Amy A Kirkwood

Adapted treatment guided by interim PET-CT scan in advanced Hodgkin's lymphoma

BACKGROUND We tested interim positron-emission tomography-computed tomography (PET-CT) as a measure of early response to chemotherapy in order to guide treatment for patients with advanced Hodgkins lymphoma. METHODS Patients with newly diagnosed advanced classic Hodgkins lymphoma underwent a baseline PET-CT scan, received two cycles of ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) chemotherapy, and then underwent an interim PET-CT scan. Images were centrally reviewed with the use of a 5-point scale for PET findings. Patients with negative PET findings after two cycles were randomly assigned to continue ABVD (ABVD group) or omit bleomycin (AVD group) in cycles 3 through 6. Those with positive PET findings after two cycles received BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone). Radiotherapy was not recommended for patients with negative findings on interim scans. The primary outcome was the difference in the 3-year progression-free survival rate between randomized groups, a noninferiority comparison to exclude a difference of 5 or more percentage points. RESULTS A total of 1214 patients were registered; 937 of the 1119 patients (83.7%) who underwent an interim PET-CT scan according to protocol had negative findings. With a median follow-up of 41 months, the 3-year progression-free survival rate and overall survival rate in the ABVD group were 85.7% (95% confidence interval [CI], 82.1 to 88.6) and 97.2% (95% CI, 95.1 to 98.4), respectively; the corresponding rates in the AVD group were 84.4% (95% CI, 80.7 to 87.5) and 97.6% (95% CI, 95.6 to 98.7). The absolute difference in the 3-year progression-free survival rate (ABVD minus AVD) was 1.6 percentage points (95% CI, -3.2 to 5.3). Respiratory adverse events were more severe in the ABVD group than in the AVD group. BEACOPP was given to the 172 patients with positive findings on the interim scan, and 74.4% had negative findings on a third PET-CT scan; the 3-year progression-free survival rate was 67.5% and the overall survival rate 87.8%. A total of 62 patients died during the trial (24 from Hodgkins lymphoma), for a 3-year progression-free survival rate of 82.6% and an overall survival rate of 95.8%. CONCLUSIONS Although the results fall just short of the specified noninferiority margin, the omission of bleomycin from the ABVD regimen after negative findings on interim PET resulted in a lower incidence of pulmonary toxic effects than with continued ABVD but not significantly lower efficacy. (Funded by Cancer Research UK and Others; ClinicalTrials.gov number, NCT00678327.).

Interpreting and reporting clinical trials with results of borderline significance.

Borderline significance in the primary end point of trials does not necessarily mean that the intervention is not effective. Researchers and journals need to be more consistent in how they report these results

PET-CT for staging and early response: results from the Response-Adapted Therapy in Advanced Hodgkin Lymphoma study

International guidelines recommend that positron emission tomography-computed tomography (PET-CT) should replace CT in Hodgkin lymphoma (HL). The aims of this study were to compare PET-CT with CT for staging and measure agreement between expert and local readers, using a 5-point scale (Deauville criteria), to adapt treatment in a clinical trial: Response-Adapted Therapy in Advanced Hodgkin Lymphoma (RATHL). Patients were staged using clinical assessment, CT, and bone marrow biopsy (RATHL stage). PET-CT was performed at baseline (PET0) and after 2 chemotherapy cycles (PET2) in a response-adapted design. PET-CT was reported centrally by experts at 5 national core laboratories. Local readers optionally scored PET2 scans. The RATHL and PET-CT stages were compared. Agreement among experts and between expert and local readers was measured. RATHL and PET0 stage were concordant in 938 (80%) patients. PET-CT upstaged 159 (14%) and downstaged 74 (6%) patients. Upstaging by extranodal disease in bone marrow (92), lung (11), or multiple sites (12) on PET-CT accounted for most discrepancies. Follow-up of discrepant findings confirmed the PET characterization of lesions in the vast majority. Five patients were upstaged by marrow biopsy and 7 by contrast-enhanced CT in the bowel and/or liver or spleen. PET2 agreement among experts (140 scans) with a κ (95% confidence interval) of 0.84 (0.76-0.91) was very good and between experts and local readers (300 scans) at 0.77 (0.68-0.86) was good. These results confirm PET-CT as the modern standard for staging HL and that response assessment using Deauville criteria is robust, enabling translation of RATHL results into clinical practice.

Application of methods for central statistical monitoring in clinical trials

Background On-site source data verification is a common and expensive activity, with little evidence that it is worthwhile. Central statistical monitoring (CSM) is a cheaper alternative, where data checks are performed by the coordinating centre, avoiding the need to visit all sites. Several publications have suggested methods for CSM; however, few have described their use in real trials. Methods R-programs were created to check data at either the subject level (7 tests within 3 programs) or site level (9 tests within 8 programs) using previously described methods or new ones we developed. These aimed to find possible data errors such as outliers, incorrect dates, or anomalous data patterns; digit preference, values too close or too far from the means, unusual correlation structures, extreme variances which may indicate fraud or procedural errors and under-reporting of adverse events. The methods were applied to three trials, one of which had closed and has been published, one in follow-up, and a third to which fabricated data were added. We examined how well the methods work, discussing their strengths and limitations. Results The R-programs produced simple tables or easy-to-read figures. Few data errors were found in the first two trials, and those added to the third were easily detected. The programs were able to identify patients with outliers based on single or multiple variables. They also detected (1) fabricated patients, generated to have values too close to the multivariate mean, or with too low variances in repeated measurements, and (2) sites which had unusual correlation structures or too few adverse events. Some methods were unreliable if applied to centres with few patients or if data were fabricated in a way which did not fit the assumptions used to create the programs. Outputs from the R-programs are interpreted using examples. Limitations Detecting data errors is relatively straightforward; however, there are several limitations in the detection of fraud: some programs cannot be applied to small trials or to centres with few patients (<10) and data falsified in a manner which does not fit the program’s assumptions may not be detected. In addition, many tests require a visual assessment of the output (showing flagged participants or sites), before data queries are made or on-site visits performed. Conclusions CSM is a worthwhile alternative to on-site data checking and may be used to limit the number of site visits by targeting only sites which are picked up by the programs. We summarise the methods, show how they are implemented and that they can be easy to interpret. The methods can identify incorrect or unusual data for a trial subject, or centres where the data considered together are too different to other centres and therefore should be reviewed, possibly through an on-site visit.

The addition of Rituximab to Fludarabine and Cyclophosphamide chemotherapy results in a significant improvement in overall survival in patients with newly diagnosed mantle cell lymphoma: results of a randomized UK National Cancer Research Institute trial

Mantle cell lymphoma is an incurable and generally aggressive lymphoma that is more common in elderly patients. Whilst a number of different chemotherapeutic regimens are active in this disease, there is no established gold standard therapy. Rituximab has been used widely to good effect in B-cell malignancies but there is no evidence that it improves outcomes when added to chemotherapy in this disease. We performed a randomized, open-label, multicenter study looking at the addition of rituximab to the standard chemotherapy regimen of fludarabine and cyclophosphamide in patients with newly diagnosed mantle cell lymphoma. A total of 370 patients were randomized. With a median follow up of six years, rituximab improved the median progression-free survival from 14.9 to 29.8 months (P<0.001) and overall survival from 37.0 to 44.5 months (P=0.005). This equates to absolute differences of 9.0% and 22.1% for overall and progression-free survival, respectively, at two years. Overall response rates were similar, but complete response rates were significantly higher in the rituximab arm: 52.7% vs. 39.9% (P=0.014). There was no clinically significant additional toxicity observed with the addition of rituximab. Overall, approximately 18% of patients died of non-lymphomatous causes, most commonly infections. The addition of rituximab to fludarabine and cyclophosphamide chemotherapy significantly improves outcomes in patients with mantle cell lymphoma. However, these regimens have significant late toxicity and should be used with caution. This trial has been registered (ISRCTN81133184 and clinicaltrials.gov:00641095) and is supported by the UK National Cancer Research Network.

A Multicenter Randomized Trial of Ibandronate Compared With Single-Dose Radiotherapy for Localized Metastatic Bone Pain in Prostate Cancer

BACKGROUND The radiotherapy or ibandronate (RIB) trial was a randomized multicenter nonblind two-arm trial to compare intravenous ibandronate given as a single infusion with single-dose radiotherapy for metastatic bone pain. METHODS Four hundred seventy prostate cancer patients with metastatic bone pain who were suitable for local radiotherapy were randomly assigned to radiotherapy (single dose, 8 Gy) or intravenous infusion of ibandronate (6mg) in a noninferiority trial. Pain was measured using the Brief Pain Inventory at baseline and four, eight, 12, 26, and 52 weeks. Pain response was assessed using World Health Organization (WHO) criteria and the Effective Analgesic Score (EAS); the maximum allowable difference was ±15%. Patients failing to respond at four weeks were offered retreatment with the alternative treatment. Quality of life (QoL) was assessed at baseline and four and 12 weeks. Because the trial was designed with a 5% one-sided test, we provide 90% confidence intervals (two-sided) for differences in pain response. RESULTS Overall, pain response was not statistically different at four or 12 weeks (WHO: -3.7%, 90% confidence interval [CI] = -12.4% to 5.0%; and 6.7%, 90% CI = -2.6 to 16.0%, respectively). Corresponding differences using the EAS were -7.5% and -3.5%. However, a more rapid initial response with radiotherapy was observed. There was no overall difference in toxicity, although each treatment had different side effects. QoL was similar at four and 12 weeks. Overall survival was similar between the two groups but was better among patients having retreatment than those who did not. CONCLUSIONS A single infusion of ibandronate had outcomes similar to a single dose of radiotherapy for metastatic prostate bone pain. Ibandronate could be considered when radiotherapy is not available.

Childhood and Adolescent nodular lymphocyte predominant Hodgkin lymphoma - A review of clinical outcome based on the histological variants

Nodular lymphocyte predominant Hodgkin lymphoma (nLPHL) comprises approximately 10–12% of all childhood Hodgkin lymphoma. As the majority have low stage disease recent years have seen a de‐escalation of treatment intensity to avoid treatment‐related morbidity. This report evaluates treatment outcome in children with histopathological variants of nLPHL after therapy de‐escalation. Biopsies from 60 patients were reviewed and histology categorized as typical (n = 47; 78%) or variant nLPHL (n = 13; 22%). Furthermore, presence of immunoglobulin D (IgD) expression by the lymphocyte predominant (LP) cells was assessed in 41 patients. Treatment outcomes were compared according to treatment received and histopathology of nLPHL. Compared to typical nLPHL, children with variant nLPHL had higher stage disease at diagnosis (stage III: 3/13; 23% vs. 3/47; 6%, P = 0·11), lower complete response rates (6/13; 46% vs. 38/47; 81%, P = 0·029) and higher relapse rates (2/13; 15% vs. 2/47; 4%, P = 0·20). Additionally, IgD expression by LP cells was associated with poorer treatment response and was more commonly seen in patients with variant nLPHL. (11/13; 85% vs. 15/28; 54%, P = 0·08). Variant histology appears to be indicative of a poorer prognosis in patients with early stage disease, and may be an important factor to take into account when moving towards reduced intensity treatment for nLPHL.

Relapsed or poorly responsive nodular lymphocyte predominant Hodgkin lymphoma in children and adolescents – a report from the United Kingdom's Children's Cancer and Leukaemia Study Group

There is a paucity of data on the treatment outcome in children with relapsed or poorly responsive nodular lymphocyte predominant Hodgkin lymphoma (nLPHL). This retrospective report evaluates the treatment outcome in a national cohort of children with relapsed or poorly responsive nLPHL. A total of 37 patients, 22 with relapsed and 15 with poorly responding disease, are the subjects of this report. Of the 22 patients with relapsed nLPHL, 11 had relapsed after primary excision biopsy, 10 after chemotherapy and 1 after chemotherapy and involved field radiotherapy. The majority had localized disease at relapse. The median time to relapse was 8 months after chemotherapy and 11 months after excision biopsy. Seven of the 15 patients with poorly responding nLPHL had variant histology. Three patients with initial poor response did not receive any further treatment and have had no disease progression. Transformation to diffuse large B cell lymphoma, in addition to evolution from typical to variant nLPHL occurred in one patient each. Thirty‐four patients have been successfully re‐treated with second chemotherapy or radiotherapy. Multiple relapses were uncommon but treatable. Relapse or poorly responsive nLPHL is fully salvageable with either additional chemotherapy and or radiotherapy.

Advanced stage nodular lymphocyte predominant Hodgkin lymphoma in children and adolescents: clinical characteristics and treatment outcome - a report from the SFCE & CCLG groups.

Advanced stage nodular lymphocyte predominant Hodgkin lymphoma (nLPHL) is extremely rare in children and as a consequence, optimal treatment for this group of patients has not been established. Here we retrospectively evaluated the treatments and treatment outcomes of 41 of our patients from the UK and France with advanced stage nLPHL. Most patients received chemotherapy, some with the addition of the anti CD20 antibody rituximab or radiotherapy. Chemotherapy regimens were diverse and followed either classical Hodgkin lymphoma or B non‐Hodgkin lymphoma protocols. All 41 patients achieved a complete remission with first line treatment and 40 patients are alive and well in remission. Eight patients subsequently relapsed and 1 patient died of secondary cancer (9 progression‐free survival events). The median time to progression for those who progressed was 21 months (5·9–73·8). The median time since last diagnosis is 87·3 months (8·44–179·20). Thirty‐six (90%), 30 (75%) and 27 (68%) patients have been in remission for more than 12, 24 and 36 months, respectively. Overall, the use of rituximab combined with multi‐agent chemotherapy as first line treatment seems to be a reasonable therapeutic option.

Treatment outcome in children and adolescents with relapsed Hodgkin lymphoma – results of the UK HD3 relapse treatment strategy

The purpose of this national retrospective study was to evaluate the outcome in children with relapsed or primary refractory Hodgkin lymphoma [HL] after a primary chemotherapy alone treatment strategy. Between 2000 and 2005, 80 children with relapsed [n = 69] or primary refractory [n = 11] HL were treated on a standardized treatment protocol of 4–6 cycles of EPIC [etoposide, prednisolone, ifosfa3mide and cisplatin] chemotherapy. Radiotherapy was recommended to all relapsed sites. High dose therapy with stem cell rescue [SCT] was recommended for patients with poor response. The 5‐year overall survival [OS] and progression‐free survival from relapse was 75·8% [64·8–83·9] and 59·9% [48·3–69·7] respectively. Duration of first remission was strongly associated with OS; risk of death was decreased by 53% [Hazard ratio (HR): 0·47, 95% confidence interval (CI): 0·19–1·18] for those with a time from end of treatment to relapse of 3–12 months (compared to <3 months) and reduced by 80% (HR 0·20, 95% CI: 0·04–0·90) for those >12 months after end of treatment. Other poor prognostic factors included advanced stage disease at relapse and B symptoms at first diagnosis. The most important factor associated with salvage failure was time to relapse. Survival outcome in children with primary refractory HL is poor.