Haluk Onat

Prognostic factors and survival in late adolescent and adult patients with small round cell tumors

The primary objective of this study is to review the clinical characteristics of 25 patients in the adult and late adolescent age group, diagnosed and treated with small round cell tumors involving soft tissues (extraosseous Ewing sarcoma, rhabdo-myosarcoma, primitive neuroectodermal tumor, and undiffer-entiated small round cell tumors). Additionally, survival and prognostic factors influencing the outcome with multimodality treatment are evaluated. There were 19 males (76%) and 6 females (24%). The median age was 26 years (range: 15-56 years). In 9 patients (36%), the tumor was located at an extremity, whereas 16 patients (64%) had central localizations. Tumor size was larger than 10 cm in 7 patients (29.2%). Six patients (24%) had metastatic disease. Twelve patients (48%) received radiation and 16 patients (64%) underwent surgery. Among the resected tumors, 2 were resected with contaminated margins (12.5%), whereas 2 were radically resected and 12 (75%) were resected with wide margins. All patients were given a median of 4 cycles of multiagent chemotherapy (1–14 cycles). With preoperative chemotherapy, complete regression (CR) of the tumor was achieved in 6 patients (24%). In 4 patients (16%), a partial response was obtained. After the completion of multimodality treatment, 12 patients (48%) had a CR. Progression-free (PFS) and overall survival (OS) for the entire group was 25.0 ± 10.8% at 1 year and 30.5 ± 15.5% at 3 years, respectively. Nonmetastatic disease, wide and radical resection, and presence of CR to multimodality treatment were associated with a significantly longer PFS and OS by univariate analysis. By multivariate analysis, CR to multimodality treat-ment was the only independent predictive factor for a longer OS (p: 0.0036, relative risk [RR]: 23.6, 95% CI: 2.8; 198.7) and metastatic presentation was the only independent factor predic-tive for a shorter PFS (p: 0.017, RR. 15, 95% CI: 1.6; 141.2). Large-scale, multicenter studies are required for a better eval-uation of the nonpediatric age group with small round cell tumors.

Prognostic significance of marker half-life during chemotherapy in non-seminomatous germ cell testicular tumors.

Decrease in serum alpha-fetoprotein (AFP) and human chorionic gonadotropin (HCG) levels is considered as a response during chemotherapy of non-seminomatous germ cell testicular tumors, but data on the prognostic significance of marker half-life remains inconclusive. Serum marker half-life was evaluated in 34 patients with elevated markers, receiving chemotherapy (CT). Marker half-life was calculated from the natural logarithm of the sequential AFP or HCG concentrations. The correlation between event-free (EFS) and overall survival (OS) with unfavorable half-lives of AFP and HCG was evaluated. Median actual half-life (AHL) AFP was 3.9 days (range, 1.4-21.5) and median AHL HCG was 4.4 days (range, 1.4-21.0); 82% of the patients had a satisfactory initial decline in AFP, and 71% had a satisfactory initial decline in HCG. There was a significant difference in EFS and OS between the two groups of patients with an AFP half-life < 7 days and > 7 days. HCG half-life did not adversely affect EFS and OS. The correlation of better EFS and OS with appropriate AFP marker half-life during chemotherapy could provide a dynamic method, which could complement the standard baseline prognostic factors, for the prediction of prognosis.

A Phase II Study of Cisplatin, Ifosfamide and Epirubicin Combination Chemotherapy in Adults with Nonmetastatic and Extremity Osteosarcomas

Background: Osteosarcoma is a rare malignancy, and patients with this disease benefit from adjuvant chemotherapy. While cisplatin, anthracyclines and ifosfamide are the most commonly used agents in the treatment of osteosarcoma, a search for the best combination with higher efficacy and minimal toxicity continues. We planned to evaluate the efficacy of epirubicin combined with cisplatin and ifosfamide in patients with localized primary osteosarcoma. Methods: Patients with nonmetastatic extremity osteosarcoma who were older than 15 years were included in the study. The preoperative chemotherapy regimen consisted of epirubicin 90 mg/m2, cisplatin 100 mg/m2 on day 1 and ifosfamide 2.0 g/m2/day with an equivalent dose of mesna on days 2–4, repeated every 21 days. Six cycles of this combination regimen were administered (3 cycles prior to surgery and 3 cycles postoperatively). Results: Forty-five patients with localized osteosarcoma entered this phase II trial. Median follow-up was 64 months. Thirty-two patients (84%) received the assigned 6 cycles of chemotherapy. Complete and good histological response to neoadjuvant chemotherapy was 26 and 37%, respectively. The 5-year disease-free and overall survival rates were 41.9% (95% CI 33.6–50.2) and 48.2% (95% CI 39.6–56.8). The most prominent grade 4 toxicity was neutropenia occurring in 32% of patients. The lungs were the most frequent site of relapse (32%). Conclusions: The combination of cisplatin, ifosfamide and epirubicin is an active, reasonably well-tolerated regimen without grade 3 or 4 cardiac toxicity in patients with nonmetastatic extremity osteosarcoma and deserves further investigation in the context of prospective phase III trials.

Prognostic factors in localized aggressive non-Hodgkin's lymphoma.

To identify the prognostic factors that specifically predict survival rates of patients with localized aggressive non-Hodgkin’s lymphoma (NHL), a retrospective study including 118 patients with clinical stage I and II NHL treated at the Institute of oncology, Istanbul University between 1989 and 1998 was conducted. Patients were treated either with radiotherapy alone, radiotherapy and adjuvant chemotherapy, or chemotherapy (with or without adjuvant radiotherapy). The 5-year disease-free survival (DFS) and overall survival rates were calculated, and univariate and multivariate analyses were performed to identify the significance of various prognostic factors such as gender, age, performance status, stage (I versus II), B symptoms, extranodal involvement, gastrointestinal tract disease, erythrocyte sedimentation rate, bulky disease, histologic grade, serum lactate dehydrogenase level, serum &bgr;2-microglobulin level, serum albumin level, treatment regimen, remission status, and the International Prognostic Index risk groups, which may have an influence on the outcome of patients with NHL. The overall 5-year survival rate was 52% with a median follow-up of 30 months. The complete response rate was 68%, and the 5-year DFS of complete responders was 70%. Cox multivariate regression analysis showed that incomplete response, low serum albumin, bulky disease (>10 cm), and high grade histology were the pretreatment factors associated with shorter survival. When remission status was included in the model, the attainment of a complete response was the major determinant of long-term survival; however, low albumin level was still a significant adverse predictor for survival in multivariate analysis. These factors need to be evaluated for analyzing the outcome of treatment and to identify better therapeutic strategies.

Treatment of aggressive non-Hodgkin's lymphoma with dose-intensified epirubicin in combination of cyclophosphamide, vincristine, and prednisone (CEOP-100): A phase II study

Epirubicin is an agent with a lower incidence of cardiotoxicity and myelotoxicity compared with doxorubicin; and it is active in patients with non-Hodgkin’s lymphoma (NHL). Our aim was to define the therapeutic efficacy and toxicity of dose-intensified epirubicin in combination with cyclophosphamide, vincristine, and prednisone (CEOP) in patients with diffuse large-cell NHL. Previously untreated patients aged between 15 and 75 years, with at least one measurable lesion, adequate liver, renal, cardiac functions, and no central nervous system involvement were included in the study. The planned chemotherapy regimen CEOP consisted of cyclophosphamide 750 mg/m2, epirubicin 100 mg/m2, and vincristine 1.4 mg/m2 intravenously on day 1 and 100 mg prednisone taken orally on days 1 to 5. Courses were repeated every 21 days. Patients with stage I and II received four cycles of chemotherapy followed by involved-field radiotherapy, and patients with stage III and IV received six cycles of chemotherapy followed by radiotherapy to bulky lymph node sites. Seventy-five patients were enrolled in the study. The complete response rate was 83.8%, and 72 patients were assessable for toxicity. The most common toxicity was myelosuppression; 13.9% of the patients had grade III-IV neutropenia. Severe mucositis, diarrhea, and emesis were uncommon (<10%). At a median follow-up period of 41 months, the 5-year progression-free survival and overall survival rates were 63.5% and 65.3%, respectively. Increasing the dose intensity of epirubicin can yield a similar complete response rate compared with the regimens used in NHL without significantly increasing the toxicity rate associated with chemotherapy. The role of dose-intensive epirubicin should be investigated further in future randomized trials.

Prognostic factors in patients with aggressive non-Hodgkin's lymphoma without complete response to first-line therapy

This study was conducted to retrospectively identify the prognostic factors that specifically predict survival rates of patients with aggressive non-Hodgkin’s lymphoma who did not achieve a complete response (CR) to first-line therapy. Prognostic factors in terms of survival were analyzed in 76 adult patients with non-Hodgkin’s lymphoma who had failed to achieve CR to first-line chemotherapy (CT) regimens administered at Istanbul University, Institute of Oncology, between February 1989 and October 1998. A total of 41 patients were female, and median age was 60 y (range, 18–87 y). Twenty-seven patients (35%) had primary refractory disease (stable disease + progressive disease). A partial response (PR) was demonstrated in 49 (65%). In all, 92% had been administered anthracycline on the basis of computed tomography findings. Of 27 patients with primary refractory disease, 20 died because of initial CT toxicity or disease progression. A total of 10 patients with primary refractory disease underwent second-line CT. CR was observed in only 1 of those patients. Of the 49 patients who had a PR to first-line therapy, 31 died because of disease progression. Of those patients, 14 underwent second-line CT. Four patients were observed to have a CR. Median overall survival (OS) in all patients was established at 15 mo (range, 11–19 mo), and 5-y OS was 25%. On the other hand, median OS in patients with primary refractory disease was 7.6 mo (range, 5.7–9.4 mo) and was observed to be 17.8 mo (range, 9.4–26.1 mo) in patients with a PR. The difference in survival rates between patients with primary refractory disease and those with a PR was significant (P=.005). Although median OS was 18.1 mo (range, 8.4–27.8 mo) in patients with intermediategrade histology, it was 6.1 mo (range, 1–11.7 mo) in patients with high-grade histology (P=.001). As a result of univariate analysis, significant prognostic factors associated with OS included histologic grade (intermediate/high) (P=.001), response to initial therapy (primary refractory disease/PR) (P=.005), performance status (0–2/2–4) (P=.024), and International Prognostic Index risk groups (low/low intermediate/intermediate-high/high risk) (P=.004). Multivariate analysis revealed that independent prognostic parameters associated with OS included response to initial therapy (P=.009) and histologic grade (P=.001). Although prognosis is rather poor in patients with high histologic grade and primary refractory disease, patients with a PR have a slightly better prognosis.

Bcl-2 gene rearrangements and apoptosis rates in patients with Non-Hodgkin’s lymphoma during chemotherapy

OBJECTIVES Overexpression of the bcl-2 gene as a result of the t(14,18) translocation leads to neoplastic transformation by suppressing apoptosis. However, apoptotic cell death in response to chemotherapy has not been investigated. This study was planned with the aim to investigate the association between bcl-2 gene rearrangements and apoptotic changes during chemotherapy in patients with non-Hodgkins lymphoma. DESIGN AND METHODS Lymphocytes from 33 patients were collected before and during chemotherapy. Bcl-2 gene rearrangements were investigated by PCR. Apoptotic cell death was analyzed by enzyme immunoassay. RESULTS In 24 cases, mbr gene rearrangements were detected. Apoptosis was successfully induced by chemotherapy in 48% of patients. Two characteristic, clearly distinguishable apoptotic response patterns with transient peaks either following the first or the third course were observed. It was found that apoptosis rates measured after the first course exactly reflect the final response. No correlation was found between bcl-2 gene rearrangements and apoptosis. CONCLUSIONS Apoptotic cell death rates show transient changes during chemotherapy. Because the midterm response can be misleading, the apoptotic response should be evaluated following the first course of chemotherapy.

The efficacy of a five-drug antiemetic combination during chemotherapy regimens containing cisplatin or cyclophosphamide-doxorubicin

A five-drug combination, including metoclopramide, thiethylperazine, diphenhydramine, dexamethasone, and diazepam, was given to 32 patients during three consecutive treatments with chemotherapy. Eighteen patients (group A) were treated with a cisplatin-containing regimen, and 14 patients (group B) were treated with a cyclophosphamide- and doxorubicin-containing chemotherapy. In group A, complete responses were lower on the first day than on the second and third days (P < 0.015 and P < 0.041, respectively), during the first and second courses. The five-drug antiemetic regimen seems safe and effective. These results show that clinical trials that evaluate antiemetic efficacy in cisplatin-containing chemotherapy regimens should evaluate at least two consecutive courses.

Relapse of non-Hodgkin's lymphoma confined to the corpus uteri.

Non-Hodgkin’s lymphoma (NHL) can involve extranodal sites, the most common being the gastrointestinal tract and the skin. However, uterine involvement by NHL is uncommon. Approximately 40% of cyclophosphamide, doxorubicin, vincristine and prednisolone (CHOP)-treated patients are cured. Most of the patients have refractory disease or relapse. Most of the relapses are nodal alone or nodal and extranodal together. In addition, there are relapses limited to extranodal locations. However, although there have been primary uterine NHL reported in published documents, there has been no report found regarding the relapse of malignant NHL confined to the uterus. We present a case of NHL relapse solely in the corpus uteri.

Aggressive non-Hodgkin's lymphoma treated at the Institute of Oncology, Istanbul: treatment, outcome, and prognostic factors.

In an unselected group of patients with aggressive non-Hodgkin’s lymphoma (A-NHL) treated at our institution during a 10-year period (1989–1998), we studied the treatment outcome and influence of possible prognostic factors. Two hundred one patients with A-NHL were analyzed retrospectively with regard to personal, treatment, and disease-specific characteristics. Median age was 55 years (range: 16–87 years) and the male:female ratio was 1.5. During a median follow-up of 26 months, the overall response rate was 74% (complete response 63%, partial response 11%). The 2- and 5-year disease-free survival rates were 49 ± 3% (mean ± SEM) and 41 ± 4%, respectively. In a univariate analysis, the following variables were associated with prognosis in terms of survival: patient age, clinical stage, performance status, B symptoms, erythrocyte sedimentation rate, treatment response, and histologic grade of tumor. In multivariate analyses, patient age, performance status, and treatment response emerged as independent prognostic factors for survival.