The clinical features, management and prognostic effects of pathological fractures in a multicenter series of 373 patients with diffuse large B-cell lymphoma of the bone.

BACKGROUND: Pathological fractures (PFs) occur in 10%-20% of patients with diffuse large B-cell lymphoma (DLBCL) of the bone. The clinical features and the effects of this severe complication on management and prognosis have not been previously analyzed in a large series. PATIENTS AND METHODS: The effects of PF on management and prognosis were reviewed in an international retrospective series of 373 patients with newly diagnosed bone DLBCL, comparing 78 patients with PF at presentation (group 'PF-BL') and 295 patients without PF ('controls'). RESULTS: At a median follow-up of 53 months (range 3-246), PF-BL patients exhibited lower rates of overall response (ORR, 78% versus 85%; P = 0.17), 5-year progression-free survival (PFS, 53 ± 6% versus 61 ± 3%; P = 0.02) and 5-year overall survival (OS, 54 ± 6% versus 68 ± 3%, P = 0.008) than controls. Initial surgical stabilization of the PF did not change therapeutic outcome (5-year OS: 45 ± 9% versus 54 ± 10%; P = 0.20). PF-BL patients referred to irradiation of the fractured bone before chemotherapy exhibited a significantly poorer outcome than patients managed with the inverse sequence (ORR: 52% versus 92%, P = 0.0005; 5-year OS: 22 ± 14% versus 64 ± 9%, P = 0.007). Multivariate analysis confirmed the independent association between PF and worse survival and the negative effect of radiotherapy as initial therapy. CONCLUSION: Fracture is an independent, adverse prognostic event in patients with bone DLBCL. Anthracycline-based chemotherapy followed by radiotherapy seems to be the better treatment sequence. Initial fracture stabilization does not seem to improve outcome; it should be used to improve patient's quality of life only if chemotherapy delays can be avoided.

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.

A population-based study of intensive multi-agent chemotherapy with or without autotransplant for the highest risk Hodgkin's disease patients identified by the Scotland and Newcastle Lymphoma Group (SNLG) prognostic index. A Scotland and Newcastle Lymphoma Group study (SNLG HD III).

The aim of the study was to identify all patients with poor risk Hodgkin's disease (HD) using a numerical prognostic index in a defined population and to recruit them into a trial of intensive chemotherapy prednisolone, vinblastine, doxorubicin, chlorambucil, etoposide, bleomycin, vincristine, procarbazine (PVACE-BOP)x3+autotransplant (Arm A) versus PVACE-BOPx5 (Arm B) in first remission. In 10 years, the Scotland and Newcastle Lymphoma Group (SNLG) registered 930 patients with HD of whom 178 (19%) were identified as 'poor risk' by the SNLG index and were aged 16-59 years. 126/178 (71%) entered the study. Of the 120 confirmed poor risk HD cases, all completed PVACE-BOPx3 with a 93% Complete Response/unconfirmed Complete Response (CR/CRu) rate. Only 65/107 in CR accepted the randomisation. With a median follow-up of 6 years, both arms of the trial have a similar time to treatment failure (TTF) (Arm A 79%+/-11 versus 85%+/-7 Arm B, P=0.35). Advanced stage 'good risk' patients not included in the trial receiving standard therapy with CLVPP or ABVD had a 75% 5-year survival. The study demonstrates that PVACE-BOP therapy in the poorest risk group (58% had an IPI>/=3) produces excellent CR rates (93%) and overall survival with minimal toxicity, and that the substitution of autotransplant in first CR does not improve outcome. The use of the objective SNLG index accurately helped in the selection of the poorest risk group in this population study. The placing of a randomised control trial within the context of a population-based study of HD enhances the validity of the outcome.

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.

UKCCSG study of accelerated radiotherapy for pediatric brain stem gliomas. United Kingdom Childhood Cancer Study Group.

PURPOSE: Between 1991 and 1994, the United Kingdom Childhood Cancer Study Group (UKCCSG) conducted a multicenter study to assess the efficiency and tolerability of accelerated radiotherapy in children with a diagnosis of poor-prognosis brain stem glioma. METHODS AND MATERIALS: Patients eligible for study were those aged 3-16 years with tumors arising in the pons, medulla, or midbrain, not previously treated with radiotherapy or chemotherapy. Histologic confirmation was not mandatory, but computed tomography or magnetic resonance imaging and clinical findings had to be typical, and patients were selected with short prediagnosis symptom history (<3 months), cranial nerve palsies or long tract signs, and intrinsic diffuse lesions on scanning. The treatment dose was 48.6 Gy in 27 fractions, increased to 50.4 Gy in 28 fractions in January 1992, delivered twice daily (except weekends) with an interfraction interval of at least 8 h. Between January 1991 and July 1994, 28 available patients were recruited: 15 boys and 13 girls with ages ranging between 3 and 13 years (median 6). RESULTS: After treatment, neurologic improvement sustained for a period of at least 6 weeks without steroids was reported in 13 children (46%). On central review of postradiotherapy imaging, 50% of children showed evidence of partial response, but none exhibited a complete response. A further six patients (22%) had stable disease. The median survival time was 37 weeks (8.5 months); 1-year survival was 32%, and 2-year survival 11%. The pattern of relapse was local in all 26 patients who died of their disease; 1 patient had evidence of leptomeningeal seeding. Acute radiation morbidity was minimal, with only three patients (11%) exhibiting mild toxicity. No evidence of radiation-induced necrosis was found radiologically or histologically at postmortem. Ability to withdraw steroids following radiotherapy was the single most important prognostic variable in our study. CONCLUSION: The results of this study are comparable to previous outcomes of studies with conventional and hyperfractionated radiotherapy in poor-prognosis brain stem glioma. The fractionation regimen was shown to be tolerable with an acceptable morbidity profile. However, further research is required to improve the poor prognosis of these unfortunate children.

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.

Patient education for self-referral and on-demand treatment for herpes zoster in lymphoma patients.

The aim of this study is to evaluate the benefit of educating lymphoma patients in early self-diagnosis of zoster and subsequent self-referral for prompt treatment. Each of 337 patients attending an out-patient lymphoma clinic was given an explanatory leaflet and photograph about shingles when they first presented with lymphoma. One to two years following the completion of therapy for lymphoma an assessment was made on these patients using a combination of questionnaire survey and retrospective analysis of case notes. Fifty-six (16.6%) of the study population developed zoster following the diagnosis of lymphoma; 29 had had zoster prior to the diagnosis (8.6%). There was an increased incidence of herpes zoster in patients with Hodgkin's disease as compared to those with non-Hodgkin's lymphoma (P < 0.01). Patients who remembered having received the shingles education leaflets were more likely to make self-referral to hospital for prompt treatment (P < 0.001). Long-term complications, eg post-herpetic neuralgia, were less prevalent in patients presenting to hospital for prompt on-demand therapy, compared to those treated in the community. Education of lymphoma patients regarding awareness of early features of zoster is beneficial in preventing complications, but the shingles information episode needs subsequent reinforcement for maximum benefit.

Early high dose chemotherapy intensification with autologous bone marrow transplantation in lymphoma associated with retention of fertility and normal pregnancies in females. Scotland and Newcastle Lymphoma Group, UK.

As more centres consider autologous bone marrow and peripheral blood stem cell transplantation for patients with high risk Hodgkin's disease (HD) and non-Hodgkin's lymphoma (NHL) in first complete remission (CR1) the long term sequelae of such treatments have to be considered. One of the most important side effects of such intensive treatment is loss of fertility. Sperm banking before treatment commences is available for males but unfortunately cryopreservation of ova/ovarian tissue is not yet possible for females. We have transplanted 30 women, 23 were under 40 years and report ten females who have had successful pregnancies (including two twin pregnancies and one triplet pregnancy), leading to live births following autologous bone marrow transplantation (ABMT) for poor prognosis HD and NHL in first or second complete remission. None of these children have shown evidence of birth defects (median follow up of two years). Of the twenty one pregnancies reported to the European Bone Marrow Transplantation Registry (EBMTR) following ABMT for lymphoma, eight of the seventeen unassisted cases came from our centres. The Newcastle/SNLG autotransplant differs from the approach in many EBMTR centres in that it uses melphalan or melphalan/etoposide alone instead of the more common four drug containing regimens and yet sustained complete remission rates indicate that the non-ablative approach is equally effective as more aggressive regimens on the disease with the huge advantage of preserved fertility in females. This approach to conditioning for ABMT should be considered when treating women in the reproductive age group.

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.

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.

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.

Primary lymphoma of bone: a review of 13 cases emphasizing orthopaedic problems.

The records of 13 patients treated in the radiotherapy department in Newcastle 1973-1988 for primary lymphoma of bone (PLB) were reviewed. Treatment was by radiotherapy in combination with surgery and/or chemotherapy. Cause-specific disease-free survival at 5 years in 75%. Eight patients had PLB in a weight-bearing bone: four of these patients suffered pathological fractures in the treated bone. The radiological differentiation of recurrent PLB and radiation osteitis remains unsatisfactory. None of the four post-treatment pathological fractures in this series was due to recurrent PLB. None of these fractures healed spontaneously. All four patients remain disease-free but all have restricted mobility and require walking aids. PLB in weight-bearing bones is associated with long-term fragility and propylactic stabilization of the affected bone should be considered.

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.

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.

Results of a randomized, double-blind comparative study of ondansetron and metoclopramide in the prevention of nausea and vomiting following high-dose upper abdominal irradiation.

Ondansetron is a 5-hydroxytryptamine 3-receptor antagonist which has shown activity in the prevention of cytotoxic-induced emesis. Preliminary non-randomized studies also indicated efficacy in preventing sickness following radiotherapy. The present study was therefore undertaken to compare the efficacy and safety of ondansetron (8 mg tds orally) and metoclopramide (10 mg tds orally) in preventing sickness after single-exposure radiotherapy treatments of 8-10 Gy to the upper abdomen. Of 82 evaluable patients 38 received ondansetron and 44 metoclopramide. On the first day after irradiation vomiting or retching was prevented in all but one of the patients on ondansetron whereas metoclopramide achieved complete control of these symptoms in only 46% of subjects (P less than 0.001). Similarly nausea was significantly better controlled by ondansetron in the first 24 hours after treatment (P = 0.001). Complete or major control of vomiting or retching was maintained for 92%-100% of patients on ondansetron during the five days of the study period. In the metoclopramide group the proportion of patients with equivalent control improved from 70% on day 1 to 95 on day 5. Both drugs were well-tolerated.

Methylprednisolone, etoposide, vindesine, and chlorambucil (PEEC) alone or alternating with CHOP as initial or salvage therapy for non-Hodgkin's lymphoma.

A novel cytotoxic drug combination, PEEC, has been tested in the initial or salvage treatment of lymphomas. The PEEC combination alone is active in high grade or intermediate grade NHL with two complete and two partial remissions out of four patients so treated. When combined with standard CHOP therapy using an alternating regime, seven out of 11 patients obtained a complete remission and four partial remission. Ten patients were well, off treatment, beyond one year from presentation. The combination was less impressive, however, as salvage therapy with two partial responses in a heavily pre-treated group of nine patients.

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.

Recommendations for the use of radiotherapy in nodal lymphoma.

These guidelines have been developed to define the use of radiotherapy for lymphoma in the current era of combined modality treatment taking into account increasing concern over the late side-effects associated with previous radiotherapy. The role of reduced volume and reduced doses is addressed, integrating modern imaging with three-dimensional planning and advanced techniques of treatment delivery. Both wide-field and involved-field techniques have now been supplanted by the use of defined volumes based on node involvement shown on computed tomography (CT) and positron emission tomography (PET) imaging and applying the International Commission on Radiation Units and Measurements concepts of gross tumour volume (GTV), clinical target volume (CTV) and planning target volume (PTV). The planning of lymphoma patients for radical radiotherapy should now be based upon contrast enhanced 3 mm contiguous CT with three-dimensional definition of volumes using the convention of GTV, CTV and PTV. The involved-site radiotherapy concept defines the CTV based on the PET-defined pre-chemotherapy sites of involvement with an expansion in the cranio-caudal direction of lymphatic spread by 1.5 cm, constrained to tissue planes such as bone, muscle and air cavities. The margin allows for uncertainties in PET resolution, image registration and changes in patient positioning and shape. There is increasing evidence in both Hodgkin and non-Hodgkin lymphoma that traditional doses are higher than necessary for disease control and related to the incidence of late effects. No more than 30 Gy for Hodgkin and aggressive non-Hodgkin lymphoma and 24 Gy for indolent lymphomas is recommended; lower doses of 20 Gy in combination therapy for early-stage low-risk Hodgkin lymphoma may be sufficient. As yet there are no large datasets validating the use of involved-site radiotherapy; these will emerge from the current generation of clinical trials. Radiotherapy remains the most effective single modality in the treatment of lymphoma. A reduction in both treatment volume and overall treatment dose should now be considered to minimise the risks of late sequelae. However, it is important that this is not at the expense of the excellent disease control currently achieved.