IIA Hodgkin Lymphoma Research Articles

Bleomycin-induced Flagellate Dermatitis: a Case Report

Abstract Flagellate dermatitis represents a unique cutaneous eruption associated with several causes, including treatment with certain chemotherapeutic agents, ingestion of toxins and rheumatologic conditions like adult-onset Still’s disease and dermatomyositis. We present the case of a 35-year-old woman with stage IIA Hodgkin lymphoma who was treated with the ABVD chemotherapy regimen (doxorubicin, bleomycin, vinblastine and dacarbazine). During the third cycle of chemotherapy, she developed multiple linear erythematous macules and hyperpigmentation in a striking flagellate-like pattern localized on the upper chest, submammary folds, neck and upper part of the back. The lesions resolved completely within three months after the withdrawal of bleomycin. Clinicians should be aware of this distinctive cutaneous toxicity in patients receiving bleomycin combination chemotherapy.

MALIGNANT HEMATOLOGIC FINDINGS BEYOND TYPICAL ENDOCRINE CONDITIONS

Endocrine morbidities are a vast panel of conditions; the most frequent diseases in daily endocrine practice are typically thyroid nodules or primary osteoporosis. We aim to introduce two cases who underlined a hematologic malignancy in association with apparently low risk endocrine conditions involving thyroid, respective osteoporosis field. A 24-year female is admitted for anterior cervical lumps which she self-detected one month ago. Normal thyroid blood assays are associated with neck ultrasound anomalies as: 2 thyroid nodules of 0.5/0.3 cm, respective of 0.5/0.2 cm; 5 left cervical lumps (largest at supraclavicle level of 1.5/ 0.7/1.5 cm); 4 right lateral cervical lymph nodes; multiple similar lesions were also revealed at others neck areas – largest at submandible level of 1.3/0.9/1.2 cm (right), respective 1.1/0.9/2.4 cm (left). Evaluation at oto-rhino-laringology, infectious disease was unrevealing; diagnosis of stage IIA Hodgkin lymphoma was established starting from ganglion biopsy. This is 78-year female, admitted for evaluation of bone loss under densumab for the latest year after a decade history of bisphosphonates. Secondary causes of osteoporosis or hypovitaminosis D were ruled out; computed tomography detected a small adrenal incidentaloma, whole body bone scintigrame did not reveal metastasis while flow cytometry of peripheral lymphocytes identified B monoclonal lymphocytosis/chronic lymphatic leukaemia with B cell starting from a mild elevation of white blood cells in routine hemogram. Behind classical endocrine conditions as goitre or osteoporosis, severe diagnosis might be found in situations as associated cervical nodes involvement, respective non-response to specific anti-osteoporotic therapy if active case finding strategies in a multidisciplinary manner are performed.

Involved-Site Image-Guided Intensity Modulated Versus 3D Conformal Radiation Therapy in Early Stage Supradiaphragmatic Hodgkin Lymphoma

Image-guided intensity modulated radiation therapy (IG-IMRT) allows for margin reduction and highly conformal dose distribution, with consistent advantages in sparing of normal tissues. The purpose of this retrospective study was to compare involved-site IG-IMRT with involved-site 3D conformal RT (3D-CRT) in the treatment of early stage Hodgkin lymphoma (HL) involving the mediastinum, with efficacy and toxicity as primary clinical endpoints. We analyzed 90 stage IIA HL patients treated with either involved-site 3D-CRT or IG-IMRT between 2005 and 2012 in 2 different institutions. Inclusion criteria were favorable or unfavorable disease (according to European Organization for Research and Treatment of Cancer criteria), complete response after 3 to 4 cycles of an adriamycin- bleomycin-vinblastine-dacarbazine (ABVD) regimen plus 30 Gy as total radiation dose. Exclusion criteria were chemotherapy other than ABVD, partial response after ABVD, total radiation dose other than 30 Gy. Clinical endpoints were relapse-free survival (RFS) and acute toxicity. Forty-nine patients were treated with 3D-CRT (54.4%) and 41 with IG-IMRT (45.6%). Median follow-up time was 54.2 months for 3D-CRT and 24.1 months for IG-IMRT. No differences in RFS were observed between the 2 groups, with 1 relapse each. Three-year RFS was 98.7% for 3D-CRT and 100% for IG-IMRT. Grade 2 toxicity events, mainly mucositis, were recorded in 32.7% of 3D-CRT patients (16 of 49) and in 9.8% of IG-IMRT patients (4 of 41). IG-IMRT was significantly associated with a lower incidence of grade 2 acute toxicity (P=.043). RFS rates at 3 years were extremely high in both groups, albeit the median follow-up time is different. Acute tolerance profiles were better for IG-IMRT than for 3D-CRT. Our preliminary results support the clinical safety and efficacy of advanced RT planning and delivery techniques in patients affected with early stage HL, achieving complete response after ABVD-based chemotherapy.

An individual patient-data comparison of combined modality therapy and ABVD alone for patients with limited-stage Hodgkin lymphoma

BackgroundTreatment options for patients with nonbulky stage IA–IIA Hodgkin lymphoma include combined modality therapy (CMT) using doxorubicin, bleomycin, vinblastine and dacarbazine (ABVD) plus involved-field radiation therapy (IFRT), and chemotherapy with ABVD alone. There are no mature randomized data comparing ABVD with CMT using modern radiation techniques. Patients and methodsUsing German Hodgkin Study Group HD10/HD11 and NCIC Clinical Trials Group HD.6 databases, we identified 588 patients who met mutually inclusive eligibility criteria from the preferred arms of HD10 or 11 (n = 406) and HD.6 (n = 182). We evaluated time to progression (TTP), progression-free (PFS) and overall survival, including in three predefined exploratory subset analyses. ResultsWith median follow-up of 91 (HD10/11) and 134 (HD.6) months, respective 8-year outcomes were for TTP, 93% versus 87% [hazard ratio (HR) 0.44, 95% confidence interval (CI) 0.24–0.78]; for PFS, 89% versus 86% (HR 0.71, 95% CI 0.42–1.18) and for overall survival, 95% versus 95% (HR 1.09, 95% CI 0.49–2.40). In the exploratory subset analysis including HD10 eligible patients who achieved complete response (CR) or unconfirmed complete response (CRu) after two cycles of ABVD, 8-year PFS was 87% (HD10) versus 95% (HD.6) (HR 2.8; 95% CI 0.64–12.5) and overall survival 96% versus 100%. In contrast, among those without CR/CRu after two cycles of ABVD, 8-year PFS was 88% versus 74% (HR 0.35; 95% CI 0.16–0.79) and overall survival 95% versus 91%, respectively (HR 0.42; 95% CI 0.12–1.44). ConclusionsIn patients with nonbulky stage IA–IIA Hodgkin lymphoma, CMT provides better disease control than ABVD alone, especially among those not achieving complete response after two cycles of ABVD. Within the follow-up duration evaluated, overall survivals were similar. Longer follow-up is required to understand the implications of radiation and chemotherapy-related late effects. Clinical trialsThe trials included in this analysis were registered at ClinicalTrials.gov: HD10 - NCT00265018, HD11 - NCT00264953, HD.6 - NCT00002561.

Patient With IgG Heavy Chain Disease Presents With Parathyroid Hormone-Related Peptide Mediated Hypercalcemia

BackgroundMultiple myeloma is associated with excessive tumor-induced, osteoclast-mediated bone destruction. Hypercalcemia remains the most frequent metabolic complication of myeloma in patients, and excessive osteolysis plays a major contributory role in its pathogenesis. Hypercalcemia caused by increased blood levels of PTHrP have been found in patients with solid tumors and are uncommon in patients with hematologic malignancies including multiple myeloma. Here we present a unique case of a rare variant of multiple myeloma, IgG heavy chain disease, presenting with PTHrP associated hypercalcemia. MethodsA retrospective chart review of one patient from 2011-2013 including clinical history, laboratory data, imaging, and pathology was performed. ResultsA 60 year old female with past medical history of stage IIA Hodgkin's lymphoma diagnosed in 1992, treated with total nodal radiation with recurrence in 1997 treated with 6 cycles of ABVD achieving complete remission. The patient was found to have hypercalcemia (11.0 mg/dL) and renal failure (1.29 mg/dL) in March 2011. Hypercalcemia workup revealed suppressed PTH (<3 pg/ml), elevated ionized calcium (6.1 mg/dL) elevated parathyroid related peptide (38pg/ml), normal vitamin D and ACE levels. Serum protein electrophoresis (SPEP) showed M-spike of 0.9 g/dL. Immunofixation electrophoresis (IFE) demonstrated an IgG monoclonal immunoglobulin without a corresponding light chain (figure 1). Free serum kappa and lamda light chains were within normal limits. Serum IgG was elevated (4678 mg/dL), normal IgA (127 mg/dL) and low IgM (39mg/dL). Also, Beta-2 microglobulin was elevated (14.3 mg/L). The patient was seen by hematology for monoclonal gammopathy and hypercalcemia and a solid tumor work up was recommended given that the most common the mechanism of hypercalcemia for multiple myeloma is osteoclast-driven and not PTHrP related. CT chest/abdomen/pelvis, bone scan, bone survey, mammography, pelvis ultrasound were negative. Bone marrow biopsy was performed November 2011 showing 10% plasma cells (PC) by CD138, non clonal by kappa/lambda. Patient was placed on zolendonic acid for hypercalcemia and her renal function and hypercalcemia continued to worsen over a period of months. A kidney biopsy was performed in April, 2012 and revealed acute and chronic tubulointerstitial nephritis with secondary glomerulosclerosis and mild interstitial fibrosis and tubular atrophy suggestive of sarcoidosis and the patient was placed on a course of prednisone with transient improvement in calcium and renal function. The patient presented in emergency room in April 2013 with altered mental status. She was found to have hypercalcemia (12.0 mg/dL), renal failure (1.55 mg/dL),). SPEP revealed M-spike 0.64 g/dl. IFE displayed a broad band of IgG heavy chain, without associated light chains and severe depression of the non-monoclonal IgG. Serum immunoglobulins demonstrated elevated IgG (2110 mg/dL), normal IgA (46 mg/dL) and decreased IgM (<21 mg/dL). Bone marrow biopsy showed 5% PCs (figure 2), non clonal by kappa/lambda- but exclusive for IgG by IHC, without any staining for IgA or IgM (figure 3). Cytogenetics were normal. Based on the constellation of findings and similarity to prior workup the patient was diagnosed with IgG heavy chain disease and therapy with cytoxan, dexamethasone, bortezomib was initiated. Calcium levels improved and she has recovered clinically; she is currently completing her second cycle of therapy. We plan to follow PTHrP levels along with routine paraprotein assessments. [Display omitted] [Display omitted] [Display omitted] ConclusionsPTHrP mediated hypercalcemia is rare in patients with multiple myeloma and the main mechanism of hypercalcemia in multiple myeloma is osteoclast-mediated bone destruction. This is the first reported case of IgG heavy chain disease presenting with PTHrP related hypercalcemia. Another critical point related to this case, is that kappa/lambda staining, the primary mechanism of determining plasma cell clonality, is not useful in exclusively heavy chain disease- and can, in such cases, obscure the diagnosis of this plasma cell malignancy. Disclosures:No relevant conflicts of interest to declare.

Involved Field Radiotherapy Versus No Further Treatment in Patients with Clinical Stages IA and IIA Hodgkin Lymphoma and a ‘Negative' PET Scan After 3 Cycles ABVD. Results of the UK NCRI RAPID Trial

AbstractAbstract ▪547▪This icon denotes a clinically relevant abstractIn early stage HL abbreviated chemotherapy (ACT) followed by involved field radiotherapy (IFRT) is the current standard of care but some patients (pts) are probably cured by ACT alone. PET imaging has the potential to identify pts with an excellent prognosis after ACT and so provide the opportunity to avoid radiotherapy and reduce late treatment toxicity in these individuals. We present results of the RAPID trial evaluating PET response directed therapy in pts with previously untreated stages I and II HL, no B symptoms or mediastinal bulk. All pts taking part in RAPID received 3 cycles ABVD followed by a PET scan at one of fifteen quality controlled/assured PET Scan Centres across the UK. Acquired images were transmitted electronically to the Core Lab in London for central review. If the PET scan was reported ‘negative' (score 1 or 2 on a 5 point scale), pts were randomised between IFRT and no further treatment (NFT). Those with a ‘positive' PET scan (score 3, 4 or 5) had a 4th cycle ABVD and IFRT. This non-inferiority trial required 400 PET negative pts to be randomised for exclusion of a ≥7% difference in 3-year progression-free survival (PFS) from 95% in the IFRT arm, with 90% power and 5% significance level.602 pts (321 male, 281 female; median age 34 years) with newly diagnosed, stages IA/IIA HL were registered into the RAPID trial between October 2003 and August 2010. Following 3 cycles ABVD, 571 pts had a PET scan of which 426 (74.6%) were classified as PET negative (score 1, n=301; score 2, n=125). 420 PET negative pts were randomised to receive IFRT (n=209) or NFT (n=211); 6 PET negative pts were not randomised (pt choice, n=3, clinician choice, n=2; error, n=1). 22 of 209 pts randomised to receive IFRT did not receive this treatment because 16 pts (PET score 1, n=14; PET score 2, n=2) declined after they became aware of the randomisation decision, 5 had died and 1 developed pneumocystis jiroveci pneumonia.After a median follow-up of 45.7 months from randomisation, 384 of 420 (91.4%) PET negative pts are alive and progression-free, 29 (6.9%) are alive and have progressed and 7 (1.7%) have died giving a combined 3-year PFS of 92.2% and overall survival (OS) of 98.3% in the randomised population. In the IFRT arm of the randomised PET negative population, 194 pts are alive and progression-free, 9 have progressed, and 6 have died (pneumonitis, n=2; HL, n=1; cardiovascular disease, n=1; intracerebal haemorrhage, n=1; angioimmunoblastic T cell lymphoma, n=1). In the NFT arm 190 pts are alive and progression-free, 20 have progressed, and 1 has died (bronchopneumonia, n=1). 3-year PFS is 93.8% IFRT versus 90.7% NFT (risk difference −2.9%, 95% CI −10.7 to 1.4%; the lower limit marginally exceeds the maximum allowable difference of −7%) and 3-year OS is 97.0% IFRT versus 99.5% NFT. For the 145 PET positive pts who received a 4thcycle ABVD and IFRT, 126 are alive and progression-free, 11 progressed, and 8 died to give a 3-year PFS of 85.9% and OS of 93.9% from registration. These results are summarized in the Table.These results show that in early stage HL, pts with a negative PET after 3 cycles of ABVD have an excellent prognosis without any further treatment. The 3-year PFS is slightly higher in the PET negative pts receiving IFRT (93.8% vs 90.7%), where a non-inferiority margin of 7% was deemed acceptable. We conclude that in stages IA/IIA HL, RT is unnecessary in the 75% of pts who become PET negative after 3 cycles ABVD. Such a response adapted approach based on centrally reviewed PET imaging reduces treatment time and costs, improves tolerability and most importantly removes the burden of early and late toxicity of radiotherapy from the PET negative population. [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Interim positron emission tomography and clinical outcome in patients with early stage Hodgkin lymphoma treated with combined modality therapy

The aim of the study was to investigate whether interim positron emission tomography (iPET) is prognostic in a cohort of patients with early stage Hodgkin lymphoma (HL) homogeneously treated with 3–4 cycles of ABVD (adriamycin, bleomycin, vinblastine and dacarbazine) followed by 30 Gy involved field radiotherapy. Eighty patients were selected (stage I–IIA HL, availability of iPET, minimum follow-up of 12 months), and after central review, 70 were judged negative (iPET−: 87.5%) and 10 positive (iPET+: 12.5%). The two groups were then analyzed for response, progression-free survival (PFS) and overall survival (OS). Only one out of 70 iPET− patients relapsed, with 69 in continuous complete remission (CCR). All 10 iPET + patients achieved a complete response and maintained persistent CCR at follow-up. The 3-year PFS and OS were, respectively, 97% and 98.4% for iPET− and 100% and 100% for iPET+ (p = 0.63). iPET positivity does not seem to be a significant prognostic factor, and change in therapeutic strategy on the basis of iPET does not appear currently advisable outside clinical trials.

Treatment for Early-Stage Hodgkin Lymphoma: Has Radiotherapy Had Its Day?

Treatment for Early-Stage Hodgkin Lymphoma: Has Radiotherapy Had Its Day?

Letter to the Editor: response to letter from Dr. Eroglu and Dr. Unal

Dear Sir,I appreciate the report of the study by Dr Eroglu and Dr Unal and their comments on my review [1]. However, I do not think that one can conclude that radiation therapy (RT) in addition to chemotherapy is necessary in most patients with early-stage Hodgkin lymphoma (HL). Dr Eroglu and Dr Unal report on the use of involved-field RT (IF RT) with or without chemotherapy in patients with relapsed or refractory HL after autologous stem cell transplantation (autoSCT). It is not clear whether this was as a part of the autoSCT programme or a treatment for patients relapsing after or refractory to autoSCT. It is also unclear as to whether they are reporting on a prospective clinical trial and, if so, whether or not it was randomized, or a retrospective treatment experience. The number of patients with limited disease (‘early stage’) was small, and it is not clear how comparable the patients were in the irradiated and nonirradiated groups. This makes conclusions about differences in survival between these two groups difficult. In any case, this is a different patient group from newly diagnosed patients with early-stage HL receiving their first treatment. The meta-analysis of randomized trials comparing chemotherapy alone with chemotherapy plus RT as first treatment in newly diagnosed early-stage HL had serious limitations [2]. It contained only five heterogeneous trials, three of which were over 20 years old. The populations of patients were different in the trials. For example, one trial treated entirely patients with initial bulky disease and another predominantly patients with large mediastinal disease. Another trial had very short follow-up. The chemotherapy was suboptimal in two trials. For these reasons, the trials do not seem to be comparable, and it is difficult to draw meaningful conclusions from pooling their data in the meta-analysis. Subsequent to the appearance of the our review, the final outcome of the randomized trial of the National Cancer Institute of Canada Clinical Trials Group and the Eastern Cooperative Oncology Group of ABVD only versus extended-field RT with or without ABVD, according to risk stratification, as first treatment for stage IA and IIA HL was published. Meyer et al. [3] demonstrated that their hypothesis was correct that survival would be superior for ABVD chemotherapy only to that for EF RT with or without chemotherapy at 12 years owing to deaths to causes other than HL, including second cancers. This was despite a small but statistically significant higher relapse rate for ABVD alone, suggesting that survival, not initial relapse, may be the most important outcome because of effective salvage treatment. The authors speculated that the survival in the RT group may decrease further with longer follow-up, as deaths owing to second cancers and cardiovascular events dramatically increase after 10 years and actually exceed those owing to HL at approximately 20 years [4, 5]. This result further established chemotherapy alone as a treatment option for early-stage HL. A criticism of this trial has been that EF RT with or without chemotherapy has been superseded by chemotherapy combined with IF or even more restricted involved-nodal (IN) RT as standards of care. The late complications of STN RT may be higher than those that will be seen with current treatment regimens employing chemotherapy with more limited RT. Recently, less extensive RT in combination with chemotherapy has provided the lowest reported rates of early relapse. The HD10 trial of the German Hodgkin Study Group found equivalent results in very favourable stages I and II HL with only two cycles of chemotherapy with doxorubicin, bleomycin, vinblastine and dacarbazine (ABVD) plus reduced-dose IF RT and with four cycles and IF RT at standard doses. The 5-year relapse rate was <10%, which established a new benchmark for treatment measured by this particular endpoint [6]. However, it is noteworthy that even in the HD10 trial, the second malignancy rate is >4% and deaths owing to second malignancies and cardiovascular events already exceed those owing to HL at a median follow-up time of 7.5 years [6]. It is possible that these complications may still increase long-term mortality despite reductions in RT doses and fields. Moreover, it has been estimated that volumes of RT actually may be increased by 10–15% using positron emission tomography (PET) imaging to plan for IN RT as compared with computerized tomography [7]. Several recent clinical trials are attempting to determine in which subgroups of patients with early-stage HL the benefits of limited RT in combination with chemotherapy may outweigh the risks using PET during ABVD chemotherapy to tailor treatment (NCT00943423, NCT00433433, NCT01132807, NCT01118026 and NCT00736320). Limiting the use of RT to the fraction of patients who require it should make an important contribution to the ultimate goal of maximizing the highest long-term cure rate whilst minimizing late morbidity and mortality. No conflict of interest to declare.

A rare pulmonary infection caused by Arthrographis kalrae

Arthrographis kalrae is a rare isolate in clinical specimens. Only ten cases of infection with this species have been described so far. To our knowledge, we report the first case of a pulmonary infection caused by A. kalrae in a patient with a past history of stage IIA Hodgkin's lymphoma and demonstrate that this organism can act as an opportunistic human pathogen.

A Phase III Study for the Treatment of Children and Adolescents with Newly Diagnosed Low Risk Hodgkin Lymphoma (HL)

AbstractAbstract 767 Introduction:Optimal therapy for favorable risk HL in children and adolescents continues to evolve. Although the great majority of children will be cured, the potential for long-term adverse sequelae of treatment remains significant. Current regimens seek to define less toxic approaches that effectively treat low risk HL patients. The Children's Oncology Group (COG) HL studies have focused on the use of a response based paradigm for reduction of therapy. Methods:COG protocol AHOD0431 was a single arm study designed to investigate: 1) the rate at which three cycles of doxorubicin, vincristine, prednisone and cyclophosphamide (AVPC) induces complete response (CR), 2) whether achieving CR after 3 cycles of chemotherapy alone allows elimination of involved-field radiation therapy (IFRT), while maintaining excellent disease control and 3) whether very early response as measured by [18F]–fluorodeoxyglucose-positron emission tomography (FDG-PET) after the first course of chemotherapy is predictive of outcome. Eligibility requirements were: ages 0–21 years with newly diagnosed Stages IA and IIA HL without bulk and without lymphocyte predominance (LP) histology. All subject received chemotherapy. Patients who achieved a CR after 3 cycles of AVPC received no further therapy. Those with a partial response (PR) received 21 Gy IFRT. CR was defined as at least 80% reduction in the size of each of the nodal masses, or return to normal size, and negative findings on FDG-PET or Gallium scanning. Imaging studies were centrally reviewed. Results:287 subjects were enrolled between February, 2006 and December, 2008. 9 subjects were subsequently found to be ineligible, and an additional 3 were inevaluable for 3-cycle response. The CR rate after 3-cycles of AVPC was 63.6%, lower than the goal rate of 80%. However, event free survival (EFS) for the entire cohort at 2 years was 84%, and overall survival (OS) was 100%. Analysis by CR vs. PR status after 3 cycles of chemotherapy showed a 2 yr EFS of 80% for those achieving CR after 3 cycles of AVPC (no IFRT) vs. 88% for those achieving PR and therefore receiving IFRT (p=0.11). 227 subjects had evaluable FDG-PET results after one cycle of chemotherapy (PET1). Among subjects who achieved a CR (no IFRT) the 2 year EFS for PET1 positive/equivocal vs. negative was 65% vs. 87% (p=0.005). Among subjects who achieved a PR after 3 cycles of chemotherapy and received IFRT per protocol, 2 year EFS for PET1 positive/equivocal vs. negative was 82% vs. 96% (p=0.047). In December, 2008 the Study Committee recommended IFRT for all CR patients who were PET1 positive or PET1 status unknown, and were within one year of completing chemotherapy. 12 subjects received IFRT based on this recommendation, and all remain in CR. At a median f/u of 25 months, 46% of the entire cohort remain in CR without receiving any radiation therapy. Conclusions:Low risk HL in pediatric and adolescents is well recognized to be a highly curable malignancy, however late toxicities of therapy are frequent and may be life threatening or substantially affect quality of life. Nearly half of our patients have not received radiation therapy on this protocol. These outcomes are similar to other published pediatric regimens for low risk HL (excluding LP histology), even those that incorporated radiation therapy for all or most patients. The OS of 100% suggests that those who did recur after limited therapy were quite salvageable, many without aggressive salvage regimens or stem cell transplant. CR status after 9 weeks of chemotherapy may not optimally identify patients in whom IFRT can be avoided. Very early response, as measured by FDG-PET after 3 weeks of therapy, had significant prognostic implications in both CR and PR subjects, suggesting that this assessment may have a role in identifying a cohort of patients for whom limited volume/low dose RT remains an important component of therapy. Alternatively, AVPC may require intensification to optimize EFS while limiting need for IFRT. The role of a limited intensity chemotherapy regimen with low-dose IFRT for those subjects that experience localized recurrence after chemotherapy alone is the subject of an ongoing investigation. Disclosures:No relevant conflicts of interest to declare.

Unintended pregnancy during radiotherapy for cancer

A 27-year-old woman with upper mediastinum stage IIA Hodgkin lymphoma was treated with six cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine chemotherapy. Two months later she received a total of 4,250 cGy to the upper mediastinum and left clavicular region over a 1-month period. One week after completion of radiotherapy she was found to be 13-weeks pregnant. Her physician advised her to terminate pregnancy. She contacted a teratology information service for further information regarding the risks of radiation exposure for her fetus. Estimation of fetal radiation exposure, literature review and synthesis of published cases and effects of fetal radiation exposure. Estimated fetal radiation dose between 5 and 18 cGy. Counseling on the possible risks to the fetus as a result of radiation exposure.

Quality Control of PET Imaging in a Multicentre Phase III Trial (RAPID) Involving Randomisation of Patients with Stages IA and IIA Hodgkin Lymphoma Who Are PET ‘negative’ after 3 Cycles of ABVD Chemotherapy.

Prospective randomised trials are required to evaluate response adapted treatment algorithms in lymphoma featuring decision making based on positron emission tomography (PET). Trial recruitment is likely to be optimised if patients can be scanned close to home but consistency in quality control (QC), scan acquisition and interpretation is needed for results to be comparable when scans are performed at different locations and to validate the eventual clinical results of the trial. We describe the arrangements for QC of PET imaging in an ongoing randomised controlled trial (RAPID) involving patients with clinical stages IA/IIA HL and 13 PET Centres across the UK. The aim of the trial is to test whether 18F-fluorodeoxyglucose PET can identify patients cured by chemotherapy who can therefore avoid consolidation radiotherapy (RT) and involves a randomisation between involved field RT and no further treatment in pts who are PET ‘negative’ (-ve) after 3 cycles ABVD. When 400 PET -ve patients have been randomised the trial is powered to reliably exclude a 7% difference in progression free survival between the trial arms. All PET Centres wishing to take part in RAPID had to have a fixed-installation PET scanner and were visited by a physicist from the ‘core lab’ in London who performed a phantom acquisition, validated data anonymisation and transfer, and confirmed adherence to a specific QC protocol. Phantom data were assessed to ensure consistency of image quality and reconstruction across all scanners. Scans are reviewed at the core lab by the same two nuclear medicine specialists using visual assessment and scored according to a 5 point scale (1, no disease; 2, probably no disease; 3, possibly disease; 4, probably disease; 5, definitely disease). For the purposes of the trial, centrally reviewed scores of 1 and 2 are considered ‘negative’ and these patients are randomised. Scores of 3, 4 and 5 are considered ‘positive’ and these patients receive a 4th cycle of ABVD and involved field RT. 331 patients who have completed initial chemotherapy have had PET scans centrally reviewed with central review scores returned to the clinical centre and trial office within 72 hours of receipt of images at the core lab. Scans have been acquired 7–15 days after day 15 of cycle 3 ABVD in 69.5% pts, 1–6 days after in 14.5% and 16 or more days after in 16%. One scan was unsatisfactory and had to be repeated because a site of original disease in the olecranon fossa was not included. The proportion of scans scored as ‘negative’ has been consistent over successive 6 month periods, varying between 72% and 85%. We conclude that central review of PET imaging can be successfully co-ordinated across multiple centres in real time using a central Core Lab featuring agreed methods for QC and image interpretation. This methodology, which can easily be applied to other clinical trial settings, provides quality assured PET data and ultimately allows robust conclusions to be drawn from trial results.

ABVD plus radiotherapy versus EVE plus radiotherapy in unfavorable stage IA and IIA Hodgkin's lymphoma: results from an Intergruppo Italiano Linfomi randomized study

BackgroundIn 1997, the Intergruppo Italiano Linfomi started a randomized trial to evaluate, in unfavorable stage IA and IIA Hodgkin's lymphoma (HL) patients, the efficacy and toxicity of the low toxic epirubicin, vinblastine and etoposide (EVE) regimen followed by involved field radiotherapy in comparison to the gold standard doxorubicin, bleomycin, vinblastine and dacarbazine (ABVD) regimen followed by the same radiotherapy program. Patients and methodsPatients should be younger than 65 years with unfavorable stage IA and IIA HL (i.e. stage IA or IIA with bulky disease and/or subdiaphragmatic disease, erythrocyte sedimentation rate higher than 40, extranodal (E) involvement, hilar involvement and more than three involved lymph node areas). ResultsNinety-two patients were allocated to the ABVD arm and 89 to the EVE arm. Complete remission (CR) rates at the end of treatment program [chemotherapy (CT)+RT] were 93% and 92% for ABVD and EVE arms, respectively (P=NS). The 5-year relapse-free survival (RFS) rate was 95% for ABVD and 78% for EVE (P<0.05). As a consequence of the different relapse rate, the 5-year failure-free survival (FFS) rate was significantly better for ABVD (90%) than for EVE (73%) arm (P<0.05). No differences in terms of overall survival (OS) were observed for the two study arms. ConclusionsIn unfavorable stage IA and IIA HL patients, no differences were observed between ABVD and EVE arms in terms of CR rate and OS. EVE CT, however, was significantly worse than ABVD in terms of RFS and FFS and cannot be recommended as intial treatment for HL.

Randomized Comparison of ABVD Chemotherapy With a Strategy That Includes Radiation Therapy in Patients With Limited-Stage Hodgkin’s Lymphoma: National Cancer Institute of Canada Clinical Trials Group and the Eastern Cooperative Oncology Group

We report results of a randomized trial comparing ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) chemotherapy alone with treatment that includes radiation therapy in patients with limited-stage Hodgkin's lymphoma. Patients with nonbulky clinical stage I to IIA Hodgkin's lymphoma were stratified into favorable and unfavorable risk cohorts. Patients allocated to radiation-containing therapy received subtotal nodal radiation if favorable risk or combined-modality therapy if unfavorable risk. Patients allocated to ABVD received four to six treatment cycles. We evaluated 399 patients. Median follow-up is 4.2 years. In comparison with ABVD alone, 5-year freedom from disease progression is superior in patients allocated to radiation therapy (P = .006; 93% v 87%); no differences in event-free survival (P = .06; 88% v 86%) or overall survival (P = .4; 94% v 96%) were detected. In a subset analyses comparing patients stratified into the unfavorable cohort, freedom from disease progression was superior in patients allocated to combined-modality treatment (P = .004; 95% v 88%); no difference in overall survival was detected (P = .3; 92% v 95%). Of 15 deaths observed, nine were attributed to causes other than Hodgkin's lymphoma or acute treatment-related toxicity. In patients with limited-stage Hodgkin's lymphoma, no difference in overall survival was detected between patients randomly assigned to receive treatment that includes radiation therapy or ABVD alone. Although 5-year freedom from disease progression was superior in patients receiving radiation therapy, this advantage is offset by deaths due to causes other than progressive Hodgkin's lymphoma or acute treatment-related toxicity.

Long-term results of a randomised trial of involved field radiotherapy vs extended field radiotherapy in stage I and II Hodgkin lymphoma

Involved field (IF) radiation was compared with extended field (EF) radiation in Hodgkin lymphoma (HL) to ascertain whether reduced radiation fields would reduce the late sequelae of radiation without compromising disease control and survival. A total of 603 patients with stage I or II HL were entered into this trial; laparotomy was carried out in 380 (63%) patients. Stage I or IIA disease patients were randomised to receive IF or EF comprising a mantle or inverted Y fields alone. Stage I and IIB patients were randomised between mantle or inverted Y fields and total nodal irradiation (TNI). The dose was 35 Gy to uninvolved sites and 40 Gy to involved sites. The median followup of surviving patients was 25.2 years with only 3.3% lost to follow-up. The treatment failure rate at 25 years in stage IA and IIA was 44% after EF and 54% after IF (P = 0.01); in stage I and IIB this was 80% (EF) and 82% (TNI) at 25 years. No difference in overall survival between the randomised groups was seen. The incidence of second malignancies was 21% after IF and 20% after EF with a slight excess of lung cancer in the EF group. No significant differences in the causes of death between the randomised arms have emerged. In conclusion, IF radiotherapy for stage I and IIA HL results in a 11% greater risk of relapse compared with EF but has no effect on overall survival, risk of second malignancy or cause of death at 25 years.

Vinblastine, bleomycin, and methotrexate chemotherapy plus irradiation for patients with early‐stage, favorable Hodgkin lymphoma

The acknowledged effectiveness of vinblastine, bleomycin, and methotrexate (VBM) chemotherapy in patients with early-stage Hodgkin lymphoma has been associated with conflicting toxicity reports. One hundred forty-three patients were evaluated clinically and had favorable Stage IA or IIA Hodgkin lymphoma. Ninety-three patients were treated with the standard VBM schedule combined with extended-field radiotherapy (EF-RT), leaving the choice of the therapeutic sequence free. Fifty subsequent patients were treated with a slightly modified VBM schedule (VbMp) combined with RT limited to involved fields (IF-RT) and delivered only after the end of chemotherapy. In the VbMp schedule, intervals between cycles were 21 days instead of 28 days, bleomycin doses were reduced, small doses of prednisone were given orally, and the interval before RT was prolonged. Clinical response was complete in 96% of patients who were treated with VBM plus EF-RT and in 94% of patients who were treated with VbMp plus IF-RT. Recurrence rates were nearly identical (12% and 11%, respectively) over necessarily different follow-up (91 months and 33 months, respectively). Hematologic toxicity was tolerable in both trials, and pulmonary side effects were moderate in the first trial and negligible in the second. On the whole, treatment was tolerated better when RT followed chemotherapy. The VBM regimen was confirmed to be effective in patients with early-stage Hodgkin lymphoma. Administration of all cycles before RT improved tolerance; pulmonary toxicity probably is mitigated further by reduced bleomycin doses, mild prednisone therapy, and a more prolonged resting interval before RT. A slightly higher recurrence rate was expectable in the VBM plus IF-RT trial despite the actual intensification of vinblastine and methotrexate.