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.

Delineating outcomes of patients with diffuse large b cell lymphoma using the national comprehensive cancer network-international prognostic index and positron emission tomography-defined remission status; a population-based analysis.

The recently devised National Comprehensive Cancer Network International Prognostic Index (NCCN-IPI) appears superior to the revised IPI (R-IPI) in delineating outcome in diffuse large B-cell lymphoma. We examined the outcome of a population-based cohort of 223 consecutive patients treated with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisolone) or R-CHOP-like immuno-chemotherapy between January 2005 and December 2011 by both the NCCN-IPI and R-IPI, and further stratified outcome by the achievement of both computerized tomography (CT) and positron emission tomography (PET)-CT complete remission (CR), with the latter reassessed using blinded central review by an independent nuclear medicine and radiology specialist. The NCCN-IPI was superior to the R-IPI in identifying patients at very high risk of systemic and/or central nervous system relapse. Notably, both the NCCN-IPI and the R-IPI remained strongly predictive of relapse irrespective of CT or PET-defined remission status following R-CHOP. Patients with high-risk NCCN-IPI scores (≥6) have a dismal outcome following R-CHOP therapy regardless of PET-defined response to R-CHOP. Moreover, such patients appear refractory to salvage chemotherapy and thus require alternative therapeutic approaches, although age and performance status may, for many patients, preclude the safe delivery of a primary intensified regimen. By contrast, patients with NCCN-IPI 1-5 who achieve PET-CR following R-CHOP have excellent outcomes and may merit reduced follow up frequency.

Diagnosis and treatment of primary CNS lymphoma in immunocompetent patients: guidelines from the European Association for Neuro-Oncology.

The management of primary CNS lymphoma is one of the most controversial topics in neuro-oncology because of the complexity of the disease and the very few controlled studies available. In 2013, the European Association of Neuro-Oncology created a multidisciplinary task force to establish evidence-based guidelines for immunocompetent adults with primary CNS lymphoma. In this Review, we present these guidelines, which provide consensus considerations and recommendations for diagnosis, assessment, staging, and treatment of primary CNS lymphoma. Specifically, we address aspects of care related to surgery, systemic and intrathecal chemotherapy, intensive chemotherapy with autologous stem-cell transplantation, radiotherapy, intraocular manifestations, and management of elderly patients. The guidelines should aid clinicians in their daily practice and decision making, and serve as a basis for future investigations in neuro-oncology.

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.

Long-Term Medical Follow-Up (for More than 15 Years) of a Patient with Stage IA Mycosis Fungoides Originally Presenting in Childhood: Remission for >15 Years with Localised Electron Beam Therapy.

A man now aged 80 years has received specialist care for stage 1A mycosis fungoides for 58 years. The disease developed in childhood. Long-term follow-up (>30 years) of patients with mycosis fungoides is infrequently described in the world literature. The disease in this patient was limited to 5 areas, but these were large (up to 25 cm in diameter). The rest of the skin was normal clinically. All 5 areas were treated separately with electron beam therapy (3-4 MeV) to a dose of 30 Gy in 15 fractions over 3 weeks between 2000 and 2005. Complete regression was obtained in all 5 areas, and the patient has been in complete remission for 15 years after living with the disease previously for over 40 years.

Preoperative radiotherapy versus selective postoperative chemoradiotherapy in patients with rectal cancer (MRC CR07 and NCIC-CTG C016): a multicentre, randomised trial.

BACKGROUND: Preoperative or postoperative radiotherapy reduces the risk of local recurrence in patients with operable rectal cancer. However, improvements in surgery and histopathological assessment mean that the role of radiotherapy needs to be reassessed. We compared short-course preoperative radiotherapy versus initial surgery with selective postoperative chemoradiotherapy. METHODS: We undertook a randomised trial in 80 centres in four countries. 1350 patients with operable adenocarcinoma of the rectum were randomly assigned, by a minimisation procedure, to short-course preoperative radiotherapy (25 Gy in five fractions; n=674) or to initial surgery with selective postoperative chemoradiotherapy (45 Gy in 25 fractions with concurrent 5-fluorouracil) restricted to patients with involvement of the circumferential resection margin (n=676). The primary outcome measure was local recurrence. Analysis was by intention to treat. This study is registered, number ISRCTN 28785842. FINDINGS: At the time of analysis, which included all participants, 330 patients had died (157 preoperative radiotherapy group vs 173 selective postoperative chemoradiotherapy), and median follow-up of surviving patients was 4 years. 99 patients had developed local recurrence (27 preoperative radiotherapy vs 72 selective postoperative chemoradiotherapy). We noted a reduction of 61% in the relative risk of local recurrence for patients receiving preoperative radiotherapy (hazard ratio [HR] 0.39, 95% CI 0.27-0.58, p<0.0001), and an absolute difference at 3 years of 6.2% (95% CI 5.3-7.1) (4.4% preoperative radiotherapy vs 10.6% selective postoperative chemoradiotherapy). We recorded a relative improvement in disease-free survival of 24% for patients receiving preoperative radiotherapy (HR 0.76, 95% CI 0.62-0.94, p=0.013), and an absolute difference at 3 years of 6.0% (95% CI 5.3-6.8) (77.5%vs 71.5%). Overall survival did not differ between the groups (HR 0.91, 95% CI 0.73-1.13, p=0.40). INTERPRETATION: Taken with results from other randomised trials, our findings provide convincing and consistent evidence that short-course preoperative radiotherapy is an effective treatment for patients with operable rectal cancer.

Effect of the plane of surgery achieved on local recurrence in patients with operable rectal cancer: a prospective study using data from the MRC CR07 and NCIC-CTG CO16 randomised clinical trial.

BACKGROUND: Local recurrence rates in operable rectal cancer are improved by radiotherapy (with or without chemotherapy) and surgical techniques such as total mesorectal excision. However, the contributions of surgery and radiotherapy to outcomes are unclear. We assessed the effect of the involvement of the circumferential resection margin and the plane of surgery achieved. METHODS: In this prospective study, the plane of surgery achieved and the involvement of the circumferential resection margin were assessed by local pathologists, using a standard pathological protocol in 1156 patients with operable rectal cancer from the CR07 and NCIC-CTG CO16 trial, which compared short-course (5 days) preoperative radiotherapy and selective postoperative chemoradiotherapy, between March, 1998, and August, 2005. All analyses were by intention to treat. This trial is registered, number ISRCTN 28785842. FINDINGS: 128 patients (11%) had involvement of the circumferential resection margin, and the plane of surgery achieved was classified as good (mesorectal) in 604 (52%), intermediate (intramesorectal) in 398 (34%), and poor (muscularis propria plane) in 154 (13%). We found that both a negative circumferential resection margin and a superior plane of surgery achieved were associated with low local recurrence rates. Hazard ratio (HR) was 0.32 (95% CI 0.16-0.63, p=0.0011) with 3-year local recurrence rates of 6% (5-8%) and 17% (10-26%) for patients who were negative and positive for circumferential resection margin, respectively. For plane of surgery achieved, HRs for mesorectal and intramesorectal groups compared with the muscularis propria group were 0.32 (0.16-0.64) and 0.48 (0.25-0.93), respectively. At 3 years, the estimated local recurrence rates were 4% (3-6%) for mesorectal, 7% (5-11%) for intramesorectal, and 13% (8-21%) for muscularis propria groups. The benefit of short-course preoperative radiotherapy did not differ in the three plane of surgery groups (p=0.30 for trend). Patients in the short-course preoperative radiotherapy group who had a resection in the mesorectal plane had a 3-year local recurrence rate of only 1%. INTERPRETATION: In rectal cancer, the plane of surgery achieved is an important prognostic factor for local recurrence. Short-course preoperative radiotherapy reduced the rate of local recurrence for all three plane of surgery groups, almost abolishing local recurrence in short-course preoperative radiotherapy patients who had a resection in the mesorectal plane. The plane of surgery achieved should therefore be assessed and reported routinely.

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).

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.

The value of 99mTc-MDP bone scintigraphy in staging primary lymphoma of bone.

AIM: To assess the value of (99m)Tc-MDP bone scintigraphy in the staging of primary bone lymphoma. MATERIALS AND METHODS: Thirteen staging scintigrams of patients with biopsy proven primary bone lymphoma were reviewed. The number and location of involved sites of disease were documented in each case. RESULTS: Seven out of 13 scintigrams (54%) demonstrated a single site of bone involvement. Six cases (46%) showed multifocal disease, including clinically silent weight-bearing sites. CONCLUSIONS: Bone scintigraphy is a valuable tool in the staging of primary bone lymphoma. It detects multifocal involvement which alters prognosis and possibly treatment. Clinically silent involvement of weight-bearing sites may be detected allowing prophylactic treatment if required.

A randomised trial of accelerated radiotherapy for localised invasive bladder cancer.

BACKGROUND AND PURPOSE: To evaluate the efficacy and toxicity of an accelerated fractionation regimen to treat localised muscle invasive bladder cancer. PATIENTS AND METHODS: A prospective randomised trial was undertaken in 229 patients randomised between 1988 and 1998 comparing accelerated fractionation (AF) to a dose of 60.8 Gy in 32 fractions over 26 days with conventional fractionation (CF) treating to 64 Gy in 32 fractions over 45 days. Accelerated fractionation was delivered using two fractions per day with a 6h gap between fractions and with the first daily fraction size being 1.8 Gy and the second daily fraction size being 2.0 Gy. There was a 1 week treatment gap after the first 12 fractions. Conventional fractionation was one fraction per day, 5 days per week. Eligible patients had clinical stage T2 or T3, N0 or N1, M0 transitional cell carcinoma. The primary endpoint of the trial was local control and the trial was powered to detect a 20% difference (alpha 0.05, power 90%). Secondary endpoints were toxicity and survival. RESULTS: In the initial phase of the trial, randomisation was unequal such that in total 129 patients were randomised to accelerated fractionation and 100 to conventional fractionation. Acute toxicity was evaluable in 121 patients treated with AF and 96 patients treated with CF. RTOG grade 2 or 3 bowel toxicity was noted in 44% of AF patients compared to 26% of CF patients (P trend =0.001). Acute grade 2 or 3 bladder toxicity was seen in 35% of AF patients compared to 36% of CF patients (P=0.99). Late radiation toxicity was evaluated in patients surviving free from local recurrence at 2 years post treatment. Late radiation toxicity equivalent to RTOG grade 2 or more had occurred in 44% (95% CI 34-55%) of AF patients and in 38% (95% CI 26-49%) of CF patients (logrank over 5 years follow-up P=0.23). There was no significant difference in analysis of time to loss of local tumour control comparing the two treatment arms; local recurrence was recorded in 29 of the 100 patients treated with CF and in 41 of 129 patients treated with AF (logrank P=0.86). There was also no significant difference between the treatment arms comparing disease-free survival and overall survival. The overall survival figures at 3 years were for AF 54% (95% CI 45-63%) and for CF 47% (95% CI 36-57%). By 5 years the overall survival was 37% for AF and 40% for CF. There were two treatment related deaths, both on the AF arm of the trial. CONCLUSIONS: This accelerated fractionation schedule did not improve on the efficacy of conventional fractionation for patients with T2 and T3 bladder cancer and accelerated fractionation was associated with increased acute bowel reactions.

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.

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.

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.

An unusual case of primary anaplastic large cell central nervous system lymphoma: an 8-year success story.

Primary central nervous system anaplastic large cell lymphoma (PCNS ALCL) is rare, with only three adult patients reported. We describe a patient with PCNS ALCL with the longest follow-up period so far reported. The patient was successfully treated with chemotherapy and radiotherapy. The patient is well, independent and in full-time employment and has no residual neurological deficit. He has normal mental status, has a full head of hair and has fathered a healthy child.

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