensively studied. For docetaxel only phase I studies have been performed, demonstrating the feasibility of this treatment approach. Intraoperative hyperthermic intraperitoneal chemotherapy with docetaxel has been performed only in a single phase I/II study, in which promising results were observed. Further clinical investigations with an adequate follow-up period are needed to confirm the promising initial results and to determine the exact efficacy of intraperitoneal instillation chemotherapy and intraoperative hyperthermic intraperitoneal chemotherapy with these drugs.#
Figures and Tables
Table 1
| Study | Year | Instillation or intraoperative hyperthermic i.p chemotherapy | Dose | Cmax i.p/Cmax plasmaa | AUCi.p./AUCplasmaa |
| Paclitaxel | |||||
| Markman et al.18 | 1992 | Instillation i.p. chemotherapy | 25–200mg/m2 per 3–4weeks | ∼1000 | 996 |
| Francis et al.19 | 1995 | Instillation i.p. chemotherapy | 60–75mg/m2 per week | ||
| Hofstra et al.20 | 2002 | Instillation i.p. chemotherapy | 75mg/m2 D1+D8/4weeks | 1350 | |
| Mohamed et al.21 | 2003 | Instillation i.p. chemotherapy | 20mg/m2 per day for 5days | ∼800 | |
| Docetaxel | |||||
| de Bree et al.22 | 2003 | Intraoperative hyperthermic i.p. chemotherapy | 75mg/m2 | 45 | 207 |
| Morgan et al.23 | 2003 | Instillation i.p. chemotherapy | 40–156mg/m2 per 3weeks | ∼120–200 | 152 and 181 |
| i.p., intraperitoneal; Cmax, maximum concentration; AUC, area under time versus concentration curve. |
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