Volume 74, Issue 3, Pages 163-174 (June 2010)

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ABSTRACT

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Review role of topotecan in gynaecological cancers: Current indications and perspectives

Accepted 11 August 2009. published online 22 September 2009.

Abstract

Background

Ovarian cancer is the fourth cause of death from gynaecological cancer and cervical cancer is the first in women <45 years old in developing countries.

The aim of this article is to review the role of topotecan (Hycamtin®), a semi-synthetic alkaloid derivative of camptothecin, in ovarian and cervical cancer in monotherapy and in combination.

Methods

This article reviews the mechanism of action, pharmacokinetics, toxicity and efficacy of topotecan. The paper also reports the principal phases II and III studies of topotecan in advanced or recurrent ovarian and cervical cancer.

Results

Topotecan (Hycamtin®), currently indicated for the treatment of relapsed ovarian cancer, has demonstrated activity both in platinum-sensitive and in platinum-resistant disease. The combination cisplatin–topotecan for the treatment of advanced and recurrent cervical cancer has demonstrated a clinical benefit in terms of response rate, overall survival and progression free survival. Haematological toxicity of topotecan also is easy to manage and not cumulative, especially with the weekly scheduled recently introduced in clinical practice.

Conclusion

Topotecan (Hycamtin®) will continue to play a role in the treatment of advanced ovarian and cervical cancer, in monotherapy or in combination with other cytotoxic agents.

Keywords: Chemotherapy, Cervical cancer, Ovarian cancer, Topotecan, Topoisomerase I inhibitor

Article Outline

• Abstract

• 1. Ovarian cancer

• 2. Cervical cancer

• 3. Topotecan: clinical and pharmacological profile

• 3.1. Mechanism of action of topotecan

• 3.2. Pharmacokinetics

• 3.2.1. Absorption, administration and distribution

• 3.2.2. Metabolism and excretion

• 3.2.3. Interaction with other drugs

• 3.3. Toxicology

• 3.4. Topotecan licensed indications in gynaecological cancers

• 3.4.1. Topotecan in the treatment of advanced ovarian cancer

• 3.4.2. Topotecan–carboplatin combination

• 3.5. Advanced cervical cancer

• 3.5.1. Topotecan–cisplatin combination

• 4. Conclusions

•

• Conflict of interest statement

• References

• Biography

• Copyright

1. Ovarian cancer

Ovarian cancer is the leading cause of death among gynaecological cancers in the Northern hemisphere and the fourth cause of death for tumors in developed Countries with an incidence of 17/100,000 women/year in Europe and Unites States [1].

The risk to be affected by ovarian cancer during lifetime is 10.4‰ (1 case out of 97 women), while the risk of death for this cancer is 5.4‰ [1].

European estimates indicate globally 42,700 new diagnosed cases/year (Fig. 1) [2].

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Fig. 1. Estimated incidence of cancer in Europe, 2004 (number of cases, both sexes) [2].

This incidence is substantially stable, while the mortality is slightly decreased in the last decade, probably due to the improvement of the medical and surgical treatments currently available.

The ovarian cancer is considered a “silent killer” due to the absolute lack of early symptoms of disease. In the majority of cases, the disease is diagnosed at FIGO stages III and IV, and the survival, is clearly conditioned by the stage of the disease, ranging from 90 to 95% for stage I to 15% for stage IV at 5 years.

The treatment is based on cytoreductive surgery, followed by combination chemotherapy with platinum and taxanes. Although 70–80% of the patients present objective responses to first line treatment, most of them will present a recurrence within the first 2 years from the end of first line chemotherapy and should receive further therapies [3], [4], [5].

The choice of second line drug is strictly related to the response obtained with the first line treatment, and is conditioned by the platinum-free interval. Patients who present a progression of disease during the first line treatment (refractory disease) or after a platinum-free interval <6 months (resistant disease) are treated with second line agents not cross-resistant with platinum, such as topotecan, liposomal pegylated doxorubicin (DLP), gemcitabine and etoposide [6], [7], [8].

Ovarian cancer that relapses 6–12 months after treatment with a platinum regimen is considered partially platinum sensitive. Phase III studies of combination regimens vs. platinum monotherapy and comparing various non-platinum agents administered as monotherapy generally do not report separate data for partially platinum-sensitive patients. Studies reporting data in patients with a platinum-free interval ≥6 months demonstrate advantages for pegylated liposomal doxorubicin (PLD) vs. paclitaxel [9] and PLD vs. topotecan [10]. For patients recurring >12 months after completion of first line platinum based chemotherapy, carboplatin paclitaxel [11] and carboplatin gemcitabine combinations [12] provided a significantly increased progression free survival and overall survival with respect to carboplatin monotherapy.

The objectives of treatment in this three patient categories are quite different; in fact while in the platinum refractory patients the palliation of symptoms and the maintenance of quality of life are the realistic goals of the treatment, in the partially platinum-sensitive disease the increase of time to progression and possibly the overall survival should be pursued and in the very sensitive patients the overall survival and the cure of the disease are the expected issues of the treatment.

2. Cervical cancer

There is a remarkable geographic variability in terms of prevalence, incidence and mortality of uterine cervical cancer; worldwide, it is the second cancer in women <45 years old and the first in the developing countries, where the incidence is >30 cases per 100,000 women/year. The more optimistic forecast indicates an increase of about 1 million new cases of uterine cervical cancer per year by 2050 [13].

Even though the modern screening procedures have reduced by 80% the incidence of uterine cervical cancer, in Europe the disease affects 9.8/100,000 women/year and 30,400 new cases of invasive cervical cancer are diagnosed every year [2].

Some specific genotypes of human papillomavirus (HPV) are recognized as the main cause of uterine cervical cancer. The HPV infection can be caused by low risk genotypes, responsible for precancerous lesions detected by Pap-smear and colposcopy, and by high risk genotypes, responsible for the malignant transformation of these lesions. The high risk genotypes are able to modify the human cell by inserting their DNA into the naïve cellular genoma, causing a pathway of biological events that lead to the development of intraepithelial lesions, which could transform into invasive.

The principal prognostic factor is the stage of disease. The majority of early stage tumours are treated with surgery, and radiation therapy is reserved for localised relapse, while those presenting with locally advanced disease are given concurrent chemoradiation as the standard of care [14]. In October of 1998, the National Cancer Institute reviewed the results of five randomized trials evaluating the role of concurrent cisplatin-based chemotherapy with ‘standard’ radiation therapy in patients with advanced cervical cancer. Collectively, all five trials involving 1894 patients, showed a significant reduction in the risk of recurrence and death with cisplatin-based chemoradiation. [14]. Another approach is represented by neoadjuvant chemotherapy or chemoradiation therapy followed by surgery [15], [16]. As a result of the increasing aggressiveness of primary strategies, the treatment of recurrent disease is a formidable problem. The patient population receiving chemotherapy for recurrent disease has changed over the last 5 years; the majority of patients will have had prior radiation therapy to at least some of their disease sites, which is known to reduce response rates by at least 50% [17], and many have received prior platinum incorporated in chemoradiation or neoadjuvant protocols. These aspects must be kept in mind in the interpretation of the results of phase III trials.

3. Topotecan: clinical and pharmacological profile

Topotecan (Hycamtin®) is a semi-synthetic alkaloid derivative of camptothecin, with similar anticancer activity and a better safety profile. The drug is indicated in the treatment of advanced or recurrent ovarian and cervical cancers.

Camptothecin was isolated from Camptotheca acuminata and Nothapodytes fetida trees during the ‘60s. Shortly afterwards, its anticancer activity was demonstrated in different experimental cancer models and, subsequently, preliminar clinical studies confirmed its cytotoxic potential [18], [19], [20], [21], [22], [23], [24], [25], [26], [27], [28]. At the end of the ‘80s, topotecan, a hydrosoluble semi-synthetic derivative of camptothecin, with a cytotoxic activity similar to the parent compound and a better toxicity profile was synthesized [18], [19].

In its molecular structure in fact topotecan presents a lateral basic group, which is responsible for hydrosolubility of the molecule at acid pH (Fig. 2) [29].

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Fig. 2. Chemical structure [29].

3.1. Mechanism of action of topotecan

Topotecan specifically inhibits the enzymatic complex topoisomerase I-DNA in the nucleous [30], [31], [32], [33], [34], [35], [36], [37], [38], [39], [40], [41], [42]. Topoisomerase I plays a key role in the replication, transcription and repair mechanisms of DNA [39], [43], [44], [45], [46]. Unlike ATP-dependent topoisomerase II that can break both strands, topoisomerase I is responsible only for temporary ruptures of the single strand of DNA without requiring ATP for the energetic activation of the process [38].

DNA is a double strand coil (double helix) contained in the nucleus; once replication is started, the process produces a torsional stress, that must be mitigated by despirilization and relaxation of the DNA. The despirilization produces the replication fork, allowing the DNA to be divided in the single filaments.

The first step of this process involves topoisomerase I, which binds to a specific fragment of supercoiled DNA; during this process, the enzyme binds covalently to the end of the cleaved strand of DNA and generates a covalent complex DNA strands—topoisomerase I (DNA–enzyme complex), that is the site of action of topotecan. The drug stabilizes the complex, causing the cleavage of DNA [42], [43], [46], [47], [48], [49] (Fig. 3, Fig. 4 [29]).

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Fig. 3. Schematic graph of DNA–topoisomerase I interaction and mechanism of action of topotecan [29]. (a) DNA. (b) During the replication phase, toposomerase I promotes the rupture of a single strand DNA. (c) Topotecan prevents topoisomerase I from binding to the strand.

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Fig. 4. Schematic graph of DNA–topoisomerase I interaction and mechanism of action of topotecan [29]. (a) The DNA replication continues. (b) The DNA replication cannot move forward due to topotecan–topoisomerase I link. The DNA damage leads to cellular death.

Unlike cycle-independent expression of topoisomerase, the cytotoxic activity of topotecan depends on cellular cycle and is more pronounced during phase S [50]; for these reasons, a sufficient time of exposition is necessary for the implementation of the cytotoxic activity of topotecan.

3.2. Pharmacokinetics

3.2.1. Absorption, administration and distribution

Camptothecin and topotecan are present in aqueous solution as lactonic form and hydroxy acid form in a pH-dependent balance [51], [52], [53], [54].

The intact lactonic ring is not only a prerequisite for any interaction between topoisomerase I and DNA complex, but it seems essential for the passive diffusion of camptothecins into the tumor cells [31].

The intravenous form of topotecan does not contain only the active lactone; at physiological pH, the hydrolysis of the intact hydroxy acid occurs until the balance between the two forms is reached.

Topotecan has also an oral formulation not licensed for ovarian cancer treatment. In several clinical studies the oral administration, that allows an absorption and a bioavailability of 30–40% of the active lactonic form, demonstrated a similar efficacy to the iv administration with only a trial reporting a small but significant benefit in overall survival for iv formulation [55], [56]. Plasma protein binding of topotecan is low (32–35%), but the volume of distribution is high (≥20l/m2) both in animal models and in human (mean 132l/m2), indicating a good tissue penetration [57].

Furthermore, topotecan has a good penetration in cerebrospinal fluid (CSF); after 30min from the administration, more than 60% of drug available in the plasma is active. Once the balance is reached, about 1h after the administration, more than 50% of active drug is present in the cerebrospinal fluid. The elimination from cerebrospinal fluid follows a timing curve equivalent to that of elimination from plasma [58].

The mean CSF/plasma AUC rate suggests that the penetration of topotecan in CSF, is significantly higher than that of most of cytotoxic agents (Table 1) [59].

Table 1.

Ability of different cytotoxic agents to penetrate in CSF [59].


	Cytotoxic agent	Ability to penetrate in CSF
	Topotecan	+++
	Nitrosoureas (ACNU, BCNU)	++
	Hydroxyureas	++
	5-FU	++ (under discussion)
	Metotrexate	++
	Etoposide	−/+ only for high dosages
	Taxanes	(+)
	CTP 11	+2–6%
	Camptothecin	+2–6%
	Cyclophosphamide	−/+
	Ifosfamide	−/+
	Adnamycin	−
	Mitoxantrone	−
	Cisplatin	−
	Vinca alkaloids	−

CSF concentration: (+++) >30% of plasmatic concentration; (++) 20–30% of plasmatic concentration; (+) ≤10% of plasmatic concentration.

3.2.2. Metabolism and excretion

The excretion of topotecan has not been completely evaluated in human; however, the kidney is an important excretion route of the drug. Through the renal emunctory in fact, the topotecan is eliminated after hydrolysis of the lactonic ring and formation of the open hydroxy acid ring.

The pharmacokinetic analysis of phase I studies showed a median half-life (t1/2) of 2.2h with all doses evaluated.

Factors, such as age, weight and presence of ascites, have not a significant effect on the clearance of topotecan; however, other factors such as renal failure, poor general status and/or loss of body weight can reduce the clearance of topotecan, increasing consequently the exposition time [60].

The plasma clearance of topotecan in patients with hepatic failure (plasma bilirubin range: 1.5–10mg/dl) decreases by 67% with respect to the control group. Furthermore, the half-life of topotecan is increased by about 30%, despite no clear changes are registered in the volume of distribution.

3.2.3. Interaction with other drugs

Sufficient data on interaction between topotecan and other simultaneously administered cytotoxic agents are not available. Theoretically, an interaction with other drugs excreted by renal route is possible but, at the present time, no clinically significant interaction has been reported. It is well known that the simultaneous administration of ondansetron, granisetron, morphine or steroids have not a significant effect on the pharmacokinetics of topotecan.

3.3. Toxicology

Toxicological studies have showed that haematopoietic system, lymphatic tissue, gastrointestinal tract, hair bulbs, testicles and ovaries are the target organs of the drug.

The haematopoietic system and the lymphatic tissue are the most susceptible organs: myelotoxicity, in terms of neutropenia, thrombocytopenia and anaemia, is the most significant treatment related toxicity. No significant toxicological effects have been observed in other organs such as heart, lungs, liver, kidneys, bladder and CNS.

The haematological adverse events of topotecan are dose-dependent. Myelotoxicity is not cumulative and can be managed by modifying the treatment schedule, by reducing the dose or with the use of hematopoietic stimulating factors.

Several studies have demonstrated that the haematological toxicities of topotecan are predictable and can be limited by reducing the initial dose of the drug [61], [62], [63], [64]. This is particularly relevant in case of previous treatment with platinum-containing regimens; a meta-analysis demonstrated in fact that, other than risk factors such as renal failure, an extensive pre-treatment with platinum increases the risk of severe neutropenia after topotecan administration [65].

The treatment is well tolerated even if prolonged until disease progression [66], [67]. The injection of iv diluted solutions did not cause any local reaction. Very few cases of extravasation, with mild local reactions not needing any specific treatment were reported. No cases of ulcerative or necrotic reaction, or permanent tissue injuries were reported. The “recall phenomenon”, usual for taxanes and anthracyclines, was never observed [68], [69].

3.4. Topotecan licensed indications in gynaecological cancers

In gynaecological oncology, topotecan is indicated as a single agent for the treatment of patients with metastatic ovarian cancer after failure of first line or subsequent treatment regimens, as well as in combination with cisplatin in patients with relapsed or metastatic uterine cervical cancer.

In the following section we report literature data supporting the licensed indications of topotecan in ovarian and cervical cancers as well as data concerning the use of different schedules, doses and drug combinations in gynaecological cancers.

3.4.1. Topotecan in the treatment of advanced ovarian cancer

Topotecan was evaluated both as single agent and in combination for the treatment of relapsed ovarian cancer.

In phase II studies, the responses in women with platinum-sensitive disease range between 12 and 33% [6], [70], [71] while in platinum-refractory patients, the obtained responses rate is 14–18% [70], [71], [72] (Table 2 [74]).

Table 2.

Phase II studies on topotecan in advanced or recurrent ovarian cancer (adapted from Herzog [74]).


Study	Platinum-resistant			Platinum-sensitive
	Evaluable patients, n	Overall response, n (%)	Stable disease, n (%)	Evaluable patients, n	Overall response, n (%)	Stable disease, n (%)
Creemers et al. (1996) [7]	28	5 (18)	30	8 (27)	5 (17)
Kudelka et al. (1996) [86]	28	4 (14)	17 (61)	–	–	–
Swisher et al. (1997) [88]a	28	4 (14)	13 (46)	–	–	–
Bookman et al. (1998) [6]	33	5 (15)	11 (33)	26	5 (19)	7 (27)
McGuire et al. (2000) [102]	–	–	–	46	15 (33)	22 (48)

Starting dose of 1.25mg/m2, then escalated.

A phase III randomized trial compared topotecan and paclitaxel in a setting of patients the majority of which presented platinum-refractory/resistant disease: patients were randomized to receive topotecan 1.5mg/m2 for 5 days vs. paclitaxel 175mg/m2 day 1 every 3 weeks [72].

The study demonstrated an equivalence between the two treatment arms in terms of objective responses (20% vs. 13% for topotecan and paclitaxel respectively), while a significant benefit in the group treated with topotecan in terms of time to progression (23 weeks vs. 14 weeks) was registered.

The authors conclude that, according to what previously reported in phase II studies, topotecan is a valid therapeutic approach for relapsed ovarian cancer, both in patients with platinum-sensitive and platinum-resistant disease.

In the study of Gordon et al. topotecan was compared to pegylated liposomal doxorubicin (PLD) in patients with recurrent ovarian cancer [10], [75]. The authors reported a significant benefit of PLD in terms of survival in the population with recurrent platinum-sensitive disease (median survival 107.9 weeks and 70.1 weeks for PLD and topotecan respectively; HR 1.432, p=0.017); on the contrary, no difference was registered in the platinum-resistant patients (median survival 36 weeks vs. 41 weeks for PLD and topotecan respectively; HR 1.069, p=0.618) (Fig. 5) [10].

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Fig. 5. Randomized phase III trial of PLD vs. topotecan in recurrent ovarian cancer: overall survival per treatment arm [10].

Unfortunately, no informations are reported regarding the chemotherapic treatments administered to the patients at progression, which could almost in part justify the better survival observed in the platinum-sensitive population treated with pegylated liposomal doxorubicin [10].

During the first year, in fact, the survival curves for the two treatment arms were superimposable, and only later the PLD survival curve looked better; this result could suggest an additional effect on survival of the drugs given at disease progression [10].

The toxicity profiles of the two drugs were significantly different: an higher incidence of hand-food syndrome was reported in the patients treated with PLD while myelotoxicity was the most frequent toxicity registered in the topotecan arm.

Several clinical experiences have been conducted on the role of topotecan in first line treatment of advanced ovarian cancer [76], [77], [78] and in the consolidation setting [73], [79].

Vecchione et al. [76] reported a 71% overall response rate (45% complete responses) and a median survival of 47 months in a population of 42 advanced chemonaive ovarian cancer patients treated with Carboplatin AUC 5 and topotecan 1.5mg/mq days 1–3 every 3 weeks. Although myelosuppression was relevant (grades 3–4 neutropenia occurred in 100% patients), it was transient and easily manageable.

Hochster et al. [77] reported a 80% objective response rate, a 19.3 months progression free survival and a 45.6 months median survival in a population of 60 stage IC-IV ovarian cancer patients treated with cisplatin and prolonged topotecan infusion. Marrow suppression was the dose limiting toxicity of the combination with 86% of patients experiencing grades 3–4 neutropenia, 55% experiencing grades 3–4 thrombocytopenia and 50% experiencing grades 3–4 anemia.

Pignata et al. [73] and Pfisterer et al. [79] failed to evidence a clinical benefit with the addiction of four cycles of topotecan in the consolidation setting of advanced ovarian cancer patients in partial or complete response after six cycles of carboplatin-paclitaxel chemotherapy.

Bookman et al. reported the data of the GOG182/ICON 5 trial in which 4312 advanced ovarian cancer patients were randomly assigned among five treatment arms that include gemcitabine, topotecan and pegylated liposomal doxorubicin in sequence or combination with carboplatin vs. carboplatin-paclitaxel alone. There were no improvements in progression free survival or overall survival associated with any experimental regimen and the authors concluded that, compared with carboplatin-paclitaxel treatment, the addiction of a third cytotoxic agent provided no benefit [80].

OV16 trial was a randomised trial in which 819 stage IIB-IV ovarian cancer patients were treated with standard carboplatin-paclitaxel combination for eight cycles (arm A) vs. four cycles of cisplatin–topotecan followed by four cycles of carboplatin paclitaxel (arm B). The trial failed to demonstrate a benefit of the experimental arm in terms of progression free survival (16.2 vs. 14.6 for arms A and B, respectively, p=0.25) being the combination treatment with topotecan more toxic [80].

In order to facilitate the management of haematological adverse events, the available guidelines recommend prophylactic therapy with haematopoietic growth factors (G-CSF) starting from the 6th day of the cycle, or a dose reduction in patients considered at risk to develop a severe myelotoxicity [81], [82].

Furthermore, several investigators evaluated the use of alternative administration schedules.

Markman et al. firstly evaluated topotecan at the dose of 1.5mg/m2 days 1–3 q 3 weeks in a population of 29 platinum-resistant recurrent ovarian cancer patients [83]. Objective response rate was reported in 7% of patient and prolonged disease stabilization (>4 months) in 21%. As far as safety is concerned, no grade 4 thrombocytopenia was observed, while a severe neutropenia occurred in 24% of patient.

In the same context, the weekly administration of topotecan is particularly attractive [84], [85].

Safra et al. [84] evaluated the efficacy and safety of topotecan 4mg/m2 days 1, 8, 15 q 28 in a population of recurrent heavily pretreated ovarian cancer patients. An objective response rate of 23.8% (complete response 17.5%), a median time to progression of 6.2 months (95% CI: 4.43–7.97) and a median survival of 22.3 months (95% CI: 14.56–30.04) were reported. Haematological toxicity was mild: grade 3 anaemia and thrombocytopenia were registered in 4.8% of patients, while grades 3–4 neutropenia was reported in 7.9% of patients.

The authors concluded that weekly administration of topotecan produces interesting results in terms of efficacy and safety. The low incidence of haematological adverse events accounts for the small use of haematopoietic growth factors and blood transfusions registered in the study, as well as the optimal compliance to treatment and the maintenance of dose intensity.

In the retrospective trial of Abushahin et al. [85] 70 patients with relapsed ovarian and peritoneal cancer were treated with weekly topotecan at the dose of 3.75mg/m2 days 1, 8, 15 q 28; the reported objective response rate was 20.3% (complete response 7.3%), prolonged disease stabilization was registered in 33.3% of patients, and progression free survival was 5.7 months. Grade 4 neutropenia was observed in 0.4% of the patients and grade 3 thrombocytopenia and anaemia in 0.9 and 0.4% of patients respectively.

These data combine with the previously reported literature on 5-day administration of topotecan in advanced ovarian cancer patients [72], [86], [87], [88] and the authors concluded that weekly administration of topotecan is a better tolerated regimen than iv 5 days schedule with equivalent clinical activity.

In the recent ASCO meeting Sehouli et al. presented the results of a randomized trial of topotecan 4mg/mq days 1, 8, 15 q 28 vs. topotecan 1.25mg/mq days 1–5 q 21 in a population of 194 recurrent platinum-resistant ovarian cancer patients. The authors concluded that weekly administration of topotecan showed no substantial differences in term of responses (47% vs. 57% for topotecan weekly and 5 days respectively; p=ns), progression free survival (3.2 months vs. 4.4 months for topotecan weekly and 5 days respectively; HR: 1.30) and overall survival (9.8 months vs. 10 months for topotecan weekly and 5 days respectively; HR: 1.08) being the weekly administration significantly less toxic [89].

The oral formulation of topotecan has been explored in the treatment of relapsed small cell lung cancer and some studies have been conducted also in gynaecological cancers.

In a retrospective trial on a population of 116 relapsed ovarian cancer patients treated with topotecan 2.3mg/m2/day per os for 5 days q 3 weeks, Clarke-Pearson et al. [90] reported an overall response rate of 21.6%, a time to progression of 14.1 weeks and a median survival 62.2 weeks. The most frequent serious adverse events were haematological: grade 4 neutropenia was registered in 50.4% of patients, grade 4 leukopenia in 15.9%, grade 4 thrombocytopenia in 22.1% and grade 4 anaemia in 2.7%. In this non-randomized phase II trial the observed response rate was comparable to what previously reported with iv topotecan [6], [7], [86] and the authors concluded that oral formulation represented an interesting strategy in terms of efficacy, safety and compliance to treatment.

In the randomized multicenter phase III trial Gore et al. [56] compared the efficacy and tolerability of oral topotecan 2.3mg/mq/day with iv topotecan 1.5mg/mq/day for 5 days every 3 weeks in a population of 266 recurrent ovarian cancer patients. The two treatment regimens showed similar response rates (13% vs. 20% for oral and iv topotecan respectively; p=ns), similar time to progression (13 weeks vs. 17 weeks for oral and iv topotecan respectively; p=ns) but a slightly superior overall survival was registered in the group of iv topotecan patients (81 weeks vs. 58 weeks for oral and iv topotecan respectively; p=0.033). The principal toxicity was myelosuppression although grades 3–4 neutropenia occurred less frequently in those receiving oral topotecan. Non-haematological toxicity was mild; grades 3–4 gastrointestinal events were slightly higher for oral than iv topotecan. The conclusion of the authors is that oral topotecan is convenient and well tolerated treatment in recurrent ovarian cancer and that the clinical significance of small increase in survival in comparison with the better toxicity profile should be interpreted in the context of second line palliative treatments.

At present oral formulation is not licensed for ovarian cancer treatment. Future studies will better clarify the activity and toxicity of oral topotecan in the treatment of ovarian cancer.

3.4.2. Topotecan–carboplatin combination

It has been demonstrated that second line chemotherapy with carboplatin paclitaxel can improve overall survival in patients with relapsed platinum-sensitive ovarian cancer [11]. The most relevant toxic effect of this regimen is the cumulative neurotoxicity, with a 20% incidence of clinically significant disorders reported during treatment. For this reason, alternative combinations of cytotoxic drugs, with a better therapeutic index and a more acceptable toxicity profile are under evaluation.

Several phase I/II studies evaluated the combination of topotecan and carboplatin in recurrent platinum-sensitive ovarian cancer [91], [92]. In a phase I study Rose et al. reported 76% response rate (24% complete response) and 12% disease stabilization in 17 relapsed platinum-sensitive ovarian cancer patients with carboplatin AUC 5 day 1 in combination with topotecan 2mg/m2 days 1, 8, 15 q 3 weeks [91]. Myelosuppression was the dose limiting toxicity with grades 3–4 neutropenia registered in 59% of patients grade 3 thrombocytopenia in 12% of patients, and grade 3 anaemia in 24% of patients.

The authors concluded that the combination of weekly topotecan with carboplatin was feasible and the results warranted further clinical evaluation in phase II studies.

Koensgen et al. [92] in a population of 26 relapsed ovarian cancer patients treated with topotecan 0.75mg/m2 days 1–3 in combination with carboplatin AUC 5 day 3 q 21 registered objective response rate in 67% of patients, and a progression free survival of 9.5 months. The most frequent grades 3–4 haematological toxicities were anaemia in 12% of patients, thrombocytopenia in 58% and leukopenia in 31% of patients.

With the same schedule but slightly increased dose of topotecan (1mg/mq days 1–3). Bolis et al. [93] reported 63.2% response rate with a median duration of response of 5 months in a population of 39 recurrent platinum-sensitive ovarian cancer patients. Myelosuppression was the dose limiting toxicity with grades 3–4 neutropenia registered in 58.9% of patients and grades 3–4 thrombocytopenia in 31% of patients.

3.5. Advanced cervical cancer

In the early ‘90s, cisplatin was recognized as the only active chemotherapy agent in the treatment of persistent, relapsed or metastatic uterine cervical cancer, but the response rates was not superior to 25% [94]. Chemotherapy alone is basically palliative. Generally, combination chemotherapy could attain higher response rates with no significant improvement in overall survival than cisplatin alone. Due to its activity in ovarian cancer and its peculiar mechanism of action, topotecan was evaluated in several phase II studies in the treatment of recurrent or metastatic uterine cervical cancer (Table 3) [95].

Table 3.

Phase II studies topotecan in advanced or recurrent cervical cancer (adapted from Randall-Whitis et al. [95], mod.).


Phase II trials	Topotecan (regimen)	Patients (n)	Response rate (%)	Progression free survival (months)	Overall survival (months)
Muderspach et al.	1.5mg/m2 days 1–5 q 4 weeks	43	18.6	2.4	6.4
Bookman et al.	1.5mg/m2 days 1–5 q 21 days	41	12.5	2.1	6.6
Abu-Rustum et al.	1.0mg/m2 days 1–5 q 21 days	12	16.7	NR	NR
Noda et al.	1.2mg/m2 days 1–5	29	18	NR	NR
Fiorica et al.	0.75mg/m2 days 1–3 q 21 days; cisplatin 50mg/m2 day 1	32	28	5	10

3.5.1. Topotecan–cisplatin combination

The activity of topotecan as single agent in advanced cervical cancer and the non-overlapping toxicity profiles support the combination of topotecan and cisplatin as a possible therapeutic strategy in patients with metastatic or recurrent cervical cancer [95].

In addiction, several in vivo and in vitro studies document the synergistic activity of the two drugs when combined [96], [97], [98].

The phase III registration study of topotecan–cisplatin in the treatment of patients with relapsed or metastatic uterine cervical cancer (GOG 179) was initially designed as a comparison between cisplatin monotherapy vs. cisplatin in combination with metotrexate, vinblastine and doxorubicin (MVAC), vs. cisplatin in combination with topotecan. The primary end-point was the overall survival; the secondary end-points were progression free survival and quality of life [99].

The MVAC arm was prematurely stopped due to treatment-related toxic deaths and the study went on as a direct comparison between cisplatin monotherapy vs. cisplatin–topotecan combination. The 293 eligible patients were treated with iv cisplatin 50mg/m2 day 1 q 21 vs. cisplatin at the same dosage in combination with iv topotecan 0.75mg/m2 days 1–3 every 3 weeks.

The trials demonstrated a significant benefit of the experimental arm in terms of overall survival (9.4 months vs. 6.5 months respectively, HR 0.76, RR=0.76, p=0.017), progression free survival (4.6 months vs. 2.9 months, RR=0.76, p=0.014) and objective response rate (27% vs. 13%, p=0.004). The quality of life analysis did not show a significant worsening of quality of life scores in the combination arm with respect to the monotherapy, although, as expected, myelotoxicity was more frequently observed in the experimental arm.

This is the first randomized trial to demonstrate a benefit in terms of overall survival for a combination therapy in comparison with the standard treatment in advanced and/or relapsed cervical cancer. The results of the ongoing GOG 0204 study evaluating platinum as a single agent vs. four different combinations of platinum with topotecan, or paclitaxel, or vinorelbine, or gemcitabine in advanced and/or metastatic cervical cancer, will clarify whether the survival benefit observed in the GOG 179 experimental arm is related to the cytotoxic activity of topotecan or to a particular weakness of the standard arm, due to the prevalence of platinum-resistant clones in the high percentage of previously irradiated patients (about 60% of study population) (Fig. 6) [99]).

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Fig. 6. Randomized trial of cisplatin vs. cisplatin–topotecan in recurrent cervical cancer: overall survival (proportion survival) by treatment group. Rx, drug treatment [98].

A field of interest in the cure of cervical cancer is represented by neo-adjuvant platinum based chemotherapy followed by radical hysterectomy with pelvic and eventually paraortic lymphadenectomy [100] commonly used in Latin American countries and in Italy.

Topotecan has been studied also in the neoadjuvant setting.

Zanaboni et al. [101] reported the results of neoadjuvant cisplatin–topotecan combination in a population of 22 locally advanced FIGO stage IB2-IIB cervical cancer. With topotecan 2mg/mq and cisplatin 40mg/mq weekly for 6 weeks the authors registered a clinical response rate of 82% and an optimal pathological response rate (complete responses plus microscopic partial responses) of 24%. The treatment was well tolerated; grades 3–4 bone marrow toxicity was observed in only 5% of cycles.

4. Conclusions

The objectives of treatment in relapsed ovarian cancer are the prolongation of survival and the preservation of quality of life. In this context, the availability of second line treatments able to satisfy both these requirements is a priority of the clinical research.

Topotecan, a chemotherapic agent currently indicated for the treatment of relapsed ovarian cancer, has demonstrated activity both in platinum-sensitive and in platinum-resistant disease. Furthermore, the haematological toxicity which represents the dose limiting toxicity appears markedly reduced by alternative schedules such as the weekly treatment recently introduced in clinical practice.

For these reasons, topotecan will continue to play a role in the treatment of advanced ovarian cancer, in monotherapy or in combination with other cytotoxic agents.

The combination cisplatin–topotecan for the treatment of advanced and recurrent uterine cervical cancer has demonstrated a clinical benefit with respect to cisplatin in monotherapy, considered the standard treatment, in terms of response rate, overall survival and progression free survival. Other randomized trials are warranted to better understand the role of monotherapies in comparison with combination regimens in the treatment of metastatic disease; the results of GOG 204 will clarify the role of topotecan in this clinical setting.

Recurrent cervical carcinoma remains a challenging clinical problem. While increases the number of patients which receive platinum as part of primary treatment in association or not with radiotherapy, lesser patients will be expected to respond to retreatment with platinum in recurrent disease so the evaluation of alternative drugs non cross resistant with platinum and presenting activity in the treatment of recurrent cervical cancer is a priority for scientific community.

In this context, the evaluation of new cytotoxic agents as far as the employment biological target therapies may represent an interesting field of the research.

Reviewer

Professor Jonathan A. Ledermann, MD, Cancer Research UK & UCL Cancer Trials Center, 90 Tottenham Court Road, London, W1T 4TJ, United Kingdom.

Conflict of interest statement

The authors declare that there are no conflicts of interest.

References

[1]. [1]Jemal A, Tiwari RC, Murray T, et al. Cancer statistics, 2004. CA Cancer J Clin. 2004;54:8–29. MEDLINE | CrossRef

[2]. [2]Boyle P, Ferlay J. Cancer incidence and mortality in Europe, 2004. Ann Oncol. 2005;16:481–488. MEDLINE | CrossRef

[3]. [3]Vasey PA, Herrstedt J, Jelic S. ESMO Minimum Clinical Recommendations for diagnosis, treatment and follow-up of epithelial ovarian carcinoma. Ann Oncol. 2005;16(Suppl. 1):i13–i15. CrossRef

[4]. [4]Herzog TJ, Holloway RW, Stuart GC. Workshop: options for therapy in ovarian cancer. Gynecol Oncol. 2003;90:S45–50. MEDLINE | CrossRef

[5]. [5]Lhomme C, Morice P, Planchamp F, et al. Clinical practice guidelines 2008 for the surgical treatment, medical first-line and consolidation treatments of patients with epithelial ovarian cancer—update. According to the methodology of Standards, Options: Recommendations (SOR). Bull Cancer. 2008;95:881–886.

[6]. [6]Bookman MA, Malmstrom H, Bolis G, et al. Topotecan for the treatment of advanced epithelial ovarian cancer: an open-label phase II study in patients treated after prior chemotherapy that contained cisplatin or carboplatin and paclitaxel. J Clin Oncol. 1998;16:3345–3352.

[7]. [7]Creemers GJ, Bolis G, Gore M, et al. Topotecan, an active drug in the second-line treatment of epithelial ovarian cancer: results of a large European phase II study. J Clin Oncol. 1996;14:3056–3061.

[8]. [8]Martin LP, Schilder RJ. Management of recurrent ovarian carcinoma: current status and future directions. Semin Oncol. 2009;36:112–125. Abstract | Full Text | Full-Text PDF (364 KB) | CrossRef

[9]. [9]O’Byrne KJ, Bliss P, Graham JD, et al. A phase III study of Doxil/Caelyx versus paclitaxel in platinum-treated, taxane-naive relapsed ovarian cancer. Proc Am Soc Clin Oncol. 2002;21:[abstr 808].

[10]. [10]Gordon AN, Tonda M, Sun S, Rackoff W. Long-term survival advantage for women treated with pegylated liposomal doxorubicin compared with topotecan in a phase 3 randomized study of recurrent and refractory epithelial ovarian cancer. Gynecol Oncol. 2004;95:1–8. MEDLINE | CrossRef

[11]. [11]Parmar MK, Ledermann JA, Colombo N, et al. Paclitaxel plus platinum-based chemotherapy versus conventional platinum-based chemotherapy in women with relapsed ovarian cancer: the ICON4/AGO-OVAR-2.2 trial. Lancet. 2003;361:2099–2106. Abstract | Full Text | Full-Text PDF (130 KB) | CrossRef

[12]. [12]Pfisterer J, Plante M, Vergote I, et al. Gemcitabine plus carboplatin compared with carboplatin in patients with platinum-sensitive recurrent ovarian cancer: an intergroup trial of the AGO-OVAR, the NCIC CTG, and the EORTC GCG. J Clin Oncol. 2006;24:4699–4707. CrossRef

[13]. [13]Ferlay J, Bray F, Pisani P, Parkin DM. GLOBO-CAN 2002: cancer incidence, mortality and prevalence worldwide. IARC Cancer Base 2004; 5 version. Lyon: IARC Press; 2004;.

[14]. [14]Green JA, De Barros Lopes A. Optimizing treatment for cervical cancer: the value of chemoradiation. Am J Cancer. 2004;3:215–227(13).

[15]. [15]Neoadjuvant Chemotherapy for Cervical Cancer Meta-analysis Collaboration. Neoadjuvant chemotherapy for locally advanced cervix cancer: a systematic review and meta-analysis of individual patient data from 21 randomized controlled trials. Eur J Cancer. 2003;39:2470–2486. Abstract | Full Text | Full-Text PDF (372 KB) | CrossRef

[16]. [16]Distefano M, Ferrandina G, Smaniotto D, et al. Concomitant radiochemotherapy plus surgery in locally advanced cervical cancer: update of clinical outcome and cyclooxygenase-2 as predictor of treatment susceptibility. Oncology. 2004;67:103–111.

[17]. [17]Brader KR, Morris M, Levenback C, Levy L, Lucas KR, Gershenson DM. Chemotherapy for cervical carcinoma: factors determining response and implications for clinical trial design. J Clin Oncol. 1998;16:1879–1884.

[18]. [18]Burris HA, Hanauske AR, Johnson RK, et al. Activity of topotecan, a new topoisomerase I inhibitor, against human tumor colony-forming units in vitro. J Natl Cancer Inst. 1992;84:1816–1820. MEDLINE | CrossRef

[19]. [19]Burris HA, Fields SM. Topoisomerase I inhibitors. An overview of the camptothecin analogs. Hematol Oncol Clin North Am. 1994;8:333–355. MEDLINE

[20]. [20]Houghton PJ, Cheshire PJ, Hallman JD, et al. Efficacy of topoisomerase I inhibitors, topotecan and irinotecan, administered at low dose levels in protracted schedules to mice bearing xenografts of human tumors. Cancer Chemother Pharmacol. 1995;36:393–403. MEDLINE | CrossRef

[21]. [21]Pappo AS, Lyden E, Breneman J, et al. Up-front window trial of topotecan in previously untreated children and adolescents with metastatic rhabdomyosarcoma: an intergroup rhabdomyosarcoma study. J Clin Oncol. 2001;19:213–219.

[22]. [22]Slichenmyer WJ, Rowinsky EK, Donehower RC, Kaufmann SH. The current status of camptothecin analogues as antitumor agents. J Natl Cancer Inst. 1993;85:271–291. MEDLINE | CrossRef

[23]. [23]Muggia FM, Creaven PJ, Hansen HH, Cohen MH, Selawry OS. Phase I clinical trial of weekly and daily treatment with camptothecin (NSC-100880): correlation with preclinical studies. Cancer Chemother Rep. 1972;56:515–521. MEDLINE

[24]. [24]Slichenmyer WJ, Rowinsky EK, Grochow LB, Kaufmann SH, Donehower RC. Camptothecin analogues: studies from the Johns Hopkins Oncology Center. Cancer Chemother Pharmacol. 1994;34(Suppl.):S53–S57. CrossRef

[25]. [25]Wall ME, Wani MC, Cook CE, et al. The isolation and structure of camptothecin, a novel alkaloidal leukemia and tumor inhibitor from Camptotheca acuminata. J Am Chem Soc. 1966;88:3888–3890. CrossRef

[26]. [26]Gottlieb JA, Guarino AM, Call JB, Oliverio VT, Block JB. Preliminary pharmacologic and clinical evaluation of camptothecin sodium (NSC-100880). Cancer Chemother Rep. 1970;54:461–470. MEDLINE

[27]. [27]Moertel CG, Schutt AJ, Reitemeier RJ, Hahn RG. Phase II study of camptothecin (NSC-100880) in the treatment of advanced gastrointestinal cancer. Cancer Chemother Rep. 1972;56:95–101. MEDLINE

[28]. [28]Potmesil M, Hsiang YH, Liu LF, et al. Resistance of human leukemic and normal lymphocytes to drug-induced DNA cleavage and low levels of DNA topoisomerase II. Cancer Res. 1988;48:3537–3543. MEDLINE

[29]. [29]Lorusso D, Mainenti S, Scambia G. Ruolo di topotecan in Ginecologia Oncologica. Pacini Editore; 2008.

[30]. [30]Eng WK, Faucette L, Johnson RK, Sternglanz R. Evidence that DNA topoisomerase I is necessary for the cytotoxic effects of camptothecin. Mol Pharmacol. 1988;34:755–760.

[31]. [31]Hsiang YH, Hertzberg R, Hecht S, Liu LF. Camptothecin induces protein-linked DNA breaks via mammalian DNA topoisomerase I. J Biol Chem. 1985;260:14873–14878. MEDLINE

[32]. [32]Hsiang YH, Lihou MG, Liu LF. Arrest of replication forks by drug-stabilized topoisomerase I-DNA cleavable complexes as a mechanism of cell killing by camptothecin. Cancer Res. 1989;49:5077–5082. MEDLINE

[33]. [33]Hsiang YH, Liu LF. Identification of mammalian DNA topoisomerase I as an intracellular target of the anticancer drug camptothecin. Cancer Res. 1988;48:1722–1726. MEDLINE

[34]. [34]Jaxel C, Kohn KW, Wani MC, Wall ME, Pommier Y. Structure–activity study of the actions of camptothecin derivatives on mammalian topoisomerase I: evidence for a specific receptor site and a relation to antitumor activity. Cancer Res. 1989;49:1465–1469. MEDLINE

[35]. [35]O’Connor PM, Nieves-Neira W, Kerrigan D, et al. Aphidicolin protects non S-phase human colon carcinoma HT-29 cells against killing by camptothecin. Proc AACR. 1991;32:336.

[36]. [36]Takimoto CH, Arbuck SG. Clinical status and optimal use of topotecan. Oncology (Williston Park). 1997;11:1635–1646[discussion 49–51, 55–57]. MEDLINE

[37]. [37]Wang JC, Liu LF. DNA topoisomerases. Enzymes that catalyze the concerted breaking and rejoining of DNA bonds. In: Tayler JH editors. Molecular genetics, Part III. Academic Press; 1979;p. 65–88.

[38]. [38]Wang JC. Interaction between DNA and an Escherichia coli protein omega. J Mol Biol. 1971;55:523–533. MEDLINE | CrossRef

[39]. [39]Wang JC. Recent studies of DNA topoisomerases. Biochim Biophys Acta. 1987;909:1–9. MEDLINE

[40]. [40]Wani MC, Nicholas AW, Manikumar G, Wall ME. Plant antitumor agents. 25. Total synthesis and antileukemic activity of ring A substituted camptothecin analogues. Structure–activity correlations. J Med Chem. 1987;30:1774–1779. MEDLINE | CrossRef

[41]. [41]Wani MC, Nicholas AW, Wall ME. Plant antitumor agents. 28. Resolution of a key tricyclic synthon, 5′(RS)-1,5-dioxo-5′-ethyl-5′-hydroxy-2′H,5′H,6′H-6′-oxopyrano[3′,4′- f]delta 6,8-tetrahydro-indolizine: total synthesis and antitumor activity of 20(S)- and 20(R)-camptothecin. J Med Chem. 1987;30:2317–2319. MEDLINE | CrossRef

[42]. [42]Zhang H, D’Arpa P, Liu LF. A model for tumor cell killing by topoisomerase poisons. Cancer Cells. 1990;2:23–27. MEDLINE

[43]. [43]Liu LF. DNA topoisomerase poisons as antitumor drugs. Annu Rev Biochem. 1989;58:351–375. MEDLINE | CrossRef

[44]. [44]Mattern MR, Zwelling LA, Kerrigan D, Kohn KW. The reconstitution of higher-order DNA structure after X-irradiation of mammalian cells. Biochem Biophys Res Commun. 1983;112:1077–1084. CrossRef

[45]. [45]Tan KB, Mattern MR, Boyce RA, Hertzberg RP, Schein PS. Elevated topoisomerase II activity and altered chromatin in nitrogen mustard-resistant human cells. NCI Monogr. 1987;95–98.

[46]. [46]Capranico G, Zunino F. DNA topoisomerase-trapping antitumour drugs. Eur J Cancer. 1992;28A:2055–2060. MEDLINE

[47]. [47]Horwitz SB, Horwitz MS. Effects of camptothecin on the breakage and repair of DNA during the cell cycle. Cancer Res. 1973;33:2834–2836. MEDLINE

[48]. [48]Kingsbury WD, Boehm JC, Jakas DR, et al. Synthesis of water-soluble (aminoalkyl)camptothecin analogues: inhibition of topoisomerase I and antitumor activity. J Med Chem. 1991;34:98–107. MEDLINE | CrossRef

[49]. [49]Sanghavi SN, Needle MN, Krailo MD, Geyer JR, Ater J, Mehta MP. A phase I study of topotecan as a radiosensitizer for brainstem glioma of childhood: first report of the Children's Cancer Group-0952. Neuro Oncol. 2003;5:8–13.

[50]. [50]Del Bino G, Lassota P, Darzynkiewicz Z. The S-phase cytotoxicity of camptothecin. Exp Cell Res. 1991;193:27–35. MEDLINE | CrossRef

[51]. [51]Davies BE, Minthorn EA, Dennis MJ, Rosing H, Beijnen JH. The pharmacokinetics of topotecan and its carboxylate form following separate intravenous administration to the dog. Pharm Res. 1997;14:1461–1465. MEDLINE | CrossRef

[52]. [52]Herben VM, ten Bokkel Huinink WW, Beijnen JH. Clinical pharmacokinetics of topotecan. Clin Pharmacokinet. 1996;31:85–102. MEDLINE | CrossRef

[53]. [53]Korfel A, Oehm C, von Pawel J, et al. Response to topotecan of symptomatic brain metastases of small-cell lung cancer also after whole-brain irradiation. a multicentre phase II study. Eur J Cancer. 2002;38:1724–1729. Abstract | Full Text | Full-Text PDF (112 KB) | CrossRef

[54]. [54]Wall JG, Burris HA, Von Hoff DD, et al. A phase I clinical and pharmacokinetic study of the topoisomerase I inhibitor topotecan (SK&F 104864) given as an intravenous bolus every 21 days. Anticancer Drugs. 1992;3:337–345. MEDLINE | CrossRef

[55]. [55]von Pawel J. The role of topotecan in treating small cell lung cancer: second-line treatment. Lung Cancer. 2003;41(Suppl. 4):S3–8. Full-Text PDF (153 KB) | CrossRef

[56]. [56]Gore M, Oza A, Rustin G, et al. A randomised trial of oral versus intravenous topotecan in patients with relapsed epithelial ovarian cancer. Eur J Cancer. 2002;38:57–63. Abstract | Full Text | Full-Text PDF (120 KB) | CrossRef

[57]. [57]Data on file. SmithKline Beecham Pharmaceuticals; 1999.

[58]. [58]Blaney SM, Cole DE, Balis FM, Godwin K, Poplack DG. Plasma and cerebrospinal fluid pharmacokinetic study of topotecan in nonhuman primates. Cancer Res. 1993;53:725–727. MEDLINE

[59]. [59]Schutte W, Manegold C, von Pawel JV, et al. Topotecan—a new treatment option in the therapy of brain metastases of lung cancer. Front Radiat Ther Oncol. 1999;33:354–363. MEDLINE

[60]. [60]van Warmerdam LJ, Creemers GJ, Rodenhuis S, et al. Pharmacokinetics and pharmacodynamics of topotecan given on a daily-times-five schedule in phase II clinical trials using a limited-sampling procedure. Cancer Chemother Pharmacol. 1996;38:254–260. MEDLINE | CrossRef

[61]. [61]Rodriguez M, Rose PG. Improved therapeutic index of lower dose topotecan chemotherapy in recurrent ovarian cancer. Gynecol Oncol. 2001;83:257–262. MEDLINE | CrossRef

[62]. [62]Huber RM, Reck M, Gosse H, et al. Efficacy of a toxicity-adjusted topotecan therapy in recurrent small cell lung cancer. Eur Respir J. 2006;27(6):1183–1189. MEDLINE | CrossRef

[63]. [63]Armstrong DK. Topotecan dosing guidelines in ovarian cancer: reduction and management of hematologic toxicity. Oncologist. 2004;9:33–42. MEDLINE | CrossRef

[64]. [64]Huber RM, Gatzemeier U, Gosse H, et al. Topotecan in second-line therapy of SCLC: impact on survival?. Onkologie. 2000;23(Suppl. 3):9–12. CrossRef

[65]. [65]Mould DR, Holford NH, Schellens JH, et al. Population pharmacokinetic and adverse event analysis of topotecan in patients with solid tumors. Clin Pharmacol Ther. 2002;71:334–348. MEDLINE | CrossRef

[66]. [66]Mobus V, Pfaff PN, Kreienberg R. Topotecan (Hycamtin) in the therapy of recurrent ovarian carcinoma. Onkologie. 1998;21(Suppl. 4):2–5. CrossRef

[67]. [67]Mobus V, Lane S, Fields SZ, et al. Topotecan: tolerability, response rate and survival associated with extended therapy in relapsed ovarian cancer—results of a pooled analysis of 523 patients. Eur J Oncol. 1999;35(Suppl. 4):.

[68]. [68]Gemmern vR. Gewebetoxizitat und Paravasatbehandlung neuer Zytostatika (Soft tissue toxicity and treatment of extravasation of new cytostatics). Krankenhauspharmazie. 1996;17:471–473.

[69]. [69]Oostweegel LMM, Varmerdam JC, Schot M, et al. Extravasation of topotecan: a report of two cases. J Oncol Pharmacy Pract. 1997;3:115–116.

[70]. [70]Rose PG, Blessing JA, Mayer AR, Homesley HD. Prolonged oral etoposide as second-line therapy for platinum-resistant and platinum-sensitive ovarian carcinoma: a Gynecologic Oncology Group study. J Clin Oncol. 1998;16:405–410.

[71]. [71]Bajetta E, Di Leo A, Biganzoli L, et al. Phase II study of vinorelbine in patients with pretreated advanced ovarian cancer: activity in platinum-resistant disease. J Clin Oncol. 1996;14:2546–2551.

[72]. [72]ten Bokkel Huinink W, Gore M, Carmichael J, et al. Topotecan versus paclitaxel for the treatment of recurrent epithelial ovarian cancer. J Clin Oncol. 1997;15:2183–2193.

[73]. [73]De Placido S, Scambia G, Di Vagno G, et al. Topotecan compared with no therapy after response to surgery and carboplatin/paclitaxel in patients with ovarian cancer: Multicenter Italian Trials in Ovarian Cancer (MITO-1) randomized study. J Clin Oncol. 2004;22:2635–2642. CrossRef

[74]. [74]Herzog TJ. Update on the role of topotecan in the treatment of recurrent ovarian cancer. Oncologist. 2002;7(Suppl. 5):3–10. CrossRef

[75]. [75]Gordon AN, Fleagle JT, Guthrie D, Parkin DE, Gore ME, Lacave AJ. Recurrent epithelial ovarian carcinoma: a randomized phase III study of pegylated liposomal doxorubicin versus topotecan. J Clin Oncol. 2001;19:3312–3322.

[76]. [76]Vecchione F, Fruscio R, Dell’Anna T, et al. A phase II clinical trial of topotecan and carboplatin in patients with newly diagnosed advanced epithelial ovarian cancer. Int J Gynecol Cancer. 2007;17:367–372. CrossRef

[77]. [77]Hochster HS, Plimack ER, Mandeli J, et al. Prolonged topotecan infusion with cisplatin in the first-line treatment of ovarian cancer: an NYGOG and ECOG study. Gynecol Oncol. 2006;100:324–329. MEDLINE | CrossRef

[78]. [78]Guppy AE, Nelstrop AE, Foster T, Agarwal R, Seckl MJ, Rustin GJ. A phase II study of sequential carboplatin, paclitaxel and topotecan in patients with previously untreated advanced ovarian cancer. Br J Cancer. 2004;90:810–814. MEDLINE | CrossRef

[79]. [79]Pfisterer J, Weber B, Reuss A, et al. Randomized phase III trial of topotecan following carboplatin and paclitaxel in first-line treatment of advanced ovarian cancer: a gynecologic cancer intergroup trial of the AGO-OVAR and GINECO. J Natl Cancer Inst. 2006;98:1036–1045. CrossRef

[80]. [80]Bookman MA, Brady MF, McGuire WP, et al. Evaluation of new platinum-based treatment regimens in advanced-stage ovarian cancer: a Phase III Trial of the Gynecologic Cancer Intergroup. J Clin Oncol. 2009;27:1419–1425. CrossRef

[81]. [81]Armstrong D, O’Reilly S. Clinical guidelines for managing topotecan-related hematologic toxicity. Oncologist. 1998;3:4–10.

[82]. [82]Cass I, Kuo DY, Fields AL, Runowicz CD, Goldberg GL. Profound thrombocytopenia in previously treated patients with recurrent ovarian carcinoma receiving topotecan. Gynecol Oncol. 1998;69:175–178. MEDLINE | CrossRef

[83]. [83]Markman M, Kennedy A, Webster K, Kulp B, Peterson G, Belinson J. Phase 2 evaluation of topotecan administered on a 3-day schedule in the treatment of platinum- and paclitaxel-refractory ovarian cancer. Gynecol Oncol. 2000;79:116–119. MEDLINE | CrossRef

[84]. [84]Safra T, Menczer J, Bernstein R, et al. Efficacy and toxicity of weekly topotecan in recurrent epithelial ovarian and primary peritoneal cancer. Gynecol Oncol. 2007;105:205–210. MEDLINE | CrossRef

[85]. [85]Abushahin F, Singh DK, Lurain JR, Grendys EC, Rademaker AW, Schink JC. Weekly topotecan for recurrent platinum resistant ovarian cancer. Gynecol Oncol. 2008;108:53–57. CrossRef

[86]. [86]Kudelka AP, Tresukosol D, Edwards CL, et al. Phase II study of intravenous topotecan as a 5-day infusion for refractory epithelial ovarian carcinoma. J Clin Oncol. 1996;14:1552–1557.

[87]. [87]McGuire WP, Hoskins WJ, Brady MF, et al. Cyclophosphamide and cisplatin compared with paclitaxel and cisplatin in patients with stage III and stage IV ovarian cancer. N Engl J Med. 1996;334:1–6. MEDLINE | CrossRef

[88]. [88]Swisher EM, Mutch DG, Rader JS, Elbendary A, Herzog TJ. Topotecan in platinum- and paclitaxel-resistant ovarian cancer. Gynecol Oncol. 1997;66:480–486. MEDLINE | CrossRef

[89]. [89]Sehouli J, Oskay-Ozcelik G. Current role and future aspects of topotecan in relapsed ovarian cancer. Curr Med Res Opin. 2009;25:639–651. CrossRef

[90]. [90]Clarke-Pearson DL, Van Le L, Iveson T, et al. Oral topotecan as single-agent second-line chemotherapy in patients with advanced ovarian cancer. J Clin Oncol. 2001;19:3967–3975.

[91]. [91]Rose PG, Smrekar M, Haba P, Visser C, Beeler JF. A phase I/II trial of weekly topotecan and carboplatin in potentially platinum-sensitive relapsed ovarian and peritoneal carcinoma. Gynecol Oncol. 2005;99:714–719. MEDLINE | CrossRef

[92]. [92]Koensgen D, Stengel D, Belau A, et al. Topotecan and carboplatin in patients with platinum-sensitive recurrent ovarian cancer. Results of a multicenter NOGGO: phase I/II study. Cancer Chemother Pharmacol. 2008;62:393–400. CrossRef

[93]. [93]Bolis G, Scarfone G, Sciatta C, et al. A phase I/II study of topotecan in combination with carboplatin in recurrent epithelial ovarian cancer. Gynecol Oncol. 2001;83:477–480. MEDLINE | CrossRef

[94]. [94]Thigpen T, Vance RB, Khansur T. The platinum compounds and paclitaxel in the management of carcinomas of the endometrium and uterine cervix. Semin Oncol. 1995;22:67–75. MEDLINE

[95]. [95]Randall-Whitis LM, Monk BJ. Topotecan in the management of cervical cancer. Expert Opin Pharmacother. 2007;8:227–236. CrossRef

[96]. [96]Ling YH, Donato NJ, Perez-Soler R. Sensitivity to topoisomerase I inhibitors and cisplatin is associated with epidermal growth factor receptor expression in human cervical squamous carcinoma ME180 sublines. Cancer Chemother Pharmacol. 2001;47:473–480. MEDLINE | CrossRef

[97]. [97]Chou TC, Motzer RJ, Tong Y, Bosl GJ. Computerized quantitation of synergism and antagonism of taxol, topotecan, and cisplatin against human teratocarcinoma cell growth: a rational approach to clinical protocol design. J Natl Cancer Inst. 1994;86:1517–1524. MEDLINE | CrossRef

[98]. [98]Romanelli S, Perego P, Pratesi G, Carenini N, Tortoreto M, Zunino F. In vitro and in vivo interaction between cisplatin and topotecan in ovarian carcinoma systems. Cancer Chemother Pharmacol. 1998;41:385–390. MEDLINE | CrossRef

[99]. [99]Long HJ, Bundy BN, Grendys EC, et al. Randomized phase III trial of cisplatin with or without topotecan in carcinoma of the uterine cervix: a Gynecologic Oncology Group Study. J Clin Oncol. 2005;23:4626–4633. CrossRef

[100]. [100]Buda A, Fossati R, Colombo N, et al. Randomized trial of neoadjuvant chemotherapy comparing paclitaxel, ifosfamide, and cisplatin with ifosfamide and cisplatin followed by radical surgery in patients with locally advanced squamous cell cervical carcinoma: the SNAP01 (Studio Neo-Adjuvante Portio) Italian Collaborative Study. J Clin Oncol. 2005;23:4137–4145. CrossRef

[101]. [101]Zanaboni FGB, Kusamura S, Ditto A, et al. Weekly topotecan and cisplatin (TOPOCIS) as neoajuvant chemotherapy for locally-advanced squamous cervical carcinoma: results of a phase II study. Proc Am Soc Clin Oncol:. 2008;[abstr 16500].

[102]. [102]McGuire WP, Blessing JA, Bookman MA, et al. Topotecan has substantial antitumor activity as first-line salvage therapy in platinum-sensitive epithelial ovarian carcinoma: a Gynecologic Oncology Group study. J Clin Oncol. 2000;18:1062–1067.

Domenica Lorusso was born in Gravina in Puglia (Bari) on 9 March 1971. She is a gynecologic oncologist and works in the Division of Gynecologic Oncology of the Catholic University of the Sacred Heart, Rome.

Antonella Pietragalla was born in Catanzaro on 31 August 1977. She is an oncologist and works in the Division of Gynecologic Oncology of the Catholic University of the Sacred Heart, Rome.

Giovanni Di Vagno was born in Bari on 22 April 1956. He is a gynecologic oncologist and works in the I.R.C.C.S. Casa Sollievo della Sofferenza, S. Giovanni R (Foggia), Italy.

Valeria Masciullo was born in Rome on 3 April 1968. She is a gynecologic oncologist and works in the Division of Gynecologic Oncology of the Catholic University of the Sacred Heart, Rome.

Sara Mainenti was born in Rome on 24 July 1982. She is a gynecologic oncology fellow and works in the Division of Gynecologic Oncology of the Catholic University of the Sacred Heart, Rome.

Giovanni Scambia was born in Catanzaro on 24 December 1959. He is at present Chief of the Department of Obstetrics and Gynecology, at the Catholic University of the Sacred Heart, Rome. He is involved as an author in over 500 publications.

a Division of Gynecologic Oncology, Catholic University of the Sacred Heart, Largo Agostino Gemelli 8, IT-00168 Rome, Italy

b Casa Sollievo della Sofferenza, S. Giovanni Rotondo (Foggia), Italy

Corresponding author. Tel.: +39 06 3550 8736; fax: +39 06 3550 8736.

PII: S1040-8428(09)00158-9

doi:10.1016/j.critrevonc.2009.08.001

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