Comment
I expect panobinostat to become an important component of myeloma treatment. However, it will probably be approved with a recommended dosing schedule that is not realistic. San-Miguel and colleagues’ trial emphasises a dilemma wherein changes in standard treatment occur during the course of a study. This issue is likely to occur more often in the future as drugs come to market before we really know the right way to use them. In this case, most patients will surely be treated with lower doses of both panobinostat and bortezomib than are likely to be specified on the prescribing label. For the first time in myeloma we have a drug that shows a meaningful clinical benefit without having single-agent activity on its own, emphasising the value of targeted treatment designed by good basic science and rationale. Although it is gratifying to have a drug from a new class, we are even more optimistic about the future. Several drugs with new mechanisms of action are showing promise, including elotuzumab (anti-CS1 antibody), daratumumab and SAR650984 (anti-CD38 monoclonal antibodies), filanesib (an inhibitor of the kinesin spindle protein), and dinaciclib (an inhibitor of cyclin-dependent kinase). Learning how to use these drugs effectively will be an exciting challenge.
S Vincent Rajkumar Division of Hematology, Mayo Clinic, Rochester, MN 55905, USA [email protected] I declare no competing interests. 1 2 3
4
5
6
7
8
9
Stewart AK. Medicine. How thalidomide works against cancer. Science 2014; 343: 256–57. Richardson PG, Barlogie B, Berenson J, et al. A phase 2 study of bortezomib in relapsed, refractory myeloma. N Engl J Med 2003; 348: 2609–17. Kumar SK, Lee JH, Lahuerta JJ, et al. Risk of progression and survival in multiple myeloma relapsing after therapy with IMiDs and bortezomib: a multicenter international myeloma working group study. Leukemia 2012; 26: 149–57. San-Miguel JF, Hungria VTM, Yoon S-S, et al. Panobinostat plus bortezomib and dexamethasone versus placebo plus bortezomib and dexamethasone in patients with relapsed or relapsed and refractory multiple myeloma: a multicentre, randomised, double-blind phase 3 trial. Lancet Oncol 2014; published online Sept 19. http://dx.doi.org/10.1016/S14702045(14)70440-1. Hideshima T, Bradner JE, Wong J, et al. Small-molecule inhibition of proteasome and aggresome function induces synergistic antitumor activity in multiple myeloma. Proc Natl Acad Sci USA 2005; 102: 8567–72. San-Miguel JF, Richardson PG, Gunther A, et al. Phase Ib study of panobinostat and bortezomib in relapsed or relapsed and refractory multiple myeloma. J Clin Oncol 2013; 31: 3696–703. Palumbo A, Bringhen S, Rossi D, et al. Bortezomib-melphalan-prednisonethalidomide followed by maintenance with bortezomib-thalidomide compared with bortezomib-melphalan-prednisone for initial treatment of multiple myeloma: a randomized controlled trial. J Clin Oncol 2010; 28: 5101–09. Mateos M-V, Oriol A, Martínez-Lopez J, et al. Bortezomib, melphalan, and prednisone versus bortezomib, thalidomide, and prednisone as induction therapy followed by maintenance treatment with bortezomib and thalidomide versus bortezomib and prednisone in elderly patients with untreated multiple myeloma: a randomised trial. Lancet Oncol 2010; 11: 934–41. Moreau P, Pylypenko H, Grosicki S, et al. Subcutaneous versus intravenous administration of bortezomib in patients with relapsed multiple myeloma: a randomised, phase 3, non-inferiority study. Lancet Oncol 2011; 12: 431–40.
Use of targeted agents with cytotoxic drugs in a maintenance setting should revolutionise treatment strategies for patients with relapsed ovarian cancer. Results from several randomised trials in first-line and salvage settings report the efficacy of anti-angiogenic agents in platinum-based combinations for prolonging progression-free survival (PFS) and overall survival.1 Studies have shown the therapeutic potential of poly(ADP-ribose) polymerase (PARP) inhibitors in patients with BRCA-mutated ovarian tumours2 or those with clinical features of the so-called BRCA phenotype (repeated platinum sensitivity, high-grade serous, or endometrioid histology).3 The marked activity of olaparib in recurrent platinum-sensitive disease has led to phase 3 randomised trials investigating the efficacy of olaparib in maintenance treatment after platinum-based chemotherapy in adjuvant (SOLO1) and recurrent (SOLO2) settings. www.thelancet.com/oncology Vol 15 October 2014
Potential cross talk between PARP-related molecular and biological pathways and anti-angiogenic activity is of interest. PARP inhibitors might lead to increased VEGF receptor 2 (VEGFR2) phosphorylation and subsequent activation of endothelial cell survival, an effect that has been shown to be reversed by a VEGFR2 inhibitor,4 and VEGFR2 inhibition leads to hypoxia, which can lead to acquisition of homologous recombination defects and sensitivity to PARP inhibitors in hypoxic cancer cells.5 Preliminary assessment of efficacy results of the combination of olaparib and cediranib in a phase 1 trial has shown an objective response rate of 44% in patients with ovarian cancer.6 In this context, the rationale of sustained olaparib plus cediranib has to be acknowledged. In The Lancet Oncology, Liu and colleagues7 present a well-conducted, multicentre, open-label study, in which patients were randomly assigned to receive olaparib 400 mg twice daily (46 patients) or a combination of
Steve Gschmeissner/Science Photo Library
Combining targeted therapies in ovarian cancer
Published Online September 11, 2014 http://dx.doi.org/10.1016/ S1470-2045(14)70421-8 See Articles page 1207
1179
Comment
olaparib 200 mg twice daily with cediranib 30 mg once daily (44 patients) until disease progression. Patients were required to have recurrent, platinum-sensitive, high-grade serous or BRCA-related ovarian cancer, measurable disease based on RECIST 1·1 criteria, and be able to receive oral drugs. PFS was the primary endpoint. With a median follow up of 16·6 months (IQR 12·1–22·2), PFS was 17·7 months (95% CI 14·7–not reached) in patients who received cediranib plus olaparib, and was 9·0 months (5·7–16·5) in patients who received olaparib alone (hazard ratio 0·42, 95% CI 0·23–0·76; p=0·005). Almost 80% of the patients given the combination had an objective response, compared with less than half of those given olaparib alone (p=0·002). Although the study had not planned PFS analysis according to BRCA mutational status, the superiority of olaparib plus cediranib versus olaparib alone was more evident in patients with wild-type or unknown BRCA status (PFS 16·5 months [95% CI 10·8–not reached] in the combination group vs 5·7 months [5·3–11·2] in the olaparib group; p=0·008), than in patients with the BRCA mutation (PFS 19·4 months [14·7–not reached] in the combination group vs 16·5 months [7·5–20·1] in the olaparib group; p=0·16). This trial is the first phase 2 study assessing the efficacy of PARP inhibitors in combination with antiangiogenic agents for patients with recurrent platinumsensitive ovarian cancer and mutated, wild-type, or unknown BRCA status. Median PFS of 17·7 months in the combination group is encouraging compared with median PFS reported in trials using platinumbased chemotherapy with and without bevacizumab (median PFS 8·4–12·4 months).8–10 These results offer new perspectives for future trials exploiting targeted combinations and avoiding conventional chemotherapy in some patients with recurrent ovarian cancer. The better PFS seen with the combination in patients with wild-type or unknown BRCA status might be ascribed to the lower activity of olaparib in patients with wild-type or unknown BRCA status, as suggested by Liu and colleagues.7 Nonetheless, although the addition of cediranib to PARP inhibitors could be useful in the population with non-mutated BRCA recurrent ovarian cancer, the real contribution of either drug cannot be assessed due to the absence of a group given cediranib alone. 1180
Conversely, the real clinical relevance of using the combination rather than olaparib alone in patients with the BRCA mutation should be carefully assessed. Although a difference in PFS curves favouring the combination group has been shown, statistical significance was not reached. Without results from larger phase 3 trials assessing PFS and overall survival, the toxicity of the combination remains an important issue. Toxicity associated with combination treatment was higher compared with olaparib alone: grade 3 or higher toxicities were documented as fatigue (27% vs 11%), diarrhoea (23% vs 0%), and hypertension (41% vs 0%), which resulted in a higher incidence of dose reduction (77%) and patient withdrawal (9%). Because it is difficult to discriminate the extent and profile of drug toxicity, as well as its management, future trials should examine quality of life, dose interruptions, dose reductions, and report single episodes of adverse events for long-term maintenance studies. Whether the combination of olaparib and cediranib will safely replace platinum-based chemotherapy might be answered by findings from upcoming phase 3 trials of the combination against a platinumbased chemotherapy combination. Several studies with novel PARP inhibitors are also at different phases of clinical development (eg, NCT00989651). *Giovanni Scambia, Vanda Salutari, Gabriella Ferrandina Gynecology Oncology Unit, Catholic University of Rome, Largo A. Gemelli 1, Rome, Italy [email protected] We declare no competing interests. 1 2
3
4
5
6
7
Perren TJ, Swart AM, Pfisterer J, et al. A phase 3 trial of bevacizumab in ovarian cancer. N Engl J Med 2011; 365: 2484–96. Ledermann J, Harter P, Gourley C, et al. Olaparib maintenance therapy in patients with platinum-sensitive relapsed serous ovarian cancer: a preplanned retrospective analysis of outcomes by BRCA status in a randomised phase 2 trial. Lancet Oncol 2014; 15: 852–61. Gelmon KA, Tischkowitz M, Mackay H, et al. Olaparib in patients with recurrent high-grade serous or poorly differentiated ovarian carcinoma or triple-negative breast cancer: a phase 2, multicentre, open-label, non-randomised study. Lancet Oncol 2011; 12: 852–61. Mathews MT, Berk BC. PARP-1 inhibition prevents oxidative and nitrosative stress-induced endothelial cell death via transactivation of the VEGF receptor 2. Arterioscler Thromb Vasc Biol 2008; 28: 711–17. Hegan DC, Lu Y, Stachelek GC, et al. Inhibition of poly(ADP-ribose) polymerase down-regulates BRCA1 and RAD51 in a pathway mediated by E2F4 and p130. Proc Natl Acad Sci USA 2010; 107: 2201–06. Liu JF, Tolaney SM, Birrer M, et al. A phase 1 trial of the poly(ADP-ribose) polymerase inhibitor olaparib (AZD2281) in combination with the anti-angiogenic cediranib (AZD2171) in recurrent epithelial ovarian or triplenegative breast cancer. Eur J Cancer 2013; 49: 2972–78. Liu JF, Barry WT, Birrer M, et al. Combination cediranib and olaparib versus olaparib alone for women with recurrent platinum-sensitive ovarian cancer: a randomised phase 2 study. Lancet Oncol 2014; published online Sept 11. http://dx.doi.org/10.1016/S1470-2045(14)70391-2.
www.thelancet.com/oncology Vol 15 October 2014
Comment
8
9
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: 2099–106. 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: 4699–707.
10
Wagner U, Marth C, Largillier R, et al. Final overall survival results of phase III GCIG CALYPSO trial of pegylated liposomal doxorubicin and carboplatin vs paclitaxel and carboplatin in platinum-sensitive ovarian cancer patients. Br J Cancer 2012; 107: 588–91.
In 2006, the American Society of Clinical Oncology (ASCO) published recommendations1 about fertility preservation in patients with cancer. This document, and its subsequent 2013 update, emphasise the importance of discussion with patients (men, women, and children), at the earliest possible time after a cancer diagnosis, about the risk of infertility associated with cancer therapies and also the options available for fertility preservation.1,2 Fertility preservation can be a difficult topic to discuss with an adult in the setting of an acute cancer diagnosis, and this issue can be even more challenging to address with a child and their parents. Although fertility preservation programmes have been implemented successfully since the release of the ASCO recommendations, this care has been largely lagging behind for paediatric patients.3,4 At the moment, no effective means exists for fertility preservation of a prepubertal boy with cancer.1,2 By contrast, most adolescent male oncology patients are capable of providing semen of sufficient quality for cryopreservation before initiation of cancer therapy.5 Fertility and reproductive health issues are known to be of paramount concern for adult survivors of paediatric cancer.6 Such survivors feel strongly that fertility preservation discussions should be routinely incorporated into paediatric cancer care. In 2011, Köhler and colleagues published the results of a survey4 of paediatric oncologists into their attitudes and practice patterns toward fertility preservation. This report emphasised several important issues of note. First, only 44% of respondents reported being familiar with the ASCO fertility preservation recommendations, and only 39% reported routine use of them to guide decision making for patient care. Second, the respondents identified several barriers to fertility preservation for their male patients, including the need to rapidly initiate cancer treatment because of www.thelancet.com/oncology Vol 15 October 2014
aggressiveness of the disease and discomfort discussing sperm banking. Several other studies have also detailed common obstacles to fertility preservation care in the paediatric population, and these hurdles can be numerous. A fundamental issue contributing to these barriers is that paediatric health-care facilities are often geographically separate from reproductive health centres. This physical distance can not only hamper logistical efforts for sperm banking but, more broadly, also restricts the routine opportunities for interdisciplinary collaboration between paediatric and adult health-care providers, including reproductive specialists. Many paediatric cancer specialists are unfamiliar with the work of reproductive specialists and do not have a contact person available to help them provide fertility preservation care. The topics of reproductive health, sperm banking, and the use of cryopreserved sperm in assisted reproductive techniques are outside of the realm of expertise for most paediatric oncologists, and discussions can be a daunting and discomfiting undertaking. For this reason, some investigators have called for the development of a “systematic and coordinated multidisciplinary strategy” for fertility preservation care in the adolescent and young adult population.7 The authors suggest a number of strategies to offload the burden of provision of fertility preservation care for the treating paediatric oncologist. Principal among these strategies is the establishment of working clinical relations with reproductive health-care specialists and the implementation of standard practices for offering of fertility preservation care to eligible adolescent patients. One issue hampering fertility preservation discussions has been a deficit of published work about long-term reproductive outcomes associated with various chemotherapeutic regimens. In this issue
Juergen Berger/Science Photo Library
Risk of infertility in male survivors of childhood cancer
Published Online September 17, 2014 http://dx.doi.org/10.1016/ S1470-2045(14)70450-4 See Articles page 1215
1181
I expect panobinostat to become an important component of myeloma treatment. However, it will probably be approved with a recommended dosing schedule that is not realistic. San-Miguel and colleagues’ trial emphasises a dilemma wherein changes in standard treatment occur during the course of a study. This issue is likely to occur more often in the future as drugs come to market before we really know the right way to use them. In this case, most patients will surely be treated with lower doses of both panobinostat and bortezomib than are likely to be specified on the prescribing label. For the first time in myeloma we have a drug that shows a meaningful clinical benefit without having single-agent activity on its own, emphasising the value of targeted treatment designed by good basic science and rationale. Although it is gratifying to have a drug from a new class, we are even more optimistic about the future. Several drugs with new mechanisms of action are showing promise, including elotuzumab (anti-CS1 antibody), daratumumab and SAR650984 (anti-CD38 monoclonal antibodies), filanesib (an inhibitor of the kinesin spindle protein), and dinaciclib (an inhibitor of cyclin-dependent kinase). Learning how to use these drugs effectively will be an exciting challenge.
S Vincent Rajkumar Division of Hematology, Mayo Clinic, Rochester, MN 55905, USA [email protected] I declare no competing interests. 1 2 3
4
5
6
7
8
9
Stewart AK. Medicine. How thalidomide works against cancer. Science 2014; 343: 256–57. Richardson PG, Barlogie B, Berenson J, et al. A phase 2 study of bortezomib in relapsed, refractory myeloma. N Engl J Med 2003; 348: 2609–17. Kumar SK, Lee JH, Lahuerta JJ, et al. Risk of progression and survival in multiple myeloma relapsing after therapy with IMiDs and bortezomib: a multicenter international myeloma working group study. Leukemia 2012; 26: 149–57. San-Miguel JF, Hungria VTM, Yoon S-S, et al. Panobinostat plus bortezomib and dexamethasone versus placebo plus bortezomib and dexamethasone in patients with relapsed or relapsed and refractory multiple myeloma: a multicentre, randomised, double-blind phase 3 trial. Lancet Oncol 2014; published online Sept 19. http://dx.doi.org/10.1016/S14702045(14)70440-1. Hideshima T, Bradner JE, Wong J, et al. Small-molecule inhibition of proteasome and aggresome function induces synergistic antitumor activity in multiple myeloma. Proc Natl Acad Sci USA 2005; 102: 8567–72. San-Miguel JF, Richardson PG, Gunther A, et al. Phase Ib study of panobinostat and bortezomib in relapsed or relapsed and refractory multiple myeloma. J Clin Oncol 2013; 31: 3696–703. Palumbo A, Bringhen S, Rossi D, et al. Bortezomib-melphalan-prednisonethalidomide followed by maintenance with bortezomib-thalidomide compared with bortezomib-melphalan-prednisone for initial treatment of multiple myeloma: a randomized controlled trial. J Clin Oncol 2010; 28: 5101–09. Mateos M-V, Oriol A, Martínez-Lopez J, et al. Bortezomib, melphalan, and prednisone versus bortezomib, thalidomide, and prednisone as induction therapy followed by maintenance treatment with bortezomib and thalidomide versus bortezomib and prednisone in elderly patients with untreated multiple myeloma: a randomised trial. Lancet Oncol 2010; 11: 934–41. Moreau P, Pylypenko H, Grosicki S, et al. Subcutaneous versus intravenous administration of bortezomib in patients with relapsed multiple myeloma: a randomised, phase 3, non-inferiority study. Lancet Oncol 2011; 12: 431–40.
Use of targeted agents with cytotoxic drugs in a maintenance setting should revolutionise treatment strategies for patients with relapsed ovarian cancer. Results from several randomised trials in first-line and salvage settings report the efficacy of anti-angiogenic agents in platinum-based combinations for prolonging progression-free survival (PFS) and overall survival.1 Studies have shown the therapeutic potential of poly(ADP-ribose) polymerase (PARP) inhibitors in patients with BRCA-mutated ovarian tumours2 or those with clinical features of the so-called BRCA phenotype (repeated platinum sensitivity, high-grade serous, or endometrioid histology).3 The marked activity of olaparib in recurrent platinum-sensitive disease has led to phase 3 randomised trials investigating the efficacy of olaparib in maintenance treatment after platinum-based chemotherapy in adjuvant (SOLO1) and recurrent (SOLO2) settings. www.thelancet.com/oncology Vol 15 October 2014
Potential cross talk between PARP-related molecular and biological pathways and anti-angiogenic activity is of interest. PARP inhibitors might lead to increased VEGF receptor 2 (VEGFR2) phosphorylation and subsequent activation of endothelial cell survival, an effect that has been shown to be reversed by a VEGFR2 inhibitor,4 and VEGFR2 inhibition leads to hypoxia, which can lead to acquisition of homologous recombination defects and sensitivity to PARP inhibitors in hypoxic cancer cells.5 Preliminary assessment of efficacy results of the combination of olaparib and cediranib in a phase 1 trial has shown an objective response rate of 44% in patients with ovarian cancer.6 In this context, the rationale of sustained olaparib plus cediranib has to be acknowledged. In The Lancet Oncology, Liu and colleagues7 present a well-conducted, multicentre, open-label study, in which patients were randomly assigned to receive olaparib 400 mg twice daily (46 patients) or a combination of
Steve Gschmeissner/Science Photo Library
Combining targeted therapies in ovarian cancer
Published Online September 11, 2014 http://dx.doi.org/10.1016/ S1470-2045(14)70421-8 See Articles page 1207
1179
Comment
olaparib 200 mg twice daily with cediranib 30 mg once daily (44 patients) until disease progression. Patients were required to have recurrent, platinum-sensitive, high-grade serous or BRCA-related ovarian cancer, measurable disease based on RECIST 1·1 criteria, and be able to receive oral drugs. PFS was the primary endpoint. With a median follow up of 16·6 months (IQR 12·1–22·2), PFS was 17·7 months (95% CI 14·7–not reached) in patients who received cediranib plus olaparib, and was 9·0 months (5·7–16·5) in patients who received olaparib alone (hazard ratio 0·42, 95% CI 0·23–0·76; p=0·005). Almost 80% of the patients given the combination had an objective response, compared with less than half of those given olaparib alone (p=0·002). Although the study had not planned PFS analysis according to BRCA mutational status, the superiority of olaparib plus cediranib versus olaparib alone was more evident in patients with wild-type or unknown BRCA status (PFS 16·5 months [95% CI 10·8–not reached] in the combination group vs 5·7 months [5·3–11·2] in the olaparib group; p=0·008), than in patients with the BRCA mutation (PFS 19·4 months [14·7–not reached] in the combination group vs 16·5 months [7·5–20·1] in the olaparib group; p=0·16). This trial is the first phase 2 study assessing the efficacy of PARP inhibitors in combination with antiangiogenic agents for patients with recurrent platinumsensitive ovarian cancer and mutated, wild-type, or unknown BRCA status. Median PFS of 17·7 months in the combination group is encouraging compared with median PFS reported in trials using platinumbased chemotherapy with and without bevacizumab (median PFS 8·4–12·4 months).8–10 These results offer new perspectives for future trials exploiting targeted combinations and avoiding conventional chemotherapy in some patients with recurrent ovarian cancer. The better PFS seen with the combination in patients with wild-type or unknown BRCA status might be ascribed to the lower activity of olaparib in patients with wild-type or unknown BRCA status, as suggested by Liu and colleagues.7 Nonetheless, although the addition of cediranib to PARP inhibitors could be useful in the population with non-mutated BRCA recurrent ovarian cancer, the real contribution of either drug cannot be assessed due to the absence of a group given cediranib alone. 1180
Conversely, the real clinical relevance of using the combination rather than olaparib alone in patients with the BRCA mutation should be carefully assessed. Although a difference in PFS curves favouring the combination group has been shown, statistical significance was not reached. Without results from larger phase 3 trials assessing PFS and overall survival, the toxicity of the combination remains an important issue. Toxicity associated with combination treatment was higher compared with olaparib alone: grade 3 or higher toxicities were documented as fatigue (27% vs 11%), diarrhoea (23% vs 0%), and hypertension (41% vs 0%), which resulted in a higher incidence of dose reduction (77%) and patient withdrawal (9%). Because it is difficult to discriminate the extent and profile of drug toxicity, as well as its management, future trials should examine quality of life, dose interruptions, dose reductions, and report single episodes of adverse events for long-term maintenance studies. Whether the combination of olaparib and cediranib will safely replace platinum-based chemotherapy might be answered by findings from upcoming phase 3 trials of the combination against a platinumbased chemotherapy combination. Several studies with novel PARP inhibitors are also at different phases of clinical development (eg, NCT00989651). *Giovanni Scambia, Vanda Salutari, Gabriella Ferrandina Gynecology Oncology Unit, Catholic University of Rome, Largo A. Gemelli 1, Rome, Italy [email protected] We declare no competing interests. 1 2
3
4
5
6
7
Perren TJ, Swart AM, Pfisterer J, et al. A phase 3 trial of bevacizumab in ovarian cancer. N Engl J Med 2011; 365: 2484–96. Ledermann J, Harter P, Gourley C, et al. Olaparib maintenance therapy in patients with platinum-sensitive relapsed serous ovarian cancer: a preplanned retrospective analysis of outcomes by BRCA status in a randomised phase 2 trial. Lancet Oncol 2014; 15: 852–61. Gelmon KA, Tischkowitz M, Mackay H, et al. Olaparib in patients with recurrent high-grade serous or poorly differentiated ovarian carcinoma or triple-negative breast cancer: a phase 2, multicentre, open-label, non-randomised study. Lancet Oncol 2011; 12: 852–61. Mathews MT, Berk BC. PARP-1 inhibition prevents oxidative and nitrosative stress-induced endothelial cell death via transactivation of the VEGF receptor 2. Arterioscler Thromb Vasc Biol 2008; 28: 711–17. Hegan DC, Lu Y, Stachelek GC, et al. Inhibition of poly(ADP-ribose) polymerase down-regulates BRCA1 and RAD51 in a pathway mediated by E2F4 and p130. Proc Natl Acad Sci USA 2010; 107: 2201–06. Liu JF, Tolaney SM, Birrer M, et al. A phase 1 trial of the poly(ADP-ribose) polymerase inhibitor olaparib (AZD2281) in combination with the anti-angiogenic cediranib (AZD2171) in recurrent epithelial ovarian or triplenegative breast cancer. Eur J Cancer 2013; 49: 2972–78. Liu JF, Barry WT, Birrer M, et al. Combination cediranib and olaparib versus olaparib alone for women with recurrent platinum-sensitive ovarian cancer: a randomised phase 2 study. Lancet Oncol 2014; published online Sept 11. http://dx.doi.org/10.1016/S1470-2045(14)70391-2.
www.thelancet.com/oncology Vol 15 October 2014
Comment
8
9
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: 2099–106. 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: 4699–707.
10
Wagner U, Marth C, Largillier R, et al. Final overall survival results of phase III GCIG CALYPSO trial of pegylated liposomal doxorubicin and carboplatin vs paclitaxel and carboplatin in platinum-sensitive ovarian cancer patients. Br J Cancer 2012; 107: 588–91.
In 2006, the American Society of Clinical Oncology (ASCO) published recommendations1 about fertility preservation in patients with cancer. This document, and its subsequent 2013 update, emphasise the importance of discussion with patients (men, women, and children), at the earliest possible time after a cancer diagnosis, about the risk of infertility associated with cancer therapies and also the options available for fertility preservation.1,2 Fertility preservation can be a difficult topic to discuss with an adult in the setting of an acute cancer diagnosis, and this issue can be even more challenging to address with a child and their parents. Although fertility preservation programmes have been implemented successfully since the release of the ASCO recommendations, this care has been largely lagging behind for paediatric patients.3,4 At the moment, no effective means exists for fertility preservation of a prepubertal boy with cancer.1,2 By contrast, most adolescent male oncology patients are capable of providing semen of sufficient quality for cryopreservation before initiation of cancer therapy.5 Fertility and reproductive health issues are known to be of paramount concern for adult survivors of paediatric cancer.6 Such survivors feel strongly that fertility preservation discussions should be routinely incorporated into paediatric cancer care. In 2011, Köhler and colleagues published the results of a survey4 of paediatric oncologists into their attitudes and practice patterns toward fertility preservation. This report emphasised several important issues of note. First, only 44% of respondents reported being familiar with the ASCO fertility preservation recommendations, and only 39% reported routine use of them to guide decision making for patient care. Second, the respondents identified several barriers to fertility preservation for their male patients, including the need to rapidly initiate cancer treatment because of www.thelancet.com/oncology Vol 15 October 2014
aggressiveness of the disease and discomfort discussing sperm banking. Several other studies have also detailed common obstacles to fertility preservation care in the paediatric population, and these hurdles can be numerous. A fundamental issue contributing to these barriers is that paediatric health-care facilities are often geographically separate from reproductive health centres. This physical distance can not only hamper logistical efforts for sperm banking but, more broadly, also restricts the routine opportunities for interdisciplinary collaboration between paediatric and adult health-care providers, including reproductive specialists. Many paediatric cancer specialists are unfamiliar with the work of reproductive specialists and do not have a contact person available to help them provide fertility preservation care. The topics of reproductive health, sperm banking, and the use of cryopreserved sperm in assisted reproductive techniques are outside of the realm of expertise for most paediatric oncologists, and discussions can be a daunting and discomfiting undertaking. For this reason, some investigators have called for the development of a “systematic and coordinated multidisciplinary strategy” for fertility preservation care in the adolescent and young adult population.7 The authors suggest a number of strategies to offload the burden of provision of fertility preservation care for the treating paediatric oncologist. Principal among these strategies is the establishment of working clinical relations with reproductive health-care specialists and the implementation of standard practices for offering of fertility preservation care to eligible adolescent patients. One issue hampering fertility preservation discussions has been a deficit of published work about long-term reproductive outcomes associated with various chemotherapeutic regimens. In this issue
Juergen Berger/Science Photo Library
Risk of infertility in male survivors of childhood cancer
Published Online September 17, 2014 http://dx.doi.org/10.1016/ S1470-2045(14)70450-4 See Articles page 1215
1181
