Background
Survivors of Hodgkin lymphoma (HL) in childhood have an increased risk of subsequent malignant neoplasms (SMNs). Herein, the authors extended the follow‐up of a previously reported Late ...Effects Study Group cohort and identified patients at highest risk for SMNs to create evidence for risk‐based screening recommendations.
Methods
The standardized incidence ratio was calculated using rates from the Surveillance, Epidemiology, and End Results program as a reference. The risk of SMN was estimated using proportional subdistribution hazards regression. The cohort included 1136 patients who were diagnosed with HL before age 17 years between 1955 and 1986. The median length of follow‐up was 26.6 years.
Results
In 162 patients, a total of 196 solid SMNs (sSMNs) were identified. Compared with the general population, the cohort was found to be at a 14‐fold increased risk of developing an sSMN (95% confidence interval, 12.0‐fold to 16.3‐fold). The cumulative incidence of any sSMN was 26.4% at 40 years after a diagnosis of HL. Risk factors for breast cancer among females were an HL diagnosis between ages 10 years and 16 years and receipt of chest radiotherapy. Males treated with chest radiotherapy at age <10 years were found to be at highest risk of developing lung cancer. Survivors of HL who were treated with abdominal/pelvic radiotherapy and high‐dose alkylating agents were found to be at highest risk of developing colorectal cancer and females exposed to neck radiotherapy at age <10 years were at highest risk of thyroid cancer. By age 50 years, the cumulative incidence of breast, lung, colorectal, and thyroid cancer was 45.3%, 4.2%, 9.5%, and 17.3%, respectively, among those at highest risk.
Conclusions
Survivors of childhood HL remain at an increased risk of developing sSMNs. In the current study, subgroups of survivors of HL at highest risk of specific sSMNs were identified, and evidence for screening provided.
Additional follow‐up of the large cohort in the current study has demonstrated that survivors of childhood Hodgkin lymphoma remain at an increased risk of solid subsequent malignant neoplasms. Subgroups of survivors of Hodgkin lymphoma at highest risk of specific solid subsequent malignant neoplasms are identified, and evidence for screening in high‐risk subgroups is provided.
Regardless of how one defines survivorship, more than 10 million individuals in the United States have been treated for a malignant disease; about 250,000 were younger than 21 years of age at ...diagnosis. Thirty years ago, pediatric oncologists recognized that children with cancer might be cured by adding chemotherapy to surgery and radiation. Studies were then begun of complications that could reduce survival or the quality of survival, and that might be associated with previous therapy. The complications were termed late effects, and studies focused on patients who were likely to be cured, or less likely to succumb to the original cancer than they were to experience disabilities. Clinical trials tested whether changes in therapy to reduce complications could maintain the same excellent survival rates. During the last 20 years, articles detailing late effects and the relationship between therapy and outcome have been published. This article reviews the progress made in understanding the outcomes reported and the efforts made to improve the quality of long-term survival for children and adolescents. Several questions remain regarding the long-term complications of therapy. Clinicians need more data regarding the effects of aging to guide them in managing former patients. Caregivers and pediatric cancer survivors who are now adults seek the optimal venue in which to receive care as independent adults. In addition, medical oncologists need to determine whether the models for research and clinical care of survivors created in pediatric oncology can be applied to survivors of adult-onset cancer.
The Children's Oncology Group Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancers are risk-based, exposure-related clinical practice guidelines intended to ...promote earlier detection of and intervention for complications that may potentially arise as a result of treatment for pediatric malignancies. Developed through the collaborative efforts of the Children's Oncology Group Late Effects Committee, Nursing Discipline, and Patient Advocacy Committee, these guidelines represent a statement of consensus from a multidisciplinary panel of experts in the late effects of pediatric cancer treatment. The guidelines are both evidence-based (utilizing established associations between therapeutic exposures and late effects to identify high-risk categories) and grounded in the collective clinical experience of experts (matching the magnitude of risk with the intensity of screening recommendations). They are intended for use beginning 2 or more years following the completion of cancer therapy; however, they are not intended to provide guidance for follow-up of the survivor's primary disease. A complementary set of patient education materials ("Health Links") was developed to enhance follow-up care and broaden the application of the guidelines. The information provided in these guidelines is important for health care providers in the fields of pediatrics, oncology, internal medicine, family practice, and gynecology, as well as subspecialists in many fields. Implementation of these guidelines is intended to increase awareness of potential late effects and to standardize and enhance follow-up care provided to survivors of pediatric cancer throughout the lifespan. The Guidelines, and related Health Links, can be downloaded in their entirety at www.survivorshipguidelines.org.
We present an update of a previously reported Late Effects Study Group cohort of 1,380 children with Hodgkin's disease (HD) diagnosed between 1955 and 1986 in patients aged 16 years or younger. We ...describe the pattern and incidence of subsequent neoplasms (SNs) occurring with extended follow-up.
Median age at diagnosis of HD was 11.7 years (range, 0.3 to 16.9 years) and at last follow-up was 27.8 years. Median length of follow-up was 17.0 years.
An additional 103 SNs were ascertained (total SNs = 212). The cohort was at an 18.5-fold increased risk of developing SNs compared with the general population (standardized incidence ratio SIR, 18.5, 95% CI, 15.6 to 21.7). The cumulative incidence of any second malignancy was 10.6% at 20 years, increasing to 26.3% at 30 years; and of solid malignancies was 7.3% at 20 years, increasing to 23.5% at 30 years. Breast cancer was the most common solid malignancy (SIR, 56.7). Other commonly occurring solid malignancies included thyroid cancer (SIR, 36.4), bone tumors (SIR, 37.1), and colorectal (SIR, 36.4), lung (SIR, 27.3), and gastric cancers (SIR, 63.9). Risk factors for solid tumors included young age at HD and radiation-based therapy. Thirty-two patients developed third neoplasms, with the cumulative incidence approaching 21% at 10 years from diagnosis of second malignancy.
Additional follow-up of this large cohort of HD survivors documents an increasing occurrence of known radiation-associated solid tumors, (breast and thyroid cancers), as well as emergence of epithelial neoplasms common in adults, (colon and lung cancers) at a younger age than expected in the general population, necessitating ongoing surveillance of this high risk population.
To determine the risk of subsequent carcinomas other than breast, thyroid, and skin, and to identify factors that influence the risk among survivors of childhood cancer.
Subsequent malignant neoplasm ...history was determined in 13,136 participants (surviving > or = 5 years postmalignancy, diagnosed from 1970 to 1986 at age < 21 years) of the Childhood Cancer Survivor Study to calculate standardized incidence ratios (SIRs), using Surveillance, Epidemiology, and End Results data.
In 71 individuals, 71 carcinomas were diagnosed at a median age of 27 years and a median elapsed time of 15 years in the genitourinary system (35%), head and neck area (32%), gastrointestinal tract (23%), and other sites (10%). Fifty-nine patients (83%) had received radiotherapy, and 42 (59%) developed a second malignant neoplasm in a previous radiotherapy field. Risk was significantly elevated following all childhood diagnoses except CNS neoplasms, and was highest following neuroblastoma (SIR = 24.2) and soft tissue sarcoma (SIR = 6.2). Survivors of neuroblastoma had a 329-fold increased risk of renal cell carcinomas; survivors of Hodgkin's lymphoma had a 4.5-fold increased risk of gastrointestinal carcinomas. Significantly elevated risk of head and neck carcinoma occurred in survivors of soft tissue sarcoma (SIR = 22.6), neuroblastoma (SIR = 20.9), and leukemia (SIR = 20.9).
Young survivors of childhood cancers are at increased risk of developing subsequent carcinomas typical of later adulthood, underscoring the importance of long-term follow-up and risk-based screening. Follow-up of the cohort is ongoing to determine lifetime risk and delineate individual characteristics that contribute to risk.
Childhood cancer survivors often experience complications related to cancer and its treatment that may adversely affect quality of life and increase the risk of premature death. The purpose of this ...manuscript is to review how data derived from Childhood Cancer Survivor Study (CCSS) investigations have facilitated identification of childhood cancer survivor populations at high risk for specific organ toxicity and secondary carcinogenesis and how this has informed clinical screening practices. Articles previously published that used the resource of the CCSS to identify risk factors for specific organ toxicity and subsequent cancers were reviewed and results summarized. CCSS investigations have characterized specific groups to be at highest risk of morbidity related to endocrine and reproductive dysfunction, pulmonary toxicity, cerebrovascular injury, neurologic and neurosensory sequelae, and subsequent neoplasms. Factors influencing risk for specific outcomes related to the individual survivor (eg, sex, race/ethnicity, age at diagnosis, attained age), sociodemographic status (eg, education, household income, health insurance) and cancer history (eg, diagnosis, treatment, time from diagnosis) have been consistently identified. These CCSS investigations that clarify risk for treatment complications related to specific treatment modalities, cumulative dose exposures, and sociodemographic factors identify profiles of survivors at high risk for cancer-related morbidity who deserve heightened surveillance to optimize outcomes after treatment for childhood cancer.
Women treated with therapeutic chest radiation may develop breast cancer.
To summarize breast cancer risk and breast cancer surveillance in women after chest radiation for pediatric or young adult ...cancer.
Studies from MEDLINE, EMBASE, the Cochrane Library, and CINAHL (1966 to December 2008).
Articles were selected to answer any of 3 questions: What is the incidence and excess risk for breast cancer in women after chest radiation for pediatric or young adult cancer? For these women, are the clinical characteristics of breast cancer and the outcomes after therapy different from those of women with sporadic breast cancer in the general population? What are the potential benefits and harms associated with breast cancer surveillance among women exposed to chest radiation?
Three investigators independently extracted data and assessed study quality.
Standardized incidence ratios ranged from 13.3 to 55.5; cumulative incidence of breast cancer by age 40 to 45 years ranged from 13% to 20%. Risk for breast cancer increased linearly with chest radiation dose. Available limited evidence suggests that the characteristics of breast cancer in these women and the outcomes after diagnosis are similar to those of women in the general population; mammography can detect breast cancer, although sensitivity is limited.
The quality of evidence for key questions 2 and 3 is limited by substantial study heterogeneity, variation in study design, and small sample size.
Women treated with chest radiation have a substantially elevated risk for breast cancer at a young age, which does not seem to plateau. In this high-risk population, there seems to be a benefit associated with early detection. Further research is required to better define the harms and benefits of lifelong surveillance.
To evaluate chemoreduction (CRD) for group E retinoblastoma.
Retrospective, comparative case series.
Seventy-six eyes of 56 patients with group E retinoblastoma were treated with CRD alone or CRD ...plus low-dose prophylactic external beam radiotherapy (CRD+P-EBR). The CRD included vincristine, etoposide, and carboplatin (6 cycles). The P-EBR was given routinely 2 months after completion of CRD at a suggested dose of 2600 cGy. Therapeutic EBR (T-EBR) was only given at the time of extensive tumor recurrence at a suggested dose of 3800 cGy.
Retrospective chart review.
Globe salvage.
Of the 76 eyes, 64 received CRD alone and 12 received CRD+P-EBR. At the 2-year follow-up, globe salvage was achieved in 29 (53%) of 55 eyes in the CRD group and in 10 (91%) of 11 eyes in the CRD+P-EBR group. At 5 years, globe salvage was achieved in 20 (48%) of 42 eyes in the CRD group and in 4 (80%) of 5 eyes in the CRD+P-EBR group (P=0.347). Of the 64 eyes in the CRD group, 16 (25%) were salvaged with CRD alone and 13 (20%) with CRD+T-EBR, whereas 22 (34%) were enucleated after CRD alone and 13 (20%) were enucleated after CRD+T-EBR. Of the 12 eyes in the CRD+P-EBR group, 10 (83%) were salvaged with CRD+P-EBR, whereas 2 (17%) were enucleated and none required T-EBR. The median dose for T-EBR was 3800 cGy, and that for P-EBR was 2600 cGy. Eyes treated with CRD+P-EBR showed significantly less recurrence, leading to less chance of enucleation or therapeutic radiotherapy than that for CRD alone (P<0.001). Visual acuity was 20/100 or better or fix and follow in 9 (32%) of 28 salvaged eyes in the CRD group and in 4 (40%) of 10 in the CRD+P-EBR group. At 5 years, there were no patients in either group with metastasis of pinealoblastoma or who had died. In one patient in the CRD group, a second cancer developed.
Group E retinoblastoma managed with CRD+P-EBR showed significantly less need for enucleation or therapeutic radiotherapy than eyes treated with CRD alone. These findings merit further study and consideration.
Survivors of malignant disease in childhood who have had radiotherapy to the head, neck, or upper thorax have an increased risk of subsequent primary thyroid cancer, but the magnitude of risk over ...the therapeutic dose range has not been well established. We aimed to quantify the long-term risk of thyroid cancer after radiotherapy and chemotherapy.
In a nested case-control study, 69 cases with pathologically confirmed thyroid cancer and 265 matched controls without thyroid cancer were identified from 14 054 5-year survivors of cancer during childhood from the Childhood Cancer Survivor Study cohort. Childhood cancers were diagnosed between 1970 and 1986 with cohort follow-up to 2000.
Risk of thyroid cancer increased with radiation doses up to 20–29 Gy (odds ratio 9·8 95% CI 3·2–34·8). At doses greater than 30 Gy, a fall in the dose-response relation was seen. Both the increased and decreased risks were more pronounced in those diagnosed with a first primary malignant disease before age 10 years than in those older than 10 years. Furthermore, the fall in risk remained when those diagnosed with Hodgkin's lymphoma were excluded. Chemotherapy for the first cancer was not associated with thyroid-cancer risk, and it did not modify the effect of radiotherapy. 29 (42%) cases had a first diagnosis of Hodgkin's lymphoma compared with 49 (19%) controls. 11 (42%) of those who had Hodgkin's lymphoma had subsequent thyroid cancers smaller than 1 cm compared with six (17%) of those who had other types of childhood cancer (p=0·07).
The reduction in radiation dose-response for risk of thyroid cancer after childhood exposure to thyroid doses higher than 30 Gy is consistent with a cell-killing effect. Standard long-term follow-up of patients who have had Hodgkin's lymphoma for detection of thyroid cancer should also be undertaken for survivors of any cancer during childhood who received radiotherapy to the thorax or head and neck region.
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