Vinorelbine and infusional 5-fluorouracil in anthracycline and taxane pre-treated metastatic breast cancer.

AIMS: To evaluate the efficacy and toxicity of a combination of intravenous vinorelbine and 5-fluorouracil (5-FU) given by continuous infusion in the treatment of metastatic breast cancer previously treated with anthracyclines and taxanes. MATERIALS AND METHODS: Sixty-one patients with metastatic breast cancer were treated with intravenous vinorelbine 30 mg/m2 on days 1 and 8 of each 21-day cycle together with 5-FU 200 mg/m2/day by continuous infusion. All had previously been treated with an anthracycline and 41% had also been previously treated with a taxane. All had normal haematological, renal and hepatic function and all but three had an Eastern Cooperative Oncology Group performance score of 2 or better. RESULTS: The overall response rate by World Health Organization criteria was 46% (28 patients); excluding nine non-evaluable patients gave a response rate of 54%. In patients who had previously been treated with both an anthracycline and a taxane, a response rate of 50% was observed (12 of 24 patients). Severe toxicity was uncommon, as was toxicity attributable to infusional 5-FU. Myelosuppression was rarely severe, but was common and led to delay or dose reduction in 38% of treatments. Eleven patients (18%) were admitted with fever and/or neutropenia and one patient died. The median received dose intensity was vinorelbine 16 mg/m2/week and 5-FU 143 mg/m2/day. CONCLUSIONS: The combination of vinorelbine and infusional 5-FU is active in metastatic breast cancer, including in patients previously treated with an anthracycline and a taxane. Toxicity is generally manageable, but myelosuppression is significant at this dose regimen. Recommended doses for routine clinical use are 5-FU 200 mg/m2/day and intravenous vinorelbine 30 mg/m2 days 1 and 15 on a 28-day cycle.

Osteomalacia as a late metabolic complication of Ifosfamide chemotherapy in young adults: illustrative cases and review of the literature.

Purpose. Ifosfamide is a drug commonly used in the management of sarcomas and other solid tumours. One potential toxicity of its use is renal tubular damage, which can lead to skeletal abnormalities; rickets in children and osteomalacia in adults. We aimed to characterise this rare complication in adults. Patients. Three illustrative patient cases treated in our institution are presented. All were treated for sarcoma, and received varying doses of ifosfamide during their therapy. Methods. We performed a review of the literature on the renal tubular and skeletal complications of ifosfamide in adults. Papers were identified by searches of PubMed using the terms "osteomalacia," "nephrotoxicity," "Fanconi syndrome," "ifosfamide," and "chemotherapy" for articles published between 1970 and 2006. Additional papers were identified from review of references of relevant articles. Results. There are only four case reports of skeletal toxicity secondary to ifosfamide in adults; the majority of data refer to children. Risk factors for development of renal tubular dysfunction and osteodystrophy include platinum chemotherapy, increasing cumulative ifosfamide dose, and reduced nephron mass. The natural history of ifosfamide-induced renal damage is variable, dysfunction may not become apparent until some months after treatment, and may improve or worsen with time. Discussion. Ifosfamide-induced osteomalacia is seldom described in adults. Clinicians should be vigilant for its development, as timely intervention may minimise complications.

HER2-positive breast cancer brain metastases: multiple responses to systemic chemotherapy and trastuzumab--a case report.

Brain metastases from metastatic breast cancer typically occur in 10-15% of patients and are associated with survival of 3-6 months. Recent series have shown that women with HER2-positive metastatic breast cancer receiving the drug trastuzumab develop brain metastases more frequently than this, but also that continuation of trastuzumab after diagnosis of brain metastases in such patients is associated with extended survival. Authors have speculated that this is due to improved systemic control of disease; however, a possibility is that trastuzumab may have a beneficial effect on cerebral metastases themselves. We report the case of a woman with HER2-positive metastatic breast cancer who developed multiple brain metastases while on trastuzumab, in whom the addition of systemic chemotherapy to continued trastuzumab has produced multiple treatment responses associated with prolonged survival. This is the first report of its kind.

A novel continuous infusional 5-fluorouracil-based chemotherapy regimen compared with conventional chemotherapy in the neo-adjuvant treatment of early breast cancer: 5 year results of the TOPIC trial.

BACKGROUND: To compare the efficacy of continuous infusional 5-fluorouracil (5-FU)-based chemotherapy against conventional bolus chemotherapy in the preoperative treatment of patients with large operable early breast cancer. PATIENTS AND METHODS: Four hundred and twenty-six women with histologically proven 3 cm invasive early breast cancer were randomised to receive pre-operative infusional 5-FU 200 mg/m(2) by daily 24 h continuous infusion via a Hickman line for 18 weeks with epirubicin 60 mg/m(2) intravenous (i.v.) bolus on day 1 and cisplatin 60 mg/m(2) i.v. bolus on day 1, both repeating 3-weekly (infusional ECisF), or conventional bolus doxorubicin 60 mg/m(2) i.v. on day 1 and cyclophosphamide 600 mg/m(2) i.v. on day 1, both repeating 3-weekly (AC), both schedules for six courses. Patients subsequently had local therapy (surgery or radiotherapy or both) and tamoxifen 20 mg orally daily as appropriate. RESULTS: The 5 year results for AC and infusional ECisF, respectively, were as follows: overall response, 75% and 77%; complete clinical remission, 31% and 34%; pathological complete remission (pathCR), 16% for both; and pathCR with residual ductal carcinoma in situ (DCIS), 25% and 24%. Mastectomy rates were 37% and 34%, respectively. Five-year overall survival was 74% for AC and 82% for infusional ECisF (hazard ratio 0.76, 95% confidence interval 0.51-1.13; P = 0.18). Both treatments were well tolerated. Grade III/IV lethargy, vomiting, alopecia and plantar-palmar erythema were significantly greater for infusional ECisF; grade III/IV leucopenia was significantly greater for AC. CONCLUSIONS: Preoperative continuous infusional 5-FU-based chemotherapy is no more active than conventional AC for early breast cancer; with a median 5 year follow-up, the infusion-based schedule shows a non-significant trend towards improved survival.

Patterns of survival in patients with recurrent follicular lymphoma: a 20-year study from a single center.

PURPOSE: To examine outcome of treatment for patients with recurrent follicular lymphoma. PATIENTS AND METHODS: Two hundred twelve newly diagnosed follicular lymphoma patients were studied. One hundred seventy-nine were initially treated successfully. Recurrent or progressive lymphoma developed in 116. Treatment was given according to disease stage and current protocols, mostly with single alkylating agents. A policy of repeated lymph node and bone marrow biopsy was pursued. RESULTS: The overall median survival duration was 9 years, with a median follow-up duration of 12 years. Following recurrence, the median survival duration was 4 1/2 years. Only eight of 116 patients with recurrent disease died of causes unrelated to lymphoma. The overall response rate to first re-treatment was 78% and showed slight decline with successive recurrences, reaching 48% after the fourth treatment. The median duration of second remission was 13 months, (v 31 months for first remission), with the only significant predictive factor being quality of remission. Multivariate analysis showed only age at recurrence and number of prior treatments to correlate with survival after first recurrence. Survival after second remission was only correlated with age and quality of response: Kaplan-Meier estimates gave 53% of patients reaching second complete remission alive 10 years later, compared with 28% in partial remission. CONCLUSION: Age and previous and continuing responsiveness of follicular lymphoma to therapy are the principal determinants of survival following recurrence. Improvement in survival with new treatments will be demonstrated most readily in older patients, while more intensive approaches should be tested in younger patients in whom remission is achieved with difficulty.

Myeloablative therapy with autologous bone marrow transplantation as consolidation therapy for recurrent follicular lymphoma.

PURPOSE: To assess myeloablative therapy with autologous bone marrow transplantation (ABMT) in younger patients with follicular lymphoma in the hope of prolonging remission duration and survival. PATIENTS AND METHODS: Since June 1985, 64 patients with follicular lymphoma have received cyclophosphamide (CY) 60 mg/kg x 2 and total-body irradiation (TBI) 2 Gy x 6 supported by ABMT as consolidation of second or subsequent remission. The marrow mononuclear cell (MNC) fraction was treated in vitro with three cycles of the monoclonal antibody (MAb) anti-CD20 and baby rabbit complement before cryopreservation. At the time of treatment, 34 patients were in complete remission (CR), and 30 had residual disease present. RESULTS: The median time to engraftment was 28 days (range, 15 to 46) for both a neutrophil count greater than 0.5 x 10(9)/L and a platelet count greater than 20 x 10(9)/L. Engraftment did not occur in one patient who died at 12 weeks, and three patients (excluded from the range) have had delayed recovery (> 6 months) of RBCs and platelets. Fifty two patients are alive; three died as a consequence of the transplant procedure, two died in remission from other causes, and seven died of recurrent lymphoma. There was a significant correlation between survival and the total number of episodes of treatment required during the course of the illness (< or = to three v > three, P = .01). With a median follow-up duration of 3 1/2 years, 35 patients continue in remission between 1 and 8 years, and 24 have developed recurrent lymphoma, five with evidence of transformation to high-grade histology. Freedom from recurrence did not correlate with the time from diagnosis, the number of previous treatments, the presence or absence of residual disease at the time of treatment, or during which specific remission the treatment was given (second v > second). However, comparison with an age-matched, remission-matched, historical control group shows a significant advantage in favor of treatment with CY plus TBI plus ABMT (P = .001); currently, there is no difference in survival. CONCLUSION: These results are encouraging, although preliminary; it remains to be established whether this treatment prolongs survival.

Detection of cells bearing the t(14;18) translocation following myeloablative treatment and autologous bone marrow transplantation for follicular lymphoma.

PURPOSE: To use the polymerase chain reaction (PCR) technique for molecular assessment of the results of myeloablative treatment of follicular lymphoma with autologous bone marrow transplantation. PATIENTS AND METHODS: Seventy-six patients with follicular or transformed follicular lymphoma were treated with cyclophosphamide 60 mg/kg x 2 and total-body irradiation 12 Gy, supported by autologous bone marrow transplantation. The bone marrow mononuclear cell fraction was treated in vitro with CD20 monoclonal antibody and baby rabbit complement. The PCR technique was used to identify 50 patients with amplifiable t(14; 18) translocations in biopsy material from lymph nodes or bone marrow infiltrated by lymphoma. RESULTS: Following treatment of the harvested bone marrow in vitro, 29 samples were tested by PCR to assess the efficacy of purging. In 25 cases, the same t(14; 18) sequences were amplified as from the patients' original biopsies, while in four cases, the marrow became PCR-negative. Three of the four patients treated with PCR-negative marrow subsequently developed recurrent lymphoma, compared with 11 of 25 in the PCR-positive group. Bone marrow and peripheral-blood mononuclear cell samples from 27 patients were studied during the follow-up period. All but one had the presence of the lymphoma-related t(14; 18) clone detectable by PCR and confirmed by direct sequencing from at least one sample between 3 months and 7 years after reinfusion of the bone marrow. With a median follow-up duration of 3 years, 13 patients developed recurrent disease, 13 remained in remission with the t(14; 18) still detectable, and one died of acute myeloid leukemia. CONCLUSION: This form of therapy does not eliminate the lymphoma-related t(14; 18)-bearing clone of cells, although the significance of its continued presence is uncertain. Improved methods for both treatment of the bone marrow in vitro and treatment of the lymphoma in vivo are required.

Copper tolerance in a population of Silene vulgaris ssp. maritima (A. & D. Love) at Dolfrwynog Bog near Dolgellau, North Wales.

Clones of Silene vulgaris ssp. maritima individuals from Dolfrwynog Bog, North Wales and from a coastal control site were propagated under standardised environmental conditions. After five months, cuttings were taken and tested for copper tolerance by means of root extension analysis in solutions of various different copper concentrations. Indices of tolerance suggested that individuals from the Dolfrwynog population were more resistant to elevated copper concentrations than were the control population individuals. Due to the initial five months under standardised conditions, it was assumed that the cloned plant material would have lost all plastic adaptive responses to its native environment. If this assumption was valid then the differences in copper tolerance observed between the two populations had a genetic basis and the Dolfrwynog Bog population is a copper tolerant ecotype.

Mitoxantrone and cytosine arabinoside as treatment for acute myelogenous leukemia (AML) at first recurrence.

A total of 107 patients with newly diagnosed acute myeloblastic leukemia (AML) were referred to the ICRF Department of Medical Oncology at St Bartholomew's Hospital between August 1986 and July 1989. Of those referred, 92 (87%) were treated with remission induction chemotherapy comprising: Adriamycin, cytosine arabinoside (ara-C) and 6-thioguanine if aged < 60 years (57 patients) or mitoxantrone (MTN) and ara-C if aged > 60 years (35 patients). Of those treated, 54 (58%) entered complete remission (CR). Recurrent AML developed in 38 out of these 54 patients (70%) of whom 25 aged 19-73 years (median 50 years) subsequently received MTN and ara-C as reinduction therapy. The 19 younger patients (under 60 years old) received MTN at 12 mg/m2, intravenously, daily for 5 days and ara-C at 100 mg/m2, intravenously, twice daily for 7 days. The six older patients received the same ara-C schedule but the dose of MTN was reduced to 10 mg/m2 for 5 days. Second CR was achieved in 16 out of 25 patients (64%) [12/19 (63%) and 4/6 (67%) for patients aged under or over 60 years, respectively]. Eight of the patients in whom second CR was achieved were aged under 50 years and were thus eligible for additional consolidation comprising myeloablative therapy with autologous bone marrow transplantation (ABMT). Four patients actually received the latter treatment: two remain in second CR at 21 and 46 months. Three of the remaining eight patients aged > 50 years in whom second CR was achieved remain in second CR 8 to 43 months later. Censored for myeloablative therapy + ABMT, the overall median duration of second CR was 5 months. Although remissions tended to be short, in younger patients the possibility of proceeding to myeloablative therapy with autologous bone marrow support makes the regimen worthwhile and, even in older patients, it was sometimes possible to achieve prolonged second remissions.

Bcl-2/JH rearrangements in benign lymphoid tissues with follicular hyperplasia.

The t(14; 18)(q32;q21) chromosomal translocation, characteristic of follicular lymphoma, couples the bcl-2 protooncogene on chromosome 18 to the immunoglobulin heavy-chain joining region (JH). This results in a deregulated transcription rate of bcl-2, suggesting a major role of the t(14;18) translocation in lymphomagenesis. By using a sensitive polymerase chain reaction technique specific for the major breakpoint region t(14;18), we now demonstrate the presence of bcl-2/JH rearrangements in lymph nodes and tonsils with follicular hyperplasia in 13 of 24 cases (54%). The approximate frequency was one translocation-positive cell in 10(5) cells. No bcl-2/JH rearrangements were detected in reactive lymph nodes without follicular hyperplasia or in bone marrow cells. Sequence analysis showed the amplified bcl-2/JH fragments to be unique to each individual sample and distinct from 24 sequenced follicular lymphoma-derived t(14;18) junctions, thus excluding contamination artifacts. The presence of random nucleotide insertions at the breakpoint junctions suggests a pre-B-cell origin of the t(14;18) translocation, in analogy with follicular lymphomas. We conclude that the t(14;18) translocation can occur in non-malignant tissue and will not, on its own, lead to malignancy.

The significance of circulating cells carrying t(14;18) in long remission from follicular lymphoma.

Peripheral blood mononuclear cell fractions from 15 patients in continuous clinical remission from follicular lymphoma for longer than 10 years were examined for cells carrying the t(14;18) translocation using the polymerase chain reaction (PCR). The assay used was able to detect one positive cell in approximately 5 x 10(5) cells (a single 14q+ molecule in 2.5 micrograms DNA). Cells positive for t(14;18) were found in six of eight patients initially presenting with stage III or IV disease, compared with zero of seven of those with stage I or II disease (P less than .05). In two cases 14q+ junction regions were also successfully amplified from formalin-fixed biopsy material obtained at presentation 12 and 17 years previously. In both, sequence analysis demonstrated that the cells circulating in remission belonged to the original clone. These results indicate that cells bearing t(14;18) frequently persist in the peripheral blood in long remission of advanced follicular lymphoma and question the value of their presence as a predictor of relapse.

Detection of additional JH/BCL2 translocations in follicular lymphoma.

In vitro enzymatic amplification and direct sequencing were used to detect and characterize t(14;18) recombination junctions in peripheral blood and bone marrow mononuclear cell preparations from patients with follicular lymphoma in remission. Samples from 24/44 patients were found to be positive for translocations involving the major breakpoint region of the BCL2 gene. In samples from seven patients two distinct t(14;18) translocations were shown to be present simultaneously; in one case the second translocation involved the minor cluster region of the BCL2 gene. Biopsy tissue obtained earlier in the course of the disease was available from five of these patients and was shown to contain one of the translocations in each case, but both translocations in only one. Further remission blood and bone marrow samples from the group were also examined. This led to the detection of both translocations in separate samples obtained at different times in a total of four out of the seven cases. In two of the remaining three patients the second translocation could not be amplified from further samples, but in both cases the search led to the identification of a third translocation, again only detectable in a single sample. These findings demonstrate that JH/BCL2 translocations can occur more than once during the course of follicular lymphoma. They suggest that biclonal follicular lymphoma may be more common than has previously been recognized but also raise the possibility that the translocation arises sporadically in the normal lymphoid cells of this group of patients.

Interferon-alpha 2b in the treatment of follicular lymphoma: preliminary results of a trial in progress.

Since 1985 the combination of chlorambucil (10 mg daily, initially for six weeks, then alternating fortnights for 12 weeks) and interferon-alpha 2b (Schering-Plough; 2 x 10(6) U/m2 three times weekly by subcutaneous injection for 18 weeks) has been compared in a randomised trial with chlorambucil alone in previously untreated patients with stage III or IV follicular lymphoma. Responding patients have subsequently been randomised to receive maintenance interferon-alpha 2b or no further treatment. Of the 124 treated patients, 108 are evaluable for response with a median follow-up of 30 months. The major toxicity was myelosuppression which was more frequent with chlorambucil and IFN alpha 2b in combination than with chlorambucil alone (P less than 0.01). There was no treatment-related mortality. Actuarial survival at three years is 75% for all patients, regardless of therapy. There was no significant difference in response rate according to initial therapy. For the 60 patients achieving a good response to initial therapy who have entered the second part of the trial, there has been a significant prolongation of remission duration in favour of maintenance IFN-alpha 2b (median not yet reached versus two years for the 'no treatment' arm, P less than 0.015). Fewest relapses have been seen in patients who received IFN-alpha 2b throughout. Accrual to this trial continues; this preliminary analysis indicates that maintenance IFN-alpha 2b may extend remission duration in follicular lymphoma.

Myeloablative therapy with autologous bone marrow transplantation as consolidation of remission in patients with follicular lymphoma.

A study has been in progress since June 1985 to evaluate the use of myeloablative therapy (cyclophosphamide [60 mg/kg x 2] and total body irradiation [200 cGy x 6]) followed by reinfusion of autologous bone marrow in patients in second or subsequent remission of B-cell non-Hodgkin's lymphoma. The marrow mononuclear cell fraction is being treated in vitro with three cycles of the monoclonal antibody anti-CD20 (anti-B1, Coulter Immunology) and baby rabbit complement (Pel-Freez). Thirty-eight patients with follicular lymphoma (age range 29-61 years, median 43) have been treated to date. At the time of treatment, 28 patients were in second remission, 7 were in third, and 3 were in more than third remission. Twenty-three patients were in complete remission, 15 had residual disease (7 had lymph nodes less than 2 cm diameter, 4 had less than 10% bone marrow infiltration, 1 had involvement of lymph nodes and bone marrow, and 3 had involvement at other sites). Of the 38 study patients, 32 are alive; 6 have died, 4 in remission. Two of the deaths were treatment related: 1 resulted from cerebral haemorrhage at 29 days; 1 resulted from systemic fungal infection at three months). One patient died from secondary acute myelogenous leukaemia at four years, and another from an unrelated cause. Two patients died following relapse. The median time to engraftment was 28 days (range 15-45 days) for neutrophils greater than 0.5 x 10(9)/L and 28 days (range 15-46 days) for platelets greater than 20 x 10(9)/L.(ABSTRACT TRUNCATED AT 250 WORDS)

Interferon alfa-2b in addition to chlorambucil in the treatment of follicular lymphoma: preliminary results of a randomized trial in progress.

One hundred and twenty four patients with follicular lymphoma (32 with Stage III and 92 with Stage IV disease) have been randomized to receive chlorambucil alone or chlorambucil plus interferon alfa-2b. Responding patients are then randomized to receive either interferon alfa-2b maintenance therapy for up to 12 months or no further treatment. One hundred and eight patients are evaluable for response, the remainder are still receiving initial therapy. Clinical remission (complete or good partial remission) was achieved in 42/59 (71%) patients receiving chlorambucil alone and in 27/49 (55%) patients receiving the combination (P = NS). Preliminary analysis of remission duration shows a trend in favour of those patients receiving interferon throughout (P = 0.02). There is no significant difference between the groups in terms of survival, at a median follow up of 2.5 years. Interferon-associated toxicity was minor in most patients but led to discontinuation of therapy in six cases. Larger trials with longer follow-up periods are needed to confirm the beneficial role of interferon in the treatment of follicular lymphoma.

Effect of ceftazidime and gentamicin on the oropharyngeal and faecal flora of patients with haematological malignancies.

Thirty-four patients with haematological malignancies were studied to investigate the effect of empirical broad-spectrum antibiotic therapy (ceftazidime and gentamicin) on the gastro-intestinal flora. Twenty-five patients with acute myeloid leukaemia or post-autologous bone-marrow transplantation were given framycetin, nystatin and colistin (Fracon), and two patients with non-Hodgkin's Lymphoma were on co-trimoxazole, as long-term gut prophylaxis. Semi-quantitative microbiology was carried out on oropharyngeal swabs and quantitative microbiology on faecal specimens. The oropharyngeal flora consisted mainly of streptococci, coagulase-negative staphylococci and coryneforms, and was little affected by ceftazidime/gentamicin. A strain of Enterobacter cloacae resistant to ceftazidime and gentamicin colonized one patient, who later developed septicaemia. The faecal flora of patients on Fracon was dominated by enterococci; the few enterobacteria present were eliminated by ceftazidime/gentamicin. The anaerobic flora was absent in 15% of patients; in the remainder, it consisted mainly of Bacteroides spp., and was little affected by ceftazidime/gentamicin. The faecal flora of patients not on Fracon always contained anaerobes, and some strains of enterobacteria persisted throughout antibiotic treatment. None of the patients was colonized by Clostridium difficile or Pseudomonas aeruginosa. Broad-spectrum therapy with ceftazidime and gentamicin appeared to have little effect on the gastro-intestinal flora, except to encourage the overgrowth of enterococci and reduce the numbers of enterobacteria.

Newer modifications of peritoneal dialysis: options in the treatment of patients with renal failure.

Experience with peritoneal dialysis for the treatment of 69 patients suffering from renal failure is reported. Chronic intermittent peritoneal dialysis (CIPD) was used in 49 patients, and continuous ambulatory peritoneal dialysis (CAPD) in 34 patients. CAPD was well accepted by patients, and resulted in maintenance of laboratory parameters in a range similar to that achieved by hemodialysis and by CIPD. However, peritonitis occurred with a higher incidence in CAPD (one per 7.2 patient-months) than in CIPD (one per 19.2 patient-months). All episodes of peritonitis were caused by only 40% of the patients, and in CAPD, patients who developed peritonitis in the first 4 weeks of treatment were the most likely to develop repeat episodes. An organism was identified in 81% of cases, of which 50% were due to Staphylococcus, 16% due to Streptococcus, 5% due to Candida and the remaining 29% were due to gram-negative organisms. In addition to CAPD, we introduced an automated modification of prolonged-dwell peritoneal dialysis (PDPD) that is applicable to a larger number of patients. In 11 patients PDPD proved comparable to CAPD in ameliorating the laboratory parameters measured, but was associated with lower incidence of peritonitis (one per 18.2 patient-months).