Intraperitoneal chemotherapy in ovarian cancer

C ANCER TREATMENT REVIEWS 2000; 26: 133–143 doi: 10.1053/ctr v.1999.0152, available online at http://www.idealibr ar y.com on

ANTITUMOUR TREATMENT

Intraperitoneal chemotherapy in ovarian cancer L. S. Hofstra, E. G. E. de Vries, N. H. Mulder and P. H. B.Willemse Division of Medical Oncology, University Hospital Groningen, P.O. Box 30.001, 9700 RB Groningen,The Netherlands From a theoretical viewpoint, intraperitoneal therapy (IP) in patients with ovarian cancer, a malignancy which remains mainly confined to the peritoneal cavity, is logical. Over the past decades this approach has evolved into a therapeutic strategy for a selected group of patients. Data available at present suggest a beneficiary role (for IP therapy) as first-line treatment in patients with small residual disease and possibly following initial reduction of tumor load by systemic chemotherapy. The theoretical basis, the present status of IP therapy in different settings, pharmacology, factors limiting its clinical utility and future directions are reviewed. © 2000 Harcourt Publishers Ltd Keywords: Ovarian cancer; intraperitoneal; chemotherapy.

INTRODUCTION Ovarian cancer is the leading cause of death from gynecologic cancer and the fifth leading cause of cancer deaths in women in developed countries (1, 2). At the time of diagnosis, most patients have widespread disease because ovarian cancer is often asymptomatic in early stages (2). Because of the often bulky presentation, surgery is usually supplemented by chemotherapy. The response to initial platinum-based chemotherapy is high and the addition of paclitaxel to cisplatin-based chemotherapy has prolonged patients’ survival (3). However, fiveyear survival in patients who present with abdominal metastases is poor being only a 10–20% (4). Since ovarian cancer remains confined to the peritoneal cavity for most of its natural course (5) and even optimal surgery leaves a number of patients with microscopic or macroscopic residual disease, the intraperitoneal (IP) administration of cytotoxic drug is a logical way to increase local exposure to these agents and lower plasma clearance (6). This review

Address for correspondence: P.H.B. Willemse, M.D. Ph.D., Division of Medical Oncology, University Hospital Groningen, P.O. Box 30.001, 9700 RB Groningen, The Netherlands, Tel: +31-503616161; Fax: +31-50-3614862; Email: [email protected] 0305-7372/00/020133 + 11 $35.00/0

will assess the present status of IP chemotherapy in ovarian cancer. The theoretical basis, practical implications, safety, pharmacological and clinical data will be discussed.

Theoretical basis Peritoneal dialysis has played an important role (7, 8) in our understanding of the permeability and pharmacokinetic characteristics of the peritoneum. The peritoneal cavity is a large membrane through which substances can pass depending on the following factors: molecular size, charge, weight, and lipid solubility. Most of the substances cleared by the peritoneal membrane are directly transported into the blood circulation and only a small fraction is cleared by lymphatic flow. The peritoneal permeability of a given substance differs depending on the four factors mentioned above and can be denoted by a transport constant, called P. Another factor influencing the permeability rate is the surface area of the peritoneum, called A. The permeability product, or P × A (PA), is expressed as clearance (ml/min). So, the PA of a specific agent determines the rate with which the agent enters the circulation. However, other mechanisms play a role. Lipid soluble agents may enter the circulation by transcellular transport and thereby increase their © 2000 HARCOURT PUBLISHERS LTD

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clearance (6, 7). Furthermore, the PA may vary between patients but also within a patient, depending on her clinical condition. Despite these variables, it is possible to estimate the PA for specific agents by animal experiments (9). The ratio of plasma to peritoneal drug concentration is proportional to the PA divided by the PA plus the elimination rate. If the elimination rate constant (K) is greater than the PA, the ratio declines, suggesting higher peritoneal concentrations compared to plasma concentrations. Thus, the peritoneal/plasma ratio becomes more favorable if the total body clearance increases.

Intracellular drug concentrations To be clinically relevant, high IP drug concentrations must result in high intracellular concentrations for tumour cell killing. Tissue penetration is therefore one of the key issues in IP therapy. A study by Ozols et al., showed in a murine model a high intracellular concentration of doxorubicin in free-floating cells from ascites and also in the outer four to six cell layers of solid tumour masses (10). Platinum distribution was studied in rat peritoneal tumours after IP installation of equimolar doses of carboplatin and cisplatin (11). Low platinum concentrations were detected at the surface of the tumour after carboplatin treatment, whereas no platinum was detected at 0.5 mm from the surface. In contrast, after cisplatin treatment, high platinum concentrations were measured in the periphery of the tumour and moderate concentrations were measured in the center. Thus, seven times more platinum was detected after cisplatin treatment than after carboplatin, and 10 times more carboplatin than cisplatin had to be injected to obtain comparable platinum concentrations in the tumour tissue. These data show a clear difference in the ability of different antineoplastic drugs to penetrate tumour cells and clinical data support these observations (12). Patients with small residual tumour nodules after initial surgery are, based on these data, the ones most likely to benefit from peritoneal administration of chemotherapy. The impact of retroperitoneal disease on survival has been studied only in salvage IP chemotherapy for which it did not appear to be a contradiction. This observation is in contrast with the theoretical basis of IP chemotherapy of local exposure to high dose cytotoxic agents, but leaves room for speculation as this was a retrospective study (13).

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cavity. Previous surgery and subsequent adhesions can prevent homogenous fluid distribution. Also, large tumour masses and adhesions can obstruct the free flow of fluid (14). Sufficient fluid volumes are needed to result in uniform IP distribution and a volume of 2 L is considered adequate for this purpose (15, 16).

Peritoneal cavity access Access to the peritoneal cavity can be easily obtained, but has potential hazards. Repeated puncture and drug administration procedures carry a risk of bowel perforation and infection (17). Open-ended percutaneous catheters used to minimize these risks still show a considerable amount of complications, most notably bacterial peritonitis and bowel perforation (18, 19). Since the introduction of subcutaneous access ports these risks have diminished (92). A review of 137 patients at the Memorial Sloan Kettering Cancer Center with subcutaneous implanted access ports showed that 16 catheters had to be removed for either poor distribution of fluid (two), infection (six) or non-function (eight). Nine episodes of infection in eight patients were observed (20). In another study of 125 patients with a subcutaneous ports, 81% of the projected treatment was given according to schedule, while treatment was terminated as a result of catheter malfunction in 7% and in relation to chemotherapy effects in 12%. The probability of a catheter properly functioning at one year was 69% (21). An analysis of a total of 281 courses of IP cisplatin or IP interferon in 53 patients with a totally implanted peritoneal access showed only two patients suffering from malfunctioning catheters without infectious complications (93). In another study of 20 patients, 81 courses of chemotherapy were given without complications (22).

Agent characteristics in IP therapy Following the theoretical concept of IP therapy, numerous phase I and pharmacokinetic studies have been performed with various agents. Dose-limiting toxicities and clinical utility have been identified, along with the peritoneal/plasma AUC ratio for those agents. The results are summarized in Table 1.

Distribution of intraperitoneal volume

Cisplatin

It is presumably important for the drug-containing fluid to distribute evenly throughout the abdominal

As cisplatin is the mainstay of treatment in ovarian cancer, its IP use has been the most extensively studied. In early dose-finding studies (23), IP cisplatin

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TABLE 1 Peritoneal/plasma AUC ratio for various chemotherapeutic drugs.

Drug Cisplatin23 Carboplatin27 Paclitaxel30–32 Topotecan35

Peritoneal/Plasma AUC Ratio

MTD (mg/m2)

21±5 10 ± 7 1000 32

270 + STS 500 150–175 4 over 24 hrs 30 over 1 hr 800 25 35 50–60 2080 30 in 120 h 40 1000 µg 15–60 mg 150 mg 10 MU 125 mg/kg 500 mg D1 + 8

Etoposide – total38 Melphalan40 Mitoxantrone42 Thiotepa48 5-Fluorouracil51 Methotrexate52,53 Doxorubicin54 Ara-C56 Bleomycin59–61

2.8 63 1000 4.8 300 18–36 975 300–1000 400

Interferon88,89 Gemcitabine91*–92

30–1000 12–26 NS

Dose-limiting toxicity myelosuppression myelosuppression abdominal pain myelosuppression, rash, hypotension neutropenia myelosuppression abdominal pain myelosuppression myelosuppression myelosuppression and abdominal pain myelosuppression and abdominal pain NS abdominal pain malaise, fever NK myelosuppression**

* in rat experiments ** combined with cisplatin 75 mg/m2 IP on D1 MTD = maximal tolerated dose; STS = sodium thiosulphate; NK = not known; NS = not stated

could be escalated to a dose of 270 mg/m2 in combination with thiosulphate as renal protection. Doselimiting toxicity was myelosuppression and a peritoneal/plasma AUC ratio of 21 was observed. These findings have been confirmed by others (24, 25). Renal and neurotoxicity were less frequent problems (62). The impact of IP cisplatin on survival has been addressed in a large randomized study and will be discussed in the next section (62).

Carboplatin As an active agent in ovarian cancer, IP carboplatin can be escalated to 500 mg/m2 with myelosuppression as dose-limiting factor (26). In this study renal and neurological toxicity were minor and the peritoneal/plasma ratio was 18. Another study showed similar results with a peritoneal/plasma ratio of 10 ± 7 (27). Poorer cell-penetration characteristics and clinical data in comparison to IP cisplatin (11, 12) have led to comparatively few clinical studies of carboplastic (28, 29).

Paclitaxel Being an active drug in ovarian cancer, IP paclitaxel has shown a >1000 fold peritoneal/plasma AUC ratio. Dose-limiting toxicity is abdominal pain at 150–175 mg/m2 and the recommended dosage for IP

therapy is between 60–75 mg/m2 with mild myelosuppression and mild abdominal discomfort as the most pronounced adverse effects (30–32).

Topotecan The topoisomerase inhibitor topotecan has shown efficacy in ovarian cancer (33, 34). So far, only two studies have appeared (35, 36) in which the feasibility of the IP approach has been evaluated. In one study, neutropenia as dose-limiting toxicity was encountered at 4 mg/m2 as a continuous 24-hour infusion, while the other study encountered mild skin-rashes and severe hypotension as dose-limiting toxicity at the 30 mg/m2 dose level. The San Diego group administered topotecan as a 24-hour infusion, while in the latter study topotecan was administered over one hour. Therefore, the recommended dose for future studies varies between 3 mg/m2 or 20 mg/m2 depending on the duration of IP administration.

Etoposide An active agent in patients with ovarian cancer, etoposide IP has been extensively used in clinical trials, mostly in combination with IP cisplatin. In a dose-finding and pharmacokinetic study dose-limiting neutropenia was observed at 800 mg/m2 (37) and the recommended dose for IP therapy is 700 mg/m2.

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Mild abdominal discomfort was noted, but did not lead to discontinuation of therapy. In a study combining a fixed IP cisplatin dose of 200 mg/m2, IP etoposide could be escalated to 350 mg/m2 (38) The peritoneal/plasma ratio was 1.5 for the total dose of etoposide, but the free (non-protein bound) etoposide ratio was 65. In a similar study with a fixed IP carboplatin dose of 300 mg/m2, etoposide could be escalated to 350 mg/m2 with myelosuppression being dose-limiting (39).

HOFSTRA ET AL.

5-Fluorouracil Most data on the role of IP 5-fluorouracil (5-FU) come from patients with gastro-intestinal malignancies (49, 50). In a dose-finding study, Speyer et al., escalated 5-FU to 2080 mg/m2 with only mild toxicities (vomiting, mucositis, myelosuppression) (51). A peritoneal/plasma ratio of 300 was found. Despite these favourable characteristics, the lack of efficacy of 5-FU in patients with ovarian cancer does not support a role for IP 5-FU in this subset of patients.

Melphalan

Methotrexate

Because of its activity in ovarian cancer, melphalan has been studied as single agent and in combination IP therapy. Howell et al., observed that melphalan could be escalated to 25 mg/m2 before dose-limiting myelosuppression occurred (40). A peritoneal/ plasma ratio of 63 was observed. In a dose-finding study of combined IP cisplatin and IP melphalan, cisplatin could be escalated to 120 mg/m2 and melphalan to 20 mg/m2 with dose-limiting myelosuppression. Pharmacokinetic analysis showed a 16-fold and 17-fold increase in peritoneal/plasma ratios for cisplatin and melphalan respectively (41). In both studies a 15–30% response rate was observed, but this has not led to a general interest in melphalan as an IP agent.

In the early 1980s, methotrexate was the focus of two IP studies. A study in 18 patients with continuous intraperitoneal, intrapleural and in one case intrapericardial infusion of 30 mg/m2 methotrexate was performed (52). Dose-limiting toxicity was dependent on the duration of infusion with doselimiting myelosuppression at 120 h. Jones et al., treated five patients with IP methotrexate (30 mg/m2) using a different schedule, but encountered abdominal pain (53). A peritoneal/plasma ratio between 18 and 36 was reported. Information on tumor responses are scanty.

Mitoxantrone Four phase I/II studies evaluated the use of IP mitoxantrone(42–45). Dose-limiting toxicity was leucopenia in one study at the 35 mg/m2 dose level (45). The three other studies failed to escalate above 25 mg/m2 owing to peritoneal irritation and pain(42–44). In all three studies, a 10–30% response rate was observed with peritoneal/plasma ratios ranging between 100–1400, but local toxicity limits its use in IP therapy. This was recently confirmed in a phase II trial of IP cisplatin (100 mg/m2) and IP mitoxantrone (10 mg/m2)(46).

Thiotepa The role of IP thiotepa has been addressed in two studies (47, 48). Both studies found myelosuppression at the 50–60 mg/m2 dose level to be dose limiting. No peritonitis, mucositis, vomiting for alopecia was observed. However, a relatively small peritoneal/plasma ratio of 4.3 combined with a rapid appearance of the active metabolite tepa in the plasma argue against an important role for IP thiotepa (47, 48). Moreover, the active thiotepa is only formed after passing through the liver (48).

Doxorubicin Ozols et al.(54) treated ten patients with advanced ovarian cancer with IP doxorubicin. Dose-limiting toxicity was abdominal pain at doses above 40 mg/m2 and myelosuppression occurred. Lowdose IP administration of doxorubicin (2–18 mg/m2) in combination with IP cisplatin and Ara-C resulted in an unacceptable incidence of abdominal discomfort (55). Doxorubicin does not appear to be suitable for IP administration.

Cytosine arabinoside King et al., studied IP cytosine arabinoside (Ara-C) in ten patients with ovarian cancer at dosages between 10–1000 µg (56). The treatment was well tolerated at the highest dose-level with a 300–1000 peritoneal/ plasma ratio. Multi-agent chemotherapy with Ara-C has been studied (57, 58), but lack of efficacy has led to its abandonment in recent years.

Bleomycin Intraperitoneal bleomycin has been studied in 10 patients with malignant ascites (59). A total of 150 mg was administered in two hours with an indwelling time of 4 hours following previous removal of ascites. All patients experienced abdominal pain which was

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TABLE 2 Randomized trials on first-line IP therapy in ovarian cancer.

Author (ref.)

No of patients

Alberts (62)

654

Kirmani (63)

62

Markman (64)

523

Polyzos (65)

90

Treatment IP + IV IP cis + IV cyclo IV cis + IV cyclo IP cis + IP etop IV cis + IV cyclo IV carbo + IP cis + IV pacl IV cis + IV pacl IP carbo + IV cyclo IV carbo + IV cyclo

PFI (mo)

Med Survival (mo)

III–IV <2.0 cm IIc–IV

NS NS

49* 41 32

III–IV <1.0 cm III

27.6 22.5 18 19

52.6** 47.6 25 26

Stage

cis = cisplatin; carbo = carboplatin; pacl = paclitaxel; cyclo = cyclophosphamide; etop = etoposide; NS = not stated *P = 0.02, **P = 0.052

manageable with acetaminophen and two patients experienced fever up to 40°C. A 400-fold in peritoneal/plasma ratio was observed, but in another study in 11 patients with malignant ascites IP bleomycin 60 mg/m2 (60) resulted in unacceptable abdominal pain, fever, skin rash and mucositis. Intraperitoneal Bleomycin in adjusted dosage (2 or 15 mg/m2) (61) has been used in multi-agent IP therapy, but abdominal pain was severe even at the lowest dose and therefore it has no role in IP therapy.

Interferon Interferon has favourable characteristics for an IP agent with a peritoneal/plasma ratio of 30–1000 (88, 89). Toxicity is substantial, with the occurrence of fever > 40°C in 43% (89) and an incidence of mild to moderate abdominal pain of 20% (88, 89).

Gemcitabine Showing modest activity in relapsed ovarian cancer when administered IV (90), IP gemcitabine has only been studied in a murine model (91). In this model, IP gemcitabine was administered at 12.5 mg/kg and 125 mg/kg dose levels and the peritoneal/plasma ratio observed in this model ranged between 12.5 and 26.8.

Clinical trials First line chemotherapy The role of IP chemotherapy as first-line treatment in ovarian cancer has been studied in four randomized phase III trials. A large phase III trial was performed in 654 patients with stage III ovarian cancer with minimal residual disease (62). A total of 546 patients

were considered eligible. Patients were randomized to received either 6 courses of IP or IV cisplatin (100 mg/m2) in combination with IV cyclophosphamide (600 mg/m2). The surgically defined complete response rate in the IP arm was 47% compared to 36% in the IV arm. IP therapy was associated with a prolonged survival: median survival was 49 months in the IP group compared with 41 months in the IV group (P < 0.05). In a study by Kirmani et al., 59% patients with newly diagnosed stage IIc-IV ovarian cancer were randomized to receive either six cycles of IP cisplatin (200 mg/m2) and IP etoposide (350 mg/m2) or IV cisplatin (100 mg/m2) and cyclophosphamide (600 mg/m2). With a median follow-up of 46 months, no difference in response rate and survival was observed (63). Why this study failed to show an advantage for the IP treated group might have several reasons. Apart from being a small study, a potentially important difference is the regimen used. It might well be that IP chemotherapy administered in combination with IV chemotherapy is superior over IP combination chemotherapy alone. A recently completed large randomized phase III study, comparing moderately high dose IV carboplatin, intended as initial tumour reducing treatment, followed by IV paclitaxel and IP cisplatin versus IV paclitaxel and IV cisplatin without carboplatin induction, has furthermore shown an improved disease free survival in the experimental arm (median 27.6 vs 22.5 months, P = 0.02). However, since the experimental arm received two cycles of IV carboplatin induction treatment in addition to IP cisplatin, these results only partly support a role for IP therapy (64). Recent data from a small (N = 90) Greek study comparing IP with IV carboplatin failed to show a benefit for IP therapy (65). Being a relatively small study with some suboptimally debulked patients might explain the inability to detect a possible difference.

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HOFSTRA ET AL.

TABLE 3 IP consolidation therapy in ovarian cancer.

IP treatment

Second look laparotomy (SLL)

Med. PFI (mo)

Med. survival (mo)

49 41

IP cis IP cis

13/20 pCR cCR before entry

NS 18

38 NS

15

IP mitox

Menczer (68) Barakat (69)

31 40

IP cis IP cis + IP etop

18/25 pCR cCR before entry

35 not reached

NS

Bruzzone (70)

28 111

Dufour (72)

50

historical controls IP carbo + INF-α vs IP carbo IP mitox

minimal residual disease cCR before entry

10 11 47%

22 29 60%

Willemse (89)

20

IP INF-α

9/17 pCR

NS

Pujade (71)

108

IP INF-γ

residual disease

NS

11 + for responders 54 <0.5 cm 25 <2.0 cm 11 >2.0 cm

Author (ref.)

No patients

Beller (66) Tarrazza (67)

Comments 10/41 PD at 24 months (25%) (cis) 4/15 PD at 30 months (27%) (mitox) projected 5-yr survival 60% at 36 months PFS in 22/40 patients 55% vs 34% in historical controls increased toxicity in INF arm 5 years (progression free) survival

at third look laparotomy 23 out of 98 pCR

cis = cisplatin; carbo = carboplatin; mitox = mitoxantrone; etop = etoposide; INF = interferon; PFI = progression free interval; PFS = progression free survival; NS = not stated; PD = progressive disease; IP = intraperitoneal; pCR = pathological complete remission

Consolidation chemotherapy The role of IP chemotherapy as consolidation chemotherapy following standard IV treatment has not been established. Trials to confirm a possible role are ongoing. So far mostly phase II studies have been performed (Table 3) using different chemotherapeutic agents in selected groups of patients. Beller et al., performed a study in 75 patients with advanced ovarian cancer using a regimen of systemic induction chemotherapy followed by IP chemotherapy (66). Of the 75 patients, 49 received IP chemotherapy consisting of six cycles IP cisplatin (60 mg/m2) and IV cyclophosphamide (600 mg/m2). Thirty-two of these 49 patients achieved a complete clinical response, which was confirmed in 20 patients by second-look laparotomy. Relapses occurred in 20 of 32 patients with a complete clinical response and in 13 of 20 patients with a surgically documented response. The projected median survival of all patients was 38 months. Patients who had bulky disease following initial surgery had a worse median survival compared to patients with minimal residual disease (23 months vs 45 months). The authors concluded that IP chemotherapy did not influence overall survival of all treated patients, but that such an effect may be limited to patients with a favourable response to IV chemotherapy and small volume residual disease. Tarraza et al treated 56 patients with either IP cisplatin (80 mg/m2, N = 41) or IP mitoxantrone (10 mg/m2, N = 15) following optimal cytoreductive

surgery and cisplatin/cyclophosphamide (67). All patients had a negative second-look laparotomy before study entry. Median time to recurrence was 18 months with 10 of the 41 recurrences in the cisplatin group and 4 of 15 recurrences in the mitoxantrone group with a median follow up of 2 years. Menczer et al., performed a study in 37 patients with ovarian cancer in complete clinical remission following initial IV cisplatin based chemotherapy (68). The median progression free interval was 35 months and the projected 5-year survival rate was 60.4%. A recent study by Barakat et al., in 40 patients treated with three courses IP cisplatin (100 mg/m2) and IP etoposide (200 mg/m2) in patients with a negative second-look laparotomy showed an increase in disease-free survival at 36 mo (39% vs 54%, P <0.05) compared to a historical control group who had observation alone (69). Pretreatment characteristics between the two groups differed significantly, which must have affected these findings. IP mitoxantrone (20 mg/m2) as consolidation treatment following cisplatin-based initial therapy resulted in a predicted disease-free survival of 47.3% and survival of 60% at 5 years. Nevertheless, all relapses observed with a median follow-up of 2 years occurred in the abdominal cavity (72). One prospective randomized trial has been performed addressing the issue of adding IP interferon to IP carboplatin (70). A total of 111 patients with minimal residual disease following second-look

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laparotomy were randomized to receive either IP carboplatin or a combination of IP carboplatin (400 mg/m2) and IP interferon-alpha (25 MU). Overall toxicity was significantly higher in the experimental arm without a difference in median progression-free survival (10 months vs 11 months); after a median follow-up of 13 months 71 patients had relapsed. Conversely, IP interferon-gamma in patients with residual disease following initial systemic chemotherapy has resulted in 23% (23/98) surgically documented responses at third-look laparotomy(71). Survival was correlated with the extent of residual disease and a response to interferon. The response to interferon was independent of the previous response to chemotherapy. Survival was 54 months for patients with microscopical disease at third look laparotomy compared to a 11 months in patients with gross microscopical disease. In two other studies, IP interferon-alpha was administered following initial IV chemotherapy (88, 89). In one study, 14 patients with residual ovarian cancer at second-look laparotomy were treated for 16 weeks with weekly escalating doses of IP interferon-alpha (5–50 × 106 U). Eleven patients underwent surgical evaluation with four complete responses and one partial response with disease progression in six patients. All responders had minimal disease at start of therapy (88). IP interferon-alpha administered weekly for 8 weeks(50 × 106 U) in 20 patients with minimal residual disease at secondlook laparotomy resulted in 9/11 responses in patients with residual tumour <5 mm at the start of therapy while six patients with residual disease >5 mm had no response observed at third-look laparotomy; three patients were not surgically reassessed (89). Once more, these results demonstrate the importance of minimal residual disease at the start of IP therapy.

Recurrent or refractory ovarian cancer Recurrent or refractory ovarian cancer is a major problem, especially in stage III and IV disease. IP chemotherapy as a means of increasing dose-intensity has been the focus of several phase II trials using different regimens of mostly cisplatin-based chemotherapy. The first large trial appeared in 1987 (73). In this study 90 patients failing first-line combination chemotherapy were treated with IP cisplatin (200 mg/m2). Sixty-five patients had residual tumor >2.0 cm at the start of treatment, while 25 had residual disease <2.0 cm. Median survival in the group with bulky disease was only 8 months, while the median survival in the other group was more than 49 months with the survival curve reaching an apparent plateau at 69%. However, other investigators have

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reported a more modest if any improvement in survival in patients with minimal residual disease (74–77). Reichman performed a study using IP cisplatin 100 mg/m2 and IP etoposide 200 mg/m2 in 67 patients who received prior platinum containing IV chemotherapy (74). Fifty-one patients had refractory disease, while 16 had experienced a disease-free interval of more than year. A laparotomy was performed before start of treatment and 18 patients had residual tumour >2.0 cm in diameter, 17 had residual tumour between 2.0 cm and 0.5 cm, while 31 had minimal residual disease (<0.5 cm). Fifty-seven patients were evaluable for response, with a laparotomy performed in 35 patients with a complete clinical remission. Twelve patients had a pathological complete response (pCR) and 11 had a partial response. Responses were observed only in patients with minimal residual disease. Duration of the complete responses ranged from 4 to 18+ months. Similarly, the efficacy of IP cisplatin (90 mg/m2) in combination with IV etoposide was studied in 36 patients with platinum sensitive disease with minimal residual disease (< 2.0 cm) at entry (75). The median progression free survival was 11 months. A study in 48 patients with recurrent or refractory ovarian cancer with IP combination cisplatin 100 mg/m2 and a total dose of 2000 mg 5-FU was performed by Braly et al. (77). Patients had surgically documented minimal residual disease (< 1.0 cm). Thirty-two patients were evaluable for response, in whom progressive disease occurred in 17. Progression-free interval (PFI) had not been reached in the platinum sensitive group at a median followup of 29 months; the PFI in the platinum-refractory group was 8.3 months. Piver et al., performed a study in 63 patients with refractory or recurrent ovarian cancer with combination of 6 courses of IP cisplatin (200 mg/m2), IP AraC (1.2 g/m2), with (N = 31) or without (N = 32) IP bleomycin (2–15 mg/m2) (N = 31)(78). A median survival of 29 months was found for the total group, but the two-year survival for patients with residual tumour <5 mm was 74% (N = 42), compared to 38% in the group of patients with residual tumour 5–2.0 mm (N = 15). It was zero for patients with residual tumor >2.0 cm (N = 6). They also noted that of the 15 patients who had platinum-resistant tumours only two responded. The authors concluded that, although the dose cisplatin used in this regimen was four times the IV dose used in first-line, it did not overcome platinum-resistance. This supports the conclusion that patients with minimal residual disease and platinum-sensitive tumours are the most likely to benefit from IP cisplatin. Similar results were reported by the Markman group

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(79, 80). Patients with minimal residual disease and a previous response to platinum-containing chemotherapy benefit the most from IP chemotherapy, but as the authors mention, this is also true for IV administration. A recent survival analysis of IP cisplatin in patients with recurrent ovarian cancer indicated a better survival in selected patients (minimal residual disease). In this group, 31% of the 63 patients included were still progression-free at 5 years (81). Given the limitations that this was not a randomized trial, these data need to be confirmed. With the introduction of paclitaxel, the feasibility and efficacy of intraperitoneal paclitaxel has been studied in phase I/II trials (82). A major pharmacological advantage has been observed for IP paclitaxel and a recent phase II trial has shown efficacy in patients with minimal residual disease. Of 28 patients with microscopic disease at the start of IP therapy, 17 patients achieved a surgically documented complete response (61%). Patients with small residual disease at start of therapy were most likely to benefit. The influence of a previous response to either paclitaxel or cisplatin could not be established (55). The impact of IP paclitaxel on survival remains to be assessed in future trials.

Future perspectives Recently, laboratory studies have pointed to new genetic targets for drugs, which have led to an increased interest in gene-therapy. The initial studies have focused on the p53 gene, which is mutated in a number of ovarian cancers and carries an inherently adverse prognosis (97). An attenuated adenovirus, ONYX 015, has been modified through deletion of the E1B region of the genome so that it replicates exclusively in cells with absent or mutated p53 (94). Mutant cells are known to be associated with resistance, e.g., to cisplatin, and the intraperitoneal approach may be particularly appropriate for this kind of treatment (95). Positive data in patients with head and neck cancer have encouraged investigators to proceed with a trial in ovarian cancer (96).

CONCLUSIONS Numerous trials using different chemotherapeutic agents have shown the feasibility and efficacy of the intraperitoneal approach. It has been shown that several agents can be delivered safely into the peritoneal cavity with a major pharmacokinetic advantage for local exposure. Because of its generally mild systemic adverse effects, IP chemotherapy offers the potential of combining different agents in dosages which can not be achieved intravenously. However,

HOFSTRA ET AL.

clinical trials in ovarian cancer have revealed a number of limitations to this approach (83). The main obstacles for IP therapy are large volume of disease, poor drug penetration characteristics and inhomogenous drug distribution. The problem of drug resistance has not been solved by this form of treatment, as a large number of patients still suffer from abdominal relapses. Patients with minimal residual disease at diagnosis are the best candidates for this approach (62, 64). The study by Alberts et al., found both increased survival benefits and less toxicity in the IP treated group (62). In the setting of consolidation therapy, further research is warranted. Present data suggest a potential benefit, but well-designed clinical trials are needed. For salvage therapy, patients with microscopic disease at second-look laparotomy, who have had a documented response to prior therapy, might benefit, but whether there is truly an increase in disease-free survival in patients with larger tumours remains uncertain. Future research should focus on these issues and on determining the IP drug or combination of choice. Novel strategies including IP immunotherapy, gene therapy or hyperthermic peritoneal perfusion with cytotoxic agents should also be explored further (84–87, 94, 95). Finally, many issues remain to be resolved for both IP and other strategies in the management in ovarian cancer. Ultimately, intraperitoneal therapy should have a significant role in the management of ovarian cancer.

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