Breast cancer risk following Hodgkin lymphoma radiotherapy in relation to menstrual and reproductive factors.

BACKGROUND: Women treated with supradiaphragmatic radiotherapy (sRT) for Hodgkin lymphoma (HL) at young ages have a substantially increased breast cancer risk. Little is known about how menarcheal and reproductive factors modify this risk. METHODS: We examined the effects of menarcheal age, pregnancy, and menopausal age on breast cancer risk following sRT in case-control data from questionnaires completed by 2497 women from a cohort of 5002 treated with sRT for HL at ages <36 during 1956-2003. RESULTS: Two-hundred and sixty women had been diagnosed with breast cancer. Breast cancer risk was significantly increased in patients treated within 6 months of menarche (odds ratio (OR) 5.52, 95% confidence interval (CI) (1.97-15.46)), and increased significantly with proximity of sRT to menarche (Ptrend<0.001). It was greatest when sRT was close to a late menarche, but based on small numbers and needing reexamination elsewhere. Risk was not significantly affected by full-term pregnancies before or after treatment. Risk was significantly reduced by early menopause (OR 0.55, 95% CI (0.35-0.85)), and increased with number of premenopausal years after treatment (Ptrend=0.003). CONCLUSION: In summary, this paper shows for the first time that sRT close to menarche substantially increases breast cancer risk. Careful consideration should be given to follow-up of these women, and to measures that might reduce their future breast cancer risk.

The management of children with lymphomas.

Lymphomas account for 10-15% of all paediatric malignancies. They are highly curable with 5 year survival rates of up to 95% for Hodgkin lymphoma and 82% for non-Hodgkin lymphoma. These excellent results have focused recent attention on reducing the burden of treatment-related morbidity while maintaining the excellent outcomes. Lymphomas are highly radiosensitive and radiotherapy was used historically in the treatment of both paediatric Hodgkin and non-Hodgkin lymphomas. As the late effects of radiotherapy, including second tumours, were recognised, successive protocols seeking to minimise late effects were developed that reduced the use of radiotherapy. Current treatment protocols for non-Hodgkin lymphoma are chemotherapy based and radiotherapy has been virtually eliminated. In contrast, current paediatric Hodgkin lymphoma protocols continue to use radiotherapy as part of combined modality treatment, targeted according to risk factors and response and at the minimum effective dose. This article reviews the treatment of Hodgkin lymphoma in children with particular emphasis on the role of radiotherapy.

Craniospinal irradiation using a forward planned segmented field technique.

Craniospinal irradiation is technically demanding due to the complex shape of the planning target volume (PTV). Radiotherapy treatment techniques have evolved over time as imaging and radiotherapy treatment technology have improved. However, most are variations on a class solution utilizing a prone patient position with two shaped lateral cranial portals and a matched posterior spinal portal with moving junctions. Major areas of difficulty remain with the accurate definition of the PTV and achieving a homogeneous dose within it, especially at the junctions. We describe a three-dimensionally (3D) planned craniospinal radiation technique that permits rapid image acquisition with reduced localization time, simplified spinal PTV definition and standardized cranial PTV definition. Improved dose homogeneity within the PTV is achieved by use of a segmented "field-in-field" technique (forward planned intensity-modulated radiotherapy (IMRT)) in place of customized compensators. This has negated the requirement for constructing physical compensators. Autosequencing for field delivery enables the junction to be "moved" during a single fraction and reduces the overall treatment time, an important consideration when treating very young patients.

The addition of oral idarubicin to a chlorambucil/dexamethasone combination has a significant impact on time to treatment failure but none on overall survival in patients with low grade non-Hodgkin's lymphoma: Results of the Scotland and Newcastle Lymphoma Group randomized NHL VIII trial.

Two hundred untreated patients with low grade NHL (KIEL), including 155 follicular NHL, were randomized to six courses of treatment with chlorambucil 20 mg m-2 for 3 days and dexamethasone 4 mg bd for 5 days (CD) vs the same regimen plus oral idarubicin 10 mg m-2 for 3 days (CID). Responding patients could be randomized to no further treatment or maintenance treatment for up to 36 months with alpha interferon. Complete remissions/CRu were more frequent in the CID arm (35% vs 24%) but the overall response rate was similar; 87/91 (96%) vs 86/92 (93%). Overall survival (OS) did not differ between the two arms. Time to treatment failure (TTTF) was prolonged in the CID arm, p = 0.03; median time 28 vs 19 months. TTTF for the B-cell follicular group alone was for CID (77 patients) 33 months vs 18 months for CD (78 patients). Interferon conferred no apparent benefit. The Follicular Lymphoma International Prognostic Index (FLIPI) is confirmed as a good predictor of risk groups including a group of 23% with shorter survival. The addition of the oral anthracycline, idarubicin, led to a significant improvement in TTTF with low toxicity. The use of radiotherapy in this sub-group may have contributed to this result. CID is a potential for combination with antibody therapy particularly in older patient groups.

Constrictive pericarditis post allogeneic bone marrow transplant for Philadelphia-positive acute lymphoblastic leukaemia.

We describe two cases of severe constrictive pericarditis arising after allogeneic BMT conditioning involving total body irradiation and melphalan to treat Philadelphia-chromosome positive ALL. Both patients required pericardectomy, resulting in marked improvement in ventricular filling. However, a degree of right-sided cardiac failure persisted in both patients secondary to restrictive cardiomyopathy. Constrictive pericarditis has not been previously described after BMT, but has been observed following thoracic radiotherapy for malignancy, usually involving a substantially higher radiation dose. Pericardial constriction and restrictive cardiomyopathy should be considered as causes of breathlessness and/or oedema occurring late after BMT. Bone Marrow Transplantation (2000) 25, 571-573.

MRI appearances of the axilla in treated breast cancer.

Differentiation between recurrent axillary disease and changes due to radiotherapy or surgery has major implications for management in patients following breast cancer treatment, but clinical examination of the axilla may be difficult. This study was undertaken to correlate the MRI appearances of the axilla following breast cancer treatment with clinical outcome. 74 women with treated breast cancer were evaluated by MRI (0.5 T) and the appearances defined by consensus. Outcome was assessed by long-term clinical follow-up. 62 women had symptoms related to the axilla while 12 were scanned to stage the axilla. None of the axillary staging group had abnormal MRI appearances and none of these subsequently developed recurrence. The 62 symptomatic women were subdivided according to MRI appearances. 22 had normal axillary appearances, 18 had an axillary mass and 22 women had abnormal axillary appearances (rated mild, moderate and severe) in the absence of a mass. Normal axillary appearances on MRI excluded recurrent disease as the cause of symptoms with a specificity of 94.7% and a positive predictive value (PPV) of 95.5%. The presence of an axillary mass was commonly but not exclusively due to recurrent disease (sensitivity 68.4%, specificity 88.4%, PPV 72.2%). Sensitivity for diagnosis of axillary recurrence was increased to 89.5% with a specificity of 76.7% if the criteria for recurrent disease were taken as either the presence of an axillary mass or severe axillary changes in the absence of a mass lesion.

Novel solutions to the problems encountered in electron irradiation to the surface of the head.

A novel treatment for two patients with mycosis fungoides involving all or most of the skin surface of the head is described using large overlapping low energy electron beams. Shielding of previously treated and uninvolved areas was achieved by encapsulating cerrobend within a thermoplastic shell in one patient. In the other patient, GE Saturnes unique asymmetric electron field definition facility was used. Satisfactory dose uniformity was demonstrated by the computation of dose distributions on the full summed electron pencil beam model on the Target Series 2 treatment planning system. Verification of the calculated dose homogeneity was confirmed with lithium fluoride (TLD-100) thermoluminescent dosimetry. The relatively simple treatment set-up was accomplished easily on a routine basis and was well tolerated by the patients, both of whom have been in complete remission since their treatment.

Brachial plexus neuropathy following mantle radiotherapy.

We report two cases of presumed radiation-induced brachial plexus neuropathy in patients with lymphoma who were treated with standard mantle radiotherapy to a dose of 40 Gy in 20 fractions. Radiation-induced brachial plexopathy has not previously been reported following mantle irradiation at this dose. Both patients received chemotherapy in relapse. We postulate three possible causes: enhanced radiation sensitivity; an interaction between the chemotherapy and the radiotherapy; or an increased dose in axilla owing to a smaller separation at that point.

Outcome and toxicity of an Ifosfamide-based soft tissue sarcoma treatment protocol in children. The importance of local therapy.

Background. Although the survival of children with soft tissue sarcoma (STS) has improved considerably, the outcome of patients with metastatic disease, and those with primary tumours of the extremities or parameningeal sites remains disappointing. We describe the clinical outcome of an ifosfamide-based regimen with local therapy directed only to children who failed to achieve a complete response to initial chemotherapy.Patients and Methods. Twenty-one children with STS (16 rhabdomyosarcoma) who presented with unresectable tumours were treated with five courses of ifosfamide (9 g/m(2)) and etoposide (600 mgm(2)). Patients who did not achieve a complete response then received local therapy. Chemotherapy with ifosfamide combined with etoposide, vincristine (1.5 mg/m(2) and doxorubicin (60 mg/m(2)) or vincristine and actinomycin D (1.5 mg/m(2)) was continued for one year.Results and Discussion. Objective responses to five courses of ifosfamide and etoposide were seen in all patients. Disease free survival (DFS) at a median follow up of 59 months was 57% (95% CI 29-75%). The DFS of children who received local therapy was 89% compared with 33% in those who received chemotherapy alone (p=0.027). Locoregional recurrences did not occur in children who received radiotherapy to the site of the primary tumour. Ifosfamide-based chemotherapy does not reduce the incidence of loco-regional recurrence in children who do not receive local therapy.

CHOP-based chemotherapy is as effective as alternating PEEC/CHOP chemotherapy in a randomised trial in high-grade non-Hodgkin's lymphoma. Scotland and Newcastle Lymphoma Group.

The aim of this study was to test whether survival for patients with high-grade non-Hodgkin's lymphoma (NHL) can be improved with a non-cross-resistant regimen as compared to a CHOP-based regimen. This is a multicentre study comprising 325 adult patients, median age 58 years, with high-grade non-Hodgkin's lymphoma: patients of any age and performance status were eligible provided they were able to receive the drugs in the regimens. Patients were randomised to either B-CHOP-M (bleomycin, cyclophosphamide, doxorubicin, vincristine, prednisolone and methotrexate) or PEEC-M (methylprednisolone, vindesine, etoposide, chlorambucil and methotrexate) alternating with B-CHOP-M. At a median follow-up of 9 years, there was no significant difference in overall survival or disease-free survival between the two arms. Toxicities for the two regimens were equivalent. This study confirms that for relatively unselected patients with high-grade non-Hodgkin's lymphoma, an alternating multidrug regimen does not improve upon the results obtained with B-CHOP-M.

Pineal tumours in the north of England 1968-93.

The records of 38 patients under 25 years of age presenting with pineal tumours between 1968 and 1993, identified from the Northern Region Children's and Young Adults' Malignant Disease Registry, were analysed retrospectively with regards to clinical presentation, diagnostic approach, treatment strategy, and outcome. The overall five year survival was 45%. Fifteen patients had a histological diagnosis: six with germinomas, three with teratomas, three with astrocytomas, and three with pinealoblastomas. One patient had a definitive diagnosis of teratoma made on the basis of raised tumour markers (alpha fetoprotein). Treatment consisted of surgery (87%) (ventriculoperitoneal or atrial shunt and/or biopsy), and/or radiotherapy (82%), and/or chemotherapy (26%). Those patients with a tissue diagnosis appeared to have a more favourable outcome, especially after 1976 when treatment was determined by tumour type (five year survival for those with a tissue diagnosis was 91% v 51% for those without, 95% confidence intervals 74 to 100% and 26 to 75%). This study suggests that tissue diagnosis allows more appropriate treatment to be delivered for children with pineal tumours resulting in improved survival. Referral to a centre with neurosurgery, radiotherapy, neuropathology, and paediatric oncology collaboration is essential.

Are moving junctions in craniospinal irradiation for medulloblastoma really necessary?

The case notes of 35 patients treated for medulloblastoma using a standard technique of craniospinal irradiation (CSI) from 1978 to 1992 were reviewed. Two large opposed lateral fields to the whole brain and an orthogonal posterior spinal field were used. The position of the junction between the fields was constant throughout treatment with no feathering and no gap. We present our results, review the literature and discuss the need for feathering. The junction between the cranial and spinal fields produces an area of dose inhomogeneity but the clinical significance of this and the effect of feathering is uncertain.

Bone marrow examination in newly diagnosed Hodgkin's disease: current practice in the United Kingdom.

In the UK Hodgkin's disease is usually treated by either clinical oncologists or haematologists. A national study of the performance of bone marrow examination in newly diagnosed Hodgkin's disease was undertaken to establish current practice. A total of 620 questionnaires were despatched, and replies were received from 60% of consultants (45% of clinical oncologists and 70% of haematologists). Bone marrow examination was performed in all new cases significantly more often by haematologists than by clinical oncologists (74% vs 40%, P < 0.001). Among haematologists, there was no correlation between the number of new patients seen annually and practice, however clinical oncologists were even less likely to perform routine bone marrow biopsies if they saw more than ten patients per year (P < 0.02). Where bone marrow examination was performed selectively, the most common criteria used were peripheral blood cytopenia and advanced-stage disease. These criteria were applied in the same way by both clinical oncologists and haematologists. Bone marrow biopsy, an invasive and often painful procedure, is currently performed more frequently in Hodgkin's disease than can be recommended on the basis of recent studies in the literature and associated guidelines. There is a significant difference in practice between clinical oncologists and haematologists, and this raises the wider issue of the influence of hospital specialisation on patient management.

An audit of craniospinal irradiation for medulloblastoma in Newcastle 1970-1992.

The case notes were reviewed of 55 patients treated with craniospinal irradiation for cerebellar medulloblastoma during the period 1970-1992. Twenty patients treated by various techniques before 1978 had a survival at both 5 and 10 years of 33%. Thirty-five patients treated from 1978 onwards were irradiated using a standard technique, which is described; their actuarial disease free survival was 59% at 5 years and 47% at 10 years. Our results are similar to those reported from other centres. The recent literature is reviewed. Irradiation of the whole craniospinal axis (CSA) is necessary for disease control, but the optimum dose of radiation is still disputed. It is likely to be in excess of 25 Gy but less than 35 Gy to the whole CSA, and 50 Gy or greater to the posterior fossa. The role of adjuvant chemotherapy is still not proven. The clinical significance of the dose inhomogeneity across the junction between the cranial and spinal fields, and the effect of feathering, are uncertain.