The treatment of advanced renal cell cancer with high-dose oral thalidomide.

Thalidomide is reported to suppress levels of several cytokines, angiogenic and growth factors including TNF-alpha, basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF) and interleukin-6 (IL-6). The resulting anti-angiogenic, immunomodulatory and growth suppressive effects form the rationale for investigating thalidomide in the treatment of malignancies. We have evaluated the use of high-dose oral thalidomide (600 mg daily) in patients with renal carcinoma. 25 patients (all men; median age, 51 years; range 34-76 years) with advanced measurable renal carcinoma, who had either progressed on or were not suitable for immunotherapy, received thalidomide in an escalating schedule up to a maximum dose of 600 mg daily. Treatment continued until disease progression or unacceptable toxicity were encountered. 22 patients were assessable for response. 2 patients showed partial responses (9%; 95% CI: 1-29), 7 (32%; 95% CI: 14-55) had stable disease for more than 6 months and a further 5 (23%; 95% CI: 8-45) had stable disease for between 3 and 6 months. We also measured levels of TNF-alpha, bFGF, VEGF, IL-6 and IL-12 before and during treatment. In patients with SD > or = 3 months or an objective response, a statistically significant decrease in serum TNF-alpha levels was demonstrated (P = 0.05). The commonest toxicities were lethargy (> or = grade II, 10 patients), constipation (> or = grade II, 11 patients) and neuropathy (> or = grade II, 5 patients). Toxicities were of sufficient clinical significance for use of a lower and well tolerated dose of 400 mg in currently accruing studies.

Continuous low dose Thalidomide: a phase II study in advanced melanoma, renal cell, ovarian and breast cancer.

To grow and metastasize, solid tumours must develop their own blood supply by neo-angiogenesis. Thalidomide inhibits the processing of mRNA encoding peptide molecules including tumour necrosis factor-alpha (TNF-alpha) and the angiogenic factor vascular endothelial growth factor (VEGF). This study investigated the use of continuous low dose Thalidomide in patients with a variety of advanced malignancies. Sixty-six patients (37 women and 29 men; median age, 48 years; range 33-62 years) with advanced measurable cancer (19 ovarian, 18 renal, 17 melanoma, 12 breast cancer) received Thalidomide 100 mg orally every night until disease progression or unacceptable toxicity was encountered. Three of 18 patients with renal cancer showed partial responses and a further three patients experienced stabilization of their disease for up to 6 months. Although no objective responses were seen in the other tumour types, there were significant improvements in patients' sleeping (P < 0.05) and maintained appetite (P < 0.05). Serum and urine concentrations of basic fibroblast growth factor (bFGF), TNF-alpha and VEGF were measured during treatment and higher levels were associated with progressive disease. Thalidomide was well tolerated: Two patients developed WHO Grade 2 peripheral neuropathy and eight patients developed WHO grade 2 lethargy. No patients developed WHO grade 3 or 4 toxicity. Further studies evaluating the use of Thalidomide at higher doses as a single agent for advanced renal cancer and in combination with biochemotherapy regimens are warranted.

Neoadjuvant chemotherapy for breast cancer.

Primary or neoadjuvant chemotherapy in early breast cancer offers the chance to use the tumour as an in vivo measure of response, with the additional possibility of downstaging and avoidance of mastectomy. Tumour response to preoperative chemotherapy correlates with the outcome and could be a surrogate for evaluating the effect of chemotherapy on micrometastases. Randomized studies have shown that preoperative chemotherapy is as effective as postoperative chemotherapy, but there has not been a significant increase in the disease-free survival or overall survival in the groups studied. The overall response rates reported have varied between 60% and 100% with complete clinical responses from 10% to almost 50%, avoiding mastectomy in most cases. Clinical responders have a better prognosis than nonresponders; pathological complete remissions at present offer the best prediction of good long-term outcome, but occur in less than 20% of patients. Biological predictors reflecting changes in apoptosis and/or proliferation may in the future offer the best surrogate markers for long-term outcome, and trials have recently begun in this area.

Follicular lymphoma. A series of 11 patients with minimal or no treatment and long survival.

Follicular lymphoma is the commonest low-grade lymphoma. Its indolent nature even in advanced stages and the failure of conservative or aggressive treatments to achieve a cure have questioned the need for immediate treatment. Eleven patients with follicular lymphoma who had minimal or no treatment were retrospectively reviewed. Median age was 44 years. Staging was: I (4), III (6) and IV (1). Eight were confirmed to have follicular lymphoma of whom six did not receive treatment at presentation. Four of these patients remain in remission after 14 to 30 years of follow-up and the other two have relapsed after 10 and 13 years of follow-up, respectively. Two patients who were treated at diagnosis remained disease free for 18 years. Three patients had diffuse large cell lymphoma on review. They received no treatment, radiotherapy or chemotherapy and have been in remission for 36, 14 and 23 years respectively. The overall survival is 58% at 30 years, and median survival has not been reached for the whole group. Observation seems to be a valid alternative to treatment in patients with stages I to III until signs of progression.

Efficacy of a vancomycin solution to prevent bacteremia associated with an indwelling central venous catheter in neutropenic and non-neutropenic cancer patients.

We evaluated the efficacy of a vancomycin solution in the prevention of bacteremia caused by vancomycin-sensitive organisms (VSO) in cancer patients with a tunneled central venous catheter (CVC). Eighty-three patients who had a single lumen CVC were randomized to use a heparin solution (25 U/ml) for daily catheter flush with (HepVan) or without (Hep) vancomycin, 25 mcg/ml. Febrile episodes were recorded, and central and peripheral blood cultures were drawn before beginning antibiotic therapy. Patients participated in follow-up to 16,677 catheter days (8,666 Hep and 8,011 HepVan), and 143 febrile episodes were recorded (82 Hep and 61 HepVan). Forty-four episodes of bacteremia occurred, 23 of them due to VSO (16 occurred in the Hep group and 7 in the HepVan group (P = 0.19). VSO bacteremia occurred in 14 neutropenic (absolute neutrophil count < 500 x 10(9)/l) episodes (7 Hep vs. 7 HepVan) and in 9 non-neutropenic episodes (9 Hep vs. O HepVan; P = 0.013). Vancomycin effectively prevented bacteremia by VSO in non-neutropenic patients, supporting the idea that intraluminal colonization of indwelling CVCs contributes to bacteremia only in these patients.

[Allogenic bone marrow transplantation in the treatment of malignant hematologic disease]. / Trasplante alogeneico de médula ósea en el tratamiento de enfermedades hematológicas malignas.

We have treated 28 patients (pts) with malignant hematological diseases with allogeneic bone marrow transplantation (BMT). 18 pts had acute lymphoblastic (ALL) and non lymphoblastic leukemia (ANLL), 5 chronic myeloid leukemia (CML), 2 severe aplastic anemia (SAA), 1 myelodisplasia, 1 Fanconi's anemia and 1 advanced Non Hodgkin's lymphoma. All but three received the graft from HLA identical sibling donors. We used conditioning with total body irradiation and chemotherapy (cyclophosphamide, cytarabine and etoposide) in 17 pts and chemotherapy alone in 11. 24 pts had full hematological recovery 18 to 25 days post BMT. 15 pts died after BMT as a consequence of toxicity or early infection (4), graft failure (2), graft versus host disease (4) or relapse (5). Actuarial event free survival for the group with favorable prognosis (SAA, ALL and ANLL in first or second remission and CML in chronic phase) is 57% at 36 months. Allogeneic BMT is an effective and feasible therapeutic procedure for selected patients with hematological malignancies.

[Infective complications of the use of permanent central venous catheters in oncology]. / Complicaciones infecciosas del uso de catéteres venosos centrales permanentes en oncología.

We analyzed the infectious complications associated with the use of permanent central venous catheters (PVC) in pediatric and adult cancer patients. 62 patients used 74 PVC (54 external, 20 subcutaneous), which were in place for an average of 200 days with a total observation period of 14,876 days, 152 febrile episodes occurred during this period, 87 in neutropenic patients (less than 500 neutrophils/mu, FN+) and 65 in non neutropenic patients (FN-). The incidence of bacteremia was 32% in febrile episodes in the first group (FN+C+ and 41% in the second (FN-C+). Overall there were 3.7 episodes of bacteremia per 1000 catheter days. We found a statistically significant difference in the incidence of bacteremia between the external and subcutaneous PVC in favor of the latter among patients over 15 years of age but not in the pediatric group. 14 PVC had to be removed due to an infection, 8 in patients with bacteremia and 6 in patients with exit site infections. We conclude that the use of PVC in the care of cancer patients is beneficial and safe, with a low incidence of infectious complications.