Nivolumab for adults with Hodgkin's lymphoma (a rapid review using the software RobotReviewer).

BACKGROUND: Hodgkin's lymphoma (HL) is a cancer of the lymphatic system, and involves the lymph nodes, spleen and other organs such as the liver, lung, bone or bone marrow, depending on the tumour stage. With cure rates of up to 90%, HL is one of the most curable cancers worldwide. Approximately 10% of people with HL will be refractory to initial treatment or will relapse; this is more common in people with advanced stage or bulky disease. Standard of care for these people is high-dose chemotherapy and autologous stem cell transplantation (ASCT), but only 55% of participants treated with high-dose chemotherapy and ASCT are free from treatment failure at three years, with an overall survival (OS) of about 80% at three years.Checkpoint inhibitors that target the interaction of the programmed death (PD)-1 immune checkpoint receptor, and its ligands PD-L1 and PD-L2, have shown remarkable activity in a wide range of malignancies. Nivolumab is an anti-(PD)-1 monoclonal antibody and currently approved by the US Food and Drug Administration (FDA) for the treatment of melanoma, non-small cell lung cancer, renal cell carcinoma and, since 2016, for classical Hodgkin's lymphoma (cHL) after treatment with ASCT and brentuximab vedotin. OBJECTIVES: To assess the benefits and harms of nivolumab in adults with HL (irrespective of stage of disease). SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, International Pharmaceutical Abstracts, conference proceedings and six study registries from January 2000 to May 2018 for prospectively planned trials evaluating nivolumab. SELECTION CRITERIA: We included prospectively planned trials evaluating nivolumab in adults with HL. We excluded trials in which less than 80% of participants had HL, unless the trial authors provided the subgroup data for these participants in the publication or after we contacted the trial authors. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data and assessed potential risk of bias. We used the software RobotReviewer to extract data and compared results with our findings. As we did not identify any randomised controlled trials (RCTs) or non-RCTs, we did not meta-analyse data. MAIN RESULTS: Our search found 782 potentially relevant references. From these, we included three trials without a control group, with 283 participants. In addition, we identified 14 ongoing trials evaluating nivolumab, of which two are randomised. Risk of bias of the three included studies was moderate to high. All of the participants were in relapsed stage, most of them were heavily pretreated and had received at least two previous treatments, most of them had also undergone ASCT. As we did not identify any RCTs, we could not use the software RobotReviewer to assess risk of bias. The software identified correctly that one study was not an RCT and did not extract any trial data, but extracted characteristics of the other two studies (although also not RCTs) in a sufficient way.Two studies with 260 participants evaluated OS. After six months, OS was 100% in one study and median OS (the timepoint when only 50% of participants were alive) was not reached in the other trial after a median follow-up of 18 months (interquartile range (IQR) 15 to 22 months) (very low certainty evidence, due to observational trial design, heterogenous patient population in terms of pretreatments and various follow-up times (downgrading by 1 point)). In one study, one out of three cohorts reported quality of life. It was unclear whether there was an effect on quality of life as only a subset of participants filled out the follow-up questionnaire (very low certainty evidence). Three trials (283 participants) evaluated progression-free survival (PFS) (very low certainty evidence). Six-month PFS ranged between 60% and 86%, and median PFS ranged between 12 and 18 months. All three trials (283 participants) reported complete response rates, ranging from 12% to 29%, depending on inclusion criteria and participants' previous treatments (very low certainty evidence).One trial (243 participants) reported drug-related grade 3 or 4 adverse events (AEs) only after a median follow-up of 18 months (IQR 15 to 22 months); these were fatigue (23%), diarrhoea (15%), infusion reactions (14%) and rash (12%). The other two trials (40 participants) reported 23% to 52% grade 3 or 4 AEs after six months' follow-up (very low certainty evidence). Only one trial (243 participants) reported drug-related serious AEs; 2% of participants developed infusion reactions and 1% pneumonitis (very low certainty evidence).None of the studies reported treatment-related mortality. AUTHORS' CONCLUSIONS: To date, data on OS, quality of life, PFS, response rate, or short- and long-term AEs are available from small uncontrolled trials only. The three trials included heavily pretreated participants, which had previously undergone regimens of BV or ASCT. For these participants, median OS was not reached after follow-up times of at least 16 months (more than 50% of participants with a limited life expectancy were alive at this timepoint). Only one cohort out of three only reported quality of life, with limited follow-up data so that meaningful conclusions were not possible. Serious adverse events occurred rarely. Currently, data are too sparse to make a clear statement on nivolumab for people with relapsed or refractory HL except for heavily pretreated people, which had previously undergone regimens of BV or ASCT. When interpreting these results, it is important to consider that proper RCTs should confirm these findings.As there are 14 ongoing trials evaluating nivolumab, of which two are RCTs, it is possible that an update of this review will be published in the near future and that this update will show different results to those reported here.

Economic evaluation of chronic lymphocytic leukemia from a hospital management perspective.

OBJECTIVES: Treatment of chronic lymphocytic leukemia (CLL) is currently undergoing dramatic changes. We analyzed economic risks in hospitalized patients with CLL from a management perspective. METHODS: One hundred and twelve patients with CLL hospitalized in 2013 and 2014 at the University Hospital of Cologne were analyzed. To assess profit margins (PMs) per case, diagnosis-related group (DRG) reimbursement data were merged with an internal cost accounting scheme depending on age, prognostic factors, and DRG key performance indicators. RESULTS: In 112 patients, 284 cases coded by 19 different DRG with strongly fluctuating cost revenue ratios were found with an overall negative PM of €137 147. The DRG R61H was identified as the one most commonly coded (174 cases, 61.3%) with a deficit per case of €814. Subanalysis demonstrated that the payments were not cost covering due to excessive length of stay and staff costs. Significant differences in PM per case concerning age, length of stay and number of operation and procedure key (OPS) codes (P < 0.05) were found. CONCLUSION: In our research-driven tertiary care hospital, inpatient treatment of patients with CLL is not cost covering. This analysis demonstrates the need for novel care/reimbursement structures in CLL. From a hospital management perspective, cost revenue controlling is crucial to avoid major economic risks.

Recommending early integration of palliative care - does it work?

BACKGROUND: In 2006, our comprehensive cancer center decided to implement early integration (EI) of palliative care (PC) by (a) literally adopting the WHO definition of PC into cancer care guidelines and (b) providing a PC consulting team (PCST) to provide EI on in- and outpatient wards. The experience with this approach was assessed to identify shortcomings. METHODS: A retrospective systematic chart analysis of a 2-year period was performed. RESULTS: A total of 862 patients were treated (May 2006-April 2008). Many patients consulted by the PCST for the first time were already in a reduced performance status (ECOG 3 & 4: 40%) or experiencing burdening symptoms (i.e., dyspnoea 27%). After the first year (period A; "getting started"), the overall prevalence of symptoms identified on first PC contact decreased from seven to three, (p < 0.001) as well as surrogate measures for advanced disease (i.e., frailty: from 63% to 33%; CI: [-36%; -23%], p < 0.001). CONCLUSION: Surrogate measures (symptom burden, performance status) indicate that PC was integrated earlier in the course of the disease after a 1-year phase of "getting started" with EI. Yet, the WHO recommendation alone was too vague to successfully trigger EI of PC. Therefore, the authors advocate the provision of disease specific guidelines to institutionalize EI of PC. Such guidelines have been developed for 19 different malignancies and are presented separately.

Standardizing integration of palliative care into comprehensive cancer therapy--a disease specific approach.

BACKGROUND: Our comprehensive cancer centre adopted the WHO recommendation literally in the cancer care guidelines to implement the early integration (EI) of palliative care (PC). Evaluation of the first 2 years of this approach revealed that this guideline was too vague to trigger EI. OBJECTIVE: As a consequence, an interdisciplinary working group was set up to propose and implement a more effective concept. METHODS: An interdisciplinary (PC, oncology, radiotherapy, etc.) working group identified the need to (a) specify the timing of EI and (b) specify PC assignments by (c) providing more clear cut semantic and clinical definitions. As a result of repeated discussion in the different interdisciplinary working groups in charge of developing and consenting a once-yearly update of treatment guidelines [standard operating procedure (SOP)] for each malignancy, the need for disease-specific EI SOPs was identified. RESULTS: SOPs were developed for 19 malignancies (a) to identify a disease-specific point in each disease trajectory to initiate EI ("green flags") and to provide (b) a clear delineation and semantic differentiation of PC assignments ["palliative care" vs. "supportive" or "palliative therapies" ("green" vs. "red flags")]. DISCUSSION: To date, ASCO and WHO recommendations for EI lack detailed information about timing and infrastructure. The guidelines presented here aim to provide the missing information by reporting our developed and consented interdisciplinary guidelines for EI. CONCLUSION: With this concept, the authors provide a framework for realizing EI and hope to initiate a discussion about specific recommendations for EI.

[Conjunctival melanoma : Standard operating procedures in diagnosis, treatment and follow-up care]. / Konjunktivales Melanom : Standardisiertes Vorgehen in Diagnostik, Therapie und Nachsorge.

BACKGROUND: In cases of rare cancer entities, such as malignant melanoma of the conjunctiva, there are often no evidence-based national guidelines available. Standard operating procedures (SOP) are an alternative in these cases. OBJECTIVE: The aim of this project was to develop a consensus SOP for diagnosis, treatment, and follow-up care of conjunctival melanomas between the 14 Centers of Excellence in Germany supported by German Cancer Aid. METHODS: The SOP was prepared according to a defined process including timelines, flow of information, and roles. RESULTS AND CONCLUSION: This is the first consensus SOP of the Centers of Excellence in Germany (certified by the German Cancer Aid) regarding diagnosis, treatment, and follow-up for malignant melanomas of the conjunctiva.

Rituximab added to an intensified salvage chemotherapy program followed by autologous stem cell transplantation improved the outcome in relapsed and refractory aggressive non-Hodgkin lymphoma.

We investigated the addition of rituximab to an intensified salvage program followed by a myeloablative course with autologous stem cell transplantation (ASCT) in patients with relapsed or refractory aggressive non-Hodgkin lymphoma (NHL). Patients with relapsed or progressive aggressive NHL were treated with two cycles of conventional salvage chemotherapy (DHAP) followed by high-dose sequential chemotherapy (cyclophosphamide, methotrexate with vincristine and etoposide) and a final myeloablative course (BEAM) with ASCT. Rituximab (375 mg/m(2)) was administered at each treatment cycle. This cohort was compared with a historical control group of patients treated with the same chemotherapy but without rituximab. Patients from both groups were matched by duration of first remission and lactate dehydrogenase serum levels. Forty-five patients were treated with chemotherapy and 22 with immunochemotherapy. The overall response rates (ORR) at the final evaluation were 63% for the immunochemotherapy group and 42% for the chemotherapy group (p = 0.330). In the historical controlled analysis freedom from second failure (FF2F) at 2 years in the immunochemotherapy group was 57% and overall survival (OS) was 77%. FF2F in the chemotherapy group was 18% (p = 0.0051) and OS was 37% (p = 0.0051). In the matched-pair analysis, FF2F was 58% in the immunochemotherapy group compared to 16% in the chemotherapy group (p = 0.0517); OS was 74 vs 33%, respectively (p = 0.0424). The toxicity was tolerable and comparable in both groups. The addition of rituximab to an intensified salvage chemotherapy regimen seems to improve the prognosis. However, only prospective randomized trial can offer sufficient data of the value of rituximab in relapsed and refractory aggressive NHL.

Salvage radiotherapy in patients with relapsed and refractory Hodgkin's lymphoma: a retrospective analysis from the German Hodgkin Lymphoma Study Group.

PURPOSE: To evaluate treatment outcome and prognostic factors in patients with refractory or first relapsed Hodgkin's disease (HD) treated with salvage radiotherapy (SRT) alone. PATIENTS AND METHODS: From 4,754 patients registered in the database of the German Hodgkin Study Group from 1988 to 1999, 624 patients were identified with progressive disease (n = 202), or with early (n = 170) or late (n = 252) relapsed HD. At first treatment failure, SRT alone was given to 100 patients. Patient characteristics were: median age, 36 years; progressive disease, 47%; early relapse, 23%; late relapse, 30%; and "B" symptoms, 14%. Eighty-five percent of the patients relapsed after cyclophosphamide, vincristine, procarbazine, and prednisone/doxorubicin, bleomycin, vinblastine, and dacarbazine (COPP/ABVD) -like regimens; 8% after bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP) regimens, 7% after first-line radiotherapy alone. RESULTS: The volume irradiated was mantle field in 43% of patients, inverted-Y in 8%, total nodal irradiation in 12%, and involved-field in 37%. The median SRT dose was 40 Gy (range, 15 to 50 Gy). Seventy-seven patients achieved a complete remission and four patients achieved a partial remission. The 5-year freedom from treatment failure and overall survival (OS) rates were 28% and 51%, respectively. In multivariate analysis, significant prognostic factors for OS were B symptoms (P = .018) and stage at relapse (P = .014). For freedom from second failure (FF2F) Karnofsky performance status (P = .0001) was significant. In patients with limited stage at progression/relapse, duration of first remission was significant (P = .04) for FF2F. CONCLUSION: SRT offers an effective treatment for selected subsets of patients with relapsed or refractory HD.

Extramedullary acute myeloid leukemia (granulocytic sarcoma) with arm paresis, maculopapular exanthema and organ involvement.

Granulocytic sarcoma (extramedullary myelosarcoma, chloroma) is a rare extramedullary myeloid tumor which can occur at any anatomical site as isolated finding or associated with acute myelogenous leukemia (AML) or myelodysplastic syndrome (MDS). In this case, we describe a 71-year-old man who presented with incomplete paresis of the left arm, periorbital swelling, a maculopapular exanthema and organ involvement including testis and stomach. The tumors responded to combination chemotherapy and the patient fully recovered. However, after five months the patient relapsed and died quickly. This case confirms the importance of including granulocytic sarcoma in the differential diagnoses of a variety of diseases. In AML, the presence of granulocytic sarcoma is associated with worse overall survival. When diagnosed, it should be treated with intensive chemotherapy as soon as possible.

[Hepatitis-C-virus-associated cryoglobulinemia. Pathogenesis, diagnosis and treatment]. / Hepatitis-C-Virus-assoziierte Kryoglobulinämie Pathogenese, Diagnostik und Therapie.

BACKGROUND: Chronic hepatitis C-virus (HCV) infection is frequently associated with a variety of autoimmune phenomenons. Mixed cryoglobulins appear in up to 50% of chronic HCV-infected patients, mostly asymptomatic. PATHOGENESIS: Cryoprecipitates present IgM with rheumatoid factor activity and development of immunocomplexes deposited in small vessels responsible for resulting vasculitis. MANIFESTATIONS: Characteristic clinical findings are weakness, arthralgia and purpura with further complications including glomerulonephritis and neuropathic lesions. Several mechanisms for HCV-induced clinical lymphoproliferation are discussed, such as chronic B-cell stimulation and activation of the antiapoptotic oncogene bcl-2 leading to immunoglobulin synthesis and eventually evolving into B-cell non-Hodgkin's lymphoma (NHL). TREATMENT: Conventional treatment of HCV-associated mixed cryoglobulinemia aimes at reducing circulating immunocomplexes and causal therapy with interferon (IFN) and ribavirin. New approaches using the anti-CD20 antibody rituximab have been described recently.

Specifying WHO recommendation: moving toward disease-specific guidelines.

INTRODUCTION: The World Health Organization (WHO) explicitly recommends the integration of palliative care (PC) early in the disease trajectory as part of the WHO definition of PC. Our comprehensive cancer center decided: (1) to include this recommendation in the administrative directives for principles of cancer care and (2) to establish a PC hospital support team. The evaluation of this approach revealed that patients with lung cancer still received PC rather late in the course of the disease. Therefore, we decided to additionally develop disease-specific standard operating procedures (SOPs) to try to overcome these deficiencies. The first SOP was completed for patients with lung cancer. STANDARD OPERATING PROCEDURE (Consensus SOP): Specifically, the SOP states that: "Specialized PC is recommended regularly for all lung cancer patients without curative treatment options, specifically patients with (i) metastasized and inoperable or (ii) locally advanced and inoperable or (iii) relapsing lung cancer. Integration of PC is recommended simultaneously to starting tumor-specific therapy. In this context, initial PC should be delivered to the patient at the same place as specific treatment, which is the interdisciplinary outpatient unit of the Center of Integrated Oncology (CIO) or an oncological ward." DISCUSSION: This SOP for the first time presents disease-specific guidelines for PC integration into comprehensive (lung) cancer therapy by (1) defining "green flags" for early integration of PC and (2) recommending PC parallel to initiation of anticancer therapy. Furthermore, clear definitions are provided to delineate PC assignments. Such disease-specific algorithms should be helpful to further reduce uncertainty about the way PC can be integrated early in the course of the disease.

Outcome of patients experiencing progression or relapse after primary treatment with two cycles of chemotherapy and radiotherapy for early-stage favorable Hodgkin's lymphoma.

PURPOSE: To evaluate treatment outcome of patients with early-stage favorable Hodgkin's lymphoma (HL) who experience disease relapse after primary treatment with two cycles of chemotherapy followed by radiotherapy (RT). PATIENTS AND METHODS: Of 1,129 patients with early-stage favorable HL enrolled onto the HD7/HD10/HD13 trials of the German Hodgkin Study Group, 42 patients were identified with treatment failure, of whom eight had primary progressive disease, seven had early relapse (< or = 12 months), and 27 had late relapse (> 12 months). We analyzed this group of patients for risk factors, salvage therapy, and treatment outcome. RESULTS: The median age was 41 years (range, 19 to 72 years); 24 patients were male, 15 patients had outfield relapse, 13 patients infield relapse, and nine patients outfield and infield relapse. At relapse, 24 patients were treated with conventional salvage chemotherapy, 14 patients were treated with high-dose chemotherapy followed by autologous stem-cell transplantation, and four patients were treated with RT alone. At 36 months median follow-up, freedom from second treatment failure (FF2F) and overall survival (OS) were 52% and 67%, respectively. According to the prognostic score for relapsed HL (duration of first remission, clinical stage, and anemia at relapse), patients with two or three poor prognostic features had a significantly worse outcome compared with patients with none or one of these factors (P < .05 for FF2F and OS). CONCLUSION: Relapse after primary treatment with two cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine followed by RT is rare. In our analysis, results were influenced by a high treatment-related mortality rate. Additional studies are needed to define the optimal salvage therapy.

Autologous tandem transplantation in patients with primary progressive or relapsed/refractory lymphoma.

Patients with primary progressive or refractory Hodgkin's disease (HD) or aggressive non-Hodgkin's lymphoma (NHL) have a particularly poor prognosis. Here we report the results of autologous tandem transplantation in these patients. Patients aged 18-55 years with primary progressive or refractory relapsed HD and aggressive NHL were included. Patients received high-dose etoposide (2000 mg/m(2)) followed by peripheral blood stem cell harvest (PBSC). The first high-dose chemotherapy (TMC) consisted of thiotepa (750 mg/m(2)), mitoxantrone (40 mg/m(2)), and carboplatin (990 mg/m(2)). Patients with no change (NC), partial remission (PR), or complete remission (CR) after TMC then received BEAM with carmustine (300 mg/m(2)), etoposide (1200 mg/m(2)), cytarabine (1600 mg/m(2)), and melphalan (140 mg/m(2)). Patients with bulky disease (>5 cm) or residual lymphoma received involved field radiotherapy. Twenty-five patients were included (HD=10, NHL=15, median age 34 years). Two patients with HD achieved a CR and five patients a PR [response rate (RR) 70%]. Three patients (30%) experienced treatment failure including two deaths due to peritransplant complications. Five patients with aggressive NHL were in CR and two patients in PR (RR 46%). Of the eight patients (56%) with treatment failure, three had progressive disease and five died from peritransplant complications. Freedom from treatment failure (FFTF) and overall survival (OS) for all patients after 12 months was 28% and 40%, respectively. Tandem HDCT followed by autologous stem cell transplantation (ASCT) offers a chance of cure in these poor prognostic patients, but is associated with risks.

New treatments for Hodgkin's disease.

Four of five patients with Hodgkin's disease (HD) will be cured with modern treatment strategies, depending on stage and risk factor profile. In early stage favorable HD, cure rates are greater than 90% with extended field (EF) irradiation, the standard treatment. However, the concept of EF irradiation therapy is being abandoned by most study groups because of the recognition of fatal long-term effects, especially the high rates of second solid tumors. Newer approaches include mild chemotherapy combined with involved field (IF) irradiation to control occult disease. Combined modality is the treatment of choice in early stages unfavorable (intermediate) HD, in which EF irradiation is substituted by IF irradiation. In the last three decades, because of the high relapse rates (30%-50%) after first-line polychemotherapy, the standard regimens were often modified. However, until recently, these efforts could not change the relatively poor outcome for patients with advanced stage disease. The introduction of a new dose-intensified regimen (BEACOPP) has significantly improved the prognosis for patients with advanced HD. Patients who relapse after radiation therapy alone for early stage HD have satisfactory results with combination chemotherapy and are not considered as candidates for high-dose chemotherapy with autologous stem cell transplantation. For patients with relapsed HD after combination chemotherapy, the data support the use of high-dose chemotherapy with autologous stem cell transplantation.