- Email: [email protected]
Childhood cancer survivors: stillbirth and neonatal death
Comment
way to encourage their introduction and to establish whether these vaccines will stand alongside smallpox, measles, and poliomyelitis vaccines in their public health benefits.1 Beyond this, there is a clear need for further research to understand why the efficacy of both live oral rotavirus vaccines is lower among children in low-income countries than high-income countries. Could simple interventions, such as slightly delaying immunisation, adding an additional dose of vaccine, or withholding breast milk around the time of vaccine administration, improve the efficacy of the vaccine in these challenging settings? Finding an answer to these questions could add value to these new vaccines while doing much to improve the health and survival of children.
4
5
6 7
8 9
10
11 12
*E Anthony S Nelson, Roger I Glass Department of Paediatrics, Chinese University of Hong Kong, Hong Kong Special Administrative Region, China (EASN); and Fogarty International Center, National Institutes of Health, Bethesda, MD, USA (RIG) [email protected] EASN has received funding from Merck and Wyeth for diarrhoeal and respiratory disease surveillance studies, has participated in vaccine studies funded by Baxter, GlaxoSmithKline, MedImmune, and Wyeth, including a phase 3 Rotarix study, and has received lecture fees and travel support from GlaxoSmithKline, Merck, Intercell, and Wyeth. RIG declares that he has no conflicts of interest. 1 2
3
Butcher J. Paper of the year 2006. Lancet 2007; 369: 91–92. Vesikari T, Matson DO, Dennehy P, et al, for the Rotavirus Efficacy and Safety Trial (REST) Study Team. Safety and efficacy of a pentavalent human-bovine (WC3) reassortant rotavirus vaccine. N Engl J Med 2006; 354: 23–33. Ruiz-Palacios GM, Perez-Schael I, Velazquez FR, et al, for the Human Rotavirus Vaccine Study Group. Safety and efficacy of an attenuated vaccine against severe rotavirus gastroenteritis. N Engl J Med 2006; 354: 11–22.
13
14
15 16 17 18
19
Widdowson MA, Steele D, Vojdani J, Wecker J, Parashar U. Global rotavirus surveillance: determining the need and measuring the impact of rotavirus vaccines. J Infect Dis 2009; 200 (suppl 1): S1–S8. Patel M, Shane AL, Parashar UD, Jiang B, Gentsch JR, Glass RI. Oral rotavirus vaccines: how well will they work where they are needed most? J Infect Dis 2009; 200 (suppl 1): S39–S48. WHO. Rotavirus vaccines. MMWR Wkly Epidemiol Rec 2007; 82: 285–95. WHO. Meeting of the immunization Strategic Advisory Group of Experts, April 2009—conclusions and recommendations. MMWR Wkly Epidemiol Rec 2009; 84: 220–36. Madhi SA, Cunliffe NA, Steele D, et al. Effect of human rotavirus vaccine on severe diarrhea in African infants. N Engl J Med 2010; 362: 289–98. Zaman K, Anh DD, Victor JC, et al. Efficacy of pentavalent rotavirus vaccine against severe rotavirus gastroenteritis in infants in developing countries in Asia: a randomised, double-blind, placebo-controlled trial. Lancet 2010; published online Aug 6. DOI:10.1016/S0140-6736(10)60755-6. Armah GE, Sow SO, Breiman RF, et al. Efficacy of pentavalent rotavirus vaccine against severe rotavirus in infants in developing countries in subSaharan Africa: a randomised, double-blind, placebo-controlled trial. Lancet 2010; published online Aug 6. DOI:10.1016/S0140-6736(10)60889-6. UN Development Programme. Human Development Report 2009 http:// hdrstats.undp.org/en/indicators/91.html (accessed Jun 12, 2010). Vesikari T, Karvonen A, Prymula R, et al. Efficacy of human rotavirus vaccine against rotavirus gastroenteritis during the first 2 years of life in European infants: randomised, double-blind controlled study. Lancet 2007; 370: 1757–63. Vesikari T, Itzler R, Matson DO, et al. Efficacy of a pentavalent rotavirus vaccine in reducing rotavirus-associated health care utilization across three regions (11 countries). Int J Infect Dis 2007; 11 (suppl 2): S29–35. Phua KB, Lim FS, Lau YL, et al. Safety and efficacy of human rotavirus vaccine during the first 2 years of life in Asian infants: randomised, double-blind, controlled study. Vaccine 2009; 27: 5936–41. WHO. Rotavirus vaccines: an update. MMWR Wkly Epidemiol Rec 2009; 84: 533–38. Cohen D, Carter P. WHO and the pandemic flu “conspiracies”. BMJ 2010; 340: 1274–79. Wardlaw T, Salama P, Brocklehurst C, Chopra M, Mason E. Diarrhoea: why children are still dying and what can be done. Lancet 2010; 375: 870–72. Curns AT, Steiner CA, Barrett M, Hunter K, Wilson E, Parashar UD. Reduction in acute gastroenteritis hospitalizations among US children after introduction of rotavirus vaccine: analysis of hospital discharge data from 18 US states. J Infect Dis 2010; 201: 1617–24. Richardson V, Hernandez-Pichardo J, Quintanar-Solares M, et al. Effect of rotavirus vaccination on death from childhood diarrhea in Mexico. N Engl J Med 2010; 362: 299–305.
Childhood cancer survivors: stillbirth and neonatal death See Articles page 624
570
As an oncologist, one assumes that the benefit of survivorship outweighs the cost of side-effects, justifying complex multidisciplinary care, including the mainstay treatments of surgery, chemotherapy, and radiotherapy. Children with cancer do not typically make the choice, as adults do, of whether to receive treatment or not, and parents understandably want to provide their children with every possible option for cure. These options can include aggressive, novel treatment strategies with unknown potential consequences decades later. Suffering severe sequelae of cancer treatment might substantially affect long-term quality of life, including the ability to bear children.
In The Lancet today, Lisa Signorello and collaborators report a retrospective cohort analysis of the Childhood Cancer Survivor Study (CCSS), looking at the rates of stillbirth and neonatal death.1 Enrolled cohort members were diagnosed between 1970 and 1986 with leukaemia, lymphoma, sarcoma, CNS cancer, Wilms’ tumour, kidney cancer, or neuroblastoma. Whereas previous reports from the CCSS and others analysed the rates of acute ovarian failure,2,3 premature menopause,4 miscarriage,5 and babies with low birthweight5–7 in female survivors, today’s analysis includes both male and female cancer survivors and reports the risk of stillbirth (defined as a fetal death occurring after the 20th gestational week) and www.thelancet.com Vol 376 August 21, 2010
neonatal death (defined as death within the first 28 days after birth). After the 20th week of gestation, the fetus grows rapidly, necessitating rapid uterine expansion. By this stage in pregnancy, fertilisation, implantation, and early fetal development have all proceeded on schedule, indicating no impairment in conception, hormonal regulation, or presence of fatal genetic malformations. From Signorello and colleagues’ analysis, one might surmise that the most likely cause of stillbirth and neonatal death would be radiation-induced toxicity to the uterus. Not surprisingly, the most significant sequelae resulted from the use of radiation in premenarchal girls, whereas chemotherapy did not affect rates of stillbirth and neonatal death for either male or female survivors of childhood cancer in this cohort. Radiation effects on pregnancy outcome in general can be divided into direct effects (gonadal) or indirect effects (hormonal). Direct effects include radiation received by the testes, ovaries, or uterus, whereas indirect effects include cranial irradiation that can affect pituitary function.8 Signorello and co-workers found no effect of indirect pituitary irradiation in this cohort; the risk of stillbirth and neonatal death increased only in women having a direct effect of radiation on uterine or ovarian tissue. In view of the proximity of the uterus and ovary, these organs probably receive equivalent radiation doses. However, ovarian hormonal production sufficed in these survivors to allow ovulation, conception, and pregnancy to the 20th week, which indicates adequate ovarian function. Importantly, Signorello and collaborators found no effect of childhood cancer treatment on the ability of male survivors to contribute to a successful pregnancy, although the radiation doses received directly by the testes were lower than the uterine/ovarian doses in this cohort. Female survivors, however, had a significantly increased risk (relative risk 12·3) of having a stillbirth and neonatal death if they had received a radiation dose greater than 2·5 Gy before menarche, because of the direct effects of radiation to the uterus/ovaries. By contrast, postmenarchal girls treated with greater than 2·5 Gy had a relative risk of 0·2. A significant test for trend on stratified analysis for increasing dose was noted only in the premenarchal group. The reasons for the difference between premenarchal and postmenarchal sensitivity to radiation are unclear. In premenopausal women, premature ovarian failure results from radiation www.thelancet.com Vol 376 August 21, 2010
Science Photo Library
Comment
doses of about 15 Gy.9 Previous studies showed that girls treated with about 10 Gy were at high risk of acute ovarian failure, whereas those treated with about 5 Gy to the uterus were more likely to have offspring that were small for gestational age.2 However, in the CCSS, the physicist estimated the dose to an area thought to be the uterus/ovaries for a girl on the basis of her age. Therefore the radiation doses only roughly approximate the doses received. Consequently, this study cannot set a threshold limit or indicate a real dose-response of the ovaries or uterus, because of the inaccuracies in retrospective dose-estimation. We do not know from the data in this report whether survivors had ever had a successful pregnancy before or after the stillbirth or neonatal death. The Children’s Oncology Group (COG) recently attempted chemotherapy alone for girls with vaginal rhabdomyosarcoma to try to eliminate radiation; the trial was closed early because of an increase in the recurrence rate and a dose of 36 Gy was reinstituted in subsequent trials.10 Since the time of the CCSS patients’ radiation treatment in 1970–86, radiation has changed substantially, with advances in imaging, therapeutic targeting, and management of side-effects. In the 1990s, older machines and techniques were used, in a period that predated the integration of CT simulation in treatment planning. Over the past 20 years, highly conformal radiation-treatment plans generated with CT imaging have shifted radiation dose focally to the areas at highest risk of local recurrence. Additionally, the use of intensity-modulated radiation in the past 5 years has 571
Comment
resulted in extremely conformal treatment capabilities. Proton radiotherapy provides the most conformal approach with the lowest likelihood of radiation penetrating unintended regions of the body, and has been used for paediatric cancers, particularly CNS tumours, in centres with a proton facility.11 Children suffer the most severe long-term sequelae from radiation and are the most likely to live decades if cured. Therefore proton facilities should make treating children with cancer a high priority, including young women requiring abdominal or pelvic radiation that might scatter to affect the uterus or ovary. For premenopausal women, potential options for preservation of fertility should be discussed.12 Should uterine irradiation be unavoidable, parents should be informed that their daughter’s offspring might be at risk of stillbirth and neonatal death when their daughter reaches adulthood. For childhood cancer survivors, reproductive counselling and testing in a specialised centre to assess the feasibility and potential risks associated with a pregnancy should be discussed, and a plan implemented to ensure a successful outcome.
I declare that I have no conflicts of interest. 1
2
3
4
5
6 7
8
9
10
11
Akila N Viswanathan Gynecologic Radiation Oncology, Brigham and Women’s Hospital/Dana-Farber Cancer Center, Harvard Medical School, Boston, MA 02115, USA [email protected]
12
Signorello LB, Mulvihill JJ, Green DM, et al. Stillbirth and neonatal death in relation to radiation exposure before conception: a retrospective cohort study. Lancet 2010; 376: 624–30. Green DM, Kawashima T, Stovall M, et al. Fertility of female survivors of childhood cancer: a report from the childhood cancer survivor study. J Clin Oncol 2009; 27: 2677–85. Chemaitilly W, Mertens AC, Mitby P, et al. Acute ovarian failure in the childhood cancer survivor study. J Clin Endocrinol Metab 2006; 91: 1723–28. Sklar CA, Mertens AC, Mitby P, et al. Premature menopause in survivors of childhood cancer: a report from the childhood cancer survivor study. J Natl Cancer Inst 2006; 98: 890–96. Green DM, Whitton JA, Stovall M, et al. Pregnancy outcome of female survivors of childhood cancer: a report from the Childhood Cancer Survivor Study. Am J Obstet Gynecol 2002; 187: 1070–80. Chiarelli AM, Marrett LD, Darlington GA. Pregnancy outcomes in females after treatment for childhood cancer. Epidemiology 2000; 11: 161–66. Green DM, Peabody EM, Nan B, Peterson S, Kalapurakal JA, Breslow NE. Pregnancy outcome after treatment for Wilms tumor: a report from the National Wilms Tumor Study Group. J Clin Oncol 2002; 20: 2506–13. Wo JY, Viswanathan AN. Impact of radiotherapy on fertility, pregnancy, and neonatal outcomes in female cancer patients. Int J Radiat Oncol Biol Phys 2009; 73: 1304–12. Adjuvant Breast Cancer Trials Collaborative Group. Ovarian ablation or suppression in premenopausal early breast cancer: results from the international adjuvant breast cancer ovarian ablation or suppression randomized trial. J Natl Cancer Inst 2007; 99: 516–25. Walterhouse D. ARST0331 Study Committee progress report on vincristine, dactinomycin, and lower doses of cyclophosphamide with or without radiation therapy for patients with newly diagnosed low-risk embryonal/botryoid/spindle cell rhabdomyosarcoma. 2009 (available from the author). Merchant TE. Proton beam therapy in pediatric oncology. Cancer J 2009; 15: 298–305. Lobo RA. Potential options for preservation of fertility in women. N Engl J Med 2005; 353: 64–73.
The India HPV-vaccine suspension
Science Photo Library
In response to demands from advocacy groups, the Indian Government has suspended demonstration projects for HPV vaccination in Andhra Pradesh and Gujarat.1,2 The episode provides salutary lessons about how a lack of public confidence can amplify if not quickly addressed. The first lesson is timing. Too often, the response to citizen advocates who question health interventions, programmes, or studies, is too late. The April, 2010, memorandum3 from 68 Indian human rights and women’s groups, academics, and individuals sent to the Indian Minister of Health and Family Welfare should not have been a surprise. A similar memo had been sent 6 months earlier.4 The April memo called for the immediate halt of the demonstration projects until “concerns relating to safety, efficacy and cost effectiveness 572
of the planned interventions are re-evaluated”.3 It also demanded an inquiry into, and compensation for, the reported side-effects and alleged vaccine-related deaths of four girls who participated in the study. The deaths have since been investigated and confirmed as unrelated to the vaccine.2,5 Similarly, the memorandum4 sent on Oct 1, 2009, demanded that “all trials and studies be immediately brought to a halt till in an open forum questions relating to safety, efficacy and cost effectiveness of the planned intervention can be justified”. On Dec 28, 2009, the groups continued their unanswered pleas and convened a public meeting that generated more attention than the October memorandum.6 By February, GlaxoSmithKline, Merck, and PATH had issued responses on the safety of the vaccine and on the process of the study.7–9 www.thelancet.com Vol 376 August 21, 2010
way to encourage their introduction and to establish whether these vaccines will stand alongside smallpox, measles, and poliomyelitis vaccines in their public health benefits.1 Beyond this, there is a clear need for further research to understand why the efficacy of both live oral rotavirus vaccines is lower among children in low-income countries than high-income countries. Could simple interventions, such as slightly delaying immunisation, adding an additional dose of vaccine, or withholding breast milk around the time of vaccine administration, improve the efficacy of the vaccine in these challenging settings? Finding an answer to these questions could add value to these new vaccines while doing much to improve the health and survival of children.
4
5
6 7
8 9
10
11 12
*E Anthony S Nelson, Roger I Glass Department of Paediatrics, Chinese University of Hong Kong, Hong Kong Special Administrative Region, China (EASN); and Fogarty International Center, National Institutes of Health, Bethesda, MD, USA (RIG) [email protected] EASN has received funding from Merck and Wyeth for diarrhoeal and respiratory disease surveillance studies, has participated in vaccine studies funded by Baxter, GlaxoSmithKline, MedImmune, and Wyeth, including a phase 3 Rotarix study, and has received lecture fees and travel support from GlaxoSmithKline, Merck, Intercell, and Wyeth. RIG declares that he has no conflicts of interest. 1 2
3
Butcher J. Paper of the year 2006. Lancet 2007; 369: 91–92. Vesikari T, Matson DO, Dennehy P, et al, for the Rotavirus Efficacy and Safety Trial (REST) Study Team. Safety and efficacy of a pentavalent human-bovine (WC3) reassortant rotavirus vaccine. N Engl J Med 2006; 354: 23–33. Ruiz-Palacios GM, Perez-Schael I, Velazquez FR, et al, for the Human Rotavirus Vaccine Study Group. Safety and efficacy of an attenuated vaccine against severe rotavirus gastroenteritis. N Engl J Med 2006; 354: 11–22.
13
14
15 16 17 18
19
Widdowson MA, Steele D, Vojdani J, Wecker J, Parashar U. Global rotavirus surveillance: determining the need and measuring the impact of rotavirus vaccines. J Infect Dis 2009; 200 (suppl 1): S1–S8. Patel M, Shane AL, Parashar UD, Jiang B, Gentsch JR, Glass RI. Oral rotavirus vaccines: how well will they work where they are needed most? J Infect Dis 2009; 200 (suppl 1): S39–S48. WHO. Rotavirus vaccines. MMWR Wkly Epidemiol Rec 2007; 82: 285–95. WHO. Meeting of the immunization Strategic Advisory Group of Experts, April 2009—conclusions and recommendations. MMWR Wkly Epidemiol Rec 2009; 84: 220–36. Madhi SA, Cunliffe NA, Steele D, et al. Effect of human rotavirus vaccine on severe diarrhea in African infants. N Engl J Med 2010; 362: 289–98. Zaman K, Anh DD, Victor JC, et al. Efficacy of pentavalent rotavirus vaccine against severe rotavirus gastroenteritis in infants in developing countries in Asia: a randomised, double-blind, placebo-controlled trial. Lancet 2010; published online Aug 6. DOI:10.1016/S0140-6736(10)60755-6. Armah GE, Sow SO, Breiman RF, et al. Efficacy of pentavalent rotavirus vaccine against severe rotavirus in infants in developing countries in subSaharan Africa: a randomised, double-blind, placebo-controlled trial. Lancet 2010; published online Aug 6. DOI:10.1016/S0140-6736(10)60889-6. UN Development Programme. Human Development Report 2009 http:// hdrstats.undp.org/en/indicators/91.html (accessed Jun 12, 2010). Vesikari T, Karvonen A, Prymula R, et al. Efficacy of human rotavirus vaccine against rotavirus gastroenteritis during the first 2 years of life in European infants: randomised, double-blind controlled study. Lancet 2007; 370: 1757–63. Vesikari T, Itzler R, Matson DO, et al. Efficacy of a pentavalent rotavirus vaccine in reducing rotavirus-associated health care utilization across three regions (11 countries). Int J Infect Dis 2007; 11 (suppl 2): S29–35. Phua KB, Lim FS, Lau YL, et al. Safety and efficacy of human rotavirus vaccine during the first 2 years of life in Asian infants: randomised, double-blind, controlled study. Vaccine 2009; 27: 5936–41. WHO. Rotavirus vaccines: an update. MMWR Wkly Epidemiol Rec 2009; 84: 533–38. Cohen D, Carter P. WHO and the pandemic flu “conspiracies”. BMJ 2010; 340: 1274–79. Wardlaw T, Salama P, Brocklehurst C, Chopra M, Mason E. Diarrhoea: why children are still dying and what can be done. Lancet 2010; 375: 870–72. Curns AT, Steiner CA, Barrett M, Hunter K, Wilson E, Parashar UD. Reduction in acute gastroenteritis hospitalizations among US children after introduction of rotavirus vaccine: analysis of hospital discharge data from 18 US states. J Infect Dis 2010; 201: 1617–24. Richardson V, Hernandez-Pichardo J, Quintanar-Solares M, et al. Effect of rotavirus vaccination on death from childhood diarrhea in Mexico. N Engl J Med 2010; 362: 299–305.
Childhood cancer survivors: stillbirth and neonatal death See Articles page 624
570
As an oncologist, one assumes that the benefit of survivorship outweighs the cost of side-effects, justifying complex multidisciplinary care, including the mainstay treatments of surgery, chemotherapy, and radiotherapy. Children with cancer do not typically make the choice, as adults do, of whether to receive treatment or not, and parents understandably want to provide their children with every possible option for cure. These options can include aggressive, novel treatment strategies with unknown potential consequences decades later. Suffering severe sequelae of cancer treatment might substantially affect long-term quality of life, including the ability to bear children.
In The Lancet today, Lisa Signorello and collaborators report a retrospective cohort analysis of the Childhood Cancer Survivor Study (CCSS), looking at the rates of stillbirth and neonatal death.1 Enrolled cohort members were diagnosed between 1970 and 1986 with leukaemia, lymphoma, sarcoma, CNS cancer, Wilms’ tumour, kidney cancer, or neuroblastoma. Whereas previous reports from the CCSS and others analysed the rates of acute ovarian failure,2,3 premature menopause,4 miscarriage,5 and babies with low birthweight5–7 in female survivors, today’s analysis includes both male and female cancer survivors and reports the risk of stillbirth (defined as a fetal death occurring after the 20th gestational week) and www.thelancet.com Vol 376 August 21, 2010
neonatal death (defined as death within the first 28 days after birth). After the 20th week of gestation, the fetus grows rapidly, necessitating rapid uterine expansion. By this stage in pregnancy, fertilisation, implantation, and early fetal development have all proceeded on schedule, indicating no impairment in conception, hormonal regulation, or presence of fatal genetic malformations. From Signorello and colleagues’ analysis, one might surmise that the most likely cause of stillbirth and neonatal death would be radiation-induced toxicity to the uterus. Not surprisingly, the most significant sequelae resulted from the use of radiation in premenarchal girls, whereas chemotherapy did not affect rates of stillbirth and neonatal death for either male or female survivors of childhood cancer in this cohort. Radiation effects on pregnancy outcome in general can be divided into direct effects (gonadal) or indirect effects (hormonal). Direct effects include radiation received by the testes, ovaries, or uterus, whereas indirect effects include cranial irradiation that can affect pituitary function.8 Signorello and co-workers found no effect of indirect pituitary irradiation in this cohort; the risk of stillbirth and neonatal death increased only in women having a direct effect of radiation on uterine or ovarian tissue. In view of the proximity of the uterus and ovary, these organs probably receive equivalent radiation doses. However, ovarian hormonal production sufficed in these survivors to allow ovulation, conception, and pregnancy to the 20th week, which indicates adequate ovarian function. Importantly, Signorello and collaborators found no effect of childhood cancer treatment on the ability of male survivors to contribute to a successful pregnancy, although the radiation doses received directly by the testes were lower than the uterine/ovarian doses in this cohort. Female survivors, however, had a significantly increased risk (relative risk 12·3) of having a stillbirth and neonatal death if they had received a radiation dose greater than 2·5 Gy before menarche, because of the direct effects of radiation to the uterus/ovaries. By contrast, postmenarchal girls treated with greater than 2·5 Gy had a relative risk of 0·2. A significant test for trend on stratified analysis for increasing dose was noted only in the premenarchal group. The reasons for the difference between premenarchal and postmenarchal sensitivity to radiation are unclear. In premenopausal women, premature ovarian failure results from radiation www.thelancet.com Vol 376 August 21, 2010
Science Photo Library
Comment
doses of about 15 Gy.9 Previous studies showed that girls treated with about 10 Gy were at high risk of acute ovarian failure, whereas those treated with about 5 Gy to the uterus were more likely to have offspring that were small for gestational age.2 However, in the CCSS, the physicist estimated the dose to an area thought to be the uterus/ovaries for a girl on the basis of her age. Therefore the radiation doses only roughly approximate the doses received. Consequently, this study cannot set a threshold limit or indicate a real dose-response of the ovaries or uterus, because of the inaccuracies in retrospective dose-estimation. We do not know from the data in this report whether survivors had ever had a successful pregnancy before or after the stillbirth or neonatal death. The Children’s Oncology Group (COG) recently attempted chemotherapy alone for girls with vaginal rhabdomyosarcoma to try to eliminate radiation; the trial was closed early because of an increase in the recurrence rate and a dose of 36 Gy was reinstituted in subsequent trials.10 Since the time of the CCSS patients’ radiation treatment in 1970–86, radiation has changed substantially, with advances in imaging, therapeutic targeting, and management of side-effects. In the 1990s, older machines and techniques were used, in a period that predated the integration of CT simulation in treatment planning. Over the past 20 years, highly conformal radiation-treatment plans generated with CT imaging have shifted radiation dose focally to the areas at highest risk of local recurrence. Additionally, the use of intensity-modulated radiation in the past 5 years has 571
Comment
resulted in extremely conformal treatment capabilities. Proton radiotherapy provides the most conformal approach with the lowest likelihood of radiation penetrating unintended regions of the body, and has been used for paediatric cancers, particularly CNS tumours, in centres with a proton facility.11 Children suffer the most severe long-term sequelae from radiation and are the most likely to live decades if cured. Therefore proton facilities should make treating children with cancer a high priority, including young women requiring abdominal or pelvic radiation that might scatter to affect the uterus or ovary. For premenopausal women, potential options for preservation of fertility should be discussed.12 Should uterine irradiation be unavoidable, parents should be informed that their daughter’s offspring might be at risk of stillbirth and neonatal death when their daughter reaches adulthood. For childhood cancer survivors, reproductive counselling and testing in a specialised centre to assess the feasibility and potential risks associated with a pregnancy should be discussed, and a plan implemented to ensure a successful outcome.
I declare that I have no conflicts of interest. 1
2
3
4
5
6 7
8
9
10
11
Akila N Viswanathan Gynecologic Radiation Oncology, Brigham and Women’s Hospital/Dana-Farber Cancer Center, Harvard Medical School, Boston, MA 02115, USA [email protected]
12
Signorello LB, Mulvihill JJ, Green DM, et al. Stillbirth and neonatal death in relation to radiation exposure before conception: a retrospective cohort study. Lancet 2010; 376: 624–30. Green DM, Kawashima T, Stovall M, et al. Fertility of female survivors of childhood cancer: a report from the childhood cancer survivor study. J Clin Oncol 2009; 27: 2677–85. Chemaitilly W, Mertens AC, Mitby P, et al. Acute ovarian failure in the childhood cancer survivor study. J Clin Endocrinol Metab 2006; 91: 1723–28. Sklar CA, Mertens AC, Mitby P, et al. Premature menopause in survivors of childhood cancer: a report from the childhood cancer survivor study. J Natl Cancer Inst 2006; 98: 890–96. Green DM, Whitton JA, Stovall M, et al. Pregnancy outcome of female survivors of childhood cancer: a report from the Childhood Cancer Survivor Study. Am J Obstet Gynecol 2002; 187: 1070–80. Chiarelli AM, Marrett LD, Darlington GA. Pregnancy outcomes in females after treatment for childhood cancer. Epidemiology 2000; 11: 161–66. Green DM, Peabody EM, Nan B, Peterson S, Kalapurakal JA, Breslow NE. Pregnancy outcome after treatment for Wilms tumor: a report from the National Wilms Tumor Study Group. J Clin Oncol 2002; 20: 2506–13. Wo JY, Viswanathan AN. Impact of radiotherapy on fertility, pregnancy, and neonatal outcomes in female cancer patients. Int J Radiat Oncol Biol Phys 2009; 73: 1304–12. Adjuvant Breast Cancer Trials Collaborative Group. Ovarian ablation or suppression in premenopausal early breast cancer: results from the international adjuvant breast cancer ovarian ablation or suppression randomized trial. J Natl Cancer Inst 2007; 99: 516–25. Walterhouse D. ARST0331 Study Committee progress report on vincristine, dactinomycin, and lower doses of cyclophosphamide with or without radiation therapy for patients with newly diagnosed low-risk embryonal/botryoid/spindle cell rhabdomyosarcoma. 2009 (available from the author). Merchant TE. Proton beam therapy in pediatric oncology. Cancer J 2009; 15: 298–305. Lobo RA. Potential options for preservation of fertility in women. N Engl J Med 2005; 353: 64–73.
The India HPV-vaccine suspension
Science Photo Library
In response to demands from advocacy groups, the Indian Government has suspended demonstration projects for HPV vaccination in Andhra Pradesh and Gujarat.1,2 The episode provides salutary lessons about how a lack of public confidence can amplify if not quickly addressed. The first lesson is timing. Too often, the response to citizen advocates who question health interventions, programmes, or studies, is too late. The April, 2010, memorandum3 from 68 Indian human rights and women’s groups, academics, and individuals sent to the Indian Minister of Health and Family Welfare should not have been a surprise. A similar memo had been sent 6 months earlier.4 The April memo called for the immediate halt of the demonstration projects until “concerns relating to safety, efficacy and cost effectiveness 572
of the planned interventions are re-evaluated”.3 It also demanded an inquiry into, and compensation for, the reported side-effects and alleged vaccine-related deaths of four girls who participated in the study. The deaths have since been investigated and confirmed as unrelated to the vaccine.2,5 Similarly, the memorandum4 sent on Oct 1, 2009, demanded that “all trials and studies be immediately brought to a halt till in an open forum questions relating to safety, efficacy and cost effectiveness of the planned intervention can be justified”. On Dec 28, 2009, the groups continued their unanswered pleas and convened a public meeting that generated more attention than the October memorandum.6 By February, GlaxoSmithKline, Merck, and PATH had issued responses on the safety of the vaccine and on the process of the study.7–9 www.thelancet.com Vol 376 August 21, 2010