童年胰腺放疗与成年罹患糖尿病相关

《柳叶刀-肿瘤学》(The Lancet Oncology)8月23日在线发表的一项纳入2500多例儿童期癌症存活者的回顾性队列研究显示，儿童期胰腺放疗可增加成年后发生糖尿病的风险(Lancet Oncology 2012 Aug. 23 [doi:10/1016/S1470-2045(12)70323-6])。

Florent de Vathaire博士

在这项研究中，法国古斯塔夫•鲁西研究所INSERM流行病学和公共卫生中心的Florent de Vathaire博士及其同事对1986年之前法国和英国8个中心收治并平均随访30年的儿童期癌症(包括实体癌或淋巴瘤，但不包括白血病)存活者进行了调查。采用数学模型、病历资料、设备和治疗技术相关信息及诊断时所用的指南来估计胰尾、胰体和胰头的放射剂量。

在发回调查问卷的2520例儿童期癌症存活者中，1632例曾在儿童期接受放疗，65例发生可证实的糖尿病，多数可能为2型糖尿病。儿童期间接受放疗者45岁时的糖尿病累计发病率显著高于未接受放疗者(6.6% vs. 2.3%)，并且儿童期间胰尾放疗剂量≥10 Gy者的累计糖尿病发病率高达16.3%。

在校正体重指数后，仍观察到这种关联(在平均放疗剂量24.2 Gy水平，相对风险为12.6)。这种风险无性别差异，随剂量增加(至20~29 Gy)而显著增加，并在较高剂量时趋于稳定。胰腺其他部位的放疗与此后糖尿病的发生之间无关联。

值得注意的是，在739例罹患癌症时年龄小于2岁的患者中，有3%被诊断出糖尿病。并且放疗剂量每增加1 Gy，这些患者的糖尿病风险比罹患癌症时年龄较大者升高得更快。此外，根据儿童期癌症类型的不同，糖尿病发生率也有明显差异：肾母细胞瘤存活者45岁时的糖尿病累计发病率高达14.7%，而其他癌症存活者为3.1%。尽管这种差异或可归因于放疗时年龄和胰尾放疗剂量的差异，但胰尾大剂量放疗的患者主要为肾母细胞瘤患者，因此难以确定真正的原因。

研究显示化疗对糖尿病风险无显著影响，而且总体上化疗也不改变放疗的剂量效应。

尽管该研究存在一些局限性，如纳入的存活者比例不高及难以估计放射剂量，但研究观察到的胰尾放射剂量的特异性或可归因于胰尾的胰岛水平高于胰体和胰头。

该研究凸显了长期随访儿童期癌症存活者的重要性，并且在对胰腺进行放疗时应尽可能使用最低的放射剂量。

该研究获法国抗癌联盟等机构资助。研究者声明无经济利益冲突。


在郎格罕细胞岛较集中的胰尾部接受较大剂量放疗的患者更易罹患糖尿病

随刊述评：又一块拼图

纽约纪念斯隆-凯特琳癌症中心的Kevin C. Oeffinger博士和Charles A. Sklar博士指出，该研究表明胰尾放疗与后续糖尿病的发生之间存在量效关系，进一步加深了对于癌症治疗影响此后糖尿病发生率的了解。此外，内脏肥胖和胰岛素抵抗也在肿瘤的发生中起着重要作用。未来有必要开展进一步研究，探讨腹部放疗后糖尿病发生的潜在机制。了解这些机制将有助于开发靶向治疗，进而降低此类患者发生糖尿病的风险(Lancet Oncology 2012 Aug. 23 [doi:10/1016/S1470-2045(12)70340-6])。

Oeffinger博士和Sklar博士声明从国立卫生研究院获得研究资金，但无经济利益冲突。

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By: SHARON WORCESTER, Clinical Endocrinology News Digital Network

Radiation therapy to the pancreas during childhood confers an increased risk of diabetes during adulthood, according to findings from a retrospective cohort study involving more than 2,500 survivors of childhood cancer.

Specifically, a dose-response relationship was seen between radiation to the tail of the pancreas – where the islets of Langerhans are concentrated – and subsequent diabetes development, reported Florent de Vathaire, Ph.D., of the Center for Epidemiology and Public Health of INSERM at Gustave Roussy Institute in Villejuif, France, and colleagues.

The findings are published online in the Aug. 23 issue of The Lancet Oncology.

Of 2,520 survivors of childhood cancer who returned a survey for the study, 1,632 received radiotherapy during childhood, and 65 had verifiable diabetes, which the authors said was likely type II in most cases. The cumulative incidence of diabetes at age 45 years was significantly greater in those who received radiation therapy (6.6% vs. 2.3%), and those who received radiotherapy to the tail of the pancreas at a dose of 10 Gy or more during childhood were significantly more likely to develop diabetes than were those who did not receive radiotherapy (cumulative incidence of 16.3%).

This relationship persisted even after adjustment for body-mass index (relative risk of 12.6 at a mean radiation dose of 24.2 Gy), the investigators said.

The risk, which was similar in men and women, increased strongly in a dose-dependent fashion up to 20-29 Gy, reaching a plateau at higher doses, they noted (Lancet Oncology 2012 Aug. 23 [doi:10/1016/S1470-2045(12)70323-6]).

No association was found between radiotherapy to other parts of the pancreas and subsequent diabetes development.

Of note, diabetes was diagnosed in 3% of 739 patients who were younger than age 2 years at diagnosis, and the increase per Gy was higher in these patients, compared with older patients. Also, diabetes incidence strongly varied based on the type of childhood cancer, with a cumulative incidence of diabetes at age 45 of 14.7% in survivors of nephroblastoma, compared with 3.1% in survivors of other cancers.

Although these variations by cancer type were explained by differences in age at radiotherapy and by radiation dose to the pancreas tail, patients with nephroblastoma comprised the majority of patients who received high radiation doses to the tail of the pancreas, which raises uncertainty about the attribution of cause, the investigators noted.

No evidence of a significant role for chemotherapy in the calculation of diabetes risk or for chemotherapy overall acting as a modifier of the dose-response for radiation was found in this study, they said.

Survivors who had more radiation to the tail of the pancreas – where the islets of Langerhans are concentrated – were significantly more likely to develop diabetes.

For the study, the investigators surveyed survivors of childhood cancer – including solid cancer or lymphoma, but excluding leukemia – who were treated in eight centers in France and the United Kingdom before 1986 and followed for a mean of 30 years. Radiation doses to the tail, body, and head of the pancreas were estimated using mathematical modeling, details from the patients’ records, and information about equipment, treatment techniques, and guideline used at the time of treatment.

Though limited by factors such as the high proportion of survivors not included in the analysis and inherent difficulties with estimating radiation dose, the findings of the specificity of the radiation dose to the tail of the pancreas is "plausibly explained by the fact that the islet of Langerhans concentration is higher in the tail than in the body and head of the pancreas," they noted.

"Our investigation emphasizes the importance of long-term follow-up of childhood cancer survivors; almost no diabetes mellitus was seen in our cohort, or those of others, before 20 years of follow-up," they said, noting that the findings also underscore the need for contouring the pancreas when planning radiation therapy to achieve the lowest possible radiation dose to the organ.

This study was funded by Ligue National Contre le Cancer, Institut de Recherche en Santé Publique, Programme Hospitalier de Recherche Clinique, Institut National du Cancer, Agence Française de Sécurité Sanitaire et des Produits de Santé and Fondation Pfizer pour la santé de l’enfant et de l’adolescent. The authors reported having no conflicts of interest.

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Another Piece in the Puzzle

The findings of Dr. de Vathaire and colleagues substantially extend the current understanding of the late effect of cancer therapy on diabetes development, and have important clinical implications, Dr. Kevin C. Oeffinger and Dr. Charles A. Sklar wrote in an accompanying editorial.

The investigators demonstrate a dose-response relationship between radiation to the tail of the pancreas and subsequent development of diabetes, and since radiation remains an integral part of therapy for many children with Wilms’ tumor or neuroblastoma, concerns about diabetes – a major risk factor for all-cause cardiovascular mortality – are valid in these patients (Lancet Oncology 2012 Aug. 23 [doi:10/1016/S1470-2045(12)70340-6]).

"Additionally, visceral adiposity and insulin resistance are important in tumorigenesis," they said, noting that further study is needed to elucidate the mechanisms underlying diabetes after abdominal radiation.

"Understanding these mechanisms will, hopefully, result in the development of targeted interventions that will lead to a reduction in risk in this population."

DR. OEFFINGER and DR. SKLAR are with Memorial Sloan-Kettering Cancer Center, New York. They reported receiving research grants from the National Institutes of Health, but had no conflicts of interest to report.