Prognostic effect of serum BDNF levels in late-life depression: Moderated by childhood trauma and SSRI usage?

BACKGROUND: Brain-derived neurotrophic factor (BDNF) levels decline during depression and normalise after remission, although studies in older patient samples are inconsistent. Whether BDNF serum levels predict depression remission is unclear. We hypothesize that the predictive value of serum BDNF levels in late-life depression is moderated by selective serotonin reuptake inhibitors (SSRI) usage and early traumatization. METHODS: Our study sample was a subset of the Netherlands Study of Depression in Older persons (NESDO), a prospective cohort study. It consisted of 267 older persons with a diagnosis of depression, for which follow-up data were available. Depression diagnosis was assessed at baseline and follow up using a structured diagnostic interview (Composite International Diagnostic Interview (CIDI), volume2.1). Logistic regression was performed (adjusted for covariates) with remission of depression after two years as the dependent variable and baseline BDNF serum levels, childhood traumatization and SSRI use as independent variables. Results - The mean age of the subjects was 70.7 years, 65.6% of them were female, their mean BDNF level was 7.7 ng/ml, 80 (30.0%) of them were traumatised in their childhood,71 (26.6%) used SSRIs and 136 (50.9%) no longer had a depressive disorder at the two year follow up. The predictive value of BDNF serum levels was conditional on traumatization and SSRI usage (threeway interaction p = .010). Higher BDNF serum levels predicted remission in traumatized depressed patients without SSRI usage (OR = 1.17, 95% C.I.: 1.00-1.36; p = .048) and in non-traumatized depressed patients who used SSRIs (OR = 1.17, 95% C.I.: 1.00-1.36; p = .052), but not in the other two subgroups. CONCLUSION: The association between BDNF serum levels and the course of late-life depression seems to depend on SSRI use and childhood trauma. Based on these results, we hypothesize that childhood trauma may permanently reduce ('blunt') the responsiveness of the neurotrophic system to SSRI usage, and that this responsiveness might be more important for depression course than the actual BDNF serum levels.

Chemotherapy with cisplatin, epirubicin and docetaxel in transitional cell urothelial cancer. Phase II trial.

Cisplatin (CDDP), epirubicin (EPI) and docetaxel have single agent activity against urothelial transitional cell carcinoma (TCC). We evaluated the efficacy and toxicity of this combination in locally advanced or metastatic urothelial TCC. Patients with urothelial TCC who had no prior chemotherapy (prior adjuvant chemotherapy > 6 months allowed) were eligible for entry the study. Eligibility criteria were performance status 0-3, granulocyte count (AGC) > or = 1.5 (10(9)/l), platelet count > or = 100 (10(9)/l), clearance creatine > or = 60 ml/min and total bilirubin level < or = 1.5 mg/dl. Treatment consisted of EPI 40 mg/m2 intravenous push, docetaxel 75 mg/m2 in 1 h infusion with premedication and CDDP 75 mg/m2 with pre- and posthydration. Treatment was repeated every 21 days. Antiemetics with dexamethasone and 5-HT3 antagonists were used routinely. Prophylactic haematopoietic growth factors were not used. Patients were evaluated for toxicity weekly and assessed for response every two cycles of treatment. 32 patients were entered into the study and 30 patients (7 with locally advanced and 23 with metastatic disease) were assessable for response. There were 9 (30.0%) complete responses (2, 28.6% in locally advanced and 7, 30.4% in metastatic disease) and 11 (36.7%) partial responses (3, 42.9% in locally advanced and 8, 34.8% in metastatic disease) with an overall response rate (RR) of 66.7% (71.5% in locally advanced, 65.2% in metastatic disease). Overall median survival was 14.5 months (15 months for locally advanced, 12.5 months for metastatic disease). The median duration of response in patients with metastatic disease was 8.5 months. 16 (53.3%) patients required one dose reduction and 5 (16.7%) patients required two dose reductions for a nadir AGC < or = 500/mm3. Four episodes of febrile neutropenia and sepsis occurred. No patient had a dose reduction or treatment delay for any other grade 3/4 toxicity. There were no treatment delays due to myelotoxicity. Alopecia was universal. Non-haematological toxicity including mucositis, fluid retention, allergy, cutaneous toxicity, diarrhoea and neurotoxicity were mild and infrequent. The combination of EPI, docetaxel and CDDP is an active regimen for urothelial TCC. The response rate and toxicity were comparable with the M-VAC (methotrexate, vinblastine, doxorubicin, cisplastin) regimen. Phase III trials comparing this regimen with M-VAC are warranted.

Paclitaxel in cisplatin or carboplatin-pretreated ovarian cancer. Phase II study.

A phase II trial was conducted in order to assess the efficacy and toxicity of paclitaxel given at a dose of 175 mg/m2 in a 3-hour infusion every 3 weeks in patients with recurrent or cisplatin (CDDP) carboplatin-refractory ovarian cancer. Forty-two patients with a median age of 61 years (range 34-76 years) entered the study. Most patients had bulky disease. Thirty-three patients (78.5 %) presented with stage III and IV diseases. Twenty-two patients (52.3%) had previously been treated with only 1 regimen and 20 patients (47.7%) with > or = 2 regimens. The median treatment interval from the last previous therapy was 4.5 months (range 2-26 months). From 41 patients evaluable for response, 3 (7.3%) achieved a complete and 4 (9.8%) a partial response. All 3 complete and 2 out of the 4 partial responders had previously received > or = 2 chemotherapeutic regimens. Grade 3-4 toxicities included granulocytopenia (35%), which was of short duration, neurotoxicity (9.75%) and alopecia (60.9%). Two patients with grade 4 neutropenia were hospitalized due to pneumonia, which was successfully treated by broad-spectrum antibiotics and administration of G-CSF. A severe hypersensitivity reaction occurred in 1 patient early during the first cycle, resulting in discontinuation of treatment. Median relapse-free survival was 6.9 months, median time to progression 6.2 months and median survival 13.2 months. In conclusion, paclitaxel given at a dose of 175 mg/m2 as a 3-hour infusion every 3 weeks appears to be an efficacious and well-tolerated treatment in patients with recurrent or CDDP/carboplatin-refractory ovarian cancer.

Chemotherapy with methotrexate, carboplatin, mitoxantrone (Novantrone) and vincristine (Oncovin) in transitional-cell urothelial cancer.

Forty-four patients with either metastatic or locally advanced transitional cell carcinoma of the bladder were treated with the MCNO regimen (methotrexate 300 mg/m2 in 1,000 ml normal saline as a 4-hour infusion on days 1 and 14 with leucovorin rescue 15 mg 6-hourly for 6 doses; carboplatin 300 mg/m2 in 250 ml 5% distilled water as a 1-hour infusion on day 1; mitoxantrone (Novantrone) 10 mg/m2 in 100 ml 5% distilled water as a 30-min infusion on day 1, and vincristine (Oncovin) 1 mg/m2 as an intravenous bolus on days 1 and 14. Patients with metastatic disease were treated with 6 cycles, while patients with locally advanced disease were treated with 4 cycles of induction chemotherapy followed by cystectomy or radiotherapy. The overall response rate was 40%, with 15% complete response (CR). The responses were better for patients with locally advanced disease (CR 25%, partial response, PR, 31.25%, response rate, RR, 56.25%) than for those with metastatic disease (CR 8.3%, PR 20.83%, RR 29.1 %). The differences in these results were probably due to the bad performance status and the presence of visceral metastases in patients with generalized disease. The overall median survival was 14 months, with responders living longer (median survival 28.8 months in patients with locally advanced disease and 22.9 months in patients with metastatic disease) than non-responders (median survival 16 months in patients with locally advanced disease and 8.9 months in patients with metastatic disease). The difference in survival between responders and non-responders was statistically significant in both groups of patients. Toxicity was moderate, but manageable. The MCNO regimen appears to have a lower efficacy than that obtained with cisplatin-based regimens for the treatment of metastatic disease and rather similar efficacy for the treatment of locally advanced urothelial-cell cancer. Therapy with this regimen, though less toxic, may not be a reliable alternative in elderly patients with visceral metastases and a performance status of > or = 2.

An outpatient phase II study of subcutaneous interleukin-2 and interferon-alpha-2b in combination with intravenous vinblastine in metastatic renal cell cancer.

A prospective phase II trial was carried out to define the activity of a low-dose subcutaneous regimen of interleukin-2 (IL-2) and interferon alpha-2b (IFN-alpha) in combination with intravenous administration of vinblastine (VLB) in patients with metastatic renal cell cancer (RCC). Thirty-one patients with advanced RCC who had received no prior biochemotherapy were treated with IL-2 4.5 MU x 2/24 h thrice weekly for 2 weeks, IFN-alpha 3 MU/24 h thrice weekly (alternating days) for 2 consecutive weeks and VLB 4 mg/m2 every 3 weeks. Patients were to have a 1-week rest period after each 2 weeks of therapy with cytokines. Treatment was repeated every 3 weeks. Maximum duration of treatment was 1 year. Treatment was administered on an outpatient basis. There were 4 complete (12.9%) and 8 partial responses (25.8%), with an overall response rate of 38.7%. The median duration of response was 6.5 months. Responses were seen in lung, lymph nodes, bones, liver and other tumor metastases. Toxicity was mild to moderate, consisting of fever, anorexia, malaise and nausea-vomiting in > 80% of patients. Hypotension and transient alopecia occurred in > 20% of patients. Liver enzyme elevation was frequently observed. Treatment-induced eosinophilia occurred in the majority of patients, while in 52% of patients granulocytopenia grade II and grade III did not require dose modification of drugs. Transient inflammation and local induration at the injection sites was observed in the majority of patients. None of the patients experienced major VLB-related toxicity and no toxic deaths occurred. This three-drug combination immunochemotherapy may be a promising regimen with modest toxicity in advanced RCC.

Comparison of two different doses of ondansetron plus dexamethasone in the prophylaxis of cisplatin-induced emesis.

This study was conducted to evaluate the efficacy of two different doses of ondansetron (8 mg vs. 24 mg) plus dexamethasone in the prevention of cisplatin (CDDP)-induced emesis and nausea (acute and delayed). The persistence of the anti-emetic efficacy during the second cycle of chemotherapy was also assessed. Eighty patients receiving high-dose CDDP (>80 mg/m2) were randomized to have either ondansetron 8 mg plus dexamethasone 20 mg (8 mg group) or ondansetron 24 mg plus dexamethasone 20 mg (24 mg group), given intravenously as a single dose before the CDDP infusion. From days 2-5, all patients received oral ondansetron 8 mg twice daily. Seventy-five patients (38 in the 8 mg group and 37 in the 24 mg group) were evaluable for analysis. Among these, there were 24 patients who received ifosfamide (IFO) on the 2nd day of treatment; these patients were evaluated separately for delayed emesis. Complete protection from acute emesis was obtained in 26 (68.4%) and 26 (70.3%) patients, in the two groups, respectively. Complete protection against acute nausea was achieved in 23 (60.5%) and 24 (64.9%) patients, respectively. With respect to the delayed emesis, complete protection was achieved in 14 (56%) and 13 (50%) patients not receiving IFO and in 4 (30.8%) and 3 (27.3%) of those receiving IFO. The figures for the delayed nausea were: 12 (48%) and 13 (50%), 2 (15.4%) and 2 (18.2%), respectively. Similar protection against emesis and nausea was recorded during the second cycle of chemotherapy. Both regimens have the same efficacy and thus, taking into account the cost-effectiveness, 8 mg of ondansetron plus dexamethasone in a single intravenous dose should be used for the prevention of high-dose CDDP-induced emesis.

Superiority of carboplatin monochemotherapy over carboplatin-based polychemotherapy in ovarian cancer.

Forty patients with previously untreated epithelial ovarian cancer (OC), with FIGO stages Ic-IV, were randomly allocated to receive intravenously either carboplatin (C) 400 mg/m2 every three weeks (C arm, 20 patients) or a combination of C 350 mg/m2, ifosfamide (I) 5 g/m2 with mesna every three weeks, vincristine (V) 1.4 mg/m2 (maximum total dose 2 mg) and bleomycin (B) 30 mg every ten days (CIVB arm, 20 patients). Responding patients received 6 courses of chemotherapy and all 40 patients were evaluable for toxicity, response and survival. Clinical characteristics of patients were similar in both arms. Clinico-imaging results with chemotherapy were as follows: in C arm, clinical complete remission (cCR) 11 (55%) and partial remission (cPR) five (25%) patients for an overall response rate (ORR) 80%. For CIVB arm, cCR ten (50%) and cPR four (20%) patients for an ORR 70%. Second look operation (SLO) was performed in three of the 11 cCR patients in the C arm and six of the ten cCR patients in the CIVB arm. Pathological CR (pCR) was confirmed in two of the three cCR C arm patients and two of the six in the CIVB patients. In the first interim analysis statistically significant differences, all favoring monochemotherapy, were seen in response duration, time to progression, disease-free and overall survival. These results along with the severe myelotoxicity resulting in dose reductions in the CIVB patients led us to stop enrolling new patients and follow this population closely for long-term results. These confirmed the first observations of the superiority of single-agent carboplatin in response duration (p = 0.034), time to progression (p = 0.028), disease-free survival (p = 0.010) and overall survival (p = 0.043). Because of the above reasons we have concluded that monochemotherapy with carboplatin is to be preferred over carboplatin in combination with other drugs.

Chemotherapy for Merkel cell carcinoma with carboplatin and etoposide.

Merkel cell carcinoma is a rare malignant tumor of the skin. We treated three patients with Merkel call carcinoma with the combination of carboplatin and etoposide, which have been mostly used in the treatment of small cell lung carcinoma. Two patients experienced partial remission of short duration. The third patient received the combination on an adjuvant basis but relapse occurred briefly. Two of these patients failed to respond to second-line chemotherapy with cisplatin, ifosfamide, and epirubicin. The patient who had the first-line treatment on an adjuvant basis, responded completely with the second-line chemotherapy plus radiotherapy and remains disease-free for 5+months. Merkel cell carcinoma appears to be a sensitive tumor to chemotherapeutic regimens used for small cell lung carcinoma, but the responses are often brief.

Adjuvant chemotherapy with dacarbazine, vindesine, and cisplatin in pathological stage II malignant melanoma.

Following curative lymph node dissection, 28 patients with pathological Stage II malignant melanoma (metastatic to regional lymph nodes) received adjuvant chemotherapy with dacarbazine, vindesine, and cisplatin (DVP); 32 more patients with similar characteristics refused adjuvant treatment. In the treated group, 15 patients (53%) developed dissemination of disease after 4 to 29 months; 20 (62%) of the patients who refused adjuvant treatment recurred after 4 to 25 months and received palliative treatment with DVP. No significant differences in survival or disease-free survival according to different patient characteristics could be detected between these two groups with the available patient population. Large and well-designed prospective randomized trials are required to determine if the adjuvant use of this treatment schedule, which includes the three most active drugs improves survival in patients with nondisseminated melanoma.

Treatment of primary fallopian tube carcinoma with cisplatin-containing chemotherapy.

Because of the rarity of the primary fallopian tube carcinoma, optimal primary therapy is still not well defined, and there is little information available regarding the efficacy of combination chemotherapy in advanced disease. The experience obtained by treating 14 patients with fallopian tube carcinoma--most of them with advanced disease--using a combination of cisplatin, adriamycin, and cyclophosphamide (CAP) (10 patients) or carboplatin plus cyclophosphamide (4 patients) is reported. One patient had Stage Ic disease, 2 had Stage II, 9 had Stage III, and 2 had Stage IV. Eleven patients had clinically measurable disease (> 2 cm) at the start of chemotherapy. Eight of these patients had a complete clinical response (CR), 2 had partial response (PR), and 1 had progressive disease (PD). Of the 8 CR patients, 5 underwent second-look operation (SLO). Pathological complete response (pCR) confirmed in 4 out of 5 patients at SLO. The 3 patients without measurable disease (< 2 cm) after primary surgery had an indeterminate response to chemotherapy. Two of them (Stages Ic and II, respectively) had a negative SLO, while the third patient with Stage IV disease, who refused the SLO, remains disease-free 41+ months. This high response rate shows that this carcinoma is very responsive to cisplatin- or cisplatin analogue-containing regimens. One pCR and two clinical CR patients relapsed after 20, 14, and 16 months, respectively, from the completion of chemotherapy and died despite the second-line treatment. The toxicity of the regimens was moderate. The median survival was 40 months, and the actuarial 5-year survival rate was 48%. Carcinoma of the fallopian tube appears to respond favorably to cisplatin- or carboplatin-containing chemotherapy.

First line combination chemotherapy with cisplatin and etoposide in advanced ovarian cancer.

Thirty-one consecutive patients with advanced epithelial ovarian cancer entered a phase II study with cisplatin and etoposide combination chemotherapy. None of them had received prior chemotherapy or radiotherapy. Most patients had advanced (88%) or far advanced (61%) disease. All 31 patients are evaluable for toxicity which was significant and led to removal of five (16%) patients from the study. Of the 23 patients evaluable for response there were four clinical complete (CR) and eight partial (PR) responders for a total clinical response rate of 52% of evaluable patients and 39% of all patients. Eight patients (four clinical CR and four good PR) have undergone second look laparotomy with pathological CR in one of the clinical CR patients. Median survival time for responders and non-responders is 19 and 8 months respectively. The results obtained appear to be inferior to other cisplatin based combinations. Although this could be attributed to the unusually high proportion of patients with bulky disease and stage IV patients, we feel that the study suggests that etoposide did not add any benefits for this patient population to cisplatin as a single agent.

Treatment of metastatic malignant melanoma with dacarbazine, vindesine and cisplatin.

Twenty-seven patients with disseminated malignant melanoma were treated monthly with cisplatin (CDDP) 120 mg m-2 on day 1, vindesine (VDS) 3 mg m-2 on day 2 and dacarbazine (DTIC) 250 mg m-2 on days 2-6. None of them had received prior chemotherapy. All patients are evaluable for response and toxicity. There were five (19%) complete (CR) and seven (26%) partial (PR) responses for a total response rate of 45%. We conclude that the combination of DTIC, VDS and CDDP is capable of producing a relatively high rate of response in patients with advanced metastatic malignant melanoma, but responses are short.

Treatment of disseminated germ cell tumours of the testis.

Between 1979 and 1987 64 men with non-seminomatous germ cell tumours of the testis were treated with chemotherapy. Nearly half of these patients had large volume disease. The most frequently used combinations were VAB-6 and POMB/ACE. Chemotherapy lasted 3.9 months for small volume disease and 5.5 months for large volume disease. Seven patients (11%) underwent resection of residual masses; viable malignancy was found in only 1 of these. Relapse occurred in 6 complete responders, 3 of whom were salvaged with further chemotherapy. Fifty-three patients are presently alive and have received no treatment for periods of 5 to 86 months. Life table analysis forecasts a survival of 81%. Adverse prognostic factors have been recognised and include high initial serum concentrations of beta-human chorionic gonadotrophin (beta-HCG) and alpha fetoprotein (AFP), large volume disease and prior irradiation. Although the survival time of patients with advanced disease has improved in recent years, it remains considerably below that of patients who present with less advanced disease. Such patients should be treated aggressively from the outset in order to obtain maximum benefit from chemotherapy. Selected cases also require adjunctive surgery.