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A randomized trial suggests that patients with negative PET-CT findings after two cycles of ABVD may have the bleomycin dropped from the regimen for the final four cycles. The omission of bleomycin reduced pulmonary toxic effects without reducing overall survival. The treatment of advanced-stage Hodgkin’s lymphoma with chemotherapy has produced high survival rates. A series of randomized trials has confirmed that doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD), first described more than 40 years ago, 1 yields cure rates of 70 to 80%, similar to the rates observed with more complex multidrug regimens. 2 – 7 The possible exception is escalated therapy with bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP), with higher-than-standard doses of etoposide, doxorubicin, and cyclophosphamide. 8 This escalated regimen has been shown to yield higher progression-free survival rates than ABVD among previously untreated patients. 9 , 10 Trials in which ABVD and . . .

The intensive polychemotherapy regimen eBEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone in escalated doses) is very active in patients with advanced-stage Hodgkin's lymphoma, albeit at the expense of severe toxicities. Individual patients might be cured with less burdensome therapy. We investigated whether metabolic response determined by PET after two cycles of standard regimen eBEACOPP (PET-2) would allow adaption of treatment intensity, increasing it for PET-2-positive patients and reducing it for PET-2-negative patients. In this open-label, randomised, parallel-group phase 3 trial, we recruited patients aged 18–60 years with newly diagnosed, advanced-stage Hodgkin's lymphoma in 301 hospitals and private practices in Germany, Switzerland, Austria, the Netherlands, and the Czech Republic. After central review of PET-2, patients were assigned (1:1) to one of two parallel treatment groups on the basis of their PET-2 result. Patients with positive PET-2 were randomised to receive six additional cycles of either standard eBEACOPP (8 × eBEACOPP in total) or eBEACOPP with rituximab (8 × R-eBEACOPP). Those with negative PET-2 were randomised between standard treatment with six additional cycles of eBEACOPP (8 × eBEACOPP) or experimental treatment with two additional cycles (4 × eBEACOPP). A protocol amendment in June, 2011, introduced a reduction of standard therapy to 6 × eBEACOPP; after this point, patients with positive PET-2 were no longer randomised and were all assigned to receive 6 × eBEACOPP and patients with negative PET-2 were randomly assigned to 6 × eBEACOPP (standard) or 4 × eBEACOPP (experimental). Randomisation was done centrally using the minimisation method including a random component, stratified according to centre, age (<45 vs ≥45 years), stage (IIB, IIIA vs IIIB, IV), international prognostic score (0–2 vs 3–7), and sex. eBEACOPP was given as previously described; rituximab was given intravenously at a dose of 375 mg/m2 (maximum total dose 700 mg). The primary objectives were to show superiority of the experimental treatment in the PET-2-positive cohort, and to show non-inferiority of the experimental treatment in the PET-2-negative cohort in terms of the primary endpoint, progression-free survival. We defined non-inferiority as an absolute difference of 6% in the 5-year progression-free survival estimates. Primary analyses in the PET-2-negative cohort were per protocol; all other analyses were by intention to treat. This trial was registered with ClinicalTrials.gov, number NCT00515554. Between May 14, 2008, and July 18, 2014, we recruited 2101 patients, of whom 137 were found ineligible before randomisation and a further 19 were found ineligible after randomisation. Among 434 randomised patients (217 per arm) with positive PET-2, 5-year progression-free survival was 89·7% (95% CI 85·4–94·0) with eBEACOPP and 88·1% (83·5–92·7) with R-eBEACOPP (log-rank p=0·46). Patients with negative PET-2 randomly assigned to either 8 × eBEACOPP or 6 × eBEACOPP (n=504) or 4 × eBEACOPP (n=501) had 5-year progression-free survival of 90·8% (95% CI 87·9–93·7) and 92·2% (89·4–95·0), respectively (difference 1·4%, 95% CI −2·7 to 5·4). 4 × eBEACOPP was associated with fewer severe infections (40 [8%] of 498 vs 75 [15%] of 502) and organ toxicities (38 [8%] of 498 vs 91 [18%] of 502) than were 8 × eBEACOPP or 6 × eBEACOPP in PET-2-negative patients. Ten treatment-related deaths occurred: four in the PET-2-positive cohort (one [<1%] in the 8 × eBEACOPP group, three [1%] in the 8 × R-eBEACOPP group) and six in the PET-2-negative group (six [1%] in the 8 × eBEACOPP or 6 × eBEACOPP group). The favourable outcome of patients treated with eBEACOPP could not be improved by adding rituximab after positive PET-2. PET-2 negativity allows reduction to only four cycles of eBEACOPP without loss of tumour control. PET-2-guided eBEACOPP provides outstanding efficacy for all patients and increases overall survival by reducing treatment-related risks for patients with negative PET-2. We recommend this PET-2-guided treatment strategy for patients with advanced-stage Hodgkin's lymphoma. Deutsche Krebshilfe, Swiss State Secretariat for Education and Research, and Roche Pharma AG.

Among patients with early-stage Hodgkin's lymphoma who have negative PET findings after three cycles of chemotherapy, radiotherapy produces a 3.8-percentage-point improvement in 3-year progression-free survival. However, 90% of patients are cured by chemotherapy alone. Long-term survival in early-stage Hodgkin’s lymphoma was first made possible by the introduction of the mantle 1 and inverted Y 2 fields of radiotherapy in the 1960s. The addition of adjuvant mechlorethamine, vincristine, procarbazine, and prednisone (MOPP)–like chemotherapies improved progression-free survival rates, 3 but these chemotherapies were associated with severe emesis, 4 gonadal dysfunction, 5 , 6 and in rare cases, secondary leukemia. 7 Evidence of late toxic effects of mantle-field radiotherapy, such as hypothyroidism, 8 second cancers (especially of the breast 9 and lung 10 ), and cardiovascular disease, 11 , 12 also emerged. Thus, it was increasingly apparent that cure was bought at a high price and that less damaging . . .

The intensity of chemotherapy and need for additional radiotherapy in patients with advanced stage Hodgkin's lymphoma has been unclear. We did a prospective randomised clinical trial comparing two reduced-intensity chemotherapy variants with our previous standard regimen. Chemotherapy was followed by PET-guided radiotherapy. In this parallel group, open-label, multicentre, non-inferiority trial (HD15), 2182 patients with newly diagnosed advanced stage Hodgkin's lymphoma aged 18–60 years were randomly assigned to receive either eight cycles of BEACOPPescalated (8×Besc group), six cycles of BEACOPPescalated (6×Besc group), or eight cycles of BEACOPP14 (8×B14 group). Randomisation (1:1:1) was done centrally by stratified minimisation. Non-inferiority of the primary endpoint, freedom from treatment failure, was assessed using repeated CIs for the hazard ratio (HR) according to the intention-to-treat principle. Patients with a persistent mass after chemotherapy measuring 2·5 cm or larger and positive on PET scan received additional radiotherapy with 30 Gy; the negative predictive value for tumour recurrence of PET at 12 months was an independent endpoint. This trial is registered with Current Controlled Trials, number ISRCTN32443041. Of the 2182 patients enrolled in the study, 2126 patients were included in the intention-to-treat analysis set, 705 in the 8×Besc group, 711 in the 6×Besc group, and 710 in the 8×B14 group. Freedom from treatment failure was sequentially non-inferior for the 6×Besc and 8×B14 groups as compared with 8×Besc. 5-year freedom from treatment failure rates were 84·4% (97·5% CI 81·0–87·7) for the 8×Besc group, 89·3% (86·5–92·1) for 6×Besc group, and 85·4% (82·1–88·7) for the 8×B14 group (97·5% CI for difference between 6×Besc and 8×Besc was 0·5–9·3). Overall survival in the three groups was 91·9%, 95·3%, and 94·5% respectively, and was significantly better with 6×Besc than with 8×Besc (97·5% CI 0·2–6·5). The 8×Besc group showed a higher mortality (7·5%) than the 6×Besc (4·6%) and 8×B14 (5·2%) groups, mainly due to differences in treatment-related events (2·1%, 0·8%, and 0·8%, respectively) and secondary malignancies (1·8%, 0·7%, and 1·1%, respectively). The negative predictive value for PET at 12 months was 94·1% (95% CI 92·1–96·1); and 225 (11%) of 2126 patients received additional radiotherapy. Treatment with six cycles of BEACOPPescalated followed by PET-guided radiotherapy was more effective in terms of freedom from treatment failure and less toxic than eight cycles of the same chemotherapy regimen. Thus, six cycles of BEACOPPescalated should be the treatment of choice for advanced stage Hodgkin's lymphoma. PET done after chemotherapy can guide the need for additional radiotherapy in this setting. Deutsche Krebshilfe and the Swiss Federal Government.

BEACOPP combination chemotherapy was compared with ABVD chemotherapy in advanced Hodgkin's disease. BEACOPP therapy was associated with higher initial rates of complete response and freedom from relapse but also with more short-term and long-term toxic effects. The regimen of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) was introduced in the mid-1970s as treatment for advanced Hodgkin's lymphoma 1 and became the standard of treatment for this disease after trials showed that ABVD was as effective as, or more effective than, the regimen of mechlorethamine, vincristine, procarbazine, and prednisone (MOPP), with fewer toxic effects. 2 More recently, the German Hodgkin Lymphoma Study Group (GHSG) has developed a front-line intensified regimen consisting of bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (escalated BEACOPP regimen, which includes higher-than-standard doses of etoposide, doxorubicin, and cyclophosphamide). This regimen, as compared with COPP-ABVD, has been . . .

In patients with limited-stage Hodgkin's disease, ABVD chemotherapy alone resulted in a higher rate of long-term (12-year) survival than either radiation therapy alone or radiation therapy plus ABVD chemotherapy, with significantly fewer late treatment-related deaths. Twenty years ago, the standard strategy in the case of patients with stage IA or IIA nonbulky Hodgkin's lymphoma included staging by means of laparotomy and subtotal nodal radiation therapy. 1 , 2 With this treatment, 70 to 80% of patients were cured, but they remained at risk for premature death from late radiation-induced adverse effects, including second cancers and cardiovascular disease. 3 – 6 Subsequent clinical trials showed that combining radiation with chemotherapy eliminated the need for staging laparotomy, allowed for reduced doses and target volumes of radiation, and resulted in long-term control of the disease for 90% of the patients. 7 – 11 A . . .

Background: A phase III trial was conducted to determine whether neoadjuvant chemotherapy (NACT) before radical surgery (RS) improves overall survival. Methods: Patients with stage IB2, IIA2, or IIB squamous cell carcinoma of the uterine cervix were randomly assigned to receive either BOMP (bleomycin 7 mg days 1–5, vincristine 0.7 mg m −2 day 5, mitomycin 7 mg m −2 day 5, cisplatin 14 mg m −2 days 1–5, every 3 weeks for 2 to 4 cycles) plus RS (NACT group) or RS alone (RS group). Patients with pathological high-risk factors received postoperative radiotherapy (RT). The primary end point was overall survival. Results: A total of 134 patients were randomly assigned to treatment. This study was prematurely terminated at the first planned interim analysis because overall survival in the NACT group was inferior to that in the RS group. Patients who received postoperative RT were significantly lower in the NACT group (58%) than in the RS group (80%; P =0.015). The 5-year overall survival was 70.0% in the NACT group and 74.4% in the RS group ( P =0.85). Conclusion: Neoadjuvant chemotherapy with BOMP regimen before RS did not improve overall survival, but reduced the number of patients who received postoperative RT.

Photochemical internalisation, a novel minimally invasive treatment, has shown promising preclinical results in enhancing and site-directing the effect of anticancer drugs by illumination, which initiates localised chemotherapy release. We assessed the safety and tolerability of a newly developed photosensitiser, disulfonated tetraphenyl chlorin (TPCS2a), in mediating photochemical internalisation of bleomycin in patients with advanced and recurrent solid malignancies. In this phase 1, dose-escalation, first-in-man trial, we recruited patients (aged ≥18 to <85 years) with local recurrent, advanced, or metastatic cutaneous or subcutaneous malignancies who were clinically assessed as eligible for bleomycin chemotherapy from a single centre in the UK. Patients were given TPCS2a on day 0 by slow intravenous injection, followed by a fixed dose of 15 000 IU/m2 bleomycin by intravenous infusion on day 4. After 3 h, the surface of the target tumour was illuminated with 652 nm laser light (fixed at 60 J/cm2). The TPCS2a starting dose was 0·25 mg/kg and was then escalated in successive dose cohorts of three patients (0·5, 1·0, and 1·5 mg/kg). The primary endpoints were safety and tolerability of TPCS2a; other co-primary endpoints were dose-limiting toxicity and maximum tolerated dose. The primary analysis was per protocol. This study is registered with ClinicalTrials.gov, number NCT00993512, and has been completed. Between Oct 3, 2009, and Jan 14, 2014, we recruited 22 patients into the trial. 12 patients completed the 3-month follow-up period. Adverse events related to photochemical internalisation were either local, resulting from the local inflammatory process, or systemic, mostly as a result of the skin-photosensitising effect of TPCS2a. The most common grade 3 or worse adverse events were unexpected higher transient pain response (grade 3) localised to the treatment site recorded in nine patients, and respiratory failure (grade 4) noted in two patients. One dose-limiting toxicity was reported in the 1·0 mg/kg cohort (skin photosensitivity [grade 2]). Dose-limiting toxicities were reported in two of three patients at a TPCS2a dose of 1·5 mg/kg (skin photosensitivity [grade 3] and wound infection [grade 3]); thus, the maximum tolerated dose of TPCS2a was 1·0 mg/kg. Administration of TPCS2a was found to be safe and tolerable by all patients. No deaths related to photochemical internalisation treatment occurred. TPCS2a-mediated photochemical internalisation of bleomycin is safe and tolerable. We identified TPCS2a 0·25 mg/kg as the recommended treatment dose for future trials. PCI Biotech.

Safety and efficacy of intrapericardial (ipc) instillation of bleomycin (BLM) following pericardial drainage in patients with malignant pericardial effusion (MPE) remain unclear. Patients with pathologically documented lung cancer, who had undergone pericardial drainage for MPE within 72 h of enrolment, were randomised to either arm A (observation alone after drainage) or arm B (ipc BLM at 15 mg, followed by additional ipc BLM 10 mg every 48 h). The drainage tube was removed when daily drainage was 20 ml or less. The primary end point was survival with MPE control (effusion failure-free survival, EFFS) at 2 months. Eighty patients were enrolled, and 79 were eligible. Effusion failure-free survival at 2 months was 29% in arm A and 46% in arm B (one-sided P =0.086 by Fisher’s exact test). Arm B tended to favour EFFS, with a hazard ratio of 0.64 (95% confidence interval: 0.40–1.03, one-sided P =0.030 by log-rank test). No significant differences in the acute toxicities or complications were observed. The median survival was 79 days and 119 days in arm A and arm B, respectively. This medium-sized trial failed to show statistical significance in the primary end point. Although ipc BLM appeared safe and effective in the management of MPE, the therapeutic advantage seems modest.

Background Bleomycin, etoposide, and cisplatin (BEP) chemotherapy administered every 3 weeks for 4 cycles remains the standard first line treatment for patients with intermediate- and poor-risk metastatic germ cell tumours (GCTs). Administering standard chemotherapy 2-weekly rather than 3-weekly, so-called ‘accelerating chemotherapy’, has improved cure rates in other cancers. An Australian multicentre phase 2 trial demonstrated this regimen is feasible and tolerable with efficacy data that appears promising. The aim of this trial is to determine if accelerated BEP is superior to standard BEP as first line chemotherapy for adult and paediatric male and female participants with intermediate and poor risk metastatic GCTs. Methods This is an open label, randomised, stratified, 2-arm, international multicentre, 2 stage, phase 3 clinical trial. Participants are randomised 1:1 to receive accelerated BEP or standard BEP chemotherapy. Eligible male or female participants, aged between 11 and 45 years with intermediate or poor-risk metastatic GCTs for first line chemotherapy will be enrolled from Australia, the United Kingdom and the United States. Participants will have regular follow up for at least 5 years. The primary endpoint for stage 1 of the trial ( n  = 150) is complete response rate and for the entire trial ( n  = 500) is progression free survival. Secondary endpoints include response following treatment completion (by a protocol-specific response criteria), adverse events, health-related quality of life, treatment preference, delivered dose-intensity of chemotherapy (relative to standard BEP), overall survival and associations between biomarkers (to be specified) and their correlations with clinical outcomes. Discussion This is the first international randomised clinical trial for intermediate and poor-risk metastatic extra-cranial GCTs involving both adult and pediatric age groups open to both males and females. It is also the largest, current randomised trial for germ cell tumours in the world. Positive results for this affordable intervention could change the global standard of care for intermediate and poor risk germ cell tumours, improve cure rates, avoid the need for toxic and costly salvage treatment, and return young adults to long, healthy and productive lives. Trial registration ACTRN 12613000496718 on 3rd May 2013 and Clinicaltrials.gov NCT02582697 on 21st October 2015.