Treatment of poorly differentiated neuroendocrine tumours with etoposide and cisplatin

The purpose of this study was to evaluate by a retrospective analysis of 53 patients the efficacy of chemotherapy combining etoposide and cisplatin in the treatment of neuroendocrine tumours. The regimen was a combination of etoposide 100 mg m(-2) day(-1) for 3 days and cisplatin 100 mg m(-2) on day 1, given by 2-h intravenous infusion, administered every 21 days. Twelve patients had a well-differentiated and 41 a poorly differentiated neuroendocrine tumour. Toxicity of treatment was assessed in 50 patients and efficacy in 52 patients. Among the 11 patients with a well-differentiated tumour evaluable for tumoural response, only one (9.4%) had a partial response for 8.5 months. Forty-one patients with a poorly differentiated tumour showed an objective response rate of 41.5% (four complete and 13 partial responses); the median duration of response was 9.2 months, the median overall survival 15 months and the median progression-free survival 8.9 months. Haematological grade 3-4 toxicity was observed in 60% of the cases with one treatment-related death, digestive grade 3-4 toxicity in 40% and grade 3 alopecia was constant. No severe renal, hearing and neurological toxicities were observed (grade 1 in 6%, 14%, 72% respectively and no grade >1). We confirm that poorly differentiated neuroendocrine tumours are chemosensitive to the etoposide plus cisplatin combination. However, the prognosis remains poor with a 2-year survival lower than 20% confirming that new therapeutic strategies have to be developed.     

Epirubicin, cisplatin, and prolonged or brief infusional 5-fluorouracil in the treatment of carcinoma of unknown primary site

The cytotoxic regimen of epirubicin, cisplatin, and continuous infusional 5-fluorouracil (ECF) has demonstrated activity in a range of malignancies, including gastroesophageal, breast, and pancreatic cancers. Prolonged infusional central venous catheter (CVC) mediated therapy is not always feasible and modifications of the 5-fluorouracil (5FU) schedule have been reported. We reviewed our experience of both the standard and a modified ECF regimen in patients diagnosed with carcinoma of unknown primary site (CUPS). A retrospective analysis of all patients diagnosed with CUPS (31 adenocarcinoma and 5 poorly differentiated carcinoma) and treated with ECF between June 1994 and June 1998 was undertaken. Thirty-six patients, median age 56 (range: 24–74), were treated thrice-weekly with 50 mg/m² epirubicin, 60 mg/m² cisplatin, and 5-FU administered either by continuous infusion 200 mg/m²/d via a CVC (standard ECF) or as a 6-h infusion 600 mg/m² through a peripheral venous catheter (modified ECF). Thirteen patients were treated with standard ECF and 23 received modified ECF. The median number of cycles administered was 4 (range: 1–10). Thirty-two patients had evaluable disease, seven (22%; 95% confidence interval: 8–36%) demonstrated a partial response, including three patients that received standard ECF and four treated with modified ECF. There were no complete responses. The median survival for all 36 patients was 9.0 mo. Median survival for patients treated with standard ECF was 11.7 mo as compared to 5.1 mo for the modified ECF schedule (p=0.052). Liver involvement and elevation of serum CA19.9 were identified as possible adverse prognostic factors. Both regimens were well tolerated, with the only grade 3/4 toxicity recorded being leukopenia (four patients), nausea/vomiting (seven patients), and diarrhea (one patient). CVC complications in the standard ECF group were thrombosis (one patient) and infection (three patients). There were no treatment-related deaths. We conclude that ECF, whether modified or standard, has modest activity in the setting of CUPS. Patient survival is comparable to survival documented in previous reports of CUPS treatment. The apparent survival difference between the two ECF schedules may be the result of patient selection factors. The optimal treatment of CUPS remains unknown and can only be determined through randomized controlled trials.     

Treatment with cisplatin and etoposide in patients with neuroendocrine tumors

BACKGROUND: Patients with malignant endocrine pancreatic tumors (EPTs) are responsive to combinations of chemotherapy with streptozotocin and 5-fluorouracil/doxorubicin, whereas patients with malignant carcinoids are not. For both categories of patients, alpha-interferon and/or somatostatin analogs can produce long-lasting responses. Cisplatin in combination with etoposide has been suggested to be effective in patients with malignant neuroendocrine carcinomas. The authors used this therapy as second-line or third-line treatment in patients with poorly differentiated and/or rapidly progressing disease. METHODS: Thirty-six patients with histopathologically verified malignant neuroendocrine tumors were included: Eighteen tumors were of foregut origin, of which 5 were atypical, and 15 tumors were EPTs, of which 4 were poorly differentiated endocrine carcinomas. Three tumors were of midgut origin. The median patient age was 47.5 years. The median duration of disease from the time of diagnosis was 12 months. All patients had metastatic disease. Thirty of 36 patients had received previous treatment. Etoposide was given at a dose of 100 mg/m(2) per day for 3 days, and cisplatin was given at a dose of 45 mg/m(2) on Days 2 and 3 as a continuous intravenous infusion that was repeated every 4 weeks. RESULTS: Ten of 18 patients with foregut carcinoids (56%) responded radiologically and/or biochemically, with a median duration of 9 months; and 7 of 14 patients with EPTs (50%) responded radiologically and/or biochemically, with a median duration of 9 months. No difference in response was seen between patients with atypical or typical foregut carcinoids or between patients with well differentiated or poorly differentiated endocrine pancreatic carcinoma. Nineteen of 36 patients (53%) experienced World Health Organization (WHO) Grade 1-2 nephrotoxicity, and 23 patients (64%) suffered from WHO Grade 3-4 neutropenia. CONCLUSIONS: The combination of cisplatin and etoposide can produce significant responses in patients with heavily pretreated and poorly differentiated/rapidly progressing neuroendocrine tumors. The toxicity is considerable, and nephrotoxicity is the dose limiting factor.     

Infusional 5-fluorouracil and cisplatin as first-line chemotherapy in patients with carcinoma of unknown primary site

A combination chemotherapy of 5-fluorouracil (5-FU) and cisplatin (CDDP) has demonstrated activities in various malignancies, including head and neck, lung, esophageal, gastric, and pancreatic cancers. We reviewed our experience of 11 patients diagnosed as carcinoma of unknown primary site (CUPS), who were treated with infusional 5-FU and CDDP between January 1998 and December 2005. The median number of cycles administered was three (range: 1-12). All patients had measurable disease. Six partial responses were obtained (response rate: 54.5%, 95% confidence interval: 23.4-83.3%). The median survival time for all patients was 10 mo (range, 2-37 mo). The median time to disease progression was 3 mo (range, 1-6 mo). This regimen was well tolerated, with grade 3-4 neutropenia (two patients), febrile neutropenia (one patient), grade 3 nausea/vomiting (one patient), and grade 3 stomatitis (two patients). Grade 2 leukoencephalopathy was observed in one patient. No treatment-related death was observed. The combination chemotherapy of infusional 5-FU and CDDP was feasible and tolerated with promising activity for CUPS.     

Cisplatin and etoposide in oesophageal cancer: a phase II study. Rotterdam Oesophageal Tumour Study Group.

In the search for effective chemotherapy regimens which can be used in multimodality treatment programmes for patients with cancer of the oesophagus, we conducted a phase II trial to determine the activity and toxicity of the combination of cisplatin and etoposide in patients with advanced squamous cell carcinoma of the oesophagus. Seventy-three consecutive patients with unresectable or metastatic squamous cell carcinoma of the thoracic oesophagus were treated with cisplatin 80 mg m-2 by 4 h infusion on day 1, etoposide 100 mg (fixed dose) by 2 h infusion on day 1 and 2, and etoposide 200 mg m-2 orally on day 3 and 5. Courses were repeated every 4 weeks, for a maximum of six courses. The oral dosages of etoposide were modified individually until a significant degree of myelosuppression was reached. Of 65 evaluable patients, five complete responses (CRs) and 26 partial responses (PRs) were seen, for an overall response rate of 48% (95% confidence interval 35-60%). Median time to progression was 7 months (range 3-72 + months). There were two toxic deaths (neutropenic sepsis). The response rate equals that of other cisplatin-based regimens. Its toxicity profile allows addition of a third active drug such as 5-fluorouracil.     

A multicentre phase II study of carboplatin and prolonged oral etoposide in the treatment of cancer of unknown primary site (CUPS).

Cisplatin-based combination chemotherapy is frequently used to treat patients with carcinoma of unknown primary site (CUPS). Response rates in the literature range from 12% to 26% and median survival from 5 to 7 months. The goal of this study was to evaluate the combination of carboplatin and prolonged oral etoposide in patients with CUPS, with the hope of minimizing toxicity but improving efficacy and convenience. Treatment consisted of carboplatin, 300 mg m(-2) on day 1, and oral etoposide 50 mg on days 1-20, every 4 weeks for up to nine cycles. A total of 33 patients were treated and all were evaluable for toxicity. Non-haematological toxicity was mild to moderate, with the exception of one case of grade 4 stomatitis. Grade 4 leucopenia was observed in eight (24%) patients and sepsis in four (12%), with two and possibly three treatment-related deaths. For the 26 patients evaluable for response, the response rate was 23% with responses lasting a median of 11 months (range 7-13 months), with one patient still responding at 12 months. An additional nine patients (35%) had stable disease. Median survival for all patients was 5.6 months (range 2 weeks to 33 months). The combination of carboplatin with prolonged oral etoposide has moderate activity similar to that of other platinum-based regimens and is a well tolerated, convenient, outpatient regimen. Dosing according to estimated creatinine clearance to achieve a carboplatin AUC of 6.0 mg ml(-1) min might have decreased the incidence of severe myelotoxicity without compromising the regimen''s efficacy.     

A phase II study of mitomycin C, etoposide, and cisplatin in advanced non-small cell lung cancer

Standard chemotherapeutic regimens, such as cisplatin and etoposide, may improve quality of life and prolong survival in patients with incurable non-small cell lung cancer (NSCLC). This trial was designed to evaluate the activity and toxicity of a regimen combining three of the most active agents against advanced-stage NSCLC: mitomycin C, etoposide, and cisplatin (MEP). Sixty-eight patients with stage IIIB (pleural effusion) or IV NSCLC received cisplatin 80 mg/m² i.v. on day 1 and etoposide 80 mg/m² i.v. on days 1, 2, and 3 every 3 weeks along with mitomycin C 10 mg/m² i.v. on day 1 of the first and third cycles for a median of four cycles (range, 1-11). Median age was 59 years, and nine patients were enrolled after relapse from previously treated early-stage NSCLC. Eighty-eight percent of patients had stage IV disease, and 14 (21%) had brain metastases at diagnosis. Palliative radiotherapy was given to 10 patients (15%) before MEP and to 17 (25%) concurrent with MEP. The major toxicity of MEP was myelosuppression, with grade 3-4 neutropenia in 74% of patients. Sixteen patients (24%) had documented infections, and there were eight (12%) treatment-related deaths. Partial response was observed in 24 patients (35%) with a median duration of 4.4 months, (range 1.4-13 months). Median survival was 8.1 months (range, 1-34 months), and 1-year survival was 32%. The addition of mitomycin C to cisplatin and etoposide resulted in response and survival rates comparable with those achieved with standard regimens in patients with advanced NSCLC but was associated with substantial hematologic toxicity and unacceptable treatment-related mortality.     

Efficacy and toxicity of intra-arterial cisplatin and etoposide for advanced hepatocellular carcinoma

OBJECTIVE: To analyze the results of an intra-arterially delivered combination chemotherapy in a group of patients with regionally advanced hepatocellular carcinoma (HCC). METHODS: 26 patients with proven locally advanced HCC treated with hepatic artery infusion of cisplatin (20 mg/m(2), days 1-5) and etoposide (75 mg/m(2), days 1-5) every 4 weeks were retrospectively studied. RESULTS: In an intention-to-treat analysis, overall and complete response rates were 38 and 7%, respectively. Median duration of response was 5 months. Median survival time was 10 months and survival rates at 6, 12 and 24 months were 53, 33 and 24%, respectively. Survival was significantly longer for responders than for non-responders (median: 13 and 3 months, respectively). There were 4 treatment-related deaths among cirrhotics. CONCLUSIONS: Intra-arterial chemotherapy using cisplatin and etoposide seems to have some anti-tumor effect against advanced HCC, although a high rate of life- threatening complications precludes the indication of this regimen at least for patients with non-compensated cirrhosis.     

Multicentric phase II study of cisplatin and etoposide in patients with metastatic carcinoma of unknown primary

The aim of this study was to determine the efficacy and toxicity of combination cisplatin and etoposide chemotherapy in patients with metastatic carcinoma of unknown primary. Patients were treated with cisplatin (100 mg/m2 iv day 1) followed by etoposide (100 mg/m2 iv days 1-3) every 3 weeks for a maximum of 6 cycles. Patients with progressive disease after two or four courses could receive FAC (fluorouracil, doxorubicin, and cyclophosphamide) until progression. Twenty-five patients were entered and were assessable for response and toxicity. Fifteen (60%) patients had adenocarcinomas. Patients received a median of four courses. Toxicity was mainly hematologic including grade III/IV neutropenia. The overall response rate was 32%. There was no complete response, 32% partial responses, 32% stable disease, and 36% disease progression. Median response duration was 4 months (range: 2-5 months). The median overall survival of the 25 patients was 8 months. No objective response could be obtained with FAC, but 33% of patients achieved stabilization of the disease for at least 3 months. This cisplatin-etoposide combination demonstrated some activity against an usually resistant disease.     

Cisplatin-based combination chemotherapy in the treatment of poorly differentiated carcinoma and poorly differentiated adenocarcinoma of unknown primary site: results of a 12-year experience.

PURPOSE: We previously reported excellent responses to cisplatin-based chemotherapy in a minority of patients with poorly differentiated carcinoma (PDC) or poorly differentiated adenocarcinoma (PDA) of unknown primary site. We have continued to study and to treat these patients, and now report clinical characteristics, treatment results, and prognostic factors in a large group of patients identified prospectively. PATIENTS AND METHODS: Between February 1978 and December 1989, we treated 220 patients with PDC or PDA of unknown primary site. The median age was 39 years; 48% of patients had predominant tumor location in the mediastinum, retroperitoneum, or peripheral lymph nodes. Specialized pathologic studies resulted in the identification of specific tumor types in only a few cases. All patients received cisplatin-based chemotherapy; between 1978 and 1984, 116 patients received cisplatin, vinblastine, and bleomycin (PVeB) +/- doxorubicin, and 104 patients treated since January 1985 received cisplatin and etoposide +/- bleomycin. RESULTS: One hundred thirty-eight patients (63%) had objective responses to therapy, and 58 (26%) had complete response. Thirty-six patients (16%) are currently disease-free at a median of 61 months following therapy (range, 11 to 142 months). Actuarial 10-year survival is 16%. Favorable prognostic factors identified by Cox regression analysis include: (1) predominant tumor location in the retroperitoneum or peripheral lymph nodes, (2) tumor limited to one or two metastatic sites, (3) no history of cigarette use, and (4) younger age. CONCLUSION: Patients with PDC or PDA of unknown primary site represent another group of patients for whom potentially curative therapy is available. Patients with this syndrome should be distinguished from patients with well-differentiated adenocarcinoma of unknown primary site, and should receive a trial of cisplatin-based chemotherapy.     

Docetaxel and Cisplatin in First Line Treatment of Patients with Unknown Primary Cancer: A Multicenter Study of the Anatolian Society of Medical Oncology

Background: The overall prognosis for cancers of unknown primary (CUP) is poor, median overall survival(OS) being 6-12 months. We evaluated our multicentric retrospective experience for CUP administered docetaxeland cisplatin combination therapy. Materials and Methods: A total of 29 patients that were pathologicallyconfirmed subtypes of CUP were included in the study. The combination of docetaxel (75 mg/m2, day 1) andcisplatin (75 mg/m2, day 1) was performed as a first line regimen every 21 days. Results: The median age was 51(range: 27-68). Some 17 patients had multimetastatic disease on the inital diagnosis. Histopathological diagnoseswere well-moderate differentiated adenocarcinoma (51.7%), undifferentiated carcinoma (27.6%), squamouscell cancer (13.8%), mucoepidermoid carcinoma (3.4%) and neuroendocrine differentiated carcinoma (3.4%).Median number of cycles was 3 (range: 1-6). Objective response rate was 37.9% and clinical benefit was 58.6%.Median progression free survival (PFS) and overall survival (OS) were 6 months (range: 4.3-7.7 months) and 16months (range: 8.1-30.9 months), respectively. Fourteen patients (60.8%) were treated in a second line setting.There was no treatment related death. Most common toxicities were nausia-vomiting (44.6%) and fatigue (34.7%),serious cases (grade 3/4) suffering nausia-vomiting (10.3%), neutropenia (13.8%) and febrile neutropenia (n=1).Conclusion: The combination of cisplatin and docetaxel is an effective regimen for selected patients with CUP.     

Combined etoposide, ifosfamide, and cisplatin in the treatment of patients with advanced thymoma and thymic carcinoma: an intergroup trial

BACKGROUND: Patients with thymic tumors (thymoma and thymic carcinoma) are known to respond to a variety of chemotherapeutic agents, including single-agent ifosfamide and cisplatin with etoposide. The purpose of this trial was to evaluate the response rate, progression free survival, overall survival, and toxicity of combined etoposide, ifosfamide, and cisplatin (VIP) in patients with advanced thymoma and thymic carcinoma. METHODS: From July 1995 through February 1997, 34 patients with advanced thymoma or thymic carcinoma were entered on trial to receive etoposide (75 mg/m2 on Days 1-4) ifosfamide (1.2 g/m2 on Days 1-4), and cisplatin (20 mg/m2 on Days 1-4). Cycles were repeated every 3 weeks for four total cycles. RESULTS: Among 28 evaluable patients (pathology review excluded 6 patients), there were no complete responses and 9 partial responses (complete and partial responses combined, 32%; 95% confidence interval, 16-52%). The median follow-up was 43 months (range, 12.8-52.3 months), the median duration of response was 11.9 months (range, < 1-26 months), and the median overall survival was 31.6 months. Based on Kaplan-Meier estimates, the 1-year and 2-year survival rates were 89% and 70%, respectively. The toxicity was predominantly myelosuppression. CONCLUSIONS: The VIP regimen has moderate activity in patients with advanced thymic malignancies. However, with limited follow-up, the results of this trial appear to be inferior to other chemotherapy regimens reported in large Phase II trials performed in patients with this disease.     

Single-agent gemcitabine: an active and better tolerated alternative to standard cisplatin-based chemotherapy in locally advanced or metastatic non-small cell lung cancer

This randomized study was designed to determine the response rates, survival and toxicities of single-agent gemcitabine (GEMZAR) and a combination of cisplatin/etoposide in chemonaive patients with non-resectable, locally advanced or metastatic non-small cell lung cancer (NSCLC). Gemcitabine 1000 mg/m2 was given as a 30-min intravenous infusion on days 1, 8, 15 of a 28-day cycle, cisplatin 100 mg/m2 on day 1, and etoposide 100 mg/m2 on days 1 (following cisplatin), 2 and 3. Major eligibility criteria included histologically confirmed non-small cell lung cancer, measurable disease, Zubrod performance status 0-2, no prior chemotherapy, no prior radiation of the measured lesion, and no CNS metastases. One hundred and forty-seven patients were enrolled, 72 in the gemcitabine and 75 in the cisplatin/etoposide arm. Patient characteristics were well-matched across both arms. Sixty-seven gemcitabine and 72 cisplatin/etoposide patients were qualified for efficacy analysis. There were no complete responses, but 12 partial responses in the gemcitabine arm and 11 in the cisplatin/etoposide arm, for protocol-qualified response but 12 partial responses in the gemcitabine arm and 11 in the cisplatin/etoposide arm, for protocol-qualified response rates of 17.9% (95%, CI: 9.6-29.2%,) and 15.3% (95% CI: 7.9-25.7%,), respectively. Median survival times were 6.6 months (95% CI: 4.9-7.3 months) for gemcitabine and 7.6 months (95% CI: 5.4-9.3 months) for cisplatin/etoposide. The 1-year survival probability estimate was 26% for gemcitabine and 24% for cisplatin/etoposide. There were no statistically significant between-group differences in time-to-event measures, but patients in the gemcitabine arm had a greater probability of achieving a tumour response after 2 months (probability estimate: 8 vs. 0%,) and of the response lasting at least 6 months (73 vs. 45%,). Clinical and haematologic toxicity was more pronounced in the cisplatin/etoposide arm. Quality-of-life measures indicated a significant worsening of symptomatology in the cisplatin/etoposide arm for hair loss, nausea and vomiting, and appetite loss. This randomized study provides further evidence that single-agent gemcitabine is an active and effective therapy for patients with non-resectable. locally advanced or metastatic NSCLC and good performance status, and that it is better tolerated than the combination cisplatin/ etoposide.     

Results of a phase II study with doxorubicin, etoposide, and cisplatin in patients with fully characterized small-cell carcinoma of the prostate.

PURPOSE: To determine the activity and toxicity of doxorubicin in combination with cisplatin and etoposide in patients with small-cell prostate carcinoma (SCPCa) and to characterize the clinicopathologic features of SCPCa. PATIENTS AND METHODS: Patients with SCPCa (pure or mixed), measurable disease, good organ function, and no prior treatment with doxorubicin, etoposide, or cisplatin were treated every 4 weeks with doxorubicin 50 mg/m(2) as a 24-hour intravenous (IV) infusion followed by etoposide 120 mg/m(2)/d and cisplatin 25 mg/m(2)/d IV on days 2 to 4. RESULTS: Thirty-eight patients (36 assessable for response) were treated for a median of four cycles. Twenty-nine (81%) of 36 patients had prior hormonal therapy. Study patients had visceral metastases, lytic bone disease, and relatively low serum prostate-specific antigen (PSA). We observed 22 partial responses (response rate, 61% in an intent-to-treat analysis); toxicity was severe (grade 3 or 4 neutropenia 100%, thrombocytopenia 66%, mucositis 21%, and infection 68%). Three patients died of toxicity. Median time to progression and overall survival time were 5.8 months and 10.5 months, respectively. Performance status, serum albumin, and number of organs involved (but not PSA, carcinoembryonic antigen, or neuroendocrine markers) were predictors of survival. CONCLUSION: SCPCa presents unique clinicopathologic features. Addition of doxorubicin to the etoposide/cisplatin regimen caused higher toxicity in this patient population and failed to improve outcome. Given these results, we do not recommend further development of this regimen for patients with SCPCa. Improvement in therapy will come from understanding the biology of SCPCa progression and integrating new targeted therapies into the treatment of SCPCa.     

ESHAP as salvage therapy for refractory non-Hodgkin's lymphoma: Taiwan experience

BACKGROUND: The ESHAP regimen, a combination of the chemotherapeutic drugs etoposide, methylprednisolone (solumedrol), high-dose cytarabine (ara-C) and cisplatin, has been shown to be active against refractory non-Hodgkin's lymphoma in therapeutic trials. We were interested in determining whether this regimen would be effective and tolerable for Chinese patients. METHODS: Thirty-two patients with refractory/relapsed non-Hodgkins lymphoma (23 intermediate-grade and nine high-grade) were enrolled in this study. Etoposide was administered at a dose of 40 mg/m2/day as a 1 h intravenous infusion from day 1 to day 4, solumedrol 500 mg/day was given as a 15 min intravenous infusion from day 1 to day 5, ara-C 2 g/m2 was given as a 2 h intravenous infusion on day 5 and cisplatin was given at a dose of 25 mg/m2/day as a continuous infusion from day 1 to day 4. Clinical efficacy and toxicity were assessed on the basis of the WHO criteria. RESULTS: Ten patients (31.3%, 95% Cl 15.2-47.4%) attained complete remission (CR) and seven had partial remission (PR). The overall response rate was 53.1% (95% Cl 35.8-70.4%). In eight of the 10 CR patients, the remission lasted for more than 8 months. The remaining two patients had CR of 5 and 6 months. The median duration of CR was 12.2 months (range 5-22 months). Myelosuppression with subsequent infections was the major toxicity. Severe leukopenia (WBC < 1000/microliter) lasted for an average of 12 days and thrombocytopenia (< 25,000/microliter) 18 days. One patient (3.1%) died of neutropenia-associated sepsis within 4 weeks after treatment. Non-myeloid toxicities included alopecia in 66% (28% grade 2, 22% grade 3), stomatitis in 72% (25% grade 2, 28% grade 3, 13% grade 4), hepatotoxicity in 9% (3% grade 2), renal toxicity in 13% (6% grade 2, 3% grade 3) and infection in 56% (18% grade 2, 25% grade 3, 13% grade 4). The majority of the responders relapsed within 2 years after ESHAP treatment. Median survival for all patients was 8.6 months. CONCLUSIONS: ESHAP is an active and tolerable regimen in Chinese patients with relapsed/refractory lymphoma, but the duration of remission is brief and without significant impact on survival.     

Phase I trial of concurrent thoracic radiation and continuous infusion cisplatin and etoposide in stage III non-small cell lung cancer.

OBJECTIVE: Although combined modality therapy appears to be superior to radiotherapy alone for the treatment of locally advanced non-small cell lung cancer (NSCLC), the optimal treatment regimen has not been determined. We designed this trial to determine the maximal tolerated doses (MTD) of continuous intravenous infusion (CI) cisplatin and etoposide that could be administered concurrently with thoracic irradiation. METHODS: 19 patients with stage IIIA or IIIB NSCLC were treated at three different dose levels of CI cisplatin and etoposide with concurrent single daily fraction thoracic radiotherapy to 4500 cGy. This chemoradiotherapy phase of treatment was followed by a 1500-2000 cGy radiotherapy boost and three cycles of standard intermittent bolus cisplatin 80 mg/m2 i.v. on day 1 and etoposide 80 mg/m2 i.v. on days 1, 2 and 3. RESULTS: The MTD of CI chemotherapy was determined to be cisplatin 5 mg/m2/day plus etoposide 18 mg/m2/day for 5 days per week over 5 weeks along with thoracic irradiation. Overall, 37% of patients required breaks in the chemoradiotherapy course and 32% required attenuation of the planned duration of CI chemotherapy. Only 42% of patients received all three planned cycles of bolus chemotherapy and 16% received < 6000 cGy of thoracic irradiation. The major toxicities during concurrent chemoradiotherapy were grade 3-4 esophagitis (42%) and myelosuppression (47%). Subsequent chemotherapy was complicated by grade 3-4 myelosuppression in 38% of patients. An objective response was documented in 58% of patients (CR 11%, PR 47%). Median survival was 18 months with 2- and 5-year survival rates of 42 and 11%, respectively. CONCLUSIONS: These results demonstrate that CI cisplatin and etoposide can be administered safely to patients with locally advanced NSCLC, and that such potentially radiosensitizing strategies deserve further evaluation in this setting.     

Phase II study of cisplatin-combined schedules as second-line chemotherapy in patients with non-small cell lung cancer

BACKGROUND: The aim of this study was to evaluate the effectiveness of cisplatin- (CDDP) combined chemotherapy in non-cisplatin pretreated patients with non-small-cell lung cancer (NSCLC). The second cytotoxic drug administered was either etoposide or gemcitabine. First-line treatment was based on paclitaxel combined with either carboplatin or vinorelbine. PATIENTS AND METHODS: Seventy-eight patients with histologically- or cytologically- confirmed NSCLC, having failed front-line treatment, were enrolled. All patients received 80 mg/m2 of cisplatin as second-line treatment, on day 1, repeated every 3 weeks; in 48 patients the second agent was etoposide (120 mg/m2) on days 1, 2 and 3, repeated every 3 weeks and in 30 patients 1 g/m2 of gemcitabine on day 1, repeated every 3 weeks. RESULTS: All patients were evaluable for response and toxicity. No complete responses were observed. Thirteen (16.67%) patients achieved partial response, 42 (53.85%) stable disease and 23 (29.49%) had disease progression. The median duration of response was 4 months (range 2-8+ months), median time to tumor progression (TTP) 5 months (range 2-9 months) and median survival time after starting second-line chemotherapy, 6 months (range 2-9+ months). Toxicity was acceptable: 9 patients presented with nephrotoxicity (11.54%) and 13 (16.67%) with grade 3-4 neutropenia. CONCLUSION: The cisplatin combination as second-line treatment in patients with NSCLC exhibited a notable degree of activity and tumor growth control was evidenced by the 16.67% partial response and 53.85% disease stability.     

Gemcitabine and cisplatin in patients with carcinoma of unknown primary site

The optimal therapy for carcinoma of unknown primary site (CUPS) is still under investigation. In this retrospective trial, we reported the response rates and overall and progression free survival of 23 CUPS patients that were treated with gemcitabine and cisplatin. The mean age of the patients was 54.95 (32–77). Sixteen (69.6%) of them were males and 7(30.4%) females. Totally 109 cycles with a mean of 6 were administered. Thirteen of 23 patients (56.5%) presented with only one metastatic site, and the liver is the most frequent metastatic site (39.1%). Histologic types were adenocarcinoma in 14 patients (60.8%), squamous carcinoma in 1 patient (4.8%), epithelioid cancer in 3 patients (13%) and undifferentiated cancer in 5 patients (21.7%). Three patient achieved a CR (13%), 4 patients achieved a PR (17.4%) and 8 patients had SD (34.8%) with an overall 30.4% response rate. However, 8 patients had progressive disease with a percentage of 34.8%. The median follow-up time was 10 months (3–42 months). The mean and median survival was 12.5 (3–42) months and 10 months (range, 3–42 months) and progression free survival was 5.5 months (range, 0–23 months). Gemcitabine plus cisplatin may be an effective treatment of CUPS. Therefore additional trials are needed especially with new chemotherapeutics.     

Cisplatin, etoposide, and ifosfamide in non-small cell lung carcinoma. A phase II randomized study with cisplatin and etoposide as the control arm

A Phase II randomized study testing the combination of cisplatin, etoposide, and ifosfamide (PEI) in non-small cell lung cancer (NSCLC) was performed. The standard combination of cisplatin and etoposide (PE) was used as the control arm. Since January 1987, 78 patients were enrolled and then stratified for previous treatments and performance status (PS). The response rate (RR) of PEI was 26% (95% confidence limits [95 CL], 12% to 40%), with one complete response (CR). The RR of PE was 26% (95 CL, 13% to 39%), with no CR. The median response duration was 5 months (range, 2 to 13 months) for PEI and 4 months (range, 2 to 6 months) for PE. The median survival time was 6 months (range, 1 to 22+ months) for PEI and 7 months (range, 1 to 21+ months) for PE. Leukopenia at recycling was similar in both arms (25% for PEI and 29% of PE). The median leukocyte nadir was 2100/microliters (range, 430 to 4870/microliters) for PEI patients and 3150/microliters (range, 500 to 5000/microliters) for PE patients. Three patients had a drug-related death secondary to infections. This Phase II randomized study suggested that the combination of cisplatin plus etoposide and ifosfamide produces results similar to those obtainable with cisplatin and etoposide.     

Treatment of patients with metastatic gastric-cancer by continuous-infusion of 5-Fluorouracil, Cisplatin and Etoposide

The therapeutic effectiveness of continuous infusion of 5-fluorouracil and cisplatin, and etoposide (FEP) for treatment of metastatic gastric cancer was examined. Studies were made on 17 patients with gastric cancer with distant metastases. 5-fluorouracil (300 mg/m(2)/day) and cisplatin (80 mg/m(2)/day) were administered by continuous intravenous infusion for 120 and 24 hours, respectively; etoposide (60 mg/m(2)/day) was injected intravenously over a 2 hour period on days 2, 3 and 4. These chemotherapy treatments were repeated every 28 days. Partial, but not complete, remission was seen in four patients (24%). The treatment increased the survival times of patients with differentiated or Borrmann 2 or 3 type cancer, but not significantly. In many cases the treatment caused myelosuppression, but side effects were usually mild or moderate. It is concluded that infusion of 5-fluorouracil, etoposide and cisplatin is effective and well tolerated.