Pediatric Normal Tissue Effects in the Clinic (PENTEC): An International Collaboration to Analyse Normal Tissue Radiation Dose-Volume Response Relationships for Paediatric Cancer Patients.

With advances in multimodality therapy, childhood cancer cure rates approach 80%. However, both radiotherapy and chemotherapy can cause debilitating or even fatal late adverse events that are critical to understand, mitigate or prevent. QUANTEC (Quantitative Analysis of Normal Tissue Effects in the Clinic) identified radiation dose constraints for normal tissues in adults and pointed out the uncertainties in those constraints. The range of adverse events seen in children is different from that in adults, in part due to the vulnerability/characteristics of radiation damage to developing tissues, and in part due to the typical body sites affected by childhood cancer that lead to collateral irradiation of somewhat different normal tissues and organs compared with adults. Many childhood cancer survivors have a long life expectancy and may develop treatment-induced secondary cancers and severe organ/tissue injury 10, 20 or more years after treatment. Collaborative long-term observational studies and clinical research programmes for survivors of paediatric and adolescent cancer provide adverse event data for follow-up periods exceeding 40 years. Data analysis is challenging due to the interaction between therapeutic and developmental variables, the lack of radiation dose-volume data and the fact that most childhood malignancies are managed with combined modality therapy. PENTEC (Pediatric Normal Tissue Effects in the Clinic) is a volunteer research collaboration of more than 150 physicians, medical physicists, mathematical modellers and epidemiologists organised into 18 organ-specific working groups conducting a critical review and synthesis of quantitative data from existing studies aiming to: (1) establish quantitative, evidence-based dose/volume/risk guidelines to inform radiation treatment planning and, in turn, improve outcomes after radiation therapy for childhood cancers; (2) explore the most relevant risk factors for toxicity, including developmental status; (3) describe specific physics and dosimetric issues relevant to paediatric radiotherapy; and (4) propose dose-volume outcome reporting standards for publications on childhood cancer therapy outcomes. The impact of other critical modifiers of normal tissue radiation damage, including chemotherapy, surgery, stem cell transplantation and underlying genetic predispositions are also considered. The aims of the PENTEC reports are to provide clinicians with an analysis of the best available data to make informed decisions regarding radiation therapy normal organ dose constraints for planning childhood cancer treatment, and to define future research priorities.

Balancing the benefits and harms of thyroid cancer surveillance in survivors of Childhood, adolescent and young adult cancer: Recommendations from the international Late Effects of Childhood Cancer Guideline Harmonization Group in collaboration with the PanCareSurFup Consortium.

Radiation exposure to the thyroid gland during treatment of childhood, adolescent and young adult cancer (CAYAC) may cause differentiated thyroid cancer (DTC). Surveillance recommendations for DTC vary considerably, causing uncertainty about optimum screening practices. The International Late Effects of Childhood Cancer Guideline Harmonization Group, in collaboration with the PanCareSurFup Consortium, developed consensus recommendations for thyroid cancer surveillance in CAYAC survivors. These recommendations were developed by an international multidisciplinary panel that included 33 experts in relevant medical specialties who used a consistent and transparent process. Recommendations were graded according to the strength of underlying evidence and potential benefit gained by early detection and appropriate management. Of the two available surveillance strategies, thyroid ultrasound and neck palpation, neither was shown to be superior. Consequently, a decision aid was formulated to guide the health care provider in counseling the survivor. The recommendations highlight the need for shared decision making regarding whether to undergo surveillance for DTC and in the choice of surveillance modality.

Early-stage mantle cell lymphoma: a retrospective analysis from the International Lymphoma Radiation Oncology Group (ILROG).

BACKGROUND: Mantle cell lymphoma (MCL) rarely presents as early-stage disease, but clinical observations suggest that patients who present with early-stage disease may have better outcomes than those with advanced-stage disease. PATIENTS AND METHODS: In this 13-institution study, we examined outcomes among 179 patients with early-stage (stage I or II) MCL in an attempt to identify prognostic factors that influence treatment selection and outcome. Variables examined included clinical characteristics, treatment modality, response to therapy, sites of failure, and survival. RESULTS: Patients were predominantly male (78%) with head and neck being the most common presenting sites (75%). Most failures occurred outside the original disease site (79%). Although the administration of radiation therapy, either alone or with chemotherapy, reduced the risk of local failure, it did not translate into an improved freedom from progression or overall survival (OS). The treatment outcomes were independent of treatment modality. The 10-year OS for patients treated with chemotherapy alone, chemo-radiation therapy and radiation therapy alone were 69%, 62%, and 74% (P = 0.79), and the 10-year freedom from progression were 46%, 43%, and 31% (P = 0.64), respectively. CONCLUSION: Given the excellent OS rates regardless of initial therapy in patients with early-stage MCL, de-intensified therapy to limit treatment-related toxicity is a reasonable approach.

Long-term survival among Hodgkin's lymphoma patients with gastrointestinal cancer: a population-based study.

BACKGROUND: The increased risk of gastrointestinal (GI) cancers after Hodgkin's lymphoma (HL) is well established. However, no large population-based study has described the actuarial survival after subsequent GI cancers in HL survivors (HL-GI). PATIENTS AND METHODS: For 209 patients with HL-GI cancers (105 colon, 35 stomach, 30 pancreas, 21 rectum, and 18 esophagus) and 484 165 patients with first primary GI cancers (GI-1), actuarial survival was compared, accounting for age, gender, race, GI cancer stage, radiation for HL, and other variables. RESULTS: Though survival of HL patients who developed localized stage colon cancer was similar to that of the GI-1 group, overall survival (OS) of HL patients with regional or distant stage colon cancer was reduced [hazard ratio, (HR)=1.46, P=0.01]. The HL survivors with regional or distant stage colon cancer in the transverse segment had an especially high risk of mortality (HR: 2.7, P=0.001 for OS). For localized stomach cancer, OS was inferior among HL survivors (HR=3.46, P=0.006). CONCLUSIONS: The HL patients who develop GI cancer experience significantly reduced survival compared with patients with a first primary GI cancer. Further research is needed to explain the inferior survival of HL patients and to define selection criteria for cancer screening in HL survivors.

The role of surveillance magnetic resonance imaging (MRI) scanning in detecting recurrent brain tumors in asymptomatic children.

BACKGROUND: There is controversy regarding the utility of routine surveillance scanning for asymptomatic children with brain tumors. Although the role of CT or magnetic resonance imaging (MRI) scanning in this setting has been examined in several studies, none have focused on children followed exclusively by MRI. The purpose of this study was to determine how often recurrent brain tumors are detected by routine MRI surveillance in asymptomatic children. METHODS: The medical records of all children with brain tumors treated at Children's Hospital at Strong from 1990-1999 were reviewed. Recurrence was defined as an increase in size of the tumor on MRI scan. Astrocytomas and gangliogliomas were classified as low-grade tumors; high-grade astrocytomas, medulloblastomas, and ependymomas were classified as high-grade tumors. RESULTS: Of the 112 evaluable children with brain tumors during this time period, 46 (41%) suffered an MRI-documented recurrence. Of these 46 patients, 13 (28%) had low-grade tumors and 33 (72%) had high-grade tumors. Twenty-seven of the 46 recurrences (59%) occurred in asymptomatic children. Ten of the 13 children (77%) with recurrent low-grade tumors were asymptomatic compared to 17 of 33 children (52%) with recurrent high-grade tumors (p = 0.18). The median survival from time of recurrence for the symptomatic children was seven months, while the median survival from time of recurrence for the asymptomatic children has not yet been reached (p = 0.025). When the analysis was confined to children with high-grade tumors, there was no difference in median survival from the time of recurrence for symptomatic versus asymptomatic children (5 mo. versus 7 mo.) (p = 0.25). The frequency of detection of recurrences by surveillance scanning in asymptomatic children was 4.2% (one recurrence detected per 24 surveillence MRI scans). CONCLUSION: The majority of recurrent brain tumors are detected by MRI surveillence in asymptomatic children. However, asymptomatic recurrences were detected in only a small proportion of surveillance scans and had no impact on survival in children with high-grade tumors.

The role of autocrine growth factors in radiation damage to the epiphyseal growth plate.

Radiation therapy plays an important role as part of the multimodality treatment for a number of childhood malignancies. Dose-limiting complications of radiotherapy include skeletal abnormalities and disturbances in skeletal development within the irradiated field. The current study was undertaken to investigate the molecular mechanisms involved in radiation-induced arrest of bone growth. Our hypotheses were: (1) Expression of autocrine growth factors that regulate chondrocyte proliferation is inhibited by radiation in a specific pattern; (2) the disparity in radiosensitivity of growth plate chondrocytes and epiphyseal chondrocytes is due to differential modulation of autocrine growth factor expression by radiation. Given the important role these cells play in skeletal growth and development, we examined the comparative effects of radiation on expression of specific mitogenic growth factors in growth plate chondrocytes. The effect of radiation on the expression of autocrine/paracrine growth factors was examined in an established avian model of epiphyseal growth plate maturation. Exposure of growth plate chondrocytes to radiation resulted in a specific pattern of biochemical and morphological alterations that were dependent on dose and were progressive over time. While radiation did not affect the mRNA expression of some of the autocrine and paracrine factors important in endochondral ossification (such as FGF2 and TGFB isoforms), it did lead to a decrease in the mRNA expression of PTHrP, a critically important mitogen in growth plate chondrocytes, and a dose-dependent decrease in the PTH/PTHrP receptor mRNA. Interestingly, PTHrP mRNA levels were not affected in irradiated epiphyseal chondrocytes, the main source of PTHrP. Given evidence indicating a role for intracellular calcium levels in regulating PTHrP expression, basal calcium levels in irradiated growth plate chondrocytes and epiphyseal chondrocytes were examined 24 h after treatment. While cytosolic calcium levels were significantly higher in irradiated growth plate chondrocytes, they were not significantly affected in irradiated epiphyseal chondrocytes. The importance of calcium in mediating radiation damage to growth plate chondrocytes was further demonstrated by the finding that the addition of 4.0 mM EGTA (a calcium chelator) to the cell cultures before irradiation prevented the decrease in PTHrP mRNA levels. Since PTHrP up-regulates BCL2 levels and prevents growth plate chondrocyte maturation and apoptosis, BCL2 mRNA levels were examined in irradiated growth plate chondrocytes, and a dose-dependent decrease was found. An increase in apoptosis was further confirmed by a fivefold increase in caspase 3 levels in irradiated growth plate chondrocytes. The results of the current study suggest that radiation may interfere with proliferation of growth plate chondrocytes in part by causing an increase in cytosolic calcium levels which in turn leads to a decrease in PTHrP mRNA. Growth plate chondrocyte PTHrP receptor mRNA expression is also inhibited by radiation, further decreasing PTHrP signaling. Despite subtle differences between the chick and mammalian growth plates, further studies should provide an enhanced understanding of the mechanism(s) of radiation injury to the growth plate, as well as possibilities for new therapeutic strategies to protect the growing skeleton from the detrimental effects of radiotherapy.

Subclinical thyroid disease after radiation therapy detected by radionuclide scanning.

PURPOSE: The actuarial risk for developing benign or malignant thyroid disease following radiation therapy (RT) is controversial, but may be as high as 50% at 20 years. An effective screening modality should be specific but not overly sensitive, a limitation of ultrasound. We questioned whether Technetium-99 m pertechnetate ((99m)Tc TcO(4)(-)) scanning could detect clinically significant disease in ostensibly disease-free cancer survivors. METHODS AND MATERIALS: Eligibility criteria included an interval of at least 5 years after RT to the cervical region, a thyroid gland that was normal to palpation, euthyroid status determined by clinical examination, free T4 and TSH. The 34 patients scanned included 16 children (<18 years old) and 18 adults at the time of RT, 16 females and 18 males. The mean age at RT was 20 years (range, 2.1-50.3 years), and the mean age at (99m)Tc TcO(4)-scanning was 33 years (range, 13.6-58 years), providing a mean interval of 13 years (range, 5.3-26.6 years). The mean RT dose to the thyroid was 36.4 Gy (range, 19.5-52.5). Thyroid scanning was performed with a 5 mCi dose of (99m)Tc TcO(4)(-) obtaining flow, immediate and delayed static, and pinhole collimator images. RESULTS: Seven patients (21.6%) had abnormal scans, and the percentage was higher among children (25%) and females (25%) compared to adults (16.7%) and males (16.7%), respectively. Two of 34 patients (5.9%) were discovered to have a thyroid cancer; histopathologies were papillary and follicular carcinoma. CONCLUSION: In this population of clinically normal cancer survivors who had been irradiated to the cervical region, subclinical thyroid disease, of potential clinical significance, was detected by (99m)Tc TcO(4)(-) in about 20%. Children may be more commonly affected. Although the cost effectiveness of screening will require a larger sample number, we propose a surveillance schema for this patient population.

Allogeneic bone marrow transplantation for children with acute leukemia: cytoreduction with fractionated total body irradiation, high-dose etoposide and cyclophosphamide.

Marrow-ablative chemo-radiotherapy followed by hematopoietic stem cell rescue from an allogeneic source improves outcomes for children with high-risk acute leukemia. The first effective pre-transplant preparative regimens consisted of high-dose cyclophosphamide (CY) and total body irradiation (TBI). Subsequent attempts have been made to improve leukemia-free survival, by adding other chemotherapy agents to these agents. In previous clinical studies of total body irradiation, etoposide, cyclophosphamide (TBI-VP-16-Cy) in adult allogeneic bone marrow transplantation, there has been a high incidence of severe regimen-related toxicity. In this study, we investigated the safety and efficacy of this combination in 41 children who received TBI (12-14 Gy), VP-16 (30 mg/kg), and CY (60 mg/kg x 2) and then either matched sibling or alternative donor transplants for acute leukemia. There was only one case of fatal regimen-related toxicity. The estimated 3-year event-free survival for patients with early or intermediate stage disease was 68% (53-88%). The estimated event-free survival of patients with advanced disease was 17% (5-59%). TBI-VP16-CY is safe in pediatric transplantation, and it has good efficacy for transplant recipients with less advanced disease. Bone Marrow Transplantation (2000) 25, 489-494.

Circulating basic fibroblast growth factor declines during Cy/TBI bone marrow transplantation.

Basic fibroblast growth factor (bFGF) inhibits radiation-induced apoptosis, and radioprotects haematopoietic, cartilage growth plate, pulmonary and gastrointestinal tissues. Conversely, chronic overexpression of bFGF may promote fibrosis. We measured the endogenous circulating bFGF in blood of patients undergoing conditioning TBI. Twenty-six patients with haematopoietic malignancies were conditioned with cyclophosphamide/TBI for allogeneic BMT. Daily blood samples were collected each morning prior to, during, and for several days after TBI. bFGF levels in plasma of normal volunteers are 0.8-26 pg/ml. bFGF was below detectability in 22%, 30% and 45% of patients pre-TBI, during TBI or post-TBI respectively. Mean circulating plasma levels of bFGF decreased from a median of 52 pg/ml pre-TBI to 26 pg/ml during TBI, and to 5 pg/ml post-TBI. Among the 26 patients, 13 had more than one non-detectable plasma bFGF level, an additional five had at least one non-detectable level, and only eight patients had detectable levels in all daily samples. Naturally high levels of bFGF were observed in some patients undergoing fractionated TBI. In contrast, as many as 79% of patients had low bFGF levels in one or more samples. The impact of endogenous bFGF on the tolerance of normal tissues to irradiation is unknown, and warrants further study.

Radiation-induced changes in bone perfusion and angiogenesis.

PURPOSE: To determine whether blood flow of bone is altered by limb irradiation and whether bFGF, an angiogenic cytokine, might alleviate any flow or growth abnormality resulting from 30 Gy single fraction irradiation. METHODS AND MATERIALS: C3H mice received whole right hind limb radiation at doses of 0 to 30 Gy. Additional groups received 30 Gy, and then beginning 1 or 5 weeks later received intravenous bFGF at a dose of 6 microg/mouse, twice a week for 4 weeks. Serial X-ray films were taken to measure the tibias. At 33 weeks, laser Doppler flow (LDF) measurements were made of both limbs. Cytokine measurements were made using ELISA and RNase protection. RESULTS: Bone growth was reduced following radiation in a dose dependent manner. bFGF improved bone growth after radiation even when begun 5 weeks after radiation, however, we detected no significant improvement in LDF of the irradiated bone or periosteum. Muscle tissue surrounding bone of the irradiated leg showed no increase in isoforms of TGFbeta, TNF, or IFN. There was also no difference in the circulating plasma TGFbeta1 in irradiated mice. In contrast, LDF increased significantly as a function of radiation dose in the nonirradiated tibia. Systemic delivery of bFGF appears to further enhance the increase in flow seen in the nonirradiated limb. CONCLUSION: Radiation induces a chronic antiangiogenic effect contributing to reduced limb growth. At 33 weeks the antiangiogenesis was not associated with local soft tissue elevations of TNF, IFN, or TGFbeta. Radiation toxicity to bone is alleviated by bFGF therapy suggesting that powerful locally-acting antiangiogenic mechanisms are involved. We postulate that the increased LDF of the contralateral tibia is due to circulating angiogenesis factors that are elevated to compensate for the radiation-induced antiangiogenesis.

Autotransplantation for relapsed or refractory Hodgkin's disease: long-term follow-up and analysis of prognostic factors.

Seventy consecutive patients with refractory or relapsed Hodgkin's disease who received high-dose chemotherapy followed by autologous stem cell rescue were analyzed to identify clinically relevant predictors of long-term event-free survival. High-dose therapy consisted primarily of carmustine (BCNU), etoposide, cytarabine and cyclophosphamide (BEAC). The 5-year Kaplan-Meier event-free survival (EFS) for the entire cohort was 32% (95% confidence interval; 18-45%) with a median follow-up of 3.6 years (range 7 months-7.6 years). The most significant predictor of improved survival was the presence of minimal disease (defined as all areas < or =2 cm) at the time of transplant: the 5 years EFS was 46 vs 10% for patients with bulky disease (P = 0.0002). Other independent predictors identified by step-wise regression analysis included the presence of non-refractory disease and the administration of post-transplant involved-field radiotherapy (XRT). Treatment-related mortality occurred in 13 of 70 patients: nine patients (13%) died within the first 100 days, mainly from cardiopulmonary toxicity. However, only one of 24 patients (4%) transplanted during the last 4.5 years died from early treatment-related complications. While high-dose therapy followed by autotransplantation led to long-term EFS of 50% for patients with favorable prognostic factors, a substantial proportion of patients relapsed, indicating that new therapeutic strategies are needed.

Treatment of multifocal lymphoma of bone with intensified ProMACE-CytaBOM chemotherapy and involved field radiotherapy.

Primary bone involvement is an unusual extranodal presentation of non-Hodgkin lymphoma (NHL). The optimal treatment for this entity has not been determined. While solitary bone lymphomas can be eradicated with local radiation in 50% of patients, distant relapses occur frequently, and the treatment of patients with multifocal osseous disease, or those presenting with associated soft tissue invasion or adenopathy is even less satisfactory. Over a 4-year period, nine patients with multifocal bone lymphoma were treated with intensified versions of the ProMACE-CytaBOM regimen and involved-field radiation. Seven patients had diffuse large cell histology and two patients had diffuse mixed type. Seven patients survived event-free at a median follow-up of 2.3 years (range .5-3.5). In most survivors, there was little or no change in the abnormal radiographic bone findings despite the clinical response to therapy. In one patient, magnetic resonance imaging (MRI) established that bone infarction rather than relapse of lymphoma was the cause of a new lytic bone lesion that developed during treatment.