Current and future potential roles of the platinum drugs in the treatment of ovarian cancer

Annals of Oncology 12 1195-1203, 2001 © 2001 Kluwer Academic Publishers Printed in the Netherlands

Review Current and future potential roles of the platinum drugs in the treatment of ovarian cancer M.J. Piccart,1 H. Lamb2 & J.B.Vermorken3 'Jules Bordet Institute (Chemotherapy Unit), Brussels, Belgium, 2R.x Communications, Mold. Flintshire, UK. 3Department of Medical Oncology. University Hospital Antwerp, Edegem, Belgium

Summary The discovery of cisplatin more than two decades ago was the most important therapeutic advance in the treatment of ovarian cancer Today, cisplatin or carboplatin in combination with paclitaxel is the most commonly used first-line treatment for patients with advanced ovarian cancer Although platinum drugs remain a critical component of chemotherapy in this type of cancer, cumulative toxicities can limit their use These toxicities include nephrotoxicity, neurotoxicity and ototoxicity with cisplatin and myelosuppression with carboplatin. Although these adverse events can often be managed, the interventions themselves can complicate and add to the costs of treatment Importantly, acquired resistance to traditional platinum drugs often develops in patients with

ovarian cancer and can limit the usefulness of these drugs. Research into new platinum drugs has focused on identifying compounds with improved tolerabihty profiles and, importantly, those which can circumvent mechanisms of platinum resistance New platinum drugs currently under development that are showing promise in ovarian cancer include oxaliplatin, nedaplatin, satraplatin, BBR3464 and ZD0473 If the encouraging in vitro activity shown by new compounds, such as ZD0473 and BBR3464, translates into efficacy in the clinic, they may offer an extended spectrum of activity which includes patients with ovarian cancer resistant to the classical platinum drugs Key words disease management, ovarian cancer, platinum drugs, platinum resistance, review, tolerabihty

Introduction

Chemotherapy of ovarian cancer

Despite advances in surgery and radiotherapy, mortality rates associated with ovarian cancer remained virtually unchanged from the 1950s to the 1970s [1]. Coupled with the fact that most new cases of ovarian cancer were diagnosed at an advanced stage, there was a clear need for identifying effective chemotherapeutic agents around this time. The discovery of cisplatin [cw-dichloro-diammineplatinum (II)] more than two decades ago was a major step forward in the treatment of advanced ovarian cancer. The drug was first admimstered to a patient with cancer in 1971 and then made available to oncology practice in 1978. Two decades later, platinum compounds remain a critical component of chemotherapeutic regimens in ovarian cancer. In spite of the progress that has been made in identifying and refining active regimens for the treatment of ovarian cancer, there remains a need for new agents with improved efficacy and tolerability profiles, and particularly for agents which lack cross-resistance with established compounds. This article provides a brief overview of the current therapeutic options for the treatment of ovarian cancer, and discusses established and emerging platinum drugs in this field

First-line therapy

Platinum-based regimens were established as first-line therapy in the treatment of ovarian cancer in the mid1980s. At this time, a platinum agent (cisplatin or carboplatin) in combination with cyclophosphamide was the accepted standard therapy for patients with advanced ovarian cancer [1, 2). Possibly the most compelling evidence in support of this regimen was from two large meta-analyses of randomized clinical trials which used updated individual patient data [3, 4]. These analyses suggested that platinum-based therapy was associated with an absolute survival benefit of 5% at two and five years compared with non-platinum regimens [4]. During the 1990s, with the discovery and development of the taxanes, paclitaxel emerged as an important new agent in ovarian cancer based on its activity in platinum-refractory disease. The landmark Gynecologic Oncology Group (GOG 111) trial [5] followed by the confirmatory trial performed by a European-Canadian consortium (OV-10) [6] showed that cisplatin in combination with paclitaxel achieved significantly greater response rates together with a survival advantage of approximately one year compared with cisplatin/cyclo-

1196 phosphamide [7]. As a result, cisplatin in combination with paclitaxel became the new standard of care [7-9]. Despite the strong and consistent evidence in favor of the cisplatin/paclitaxel regimen, some remain reluctant to accept it as the treatment of choice [10, 11]. Concerns raised include issues of cost, toxicity, and the appropriateness of the cisplatin/cyclophosphamide control used in the GOG 111 and OV-10 trials [10] In addition, the results of two other large randomized trials - GOG 132 [12] and ICON2 (International Collaborative Ovarian Neoplasm 2) [13] - have also been interpreted by some as raising questions about the validity of the platinum/ paclitaxel regimen. GOG 132 showed that single-agent cisplatin was as effective in terms of survival as cisplatin/paclitaxel [12], although the high early crossover to paclitaxel before documented disease progression in this trial may have confounded any survival differences between treatment groups [1, 14, 15] ICON2, which showed that single-agent carboplatin and cyclophosphamide/ doxorubicin/cisplatin (CAP) were equivalent [13], also signaled to some that single-agent carboplatin might still be considered as a viable treatment option [10, 13] Another ongoing and, as yet, unresolved debate concerns the role of the anthracyclines in advanced ovarian cancer There is strong evidence for the efficacy of anthracyclme-based chemotherapy in ovarian cancer (reviewed by Vermorken et al. [16], something that has been largely overlooked as standard practice moved towards the taxanes For example, one meta-analysis showed that CAP provided a 7% absolute improvement in survival after six years versus cisplatin/cyclophosphamide [17]. Provocative interim results from the ICON3 trial [18], which compared CAP or carboplatin with carboplatin/paclitaxel, showed similar overall survival rates between the regimens after two years, although there was a trend (P - 0.06) towards improved survival in favor of carboplatin/paclitaxel in patients with greater residual bulk. In any case, the primary management approach recommended by current treatment guidelines for patients with ovarian cancer includes surgical staging and radical cytoreduction followed by systemic chemotherapy in most patients [8, 9] For those who require chemotherapy, cisplatin 75 mg/m2 with a 24-hour infusion of paclitaxel 135 mg/m2 or carboplatin (AUC 7.5) with a three-hour infusion of paclitaxel 175 mg/m2 is recommended as the first-line chemotherapeutic regimen [9]. Neoadjuvant chemotherapy (followed by interval cytoreductive surgery) should be considered in those with bulky stage III or IV disease who do not benefit from optimal surgery upfront [9]. More recently, trials have focused on establishing if carboplatin can be substituted for cisplatin. Carboplatin offers several advantages over cisplatin in terms of tolerability and convenience of administration (see Tolerabiltty Issues), although it has yet to be established conclusively if the two agents have equivalent efficacy. To this end, three comparative trials have been conducted to compare cisplatin and carboplatin in combination

with paclitaxel [19-21]. Available results suggest that both regimens offer similar efficacy, although carboplatin-based therapy is associated with less non-hematological toxicity (neurotoxicity, nausea and vomiting) [1921] and significantly better patient quality of life [19]. On the basis of these results, it is generally agreed that carboplatin can be used instead of cisplatin because of its improved tolerability profile, and it is hoped that this will be confirmed by mature survival data from the above-mentioned studies [8]. Another unanswered issue is that of dosage and whether there is any further survival benefit to be derived from dose intensification of platinum therapy. Of 11 randomized trials which have investigated the relationship between platinum dose and patient survival, only two have shown a significant survival benefit with dose-intensified platinum therapy [22]. Collectively, these data suggest that intensifying the platinum dose by a factor of two does not improve survival [22] and dose intensification is currently not supported by treatment guidelines [8]. Intensifying the dose by a factor of > 2 may possibly produce a better result, but cumulative toxicities (neurotoxicity and myelosuppression), and the limited protection offered by supportive care, are likely to prevent sustained delivery of high doses of either cisplatin or carboplatin [23] For the future, research is still ongoing to identify better first-line chemotherapeutic regimens, particularly for patients with suboptimally debulked or stage IV disease [24] One rational approach is triple combination therapy with a platinum drug/paclitaxel plus a third active agent, for example gemcitabine, topotecan, hposomal doxorubicin or etoposide. Another approach, and one that may be more successful, is sequential administration of two agents with complementary mechanisms of action, e.g. cisplatin combined with gemcitabine [25] or topotecan [26]. Second-line therapy Although up to 50% of women with ovarian cancer will achieve complete remission in response to taxane/platinum therapy, most will have persistent disease or will relapse within the first three years [27]. Thus, second-line options are an important aspect of treating this disease. Although a clinically meaningful response can be achieved in some patients with recurrent disease [28], in general, second-line treatment is not curative and its intent is palliative. Toxicity and patient quality of life are, therefore, important considerations in this setting. There is considerable heterogeneity among patients requiring second-line treatment. Depending on their response to primary treatment, patients can be characterized as having recurrent, intermediate or refractory disease (Table 1). This will also determine the range of treatment options available to them (Table 1). In particular, the duration of the treatment-free interval has been identified as an important predictor of response to second-line therapy [8] For the purposes of

1197 Table 1 Second-line treatment options for ovarian cancer [8] Duration of treatmentfree interval (months)

Treatment options

Recurrent (sensitive)

>12

Retreatment with platinum + pachtaxel Single agent carboplatin or pachtaxel Second-line agents" Secondary cytoreductive surgery in low-grade/focal disease after > 1 year disease-free interval [9]

Intermediate

4-12

Retreatment with platinum ± pachtaxel Second-line agents"

Refractory

<4

Investigational treatments/clinical trials Second-line agents"

Disease category

° Pachtaxel, docetaxel, eloposide, vinorelbine, topotecan, altretamine, hposomal doxorubicin, gemcitabine, docetaxel, oxaliplatin

standardization, sensitive recurrent disease is defined as that with a progression-free interval of over 12 months (Table 1) [8]. Other groups, however, have used a sixmonth cut-off to differentiate between platinum-sensitive (progression after > 6 months) and platinum-resistant (progression after < 6 months) disease [9, 28, 30]. For patients with sensitive recurrent disease, the chance of a durable response to second-line therapy is increased if the patient has had a long treatment-free interval. Treatment options for this patient group include reinitiation of the primary chemotherapy regimen as combination therapy or as individual agents, although there is no evidence to favour one approach over the other [9]. Second-line treatment options (Table 1) may also be considered in this patient group [8,9]. Since early retreatment with a platinum agent carries a risk of cumulative toxicity, it may be possible to use non-platinum agents in selected patients to extend the platinumfree interval thereby reducing the risk of cumulative toxicity [28]. This approach may also improve the likelihood of a response because it allows partial reversal of any acquired drug resistance [28, 29]. Non-platinum agents, which have moderate activity in sensitive recurrent disease, include pachtaxel, docetaxel, topotecan, liposomal doxorubicin, oxaliplatin, etoposide, gemcitabine, vinorelbine and altretamine (Table 1), although the options available for second-line treatment continue to evolve. According to phase II data, these agents are generally associated with objective response rates of between 10% and 35% which are sustained for up to eight months. Stable disease, a positive outcome in this scenario, is achieved in a further 35% to 50% of patients [28], For those patients with refractory disease, investigational or second-line treatment options should be considered (Table 1), although no single agent is recommended as the treatment of choice [9]. Response should be evaluated after two cycles of chemotherapy.

Limitations of current platinum-based regimens Tolerabihty issues Metals and metal complexes are well known for their toxic effects. These include abdominal pain, diarrhea and emesis and represent important mechanisms by which the body prevents further absorption of the compounds. Other effects include neuromuscular toxicity after prolonged exposure, and nephrotoxicity as a result of the molecules concentrating in the renal tubular fluid [31]. These events typify the tolerability profile of platinum drugs as a class. Nephrotoxicity, the principal dose-limiting toxicity of cisplatin, becomes prolonged and more severe with repeated courses of the drug. Its severity almost led to abandonment of the compound until it was discovered that it could be managed through the use of hydration [32]. Pre- and post-treatment hydration with intravenous saline and mannitol diuresis effectively reduces cisplatin-associated nephrotoxicity, although renal toxicity may still occur even after adequate hydration. Unlike cisplatin, carboplatin is associated with a much lower risk of nephrotoxicity and does not require hydration therapy [33]. Gastrointestinal toxicity is also common with platinum drugs, although the emetogenic potential of each compound differs. Cisplatin is recognised as one of the most emetogenic chemotherapeutic agents in that almost all patients will experience multiple episodes of nausea and vomiting within two to three hours of drug administration if no intervention is offered [31]. Carboplatin, on the other hand, is associated with less severe and fewer gastrointestinal events than cisplatin [34] Patients may also experience nausea and vomiting before treatment (anticipatory emesis) or delayed symptoms which begin 24 hours or more after chemotherapy [31]. As well as being rated by patients as one of the most distressing adverse effects of chemotherapy, poorly controlled nausea and vomiting can result in dosage reduction or interruption or termination of potentially effective chemotherapy [35]. A range of antiemetic agents are available for the control of chemotherapy-related nausea and vomiting, of which a 5HT 3 antagonist together with a glucocorticoid steroid is currently preferred for chemotherapeutic regimens which carry a moderate to severe emetic risk [36] 5HT 3 antagonists have marked efficacy in the prevention of acute chemotherapy-induced nausea and vomiting [37], although their efficacy in the management of delayed emesis is equivocal [36]. It should not be forgotten that antiemetic regimens carry their own risk of adverse events which include mild headache, constipation or diarrhea with 5HT 3 antagonists and sleep disturbances with corticosteroids [36]. It is also interesting to note that, despite the use of a 5HT 3 antagonist (with or without a steroid), patients still ranked nausea and vomiting among the top three most distressing chemotherapy-associated adverse events [38].

1198 Given that there are options available to manage platinum-associated nephrotoxicity and gastrointestinal events, for cisplatin the most important dose-limiting event is neurotoxicity This includes peripheral sensory neuropathy and manifests as autonomic neuropathy, Lhermitte's sign, seizures, encephalopathy, muscle cramps and loss of taste. This form of toxicity is cumulative and, although it is usually reversible, recovery can be slow Another form of cumulative, but irreversible, toxicity associated with cisplatin is ototoxicity of the inner ear which manifests as tinnitus or hearing loss at high frequencies. Occasionally the ability to hear normal conversation may be affected [31]. By comparison, neurotoxicity and ototoxicity are virtually absent with carboplatin [39]. Cisplatin-induced neurotoxicity is additive with other neurotoxic compounds, for example pachtaxel [34], which has important ramifications for patients with ovarian cancer In addition, while carboplatin can be administered with a three-hour infusion of paclitaxel, paclitaxel is better administered as a 24-hour infusion in combination with cisplatin to reduce the risk of severe neuropathy [8] Patients must therefore be hospitalized for at least 48 hours if they are to receive cisplatin [2], whereas carboplatin-based therapy can be administered on an outpatient basis. The dose-limiting toxicity of carboplatin is myelosuppression, notably thrombocytopenia [34]. Platelet count nadirs are generally observed from days 21 to 28, which can preclude administration of the drug every three weeks and has the potential to complicate its administration with other agents [34, 39]. Infectious and hemorrhagic events are, however, unusual and occur in < 6% of patients [34]. By comparison, cisplatin causes myelosuppression in 25% to 30% of patients and is considered to have a mild hematological toxicity profile [31]. Another approach for the management of platinum drug-related neuro-, nephro- and hematological toxicities is through the use of chemoprotective agents, such as amifostine or glutathione [40]. Both agents have demonstrated selective protection against these toxicities [40, 41], although the exact clinical benefit offered is unclear [40] Amifostine, in particular, is also associated with adverse events which include hypotension, nausea and vomiting and flushing, and these events need to be weighed against the potential benefits of chemoprotective therapy [40] Dosage issues The toxicity of most drugs can be correlated with their area under the concentration-time curve (AUC) Unlike cisplatin, 90% of a carboplatin dose is eliminated by the renal route [39]. For carboplatin, clearance is linearly related to glomerular filtration rate which in turn is related to its AUC [34]. From this observation, Calvert et al. [42] developed a formula to predict the dose of carboplatin needed to achieve a target AUC. This formula allows for variation in pretreatment renal func-

Table 2 Mechanisms of resistance to cisplatin [44] Mechanisms which prevent binding to DNA • Decreased drug transport • Increased intracellular drug detoxification/inactivation by conjugation to thiol-containing species Mechanisms which prevent cell death after binding to DNA • Increased repair of platinum-DNA adducts • Ability to tolerate increased levels of drug-induced DNA damage • Failure to engage programmed cell death (apoptosis)

tion Target AUCs for single agent carboplatin range from 5 to 7 mg/ml/min which have been shown to lead to an acceptable level of thrombocytopenia The AUC of cisplatin, on the other hand, is not related to renal function [43] and therefore the drug is dosed empirically based on body surface area.

Resistance Cisplatin exerts its antitumor activity through binding to DNA and forming adducts which then block replication and/or prevent transcription. A variety of monofunctional (single linkage with DNA) or bifunctional (two linkages) adducts are possible, although which adduct(s) is the most important for the antitumor activity of cisplatin remains uncertain (reviewed by Kelland [44]). Resistance to cisplatin can arise as a result of various different biochemical mechanisms (Table 2), several of which are relevant to ovarian cancer. A common mechanism observed in ovarian cancer cell lines is an increase in cytoplasmic levels of thiol-containing species (specifically glutathione and metallothioneins). Thiol substitutes for platinum, thereby inactivating many platinum compounds. In human ovarian carcinoma cells, intracellular glutathione levels correlate with cisplatin sensitivity [45], although the relevance of this mechanism in a clinical setting is unknown [30]. An important post-binding mechanism is the removal of platinum-DNA adduct by damage-recognition proteins, supportive evidence for this mechanism of resistance in ovarian cancer has been observed both in vitro [46,47] and in patients [30]. The p53 tumour suppressor gene which mediates apoptosis is commonly mutated in patients with ovarian cancer (50% to 70% of patients) [48] and would therefore appear to be an important mechanism of resistance in this type of cancer. Although increased levels of p53 expression confer resistance to cisplatin in vitro [49], other molecules are involved and the exact role of p53 status and platinum resistance has yet to be fully elucidated [30]. Several possibilities exist for circumventing mechanisms of resistance to the platinum drugs. These include use of high-dose or localized chemotherapy, improved drug delivery (e.g. liposomal formulations), combination chemotherapy, gene therapy, coupling platinum

1199 drugs with agents that overcome known mechanisms of resistance (e.g. buthionine sulfoximine which depletes glutathione levels), and developing agents with increased potency or with activity that is unaffected by intrinsic or acquired mechanisms of resistance [30, 50, 51]

ci

\

O C O

H,N

\

/ Pt

pt

•V

a

oco

Clsflattn

Emerging platinum compounds H,N

Since the availability of carboplatin, a platinum drug with an improved tolerability profile, the major thrust of platinum drug development has been to identify agents with activity against tumors which are or may become resistant to traditional platinum drugs. With this goal in mind, various platinum analogs have been identified from screening including 1,2-diamminocyclohexane (DACH) derivatives, of which oxaliplatin is the most successful, platinum IV compounds (e.g. satraplatin), bi- and trinuclear platinums (e.g. BBR3464) and sterically hindered complexes (e.g ZD0473). Compounds which are showing promise in ovarian cancer are reviewed below (Figure 1).

0

C.

OCO NedaptatJn

OCOCH,

a OCOCH,

SatraplaUn

Oxaliplatin Oxaliplatin (trans-L-diamminocyclohexane oxalatoplatinum II, L - O H P ) is a derivative of cisplatin in which the ammine ligands have been replaced by a DACH group This structural difference appears to confer a different spectrum of activity, including activity against some cisplatin-resistant cancers [52-54] Oxaliplatin has been developed in France and is approved for the treatment of advanced colorectal cancer in some European countries. The agent also has efficacy in the treatment of ovarian cancer including patients with platinum-resistant disease [53, 54]. This was confirmed in a recent randomized phase II trial in which oxaliplatin demonstrated equivalent efficacy to pachtaxel in 86 patients with platinumpretreated advanced ovarian cancer [55]. An overall response rate of 16% was achieved with oxaliplatin 130 mg/m 2 every three weeks compared with 17% with paclitaxel 175 mg/m 2 every three weeks, with respective median overall survival times of 42 and 37 weeks. Among patients with platinum-resistant ovarian cancer, oxaliplatin achieved an objective response in 2 of 32 patients and paclitaxel in 5 of 31 patients [55] In the largest randomized trial performed to date, oxaliplatin 130 mg/m 2 or cisplatin 100 mg/m 2 both in combination with cyclophosphamide 1000 mg/m 2 were compared in previously untreated patients with advanced ovarian cancer [56]. The two regimens were similar in terms of efficacy with overall response rates of 52% in the oxaliplatin group and 65% in the cisplatin group and respective median survival times of 21 and 26 months. Although the cisplatin-containing regimen was associated with more hematological, gastrointestinal and renal toxicity, the oxaliplatin-containing regimen resulted in a higher incidence of neuropathy [56].

BBR3404

Figure I Structures of the platinum complexes cisplatin, carboplatin. oxaliplatin, nedaplatin, satraplatin. BBR3464 and ZD0473

Of interest, oxaliplatin has been tested in combination with cisplatin in 25 patients with heavily pretreated ovarian cancer, 13 of whom were considered to be platinum refractory [23]. Patients had received a median of three previous chemotherapeutic regimens of which at least one included a platinum agent. The rationale for this biplatin regimen was based on the concept of doseintensification and on prechnical data which showed additive in vitro activity with the two agents [54]. 40% of patients achieved an objective response following treatment with oxaliplatin 130 mg/m 2 and cisplatin 100 mg/m 2 administered sequentially on the same day every three weeks, with a response duration of 2 to 15+ months [23] The dose-limiting toxicity of the regimen was peripheral neuropathy These promising results provide an indication that non-cross-resistant platinum agents may play a useful role both in first- and second-line treatment regimens [23]. The dose-limiting toxicity of oxaliplatin is an unusual form of sensory neuropathy [32] which is triggered or enhanced by the cold [54]. Oxaliplatin-related neurotoxicity appears to be cumulative, although it generally reverses within four to six months of stopping treatment [32]. Oxaliplatin lacks the nephrotoxicity and ototoxicity of cisplatin.

1200 Nedaplatin (254-S)

BBR3464

Nedaplatin (cis-diammine-glycolato-0,0' platinum II, CDGP) is an analog of cisplatin which has been developed primarily in Japan. It has been available for use there since 1995. According to a recent in vitro study conducted in the US, nedaplatin has cytototoxic activity similar to both cisplatin and carboplatin in human ovarian tumor specimens. At clinically achievable plasma concentrations, an estimated 42%, 36% and 36% of tumor specimens were sensitive to nedaplatin, cisplatin and carboplatin, respectively. Nedaplatin is, however, relatively cross-resistant with cisplatin; of 18 cisplatin-resistant tumors, 28% were sensitive to nedaplatin and 18% to carboplatin [57]. Response rates of at least 25% have been achieved with nedaplatin monotherapy in a range of different cancer types, including ovarian cancer [53]. Of interest, two patients with recurrent ovarian cancer following therapy with cisplatin/carboplatin and cyclophosphamide with or without doxorubicin, demonstrated a partial and a complete response with up to seven cycles of nedaplatin 100 mg/m 2 One patient had also failed to respond to second-line treatment with irinotecan and intraperitoneal cisplatin. Responses lasted for four months in both patients [58]. The dose-limiting toxicity of nedaplatin is myelosuppression, specifically thrombocytopenia, and a platelet count nadir is observed four weeks after drug administration [59] Non-hematological toxicities include mild nausea and vomiting, renal toxicity and peripheral neuropathy [59]. Although the agent has less nephrotoxicity than cisplatin, rare cases of severe nephrotoxicity have been reported [52]. Ototoxicity, similar to that observed with cisplatin, has also been documented [60]

BBR3464 is a novel cationic trinuclear platinum which is structurally distinct from cisplatin and carboplatin. Multinuclear platinum compounds, such as BBR3464, are thought to form different types of DNA adducts not encountered with traditional mononuclear compounds [63]. In vitro testing showed that BBR3464 possesses a spectrum of activity different from that of cisplatin according to a 60-cell line screening panel, suggestive of a different mechanism of action [64]. BBR3464 also showed activity in three ovarian cancer cell lines intrinsically resistant to cisplatin; IC 50 values ranged from 0.08 to 0.6 umol/1 versus 21 to 42 umol/1 with cisplatin [64]. Its activity also included a p53-containing mutant ovarian cancer cell line [63]. Interestingly, the sensitivity of an osteosarcoma cell line to BBR3464 decreased by approximately 10-fold after the introduction of a functional p53 gene [63] According to a phase I study, the dose-limiting toxicities of BBR3464 were neutropenia and diarrhea (preceded by abdominal cramps). Nausea and vomiting were rarely reported. Neurotoxicity and renal toxicity were not observed, although patients had received preand post-treatment hydration. The maximum tolerated dose was 0.12 mg/m 2 [65]. One patient with progression of ovarian cancer after treatment with paclitaxel, carboplatin and topotecan had a 50% decrease in CA125 levels and stabilization of abdominal and pelvic tumors after treatment with BBR3464 0.12 mg/m 2 [65]. An intermittent monthly dose schedule has been selected for further phase I trials [66].

Satraplatin (JM216. BMS-18275I) Satraplatin (i/j-acetato-ammine-dichloro-cyclohexylamine platinum IV) is a platinum IV compound and is the first oral agent to be developed [53], Satraplatin has in vitro and in vivo activity against human ovarian carcinomas similar to that of cisplatin [61] Although satraplatin showed activity in two of four cisplatin-resistant ovarian cell lines in vitro [61], this noncross-resistant activity has not been confirmed in vivo [53] Phase I clinical studies suggest that oral satraplatin has a toxicity profile similar to that of carboplatin with myelosuppression as the dose-limiting toxicity [53]. Non-hematological toxicities include emesis (generally mild), stomatitis and diarrhea with no evidence of neurotoxicity, nephrotoxicity or ototoxicity [53, 62]. One patient who had previously received cisplatin demonstrated a partial response for over four months with six courses of oral satraplatin 120 mg/m 2 , and two other patients with recurrent ovarian cancer showed 3- to 4-fold decreases in serum CA125 levels [62]. Satraplatin is currently in phase III trials.

ZD0473 (AMD473, JM473) ZD0473 [c«-amminedichloro(2-methylpyndine) platinum II] is a novel agent which was identified as part of a research program aimed at finding platinum drugs able to overcome mechanisms of platinum drug resistance and, in the first instance, thiol-mediated resistance (Table 2). ZD0473 contains a methyl-substituted pyridine chain which hinders thiol substitution in the cytoplasm, while retaining the ability to form cytotoxic lesions with DNA [52, 67] However, it soon became apparent that, in addition to overcoming thiol resistance, ZD0473 was able to effectively overcome other major mechanisms of biochemical resistance to cisplatin [67]. In a panel of human ovarian carcinoma cell lines, ZD0473 had intermediate activity between that of cisplatin and carboplatin [67]. Unlike cisplatin and carboplatin, the activity of ZD0473 was virtually unaffected in a cell line in which thiol substitution was the key mechanism of resistance [67], Importantly, ZD0473 also showed activity in ovarian cell lines in which resistance was attributable to reduced drug transport or enhanced DNA repair/increased tolerance to platinum-DNA adducts [67]. ZD0473 and paclitaxel were synergistic in

1201 ZDO473 HS«r«pkto • Chpfafti

was well tolerated. The dose-limiting toxicity of ZD0473 was myelosuppresston (thrombocytopenia, neutropenia and anemia), no clinically significant nephrotoxicity or neurotoxicity was observed [71].

Conclusions

Figure 2 Overview of comparative antitumor activity of platinum agents against human ovarian carcinoma xenografts in nude mice All drugs were administered at the maximum tolerated dose every seven days for four doses ZD0473 30-40 mg/kg intraperitoneally, satraplatin 90 mg/kg orally, cisplatin 4 mg/kg intraperitoneally, carboplatin 80 mg/kg intraperitoneally Tumors were relatively sensitive (PXN/65, CHI), intermediately sensitive (HX/110) or refractory (SK.OV-3, HX/ 62) to cisplatin CHlcisR and HX/110P were models of acquired cisplatin/carboplatin resistance For ZD0473, the growth delays in xenografts PXN/65 and CHI were > 215 and > 139 days, respectively [69]

In conclusion, the platinum drugs continue to hold a pivotal place in the management of patients with ovarian cancer. Although these agents offer exceptional activity in this cancer type, resistance to therapy can limit their efficacy. Serious toxicities can also pose problems with the classical agents. The development of new platinum compounds with improved tolerability profiles and, importantly, the ability to overcome mechanisms of resistance holds much promise for the future. If the encouraging in vitro activity shown by new compounds, such as ZD0473 and BBR3464, translates into efficacy in the clinic, they may offer an extended spectrum of activity which includes patients with ovarian cancer resistant to the classical platinum drugs

References

four human carcinoma cell lines (two of which were cisplatin resistant), although the sequence of exposure was important for the degree of growth inhibition achieved [68]. In vivo, ZD0473 showed antitumor efficacy in human ovarian cancer xenografts with differing sensitivities and acquired resistance to cisplatin (Figure 2). The efficacy of ZD0473 was retained following oral administration [69]. In phase I trials, 36 patients received a total of 111 courses of ZD0473, dosed at 12 to 150 mg/m 2 . Thrombocytopenia and neutropenia were the dose-limiting toxicities observed at the higher doses of 130 to 150 mg/m 2 [70.] Other grade 3-4 toxicities included dyspnea, nausea, pain, vomiting, infection, anemia and leukopenia. Interestingly, no neurotoxicity, ototoxicity or renal toxicity was reported [66, 70]. In eight patients with ovarian cancer, one patient with recurrent disease achieved a partial response and two achieved a stable response at a dose of 150 mg/m 2 [70]. In an ongoing phase II trial, ZD0473 was administered as second-line therapy in patients with ovarian cancer who had failed one previous regimen of platinum-based therapy An objective response was achieved with ZD0473 monotherapy in 2 of 14 evaluable patients with resistant disease (relapse/progression ^ 2 6 weeks following completion of first-line platinum-based therapy) and 5 of 12 evaluable patients with sensitive disease (relapse/progression > 2 6 weeks); stable disease was achieved in a further two and three patients, respectively. ZD0473 was administered initially at a three-weekly dose of 120 mg/m 2 ; the dose was increased to 150 mg/m 2 as the trial progressed because the initial dose

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Received 2 May 2001, accepted 6 June 2001 Correspondence to M J Piccart, MD Jules Bordet Institute (Chemotherapy Unit) Rue Heger-Bordet I, 1000 Brussels Belgium E-mail martine piccart@bordet be