Improved survival outcomes despite older age at diagnosis: an era-by-era analysis of patients with primary central nervous system lymphoma treated at a single referral centre in the United Kingdom.

Observational studies with long-term follow-up of patients with primary central nervous system lymphoma (PCNSL) are scarce. Patient data over a period of four decades were retrospectively analysed from databases at Nottingham University Hospitals Trust, UK. The cohort was delineated by two distinct therapeutic eras; the first from 01/01/1982 to 31/12/2010 (n = 147) and the second 01/01/2011 to 31/07/2020 (n = 125). The median age at diagnosis was significantly older in the second era compared to the first (69 and 65 years respectively, P = 0·003). The 3-, 6- and 12-month overall survival (OS) rates in the second era were significantly higher compared to the first, at 85%, 77%, 62% versus 56%, 49%, 38% respectively (log-rank test P < 0·0001). On multivariate analysis, high-dose methotrexate (HD-MTX)-based induction protocols employed in the second era were associated with improved OS compared to those used in the first [hazard ratio (HR) 0·40, 95% confidence interval (CI) 0·28-0·57]. Within the second era, superior OS rates were seen with the use of intensive HD-MTX protocols (including consolidation with high-dose chemotherapy and autologous stem cell transplantation) compared to non-intensive HD-MTX schedules (HR 0·47, 95% CI 0·22-0·99). Initiating chemotherapy within 14 days of biopsy and use of rituximab were independently associated with improved OS and progression-free survival during the second era. These data suggest that prompt treatment initiation and use of intensive HD-MTX- and rituximab-based protocols have resulted in improved survival outcomes for patients.

Hodgkin disease (1973-2002): long-term survival and cure fractions.

The Nottinghamshire Lymphoma Registry contains the details of all patients diagnosed with lymphoma (since 1 January 1973) within a defined geographical area with a stable population of 1.1 million. The aim of this study was to investigate the relative survival and estimate the cure fraction for patients with Hodgkin disease (HD) using various cure fraction models. Five- and 10-year survival was estimated in comparison to the general population of the same age, gender and year of diagnosis. Relative survival probabilities at 10 years were 52.3% for the 1973-1982 cohort, 67.8% (1983-1992) and 75.7% (1993-2002). The estimated cured fraction (π) was 45%, 65% and 75%, respectively, for the same cohorts. There was very little excess mortality after 4 years from treatment. The prognosis of patients with HD has improved progressively within a defined unselected population over this 30-year period. In the 1993-2002 cohort the prognosis after 4 years of treatment is almost the same as for a normal population.

Intermittent versus continuous oxaliplatin and fluoropyrimidine combination chemotherapy for first-line treatment of advanced colorectal cancer: results of the randomised phase 3 MRC COIN trial.

BACKGROUND: When cure is impossible, cancer treatment should focus on both length and quality of life. Maximisation of time without toxic effects could be one effective strategy to achieve both of these goals. The COIN trial assessed preplanned treatment holidays in advanced colorectal cancer to achieve this aim. METHODS: COIN was a randomised controlled trial in patients with previously untreated advanced colorectal cancer. Patients received either continuous oxaliplatin and fluoropyrimidine combination (arm A), continuous chemotherapy plus cetuximab (arm B), or intermittent (arm C) chemotherapy. In arms A and B, treatment continued until development of progressive disease, cumulative toxic effects, or the patient chose to stop. In arm C, patients who had not progressed at their 12-week scan started a chemotherapy-free interval until evidence of disease progression, when the same treatment was restarted. Randomisation was done centrally (via telephone) by the MRC Clinical Trials Unit using minimisation. Treatment allocation was not masked. The comparison of arms A and B is described in a companion paper. Here, we compare arms A and C, with the primary objective of establishing whether overall survival on intermittent therapy was non-inferior to that on continuous therapy, with a predefined non-inferiority boundary of 1.162. Intention-to-treat (ITT) and per-protocol analyses were done. This trial is registered, ISRCTN27286448. FINDINGS: 1630 patients were randomly assigned to treatment groups (815 to continuous and 815 to intermittent therapy). Median survival in the ITT population (n=815 in both groups) was 15.8 months (IQR 9.4-26.1) in arm A and 14.4 months (8.0-24.7) in arm C (hazard ratio [HR] 1.084, 80% CI 1.008-1.165). In the per-protocol population (arm A, n=467; arm C, n=511), median survival was 19.6 months (13.0-28.1) in arm A and 18.0 months (12.1-29.3) in arm C (HR 1.087, 0.986-1.198). The upper limits of CIs for HRs in both analyses were greater than the predefined non-inferiority boundary. Preplanned subgroup analyses in the per-protocol population showed that a raised baseline platelet count, defined as 400,000 per µL or higher (271 [28%] of 978 patients), was associated with poor survival with intermittent chemotherapy: the HR for comparison of arm C and arm A in patients with a normal platelet count was 0.96 (95% CI 0.80-1.15, p=0.66), versus 1.54 (1.17-2.03, p=0.0018) in patients with a raised platelet count (p=0.0027 for interaction). In the per-protocol population, more patients on continuous than on intermittent treatment had grade 3 or worse haematological toxic effects (72 [15%] vs 60 [12%]), whereas nausea and vomiting were more common on intermittent treatment (11 [2%] vs 43 [8%]). Grade 3 or worse peripheral neuropathy (126 [27%] vs 25 [5%]) and hand-foot syndrome (21 [4%] vs 15 [3%]) were more frequent on continuous than on intermittent treatment. INTERPRETATION: Although this trial did not show non-inferiority of intermittent compared with continuous chemotherapy for advanced colorectal cancer in terms of overall survival, chemotherapy-free intervals remain a treatment option for some patients with advanced colorectal cancer, offering reduced time on chemotherapy, reduced cumulative toxic effects, and improved quality of life. Subgroup analyses suggest that patients with normal baseline platelet counts could gain the benefits of intermittent chemotherapy without detriment in survival, whereas those with raised baseline platelet counts have impaired survival and quality of life with intermittent chemotherapy and should not receive a treatment break. FUNDING: Cancer Research UK.

Increasing age at diagnosis and worsening renal function in patients with primary central nervous system lymphoma.

High-dose Methotrexate (MTX) is the most useful cytotoxic drug used in the treatment of primary central nervous system lymphoma (PCNSL). Dose reduction should be made in patients with reduced renal function. We evaluated the age of patients over a period of 22 years and estimated their glomerular filtration rate. One hundred and two patients were treated in Nottingham University Hospitals (a regional centre for neurosurgery) during the period 1986-2008. Patients were treated either with the BVAM regimen (carmustine, vincristine, cytarabine, MTX) or with CHOD (cyclophosphamide, doxorubicin, vincristine and dexamethasone) given for one cycle prior to BVAM. The age at which patients were diagnosed with PCNSL increased during the period of the study. During the first half of the study period (1986-1997) the median age was 60.5 years, compared to a median age of 65 years during the second half of the study period (1998-2008) (P = 0.001). The estimated glomerular filtration rate decreased with age over 40 years in a similar way to the general population. The increasing age of patients with PCNSL and decreasing renal function limit the intensity of chemotherapy with MTX containing regimens.

The pathological response to neoadjuvant chemotherapy with FOLFOX-4 for colorectal liver metastases: a comparative study.

FOLFOX-4 (folinic acid/5-fluorouracil/oxaliplatin) chemotherapy is used to treat patients with colorectal liver metastases. We aimed to assess hepatic histopathological responses to neoadjuvant FOLFOX-4 chemotherapy in patients with colorectal liver metastases. We selected all patients (n = 54) treated with FOLFOX-4 for colorectal liver metastases between June 2002 and June 2005. Only 25 underwent hepatectomy and formed the study group. Histological responses were assessed in the study group and a matched control group (n = 25) that did not receive neoadjuvant chemotherapy. The median (IQR) body mass index in the study and control groups was 24 (22-26) and 24 (23-25) kg/m(2), respectively, (P = NS). Complete histological resolution of tumour occurred in six (24%) patients in the study group. Median residual tumour cellularity was less (35 vs 70%) and fibrosis greater (50 vs 5%) in patients in the study group when compared with controls (P < 0.001). The liver surrounding the tumour was steatotic in 17 (68%) patients in the study group and five (20%) controls (P = 0.001). Hepatic sinusoidal dilatation was more pronounced in patients in the study group than in controls (P < 0.001). The response to FOLFOX-4 was associated with tumour necrosis, fibrosis and inflammation. More than two thirds of patients undergoing hepatectomy after FOLFOX-4 had steatosis despite being non-obese.

Primary central nervous system lymphoma: biological aspects and controversies in management.

INTRODUCTION: This review was produced from the workshop on primary central nervous system lymphoma (PCNSL) at the European Cancer Conference (ECCO 13) in Paris in 2005. It covers the presentation and biological features of the disease (Professor Khe Hoang-Xuan). The role of chemotherapy, including the management of intraocular lymphoma and the use of high dose chemotherapy followed by autologous stem cell transplantation for PCNSL, is discussed (Dr. Andres Ferreri) as well as controversies in the use of whole brain radiotherapy (WBRT) after chemotherapy (Dr. Michele Reni). The topics covered with discussants at the workshop are also summarised. CONCLUSION: The imaging of the brain and the histopathology including detailed immunohistochemistry is of vital importance in making an accurate diagnosis of the disease and understanding the extent of spread of the disease in the CNS. The importance of high dose methotrexate (HDMTX; dose > or = 1g/m(2)), as the most active drug in the treatment of PCNSL, is stressed. The authors recommend that HDMTX alone or in combination with other active chemotherapy agents should be used to treat PCNSL followed by whole brain radiotherapy (WBRT) unless contraindicated because of the advanced age of the patient and existing cognitive impairment. Only published protocols should be used unless the patient is to be offered a trial that has either national or international support. Baseline neuropsychological tests should be carried out before treatment and repeated during and after treatment. The risks of cognitive impairment associated with the disease, with methotrexate - containing chemotherapy and with whole brain radiotherapy should be explained to patients and relatives when obtaining informed consent. Long-term survival, with current treatment regimes, is possible with PCNSL but this appears limited to patients less than 60 years of age at presentation (mostly patients less than 50 years of age).

Primary non-Hodgkin's lymphoma of the CNS treated with CHOD/BVAM or BVAM chemotherapy before radiotherapy: long-term survival and prognostic factors.

PURPOSE: To assess the long-term survival and prognostic factors associated with the cyclophosphamide, doxorubicin, vincristine, and dexamethasone (CHOD)/carmustine, vincristine, methotrexate, and cytarabine (BVAM) and BVAM chemotherapy regimens followed by cranial radiotherapy in the treatment of primary central nervous system (CNS) non-Hodgkin lymphoma. METHODS AND MATERIALS: Since 1986, high-dose methotrexate (1.5 g/m(2)), cytarabine, vincristine, and carmustine have been used in the BVAM chemotherapy regimen for primary CNS non-Hodgkin's lymphoma, with one cycle of CHOD given before BVAM in patients or=60 years, performance status >or=2, and multifocal and/or meningeal disease [advanced stage]), a score of 0 (8 patients) was associated with a median survival of 55 months, a score of 1 (29 patients) of 41 months, a score of 2 (28 patients) of 32 months, and a score of 3 (12 patients) a median survival of 1 month (p <0.001). The actuarial overall survival for the 35 patients aged <60 years was 32.4% (95% confidence interval, 14.1-50.8%) at 10 years. CONCLUSION: The Nottingham/Barcelona prediction score, which is similar to the International Prognostic Index, may be useful in comparing survival with different regimens studied in Phase II trials. Patients with primary CNS non-Hodgkin's lymphoma aged <60 years treated with CHOD/BVAM or BVAM followed by radiotherapy have a similar long-term survival to that of patients with large B cell non-Hodgkin's lymphoma at other extranodal sites.

Salvage treatment with etoposide (VP-16), ifosfamide and cytarabine (Ara-C) for patients with recurrent primary central nervous system lymphoma.

BACKGROUND: Survival of patients with primary central nervous system lymphoma (PCNSL) has improved with methotrexate-based combination regimens and radiotherapy (RT). However, the prognosis of patients who fail or relapse after initial response is poor. Very little data is available on salvage treatment at recurrence. PATIENTS AND METHODS: Sixteen immunocompetent patients (13 males/three females, median age 54 yr) with refractory (one patient) or recurrent (15 patients) PCNSL, homogeneously treated at diagnosis with the cyclophosphamide, doxorubicin, vincristine, dexamethasone/carmustine, vincristine, cytarabine and methotrexate (CHOD/BVAM) and RT regimen, received etoposide (VP-16), ifosfamide and cytarabine (Ara-C) (VIA) chemotherapy as a salvage treatment. VIA included etoposide 100 mg/m2/d days 1-3, ifosfamide 1000 mg/m2/d days 1-5, and cytarabine 2000 mg/m2/12 h day 1. The therapy was repeated every 28 d for a total of planned six cycles. RESULTS: Median time between first complete response (CR) and relapse was 19 months (range: 6-46 months). Thirteen patients (81%) had a performance status

A case of primary non-Hodgkin's lymphoma of the transverse colon presenting as inflammatory bowel disease.

Primary colonic lymphoma (PCL) is uncommon. We report such a case in a 76-year-old man who presented with diarrhoea and a barium enema that suggested a diagnosis of inflammatory bowel disease (IBD). However, subsequent endoscopy confirmed the diagnosis of PCL. PCL is a rare entity and can be misdiagnosed as IBD because of the symptoms and radiological findings. The correct diagnosis is important, since the management of these two conditions is entirely different.