Alexander Fosså

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.).

Procarbazine-Free OEPA-COPDAC Chemotherapy in Boys and Standard OPPA-COPP in Girls Have Comparable Effectiveness in Pediatric Hodgkin's Lymphoma: The GPOH-HD-2002 Study

PURPOSE Vincristine, etoposide, prednisone, and doxorubicin (OEPA)-cyclophosphamide, vincristine, prednisone, and dacarbazine (COPDAC) is derived from standard vincristine, procarbazine, prednisone, and doxorubicin (OPPA)-cyclophosphamide, vincristine, procarbazine, and prednisone (COPP) chemotherapy by replacing procarbazine with etoposide and dacarbazine for a potentially less gonadotoxic regimen for boys with Hodgkins lymphoma (HL). PATIENTS AND METHODS Five hundred seventy-three pediatric patients with classical HL were enrolled onto the German Society of Pediatric Oncology and Hematology-Hodgkins Disease (GPOH-HD) -2002 study between November 2002 and December 2005. Boys received two courses of OEPA and girls received two courses of OPPA for induction. Treatment group (TG) -2 (intermediate stages) and TG-3 (advanced stages) patients received further two or four cycles COPP (girls) or COPDAC (boys), respectively. After chemotherapy all patients received involved-field irradiation with 19.8 Gy, except for patients with early-stage disease (TG-1) in complete remission. RESULTS Five hundred seventy-three patients (287 males and 286 females) were less than 18 years old and fulfilled all inclusion criteria; 195 patients (34.0%) were allocated to TG-1, 139 (24.3%) were allocated to TG-2, and 239 (41.7%) were allocated to TG-3. Toxicity of OEPA-COPDAC was tolerable overall. Hematotoxicity was more pronounced with OEPA than OPPA, whereas it was less pronounced with COPDAC compared with COPP. The median observation time was 58.6 months. Overall survival and event-free survival (EFS) rates (+/- SE) at 5 years were 97.4% +/- 0.7% and 89.0% +/- 1.4%, respectively. In TG-1, overall EFS was 92.0% +/- 2.0%. EFS of patients without irradiation (93.2% +/- 3.3%) was similar to that of irradiated patients (91.7% +/- 2.5%), confirming results of the previous GPOH-HD-95 study. In TG-2+3, EFS did not significantly differ between boys and girls (90.2% +/- 2.3 v 84.7% +/- 2.7, respectively; P = .12). CONCLUSION In TG-2+3, results in boys and girls are superimposable. OPPA-COPP and OEPA-COPDAC seem to be exchangeable regimens in intermediate- and advanced-stage classical HL in pediatric patients.

Siltuximab for multicentric Castleman's disease: a randomised, double-blind, placebo-controlled trial

BACKGROUND Multicentric Castlemans disease is a rare lymphoproliferative disorder driven by dysregulated production of interleukin 6. No randomised trials have been done to establish the best treatment for the disease. We assessed the safety and efficacy of siltuximab-a chimeric monoclonal antibody against interleukin 6-in HIV-negative patients with multicentric Castlemans disease. METHODS We did this randomised, double-blind, placebo-controlled study at 38 hospitals in 19 countries worldwide. We enrolled HIV-negative and human herpesvirus-8-seronegative patients with symptomatic multicentric Castlemans disease. Treatment allocation was randomised with a computer-generated list, with block size six, and stratification by baseline corticosteroid use. Patients and investigators were masked to treatment allocation. Patients were randomly assigned (2:1) to siltuximab (11 mg/kg intravenous infusion every 3 weeks) or placebo; all patients also received best supportive care. Patients continued treatment until treatment failure. The primary endpoint was durable tumour and symptomatic response for at least 18 weeks for the intention-to-treat population. Enrolment has been completed. The study is registered with ClinicalTrials.gov, number NCT01024036. FINDINGS We screened 140 patients, 79 of whom were randomly assigned to siltuximab (n=53) or placebo (n=26). Durable tumour and symptomatic responses occurred in 18 (34%) of 53 patients in the siltuximab group and none of 26 in the placebo group (difference 34·0%, 95% CI 11·1-54·8, p=0·0012). The incidence of grade 3 or more adverse events (25 [47%] vs 14 [54%]) and serious adverse events (12 [23%] vs five [19%]) was similar in each group despite longer median treatment duration with siltuximab than with placebo (375 days [range 1-1031] vs 152 days [23-666]). The most common grade 3 or higher were fatigue (five vs one), night sweats (four vs one), and anaemia (one vs three). Three (6%) of 53 patients had serious adverse events judged reasonably related to siltuximab (lower respiratory tract infection, anaphylactic reaction, sepsis). INTERPRETATION Siltuximab plus best supportive care was superior to best supportive care alone for patients with symptomatic multicentric Castlemans disease and well tolerated with prolonged exposure. Siltuximab is an important new treatment option for this disease. FUNDING Janssen Research & Development.

Left Ventricular Function Assessed by Two-Dimensional Speckle Tracking Echocardiography in Long-Term Survivors of Hodgkin's Lymphoma Treated by Mediastinal Radiotherapy With or Without Anthracycline Therapy

Anthracycline therapy is well known for its adverse cardiac effects. However, few studies have been performed of the long-term follow-up of myocardial function in adult survivors of Hodgkins lymphoma receiving anthracycline. Two-dimensional speckle tracking echocardiography is an accurate angle-independent modality for the quantification of left ventricular (LV) function. The aim of the present study was to investigate the long-term effect of anthracycline on LV systolic function. Echocardiography was performed in 47 survivors of Hodgkins lymphoma 22 ± 2 years after successful mediastinal radiotherapy with (n = 27) or without (n = 20) anthracycline (doxorubicin) treatment and in 20 healthy controls. LV function was assessed by the LV ejection fraction and global longitudinal and circumferential strain. Both patient groups had received a similar dosage of radiation, and doxorubicin was given at a total dose of 309 ± 92 mg. The global longitudinal strain was reduced in patients receiving anthracycline with mediastinal radiotherapy compared to the other group receiving mediastinal radiotherapy alone or combined radiotherapy and regimens without anthracyclines (-16.1 ± 1.9% vs -17.5 ± 1.7%, respectively, p <0.05). Both patient groups had reduced strain compared to the healthy controls (-20.4 ± 1.7%, both p <0.001). The circumferential strain was also reduced in the treatment groups (-18.3 ± 3.2% and -17.8 ± 3.6% vs -22.5 ± 2.1%, both p <0.001). The LV ejection fraction did not differ between the patient groups (55 ± 8% vs 56 ± 6%, p = 1.0) but was reduced compared to that of the controls (62 ± 5%, both p <0.05). In conclusion, myocardial function was reduced in the survivors of Hodgkins lymphoma 2 decades after successful treatment consisting of mediastinal radiotherapy with or without chemotherapy. Patients receiving anthracycline therapy had additional negative long-tem effects on LV systolic function.

Valvular dysfunction and left ventricular changes in Hodgkin's lymphoma survivors. A longitudinal study

Purpose:Hodgkins lymphoma survivors (HLSs) have an elevated risk for cardiovascular diseases that appear several years after radiotherapy. This study examined the time-dependent development and evolution of valvular and myocardial function related to treatment with mediastinal radiotherapy and anthracyclines in HLSs.Patients and methods:In 1993, echocardiography was performed in 116 HLSs median 10 years (range 6–13 years) after treatment with mediastinal radiotherapy. None of the 116 patients had valvular stenosis in 1993 whereas 36 (31%) had moderate valvular regurgitation. In 2005–2007, 51 of 57 invited patients were included in a second echocardiographic study – median 22 years (range 11–27 years) after treatment. Of these patients, 28 (55%) had also received anthracyclines. The patients were selected on the basis of the presence or absence of moderate valvular regurgitation in 1993.Results:The second echocardiographic study demonstrated that 10 out of 27 (37%) patients with only mild or no aortic or mitral regurgitation in 1993 had developed moderate regurgitation in either or both the aortic or mitral valve. Of the 24 patients with moderate (n=23) or severe (n=1) regurgitation in the aortic or mitral valve in 1993, 8 (33%) had progressed to severe regurgitation, developed moderate regurgitation in a previously normal or mild regurgitant valve or had received valvular replacement. In total, of all patients, 20 (39%) had developed mild to severe aortic stenosis and 3 patients had received valvular replacement. In a multiple linear regression the use of anthracyclines predicted left ventricular remodelling between ECHO 1993 and 2005 as demonstrated by increased left ventricular end systolic diameter (β =0.09 (95% CI 0.01–0.17), P=0.04) and reduced thickness of the left ventricular posterior wall (β =−0.18 (95% CI −0.33 to −0.03), P=0.02) and interventricular septum (β =−0.16 (95% CI −0.30 to −0.03), P=0.02).Conclusion:Given the progressive nature of valvular dysfunction and left ventricular remodelling 20–30 years after diagnosis, we recommend life-long cardiological follow-up of HLSs treated with mediastinal radiotherapy.

Serological cloning of cancer/testis antigens expressed in prostate cancer using cDNA phage surface display

Serological cloning of tumor-associated antigens (TAAs) using patient autoantibodies and tumor cDNA expression libraries (SEREX) has identified a wide array of tumor proteins eliciting B-cell responses in patients. However, alternative cloning strategies with the possibility of high throughput analysis of patient sera and tumor libraries may be of interest. We explored the pJuFo phage surface display system, allowing display of recombinant tumor proteins on the surface of M13 filamentous phage, for cloning of TAAs in prostate cancer (PC). Control experiments established that after a few rounds of selection on immobilized specific IgG, a high degree of enrichment of seroreactive clones was achieved. With an increasing number of selection rounds, a higher yield of positive clones was offset by an apparent loss of diversity in the repertoire of selected clones. Using autologous patient serum IgG in a combined biopanning and immunoscreening approach, we identified 13 different TAAs. Three of these (NY-ESO-1, Lage-1, and Xage-1) were known members of the cancer/testis family of TAAs, and one other protein had previously been isolated by SEREX in cancer types other than PC. Specific IgG responses against NY-ESO-1 were found in sera from 4/20 patients with hormone refractory PC, against Lage-1 in 3/20, and Xage-1 in 1/20. No reactivity against the remaining proteins was detected in other PC patients, and none of the TAAs reacted with serum from healthy subjects. The results demonstrate that phage surface display combined with postselection immunoscreening is suitable for cloning a diverse repertoire of TAAs from tumor tissue cDNA libraries. Furthermore, candidate TAAs for vaccine development of PC were identified.

Dose-densified chemoimmunotherapy followed by systemic central nervous system prophylaxis for younger high-risk diffuse large B-cell/follicular grade 3 lymphoma patients : results of a phase II Nordic Lymphoma Group study

BACKGROUND Many patients with aggressive B-cell lymphomas and high clinical risk score still die of lymphoma after conventional R-CHOP chemoimmunotherapy. We hypothesized that intensified chemoimmunotherapy including systemic central nervous system (CNS) prophylaxis improves outcome and reduces the incidence of CNS-related events. PATIENTS AND METHODS Inclusion criteria were age 18-65 years, primary diffuse large B-cell lymphoma or grade III follicular lymphoma without clinical signs of CNS disease and negative cerebrospinal fluid cytology, age-adjusted International Prognostic Index 2-3 and WHO performance score 0-3. Treatment consisted of six courses of R-CHOEP-14 followed by a course of high-dose cytarabine and a course of high-dose methotrexate. Primary end point was failure-free survival (FFS) at 3 years. RESULTS A total of 156 eligible patients with a median age of 54 years (range 20-64) were included. Three toxic deaths were observed. Three-year overall survival (OS) and FFS rates (median observation time 52 months for survivors) were 81% and 65%, respectively. Seven patients experienced CNS relapse, all within 6 months. CONCLUSIONS The results are promising with favorable 3-year OS and FFS rates, a low toxic death rate and a lower than expected number of CNS events. CNS progression might be further reduced by earlier CNS prophylaxis. CinicalTrials.gov. identifier NCT01502982.

Independent prognostic significance of HER-2 oncoprotein expression in pN0 prostate cancer undergoing curative radiotherapy.

Existing prognostic algorithms for localized prostate cancer (PC) are hampered by poor validation for endpoints other than biochemical relapse such as clinical disease progression or survival. Therefore, the prognostic relevance of Her‐2 (Her‐2/neu, c‐erbB2) protein expression in patients undergoing curative radiotherapy (RT) was compared to widely accepted prognostic factors such as pretreatment prostate‐specific antigen (PSA) levels, biopsy Gleason score and T category of the primary tumor. Biopsies from 112 homogeneously treated patients with T1‐4pN0M0 PC were examined by immunohistochemistry and 37% of cases showed membrane‐bound Her‐2 expression in more than 10% of cancer cells. No definite membrane staining was seen in normal prostate epithelium. With 25 patients dead of PC and a median follow‐up of surviving patients of 71 months (range 48–144), the prognostic relevance of Her‐2 expression was univariately associated with adverse outcome in terms of biochemical or clinical progression‐free survival (B/C‐PFS; p = 0.04), clinical progression‐free survival (C‐PFS; p = 0.02) and disease‐specific survival (DSS; p = 0.02). In multivariate analysis, Her‐2 expression, T category and Gleason score were independently associated with C‐PFS, whereas only Her‐2 expression and Gleason score were associated with DSS. Her‐2 expression and Gleason score together discriminated 2 groups of patients with 5‐year DSS of 95% and 79%, respectively (p < 0.001). Pretreatment PSA levels were associated only with B/C‐PFS but not with C‐PFS or DSS. Together the data show for the first time that expression of Her‐2 is of prognostic relevance in localized PC undergoing RT and suggest that analysis for Her‐2 may improve prognostic algorithms for clinically relevant endpoints other than biochemical relapse.

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.

Post-treatment parenthood in Hodgkin's lymphoma survivors

Attempted and achieved post-treatment parenthood, with or without use of assisted reproduction techniques (ARTs), was assessed in Hodgkins lymphoma survivors treated from 1971–1998, aged below 50 (females) or 65 (males) at diagnosis, aged 18 to 75 at survey. Four treatment groups were constructed: radiotherapy only, low -, medium - and high gonadotoxic chemotherapy (with or without radiotherapy in the three chemotherapy groups). Using Kaplan–Meier estimates, log-rank tests and Cox regression analyses, factors influencing post-treatment parenthood were investigated, with birth of the first child after treatment as the end point. Forty-five per cent (120/269) of males and 50% (91/184) of females reported attempted post-treatment parenthood. Of these, 76 (63%) males and 68 (75%) females had a child without use of ARTs. In addition 10 males and one female achieved post-treatment parenthood with use of ARTs. Treatment group was significantly associated with post-treatment parenthood, with highest probabilities after radiotherapy only and low gonadotoxic chemotherapy. In univariate analyses, age at diagnosis was a significant factor related to post-treatment parenthood in females.