Annals of Oncology Advance Access published online on March 12, 2007
Annals of Oncology, doi:10.1093/annonc/mdm002
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© 2007 European Society for Medical Oncology
A phase II study using a topoisomerase I-based approach in patients with multiply relapsed germ-cell tumours
The Department of Medical Oncology, St Bartholomew's Hospital, London, UK
* Correspondence to: Dr J. Shamash, Department of Medical Oncology, St Bartholomew's Hospital, 7th Floor, Gloucester House, London EC1A 7BE, UK. Tel: +44-207-6017313; Fax: +44-207-6017577; E-mail: jonathan.shamash{at}bartsandthelondon.nhs.uk
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Abstract |
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Background: The outcome of patients with germ-cell tumours (GCTs), who relapse more than once or relapse with a mediastinal primary is poor. We have shown that topoisomerase 1 may be an attractive target in relapsed GCT. We investigated the role of irinotecan, paclitaxel and oxaliplatin (IPO) followed by topotecan-based high-dose therapy in responding patients, in this patient population.
Patients and methods: Twenty-eight patients with multiply relapsed gonadal and mediastinal GCT were recruited to this phase 2 study. All patients received IPO chemotherapy and 12 (43%) went on to receive high-dose therapy. The outcome of these patients was assessed using the Kaplan–Meier method with a median progression-free follow-up of 1 year.
Results: Twenty patients (71%) responded to the therapy including five complete remissions (18%), 13 (46%) marker-negative partial responses and two (7%) marker-positive partial responses. Nine (32%) patients continue to be progression free, and the median survival for the whole group currently measures 17 months. Out of 12 individuals who received subsequent high-dose therapy consolidation, seven (58%) remain progression free. The commonest grade III/IV toxicity was infection (68%) and there were no IPO-related toxic deaths; there was one death from high-dose therapy.
Conclusion: Topoisomerase I-based IPO chemotherapy that lacks etoposide is very active in multiply relapsed GCT. This data merit further investigation.
germ-cell tumour, mediastinal, phase 2, relapsed
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introduction |
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TopAbstractintroductionpatients and methodsresultsdiscussionAcknowledgementsReferences |
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The optimal treatment of relapsed germ-cell tumours (GCTs) remains unclear. The standard approach has been to offer cisplatin and ifosfamide-based therapy on relapse with a third drug being chosen from etoposide, vinblastine or more recently paclitaxel [1–3]; the results of the latter (paclitaxel, ifsofamide and cisplatin) have been encouraging. The role of high-dose chemotherapy (HDCT) and autologous stem-cell transplantation remains uncertain at first relapse, although phase 2 studies in unselected patients indicate a higher long-term progression-free survival using this approach [4]. The use of sequential treatment (tandem or triple high-dose chemotherapy with stem cell rescue consolidation using carboplatin and etoposide) is effective, especially in patients who appear to be refractory to initial therapy [5]. Further therapy particularly in those who have relapsed despite second-line cisplatin-based therapy has varied, with the use of paclitaxel, gemcitabine or oxaliplatin as single agents or in combination. The outcome of these patients is poor with a median survival between 4 and 8 months in most published series [6–10]. There is no clear consensus as to third-line chemotherapy in such patients or in those with mediastinal primaries on first relapse whose outcome is very poor [11].
We have shown that many patients who have viable GCTs at surgery following chemotherapy have enhanced topoisomerase 1 staining on immunohistochemistry [12]. Despite these observations, the activity of irinotecan in these patients is contradictory. Kollmannsberger et al. [13] failed to observe any response to the drug when evaluated as a single agent in a heavily pretreated group, however in combination with cisplatin or oxaliplatin results are more favourable [14, 15].
Oxaliplatin is a third-generation diammine cyclohexane derivative with evidence of non-cross-resistance to cisplatin. This has been shown in vitro in GCT cell lines and has a overall response rate (complete plus partial) of 13%–19% in phase 2 studies in cisplatin refractory cases [16].
It has been argued in breast cancer that weekly administration of paclitaxel is superior to standard three weekly with less myelosupression, therefore in this study weekly paclitaxel was used [17].
High-dose therapy has frequently been on the basis of intensified carboplatin and etoposide in GCTs and thiotepa has also shown activity in this setting [18]. In order to dose intensify the topoisomerase I inhibitor topotecan was substituted for irinotecan because of the latter's dose-limiting toxicity. In this study, high-dose carboplatin (AUC21), topotecan (30 mg/m2) and thiotepa 500 mg/m2 were used to consolidate responses to irinotecan, paclitaxel and oxaliplatin (IPO). Carboplatin rather than oxaliplatin was chosen in view of the lack of information on dose escalation of the latter.
We therefore investigated the activity of the combination of these three potentially active agents in multiply relapsed GCT patients followed by high-dose topoisomerase I-based therapy.
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patients and methods |
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TopAbstractintroductionpatients and methodsresultsdiscussionAcknowledgementsReferences |
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From March 2001 to September 2004, 28 patients with GCTs were recruited to this study, which was approved by the local ethics committee and all patients gave written informed consent. An assessment of efficacy and toxicity was made after the first 10 patients had been recruited. On the basis of previously reported series, if less than four patients responded, the study would be terminated.
Patients who had failed at least two lines of cisplatin-based regimens or who had mediastinal primaries which had relapsed despite first-line cisplatin-based therapy were eligible. One patient who developed rhabdomyoblastic sarcomatous transformation within teratoma received ifosfamide (Bohringer) and doxorubicin (Pharmacia) as second-line treatment was also included. Twenty-three patients received IPO after failure of two lines of therapy. This was cisplatin and ifosfamide based in 11 patients, dose-dense cisplatin based in eight and other cisplatin-based treatments in the remaining three. The prior use of a taxane was permitted but not that of oxaliplatin (Sanofi-Aventis) or irinotecan (Pfizer).
A calculated creatinine clearance of >20 ml/min and liver function tests less than three times the upper limit of normal were required before entry. Tumour markers (
-fetoprotein, human chorionic gonadotropin and lactate dehydrogenase) were measured before therapy and patients were staged with computed tomography scanning of chest, abdomen and pelvis and brain. All pathology was centrally reviewed by a genitourinary pathologist and classified according to World Health Organisation 2004 criteria.
response criteria
The following responses were recorded according to published criteria [19]. Progressive disease (PD): development of new sites of disease with rising tumour markers if present. Stable disease: no new sites of disease and <33% increase in the unidimensional size of any existing masses. Marker-positive partial response (m+ve PR): >90% reduction in tumour markers (without normalisation) for >28 days, and no new sites of disease. Marker-negative partial response (m–ve PR): normalisation of tumour markers and no new sites of disease for at least 28 days. For those patients who had normal tumour markers before chemotherapy a m–ve PR required a 50% reduction in the bidimensional measurements of the residual masses to be maintained for at least 28 days. Complete remission (CR): normalisation of tumour markers with disappearance of all sites of disease. Postsurgical outcome: where surgery was carried out to remove all sites of disease, if the postsurgical scan showed CR and the surgical specimens contained necrosis or mature teratoma only, the patient was judged to be in surgically confirmed complete remission (sc CR). If viable cancer was found then the patient was deemed to be in surgically induced complete remission (si CR). Patients who achieved a radiological CR to chemotherapy alone or a sc CR or si CR were deemed to have no evidence of disease (NED).
cisplatin sensitivity
The determination of cisplatin sensitivity was defined according to the method of Beyer et al. [20].
statistics
To assess the correlation between the various categorical variables and being progression free to IPO, Fisher's exact test was used. The continuous variable (age) and the relationship to being progression free were examined using the Mann–Whitney test. The graph showing overall survival are Kaplan–Meier curves [21].
regimen
IPO chemotherapy was given as follows: irinotecan 200 mg/m2 over 1 h on day 1, paclitaxel (Bristol Myers Squibb) 80 mg/m2 over 1 h on days 1, 8 and 15, oxaliplatin 200 mg/m2 over 2 h on day 1. Premedication for paclitaxel was given as follows: chlorpheniramine 10 mg i.v., ranitidine 50 mg i.v. and dexamethasone 20 mg i.v. If no reaction occurred no further premedication was given on subsequent administrations of paclitaxel. Filgrastim 300 mcg sc on alternate days from day 1 to 15 was administered.
Patients required a neutrophil count of >1 x 109/l and platelets of >100 x 109/l on day 1 to commence treatment. Similarly, a neutrophil count of >0.5 x 109/l and platelets of >20 x 109/l on days 8 and 15 were required before treatment was given. If patients did not meet these criteria on days 8 and 15, paclitaxel was omitted and the 21-day scheduling of irinotecan and oxaliplatin was maintained.
Patients were scanned after two cycles and individuals who showed some response went on to have two further cycles. Patients who did not respond to IPO went off study and were treated according to the preference of their physician.
high-dose chemotherapy
Autologous blood stem cells were harvested following mobilisation using filgrastim at 16 mcg/kg for 4 days. A minimum of 1 x 106 CD34 cells/kg were required. Patients who showed evidence of response after two cycles received a further two cycles. For those responding patients (at least m+ve PR) high-dose chemotherapy was given. This consisted of carboplatin area under the curve (AUC) 7 mg/ml/min over 1 h on days 1, 2 and 3 followed 12 h later by topotecan 10 mg/m2 over 30 min on days 1, 2 and 3. Thiotepa (500 mg/m2) was given as a continuous infusion over days 1–4, followed by stem cell return 2 days later.
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results |
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TopAbstractintroductionpatients and methodsresultsdiscussionAcknowledgementsReferences |
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The patients' characteristics are shown in Table 1. Twenty of 28 patients (71%) responded to the therapy and five (18%) obtained a CR. Thirteen (46%) obtained a marker-negative PR and two (7%) had marker-positive PR (Table 2). Five patients underwent surgery, four had necrosis only at histology and three of these four patients are currently with NED. The one remaining patient had active cancer (seminoma) at histology and has subsequently progressed.
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Overall at follow-up, nine (32%) patients were progression free, seven had NED, two had residual masses which were unresectable and were therefore irradiated. Seven of the 12 who received HDCT were progression free (Figure 1). Two who did not receive subsequent HDCT have NED. The overall median survival for the whole group was 17 months (Figure 2) with a median follow-up of 14.3 months.
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Five patients had absolutely refractory disease to cisplatin of whom three responded (one CR, two m–ve PR), two had HDCT, all three are currently with NED. Two patients had refractory disease to cisplatin, one responded (m–ve PR) but relapsed before HDCT, both died. All the patients with refractory and absolutely refractory disease had gonadal primaries.
Five patients had mediastinal primaries, four responded to IPO (one m+ve PR, three m–ve PR). Three received HDCT of whom two are currently with NED.
Six patients had prior paclitaxel, five responded (one m+ve PR, three m–ve PR and one CR). Three went on to have HDCT and all relapsed. One patient received IPO following failure of HDCT and is currently with NED 8 months after IPO.
consolidation high-dose therapy
Twelve patients received high-dose consolidation therapy at completion of IPO. In 11 cases this was with topotecan, carboplatin and thiotepa. In one case the patient returned to his referring centre and had consolidation with high-dose carboplatin AUC 20, etoposide 1600 mg/m2 and cyclophosphamide 6000 mg/m2; he responded to IPO as third-line therapy achieving m–ve PR and had surgery after HDCT (sc CR), he subsequently relapsed. Eight patients who responded to IPO did not receive HDCT, two had previously received HDCT, stem cell collection was unsuccessful in one patient, two had PD before HDCT, one patient declined therapy and two were judged unfit for HDCT.
toxic effects
There were no toxicity-related deaths to IPO (Table 3). Grade 3/4 infection was the most common side-effect which occurred in 18 (64%) patients. Grade 3/4 neutropenia was seen in 46% of cycles and grade 3/4 thrombocytopenia in 35% of cycles. The regimen was suitable for outpatient administration and no renal dysfunction was apparent.
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The regimen was deliverable with 100% of patients receiving full-dose oxaliplatin, 96% receiving full-dose irinotecan. Paclitaxel was given in full dose to 50% of patients, 32% omitted one dose, 4% omitted two doses, 11% omitted three doses and 4% omitted four doses.
Toxic effects associated with HDCT are shown in Table 4. This included one death due to infection in a patient with sarcomatoid transformation and progression of disease following surgery and two lines of chemotherapy. He had a PR to IPO.
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prognostic factors
None of the prognostic factors investigated were significant for response by univariate analysis, these included initial International Germ Cell Cancer Collaborative Group, mediastinal primary site, cisplatin sensitivity and previous high-dose therapy.
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discussion |
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TopAbstractintroductionpatients and methodsresultsdiscussionAcknowledgementsReferences |
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The IPO regimen appears active in relapsed GCT. The response rate and overall survival appear higher than has previously been described for this patient group, although in some series a greater proportion had received prior high-dose chemotherapy (Table 5). The results were particularly encouraging in those who went on to receive high-dose therapy as consolidation after IPO chemotherapy.
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This treatment was well tolerated with infection and diarrhoea being the most significant side-effects. It was reassuring that neuropathy was not a major side-effect despite the combination of oxaliplatin and paclitaxel. An additional favourable factor for this regimen was that IPO could be administered as a day case.
Due to the relative rarity of the disease and the success of initial therapy, there are limited data and no clear consensus regarding the treatment of multiply relapsed GCTs. Several groups have reported on the management and outcomes of these patients with varying results. These studies did not routinely use high-dose consolidation as part of the therapy. It should be noted that in these series m+ve PR have been included as responses, although these have tended to be very transient.
Oxaliplatin as a single agent has a low response rate in this setting with a 19% response rate when given at 130 mg/m2 every 3 weeks [7]. The role of irinotecan as a single agent is worthy of mention as it illustrates the difficulty of developing regimens when patient numbers are likely to be small. Kollsmannsberger et al. [13] investigated irinotecan alone in a heavily pretreated group of GCT patients (87% having had prior HDCT and 74% having platinum refractory or absolutely refractory disease). They observed no responses and concluded that irinotecan was not effective in this condition. In combination with platinum (either cisplatin or nedaplatin) results were, howeve more encouraging (Table 5). For example, Pectasides et al. [15] reported a 40% response rate to oxaliplatin and irinotecan, 78% had had prior paclitaxel but none had HDCT. The survival for this group was 7.5 months. These results indicate these drugs may be active in combination.
Other regimens showing promise in this setting include gemcitabine and paclitaxel (21% response rate) [6], gemcitabine and oxaliplatin (32%–46% response rate) [8, 9] and cisplatin and epirubicin [22].
The induction and high-dose therapy used in this approach differs from previously published data in that etoposide was not given. Following the description that refractory GCTs frequently overexpress topoisomerase I, camptothecins were used and this may account for the encouraging results.
The management of relapsing or refractory mediastinal GCTs are a particular problem with conventional cisplatin and ifosfamide-based therapy failing to salvage a vast majority of patients [23]. However, Motzer et al. [5] reported on eight mediastinal GCTs treated with sequential dose-intense paclitaxel, ifosfamide followed by three cycles of high-dose carboplatin and etoposide. Four of these patients responded and two are long term with NED. In our series, three out of five patients with mediastinal GCTs responded to IPO and two are progression free 15 and 27 months after IPO. In both studies, the salvage therapy was used as initial relapse therapy and both regimens utilised paclitaxel.
Overall, it appears that IPO with high-dose consolidation is an effective and promising therapy in multiply relapsed GCTs.
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Acknowledgements |
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We would like to thank the Orchid Cancer Appeal for their support of data management and the Anglian Germ Cell Cancer Group for referring the patients.
Received for publication August 22, 2006. Revision received January 9, 2007. Accepted for publication January 10, 2007.
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References |
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