Correspondence
Salvage treatment of relapsed or refractory germ-cell tumours In a recent phase 2 trial by the MAKEI study group, regional deep hyperthermia and a standard chemotherapy regimen showed impressive results in children and adolescents with refractory or recurrent germ-cell tumours.1 The authors stated that the proportion of patients with a successful salvage were “unmatched by all other reports on recurrent childhood malignant germ-cell tumours”. However, we have some concerns about the potential effect of prognostic factors on the salvage outcome of different treatments. Most of the reports in the literature include cases with either distant metastases or other poor prognosis extragonadal primary sites. Few data are available for patients with locoregional relapse of a primary sacrococcygeal or retroperitoneal germ-cell tumour. Early MAKEI protocols with standard-dose chemotherapy enrolled 17 patients with localised disease only, achieving a 5-year overall survival of 47%, and five patients with distant metastases, who had a 5-year overall survival of 20%.2 A preliminary study using highdose chemotherapy included seven patients with localised disease, who achieved a 5-year overall survival of 71%, and five patients with distant metastases, who had a 5-year overall survival of 20%.3 Preliminary data for high-dose chemotherapy were at the time not so different from those with hyperthermia plus standard-dose chemotherapy. A larger retrospective study on high-dose chemotherapy in germ-cell tumours in children and adolescents has been recently launched by the European Group for Blood and Marrow Transplantation. An analysis of the prognostic factors for these patients at relapse is not available. The effect of metastases at diagnosis was assessed
in a retrospective analysis of patients with sacrococcygeal primary germcell tumour:4 relapse-free survival seemed to be better for patients without distant metastases (82%) than for those with metastases (71%), even if not statistically significant (p=0·33).4 However, a recent report based on data for 1984 adult patients with relapsed or refractory germ-cell tumours after first-line chemotherapy identified the presence of metastases to the liver, bone, or brain as independent prognostic variables and were included in the development of a prognostic score.5 High-dose chemotherapy seemed to improve survival in each prognostic category except for low-risk patients, for whom similar survival data were recorded with standard-dose chemotherapy.6 Thus, results with high-dose chemotherapy could be even better in patients with poor prognostic features. Despite all limitations and biases inherent in the analysis of a small and heterogeneous patient population, a cooperative effort should be made to collect information on disease and treatment characteristics from the largest number of children and adolescents with refractory or recurrent germ-cell tumours treated with salvage conventional dose chemotherapy (with or without hyperthermia) or high-dose chemotherapy to identify prognostic variables and patients who could benefit from these treatments. Finally, hyperthermia increasing cellular uptake of platinum drugs and overcoming the platinum resistance might also improve the effect of carboplatin-based high-dose chemotherapy.7 Therefore, future studies should also consider combining hyperthermia and highdose chemotherapy to further improve survival of these patients. We declare that we have no conflicts of interest.
*Ugo De Giorgi, Dino Amadori [email protected]
www.thelancet.com/oncology Vol 14 November 2013
Department of Medical Oncology, IRCCS Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST), Via Piero Maroncelli 40, 47014 Meldola, Italy (UDG, DA) 1
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Wessalowski R, Schneider DT, Mils O, et al. Regional deep hyperthermia for salvage treatment of children and adolescents with refractory or recurrent non-testicular malignant germ-cell tumours: an open-label, non-randomised, single-institution, phase 2 study. Lancet Oncol 2013; 14: 843–52. Schneider DT, Wessalowski R, Calaminus G, et al. Treatment of recurrent malignant sacrococcygeal germ cell tumors: analysis of 22 patients registered in the German protocols MAKEI 83/86, 89, and 96. J Clin Oncol 2001; 19: 1951–60. De Giorgi U, Rosti G, Slavin S, et al. Salvage high-dose chemotherapy for children with extragonadal germ-cell tumours. Br J Cancer 2005; 93: 412–17. Calaminus G, Schneider DT, Bökkerink JP, et al. Prognostic value of tumor size, metastases, extension into bone, and increased tumor marker in children with malignant sacrococcygeal germ cell tumors: a prospective evaluation of 71 patients treated in the German cooperative protocols Maligne Keimzelltumoren (MAKEI) 83/86 and MAKEI 89. J Clin Oncol 2003; 21: 781–86. Lorch A, Beyer J, Bascoul-Mollevi C, et al, for the International Prognostic Factors Study Group. Prognostic factors in patients with metastatic germ cell tumors who experienced treatment failure with cisplatin-based first-line chemotherapy. J Clin Oncol 2010; 28: 4906–11. Lorch A, Bascoul-Mollevi C, Kramar A, et al. Conventional-dose versus high-dose chemotherapy as first salvage treatment in male patients with metastatic germ cell tumors: evidence from a large international database. J Clin Oncol 2011; 29: 2178–84. Zaffaroni N, Fiorentini G, De Giorgi U. Hyperthermia and hypoxia: new developments in anticancer chemotherapy. Eur J Surg Oncol 2001; 27: 340–42.
Authors’ reply Data from our study of regional deep hyperthermia for salvage treatment of children and adolescents with refractory or recurrent non-testicular malignant germ-cell tumours (GCTs)1 does not support the opinion that hyperthermia and high-dose chemotherapy have similar efficacies among different patient subgroups. For instance, for patients with sacrococcygeal and retroperitoneal tumours without distant metastases, ongoing remission was detected in 15 (79%) of 19 patients receiving additional hyperthermia treatment, and in only three (60%) of five patients receiving additional highdose chemotherapy.1,2 Among such e486
Salvage treatment of relapsed or refractory germ-cell tumours In a recent phase 2 trial by the MAKEI study group, regional deep hyperthermia and a standard chemotherapy regimen showed impressive results in children and adolescents with refractory or recurrent germ-cell tumours.1 The authors stated that the proportion of patients with a successful salvage were “unmatched by all other reports on recurrent childhood malignant germ-cell tumours”. However, we have some concerns about the potential effect of prognostic factors on the salvage outcome of different treatments. Most of the reports in the literature include cases with either distant metastases or other poor prognosis extragonadal primary sites. Few data are available for patients with locoregional relapse of a primary sacrococcygeal or retroperitoneal germ-cell tumour. Early MAKEI protocols with standard-dose chemotherapy enrolled 17 patients with localised disease only, achieving a 5-year overall survival of 47%, and five patients with distant metastases, who had a 5-year overall survival of 20%.2 A preliminary study using highdose chemotherapy included seven patients with localised disease, who achieved a 5-year overall survival of 71%, and five patients with distant metastases, who had a 5-year overall survival of 20%.3 Preliminary data for high-dose chemotherapy were at the time not so different from those with hyperthermia plus standard-dose chemotherapy. A larger retrospective study on high-dose chemotherapy in germ-cell tumours in children and adolescents has been recently launched by the European Group for Blood and Marrow Transplantation. An analysis of the prognostic factors for these patients at relapse is not available. The effect of metastases at diagnosis was assessed
in a retrospective analysis of patients with sacrococcygeal primary germcell tumour:4 relapse-free survival seemed to be better for patients without distant metastases (82%) than for those with metastases (71%), even if not statistically significant (p=0·33).4 However, a recent report based on data for 1984 adult patients with relapsed or refractory germ-cell tumours after first-line chemotherapy identified the presence of metastases to the liver, bone, or brain as independent prognostic variables and were included in the development of a prognostic score.5 High-dose chemotherapy seemed to improve survival in each prognostic category except for low-risk patients, for whom similar survival data were recorded with standard-dose chemotherapy.6 Thus, results with high-dose chemotherapy could be even better in patients with poor prognostic features. Despite all limitations and biases inherent in the analysis of a small and heterogeneous patient population, a cooperative effort should be made to collect information on disease and treatment characteristics from the largest number of children and adolescents with refractory or recurrent germ-cell tumours treated with salvage conventional dose chemotherapy (with or without hyperthermia) or high-dose chemotherapy to identify prognostic variables and patients who could benefit from these treatments. Finally, hyperthermia increasing cellular uptake of platinum drugs and overcoming the platinum resistance might also improve the effect of carboplatin-based high-dose chemotherapy.7 Therefore, future studies should also consider combining hyperthermia and highdose chemotherapy to further improve survival of these patients. We declare that we have no conflicts of interest.
*Ugo De Giorgi, Dino Amadori [email protected]
www.thelancet.com/oncology Vol 14 November 2013
Department of Medical Oncology, IRCCS Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST), Via Piero Maroncelli 40, 47014 Meldola, Italy (UDG, DA) 1
2
3
4
5
6
7
Wessalowski R, Schneider DT, Mils O, et al. Regional deep hyperthermia for salvage treatment of children and adolescents with refractory or recurrent non-testicular malignant germ-cell tumours: an open-label, non-randomised, single-institution, phase 2 study. Lancet Oncol 2013; 14: 843–52. Schneider DT, Wessalowski R, Calaminus G, et al. Treatment of recurrent malignant sacrococcygeal germ cell tumors: analysis of 22 patients registered in the German protocols MAKEI 83/86, 89, and 96. J Clin Oncol 2001; 19: 1951–60. De Giorgi U, Rosti G, Slavin S, et al. Salvage high-dose chemotherapy for children with extragonadal germ-cell tumours. Br J Cancer 2005; 93: 412–17. Calaminus G, Schneider DT, Bökkerink JP, et al. Prognostic value of tumor size, metastases, extension into bone, and increased tumor marker in children with malignant sacrococcygeal germ cell tumors: a prospective evaluation of 71 patients treated in the German cooperative protocols Maligne Keimzelltumoren (MAKEI) 83/86 and MAKEI 89. J Clin Oncol 2003; 21: 781–86. Lorch A, Beyer J, Bascoul-Mollevi C, et al, for the International Prognostic Factors Study Group. Prognostic factors in patients with metastatic germ cell tumors who experienced treatment failure with cisplatin-based first-line chemotherapy. J Clin Oncol 2010; 28: 4906–11. Lorch A, Bascoul-Mollevi C, Kramar A, et al. Conventional-dose versus high-dose chemotherapy as first salvage treatment in male patients with metastatic germ cell tumors: evidence from a large international database. J Clin Oncol 2011; 29: 2178–84. Zaffaroni N, Fiorentini G, De Giorgi U. Hyperthermia and hypoxia: new developments in anticancer chemotherapy. Eur J Surg Oncol 2001; 27: 340–42.
Authors’ reply Data from our study of regional deep hyperthermia for salvage treatment of children and adolescents with refractory or recurrent non-testicular malignant germ-cell tumours (GCTs)1 does not support the opinion that hyperthermia and high-dose chemotherapy have similar efficacies among different patient subgroups. For instance, for patients with sacrococcygeal and retroperitoneal tumours without distant metastases, ongoing remission was detected in 15 (79%) of 19 patients receiving additional hyperthermia treatment, and in only three (60%) of five patients receiving additional highdose chemotherapy.1,2 Among such e486
