Paul Smith

Results of a Trial of PET-Directed Therapy for Early-Stage Hodgkin’s Lymphoma

BACKGROUNDnIt is unclear whether patients with early-stage Hodgkins lymphoma and negative findings on positron-emission tomography (PET) after three cycles of chemotherapy with doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) require radiotherapy.nnnMETHODSnPatients with newly diagnosed stage IA or stage IIA Hodgkins lymphoma received three cycles of ABVD and then underwent PET scanning. Patients with negative PET findings were randomly assigned to receive involved-field radiotherapy or no further treatment; patients with positive PET findings received a fourth cycle of ABVD and radiotherapy. This trial assessing the noninferiority of no further treatment was designed to exclude a difference in the 3-year progression-free survival rate of 7 or more percentage points from the assumed 95% progression-free survival rate in the radiotherapy group.nnnRESULTSnA total of 602 patients (53.3% male; median age, 34 years) were recruited, and 571 patients underwent PET scanning. The PET findings were negative in 426 of these patients (74.6%), 420 of whom were randomly assigned to a study group (209 to the radiotherapy group and 211 to no further therapy). At a median of 60 months of follow-up, there had been 8 instances of disease progression in the radiotherapy group, and 8 patients had died (3 with disease progression, 1 of whom died from Hodgkins lymphoma); there had been 20 instances of disease progression in the group with no further therapy, and 4 patients had died (2 with disease progression and none from Hodgkins lymphoma). In the radiotherapy group, 5 of the deaths occurred in patients who received no radiotherapy. The 3-year progression-free survival rate was 94.6% (95% confidence interval [CI], 91.5 to 97.7) in the radiotherapy group and 90.8% (95% CI, 86.9 to 94.8) in the group that received no further therapy, with an absolute risk difference of -3.8 percentage points (95% CI, -8.8 to 1.3).nnnCONCLUSIONSnThe results of this study did not show the noninferiority of the strategy of no further treatment after chemotherapy with regard to progression-free survival. Nevertheless, patients in this study with early-stage Hodgkins lymphoma and negative PET findings after three cycles of ABVD had a very good prognosis either with or without consolidation radiotherapy. (Funded by Leukaemia and Lymphoma Research and others; RAPID ClinicalTrials.gov number, NCT00943423.).

Concordance between four European centres of PET reporting criteria designed for use in multicentre trials in Hodgkin lymphoma

PurposeTo determine if PET reporting criteria for the Response Adapted Treatment in Hodgkin Lymphoma (RATHL) trial could enable satisfactory agreement to be reached between ‘core’ laboratories operating in different countries.MethodsFour centres reported scans from 50 patients with stage II–IV HL, acquired before and after two cycles of Adriamycin/bleomycin/vinblastine/dacarbazine. A five-point scale was used to score response scans using ‘normal’ mediastinum and liver as reference levels. Centres read scans independently of each other. The level of agreement between centres was determined assuming (1) that uptake in sites involved at diagnosis that was higher than liver uptake represented disease (conservative reading), and (2) that uptake in sites involved at diagnosis that was higher than mediastinal uptake represented disease (sensitive reading).ResultsThere was agreement that the response scan was ‘positive’ or ‘negative’ for lymphoma in 44 patients with a conservative reading and in 41 patients with a sensitive reading. Kappa was 0.85 (95% CI 0.74–0.96) for conservative reading and 0.79 (95% CI 0.67–0.90) for sensitive reading. Agreement was reached in 46 and 44 patients after discussion for the conservative and sensitive readings, respectively.ConclusionThe criteria developed for reporting in the RATHL trial are sufficiently robust to be used in a multicentre setting.

Reduced dose radiotherapy for local control in non-Hodgkin lymphoma: A randomised phase III trial

PURPOSEnThis multicentre, prospective, randomised-controlled trial compared efficacy and toxicity of differing radiotherapy doses in non-Hodgkin lymphoma (NHL).nnnPATIENTS AND METHODSnPatients with any histological subtype of NHL, requiring radiotherapy for local disease control, whether radical, consolidative or palliative, were included. Three hundred and sixty one sites of indolent NHL (predominantly follicular NHL and marginal zone lymphoma) were randomised to receive 40-45Gy in 20-23 fractions or 24Gy in 12 fractions. Six hundred and forty sites of aggressive NHL (predominantly diffuse large B cell lymphoma as part of combined-modality therapy) were randomised to receive 40-45Gy in 20-23 fractions or 30Gy in 15 fractions. Patients with all stages of disease, having first-line and subsequent therapies were included; first presentations of early-stage disease predominated.nnnRESULTSnThere was no difference in overall response rate (ORR) between standard and lower-dose arms. In the indolent group, ORR was 93% and 92%, respectively, (p=0.72); in the aggressive group, ORR was 91% in both arms (p=0.87). With a median follow-up of 5.6years, there was no significant difference detected in the rate of within-radiation field progression (HR=1.09, 95%CI=0.76-1.56, p=0.64 in the indolent group; HR=0.98, 95%CI=0.68-1.4, p=0.89 in the aggressive group). There was also no significant difference detected in the progression free or overall survival. There was a trend for reduced toxicities in the low-dose arms; only the reduction in reported erythema reached significance.nnnCONCLUSIONnIn a large, randomised trial, there was no loss of efficacy associated with radiotherapy doses of 24Gy in indolent NHL and 30Gy in aggressive NHL, compared with previous standard doses of 40-45Gy.

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

BACKGROUNDnWe 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.nnnMETHODSnPatients 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.nnnRESULTSnA 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%.nnnCONCLUSIONSnAlthough 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.).

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.

De Novo Treatment of Diffuse Large B-Cell Lymphoma With Rituximab, Cyclophosphamide, Vincristine, Gemcitabine, and Prednisolone in Patients With Cardiac Comorbidity: A United Kingdom National Cancer Research Institute Trial

PURPOSEnThe treatment of patients with diffuse large B-cell lymphoma (DLBCL) with cardiac comorbidity is problematic, because this group may not be able to receive anthracycline-containing chemoimmunotherapy. We designed a single-arm phase II multicenter trial of rituximab, gemcitabine, cyclophosphamide, vincristine, and prednisolone (R-GCVP) in patients considered unfit for anthracycline-containing chemoimmunotherapy because of cardiac comorbidity.nnnPATIENTS AND METHODSnSixty-one of 62 patients received R-GCVP, administered on day 1 with gemcitabine repeated on day 8 of a 21-day cycle. Median age was 76.5 years. All patients had advanced disease; 27 (43.5%) had left ventricular ejection fraction of ≤ 50%, and 35 (56.5%) had an ejection fraction of > 50% and comorbid cardiac risk factors such as ischemic heart disease, diabetes mellitus, or hypertension [Corrected]. Primary end point was overall response rate at the end of treatment.nnnRESULTSnThirty-eight patients (61.3%; 95% CI, 49.2 to 73.4) achieved disease response (complete response [CR], n = 18; undocumented/unconfirmed CR, n = 6; partial response, n = 14). Two-year progression-free survival for all patients was 49.8% (95% CI, 37.3 to 62.3), and 2-year overall survival was 55.8% (95% CI, 43.3 to 68.4). Thirty-four patients experienced grade ≥ 3 hematologic toxicity. There were 15 cardiac events, of which seven were grade 1 to 2, five were grade 3 to 4, and three were fatal, reflecting the poor cardiac status of the study population.nnnCONCLUSIONnOur phase II multicenter trial showed that the R-GCVP regimen is an active, reasonably well-tolerated treatment for patients with DLBCL for whom anthracycline-containing immunochemotherapy was considered unsuitable because of coexisting cardiac disease.

Promoting physical activity in general practice: should prescribed exercise be free?

In the UK there are numerous schemes whereby general practitioners can prescribe exercise programmes, usually based in leisure centres. Of the factors that discourage adherence to such programmes in the USA, cost has proved important. We collected demographic and questionnaire data from 152 inner-London patients (108 women, 44 men) before they started an exercise programme on a National Health Service prescription, and analysed the results according to whether they dropped out of the programme (78%) or not. Use of logistic regression revealed only one previous barrier to exercise, ‘not knowing about local exercise facilities’, as a significant positive determinant of adherence (adjusted odds ratio 3.51,95% confidence interval, 1.04 to 11.86). For ‘lack of money patients were more likely to drop out of the programme (adjusted odds ratio 0.25, 95% CI 0.07–0.85). The very low cost of participation in this scheme, did not encourage adherence, particularly by those who had cited ‘lack of money as a previous barrier. The case of making prescribed exercise free or even low-cost remains unproven.

Comparison of CHOP versus CIOP in good prognosis younger patients with histologically aggressive non‐Hodgkin lymphoma

CHOP (cyclophosphamide, doxorubicin, vincristine and prednisolone) has been the standard chemotherapy regimen used for diffuse large cell lymphomas for over 30u2003years. Idarubicin is a 4‐demethoxy‐anthracycline analogue of daunorubicin that has proven activity in non‐Hodgkin lymphoma, and has been reported to cause less cardiotoxicity. We therefore initiated a randomised trial of standard dose CHOP versus CIOP (cyclophosphamide, idarubicin, vincristine and prednisolone), in which doxorubicin 50u2003mg/m2 was substituted by idarubicin 10u2003mg/m2, a dose thought to have equivalent anti‐lymphoma activity. This trial was closed prematurely after 211 patients had completed therapy when a lower complete remission (CR) rate was noted in the CIOP arm. The formal results with long‐term follow up are now reported. Overall response rate was 84% in the CHOP arm and 78% in the CIOP arm, CR rates were 70% and 52% respectively in all patients (Pu2003=u20030·013) and 73% and 52% respectively for the eligible patients (Pu2003=u20030·0084). At a median of 8u2003years follow‐up, 4‐year progression‐free survival for all patients was 56% in the CHOP arm and 40% in the CIOP arm (Pu2003=u20030·0096). Overall survival for all patients was 65% in the CHOP arm and 56% in the CIOP arm (Pu2003=u20030·14). Results for eligible patients were comparable. CIOP containing idarubicin at a dose of 10u2003mg/m2 is clearly inferior to standard CHOP.

Exercise as therapy? Results from group interviews with general practice teams involved in an inner-London 'prescription for exercise' scheme

As part of an inner-London prescription for exercise scheme, group interviews were conducted with clinical and support staff from participating general practices. Interviews took place between August and November 1995 to identify the practices reasons for joining the scheme, the perceived health benefits to patients of the scheme, and criteria for selection and referral of patients onto the scheme. The results showed that the referring practice members saw exercise promotion as a therapeutic option, rather than an instrument for primary prevention. They were cautious in their referral criteria because of family health services authority guidelines. If future schemes are to develop they must distinguish between these perspectives in their promotion of physical activity.

Final analysis of the UKLG LY02 trial comparing 6-8 cycles of CHOP with 3 cycles of CHOP followed by a BEAM autograft in patients <65 years with poor prognosis histologically aggressive NHL

This trial involved 457 patients and sought to assess the value of early intensification with autologous transplantation in patients with poor prognosis histologically aggressive non‐Hodgkin lymphoma (NHL) showing a response to initial CHOP (cyclosphosphamide, doxorubicin, vincristine, prednisolone) chemotherapy. Randomization was made at the time of diagnosis with 223 assigned to continuing CHOP and 234 to 3 cycles of CHOP followed by a BEAM (carmustine, etoposide, cytarabine, melphalan) autograft. Analysis was on an intention to treat basis. After the initial three cycles of CHOP 19% of the whole group were in complete response (CR) and 53% in partial remission (PR). At the end of treatment 86% of patients in the CHOP arm had responded with 58% in CR. In the high‐dose therapy arm the overall response rate was 83% with 64% in CR (difference between arms not significant). The progression‐free survival (PFS) and overall survival at 5u2003years for the continuing CHOP arm were 38% and 50% respectively, and for the autograft arm were 44% and 50% (differences not significant). Of the patients who attained CR and subsequently relapsed, there were no long‐term survivors in the autograft recipients compared to 46% of the continuing CHOP recipients (Pu2003=u20030·0008). In conclusion, no survival benefit was demonstrated for an early autograft in first response.