High Dose Chemotherapy Without Hematopoietic Cell Support for the Treatment of Refractory Lymphoma

Conventional dose combination chemotherapy for patients with relapsed or refractory lymphoma is rarely curative. High dose chemotherapy followed by hematopoietic progenitor cell transplant (HPCT) has a clearly defined role in patients who have first relapsed after standard CHOP chemotherapy for lymphoma. However, the role of HPCT is less well defined for patients with chemo-resistant, or chemo-refractory disease. Sixteen patients (15 Non-Hodgkin's, 1 Hodgkin's Disease) were entered into a phase II study to determine if a dose intensive induction regimen in heavily pre-treated refractory lymphoma patients could permit further consolidation with HPCT. The primary endpoints were survival, response, tox-icity, and resource utilization. The regimen consisted of continuous infusion etoposide I or 2 gm/m²/72 hours, idarubicin 12mg/m²/d for 3 days followed by cytarabine 2gm/m²/72 hours on days 8,9, and 10 (VIC). Fifteen patients were evaluable for objective response. The overall response rate was 53% with 7 patients achieving a partial response and 1 patient achieving a complete response. Of the 8 responders, 6 patients subsequently received high dose chemotherapy followed by HPCT (4 autologous, 2 allogeneic). The median survival was 176 days for the non-responders contrasted with 722 days for the responders. The average duration of hospitalization was 38 days. Toxicity was mainfest primarily as mucositis with a median grade of 3 among the first 13 patients, and a median grade of 2 in three subsequent patients who received an etoposide dose of lgm/m²/72 hours. All patients had an episode of neutro-penic fever and 5 patients developed clinically significant pneumonitis during therapy.

The VIC regimen is active in the treatment of chemo-refractory lymphoma with clinically significant differences in survival for patients who respond to therapy. Further modifications to the regimen could include the addition of a topoisomerase I inhibitor for synergy with etoposide, and using VIC as part of a tandem transplant regimen where response to VIC would allow further therapy with a myeloablative induction followed by HPCT.     

Intensive dose ifosfamide and etoposide with G-CSF for stem cell mobilization in patients with non-Hodgkin's lymphoma

We studied 36 patients with non-Hodgkin's lymphoma to evaluate the stem cell yield following recovery from intensive dose ifosfamide and etoposide given as mobilization chemotherapy. We also assessed the toxicity of the regimen and engraftment kinetics. All patients had intermediate grade lymphoma and had either failed to achieve a complete remission to induction chemotherapy or had relapsed. Patients received ifosfamide 10 g/m2 IV total dose given over 72 hours, etoposide 150 mg/m2 IV every 12 hours for 6 doses and G-CSF 10 microg/kg/d. Thirty-four patients went on to receive high-dose chemotherapy with BEAM or with CVP and BEAM. A median of 2 (1-10) apheresis was required to reach the target CD34+ count of >4 x 10(6)/kg. A median of 13.1 CD34+ cells/kg (4.1-148) was obtained. Toxicity was limited to mucositis in 3 patients, transient confusion and transient rise in liver function tests in 3 and 2 patients respectively. The median time to engraftment was 10 days (8-17) for all the patients undergoing high-dose chemotherapy. The regimen of intensive dose ifosfamide and etoposide along with G-CSF is well tolerated and in this group of patients has lead to successful stem cell harvests and sustained engraftment.     

E-SHAP: An effective treatment in selected patients with relapsed non-Hodgkin's lymphoma

BACKGROUND:: The optimal treatment of relapsed or refractory non-Hodgkin'slymphoma is unknown. The reported encouraging results of a salvageregimen, E-SHAP (etoposide 40 mg/m²/day x 4, methyl prednisolone500 mg daily x 4, cytosine arabinoside 2 gm/m² one dose andcisplatinum 25 mg/m²/day x 4), at the MD. Anderson Hospitalin Texas, which resulted in a 65% response rate, could not bereproduced in the United Kingdom (0% response). PATIENTS AND METHODS:: Twenty-six patients with relapsed (n = 16) or refractory (n= 10) non-Hodgkin's lymphoma were treated at our Centre by amodified E-SHAP regimen (cytosine arabinoside 1 gm/m² one dose).The treatment was intended as remission induction before BMT(n = 16), as salvage by itself (n = 5) and for palliation ofsymptoms (n = 5). RESULTS:: The overall response rate was 72% (CR = 7 and PR = 11). A comparisonof Kaplan-Meier curves showed a statistically significant improvementin median relapse-free survival in patients who had previouslyachieved CR (p = 0.0012), no bulky disease (P = 0.0006) andno B-symptoms (P = 0.0004). The toxicity was acceptable: 8 instancesof febrile neutropenia, 2 of reversible renal impairment and2 symptomatic electrolyte abnormalities. No fatal toxicitieswere encountered. The median time to treatment failure was 191days and median overall survival was 190 days. CONCLUSIONS:: E-SHAP is an active combination chemotherapy when used as asalvage regimen or for remission induction before bone marrowtransplantation in selected patients with relapsed non-Hodgkin'slymphoma. Patients who previously achieved CR, with low tumourburden and no B-symptoms are the best candidates for this treatment.It has a limited palliative effect. non-Hodgkin's lymphoma, salvage chemotherapy, etoposide, cisplatinum     

Chemotherapeutic intensification in germ cell tumors

Chemotherapy has dramatically improved the prognosis of non-seminomatous germ cell tumors (NSGCT). However, some patients relapse and others are refractory to first line chemotherapy. We studied a salvage chemotherapeutic regimen with etoposide 75 gm/m2/day, and cisplatin 40 mg/m2/day, days 1-5 and Ifosfamide 3 g/m2/day, days 1 and 2 (VIhP regimen) in 32 patients. We observed 8 complete remissions with 4 long-term NED patients. Hematological, neurological and renal complications were frequent. In 16 other cases, a protocol using high dose chemotherapy, followed by autologous bone marrow rescue was studied. We observed 8 complete remissions with 4 long-term NED patients. These observations support a dose/effect relationship. A French randomized trial testing high dose chemotherapy, followed in some cases by an autologous marrow graft in poor risk advanced NSGCT, has recently been activated.     

Mitoxantrone, Etoposide and bleomycin (meb) chemotherapy in non-hodgkins-lymphoma patients non-elegible for standard cyclophosphamide, Doxorubicin, vincristine and prednisone (chop) combination

The antitumor activity and toxicity profile of a new therapeutic combination was investigated for patients with non-Hodgkin's lymphoma (NHL). The regimen consisted of mitoxantrone (10 mg/m(2)/day by intravenous (i.v.) bolus injection on day 1), etoposide (100 mg by 24 hours continuous i.v. infusion on days 1, 2, 3) and bleomycin (4 mg by i.v. bolus injection on day 1 followed by 24 hours continuous i.v. infusion at 4 mg/m2/day dose on days 1, 2, 3) (MEB). MEB chemotherapy was administered to 22 patients affected by intermediate/high grade or clinically symptomatic low grade NHL who were considered non-elegible for standard cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) chemotherapy. Major responses were achieved in 11/22 (50%) patients with 5 (23%) complete responses. Grade 3-4 neutropenia occurred in 59% of patients. The results of this study demonstrate that MEB chemotherapy possesses good antitumor activity and a manageable toxicity in a prognostically unfavourable subset of lymphoma patients.     

High dose chemotherapy with autologous stem cell support in the treatment of germ cell tumors: experience of the centre Léon-Bérard between 1982 and 1996]

More than 80% patients with metastatic germ cell tumors are cured by chemotherapy and surgery. Since 1980, intensive chemotherapy with autologous bone marrow was developed for the patients who where not cured by conventional chemotherapy. We present the experience of the Centre Léon-Bérard, between 1982 and 1996, seventy-five metastatic germ cell tumors patients were treated with high dose chemotherapy and autologous stem cell support. Forty-six patients received cisplatin, etoposide, ifosfamide (VIC regimen), 17 carboplatin, etoposide, cyclophosphamide (CarboPEC regimen), 9 cisplatin, etoposide, cyclophosphamide (PEC) and 10 had another regimen. The chemotherapy was administred in different situations: 31 patients with poor prognosis in first line, 15 in salvage of sensitive relapse, 15 in salvage of incomplete response, and 14 with a cisplatin refractory disease. The complete response rate was 31% among the 54 evaluable patients. Seven patients died as a consequence of the treatment. The two-year overall actuarial survival and the event free survival were respectively 67% and 57% (median 42 months). Only 2 patients who had a refractory disease are continuously disease-free at 42 and 87 months after regimen. The renal toxicity was more severe with regimen VIC than with CarboPEC 30% versus 60%, whereas the hematologic toxicity are similar with both. This study shows the feasability of high dose chemotherapy. Two refractory patients are alive, and the results seem to be interesting for the patients in salvage treatment. But this treatment is not a standard for germinal cell tumors and randomized trials are ongoing.     

Infusional fluorouracil,etoposide, and cisplatin (FEP) in advanced and relapsed gastric cancer

We evaluated the efficacy and tolerability of a combination chemotherapy including infusional fluorouracil (5-FU), etoposide, and cisplatin (FEP) in 89 patients with advanced/relapsed gastric cancer. Primary endpoints were progression-free and overall survival. Secondary endpoints were response rates, response duration, and toxicity. The treatment schedule was as follows: 5-FU 1,000 mg/m2 and etoposide 100 mg/m2 were administered on 3 consecutive days and cisplatin at 80 mg/m2 was administered on day 2, and repeated every 3 weeks. The median times to progression and overall survival were 4 and 8 months, respectively. One-year progression-free and overall survival rates were 10% and 33%, respectively. The overall response rate for 25 eligible patients with measurable disease was 20% (5/25, complete response 2, partial response 3) with median response duration of 7 months. Median actual dose intensities of 5-FU, etoposide, and cisplatin were 700 mg/m2/wk, 70 mg/m2/wk, and 21 mg/m2/wk, respectively. Median relative dose intensities of 5-FU, etoposide, and cisplatin were 0.70, 0.70, and 0.63, respectively. In conclusion, the FEP regimen was found to produce therapeutic results similar to those of other combination chemotherapeutic studies and to have an acceptable toxicity. This regimen could be used as one of the options for advanced gastric cancer chemotherapy in patients unsuitable for doxorubicin-based regimens.     

Granulocyte-macrophage colony-stimulating factor or granulocyte colony-stimulating factor infusion makes high-dose etoposide a safe outpatient regimen that is effective in lymphoma and myeloma patients.

PURPOSE: This study assessed the efficacy of recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) or recombinant human granulocyte colony-stimulating factor (rhG-CSF) in ameliorating the extent and duration of hematologic toxicity after high-dose etoposide cancer therapy. PATIENTS AND METHODS: Thirty-two non-Hodgkin's lymphoma and myeloma patients were treated with 2 to 2.4 g/m2 etoposide infused intravenously (IV) during a 10- to 12-hour period, followed 72 hours later by subcutaneous administration of rhGM-CSF or rhG-CSF. Hematologic toxicity was compared with that observed in 29 patients who were treated with high-dose etoposide without growth factors. RESULTS: The median duration of grade 4 neutropenia in growth factor-treated patients was 3 days, and granulocyte counts never decreased to less than 100/microL in approximately half of the patients. The corresponding figures in the control patients were 8 and 3 days, respectively (P < .0001). No effect was observed in platelet and RBC recovery. Growth factor-treated patients became eligible to receive additional myelotoxic chemotherapy a median of 5 days earlier than controls. Nonhematologic toxicity was minimal. Grade 1 mucositis was observed in two of 61 patients (3%). Antitumor activity assessed within 1 month after etoposide administration was documented in 58% of 38 assessable patients. Finally, high-dose etoposide expanded and mobilized the pool of peripheral-blood hematopoietic progenitors. CONCLUSION: The use of rhGM-CSF or rhG-CSF makes high-dose etoposide a safe outpatient regimen and should encourage the inclusion of this highly effective and well-tolerated drug in novel treatment strategies that use high-dose therapy early in the clinical course of chemosensitive tumors.     

Effect of pirarubicin for elderly patients with malignant lymphoma

To determine the effect of a chemotherapy regimen containing pirarubicin, a multicenter clinical trial was performed in naive patients > or = 65 years with malignant lymphoma, between January 1990 and December 1992. The total number of patients was 37 (median age 74.2 years). One of three different types of chemotherapy regimens, which was administered every 3 to 5 weeks, was chosen for each patient at random. Regimen A (THP-COP) included pirarubicin (30 mg/m2; day 1), cyclophosphamide (500 mg/m2; day 1), vincristine (1 mg/m2; day 1) and prednisolone (30 mg/m2; days 1-5), regimen B, modified "CHOP", included doxorubicin (30 mg/m2; day 1), cyclophosphamide (500 mg/m2; day 1) vincristine (1 mg/m2; day 1) and prednisolone (30 mg/m2; days 1-5); regimen C (THP-COPE) included etoposide (80 mg/m2; day 1) in addition to regimen A. The complete response (CR) rate was 60.0%, 45.5% and 62.5% with regimen A, B and C. The partial response (PR) rate with regimen A was 20.0%, 18.2% with B and 25.0% with C. The 50% survival period with regimen A was more than 1,000 days, with C 643 days but it was only 365 days with B. The adverse effects related to these treatments occurred more frequently in regimen B than A and C showing a statistically significant difference. We concluded that chemotherapy regimens containing pirarubicin are useful and safe for the elderly patients with malignant lymphoma.     

A phase I dose escalation of combination chemotherapy with granulocyte-macrophage-colony stimulating factor in patients with neuroblastoma

BACKGROUND: Dose intensity is important in the response to chemotherapy in patients with advanced neuroblastoma. The aim of the current study was to determine the maximum tolerated dose of a combination chemotherapy regimen in the treatment of patients with recurrent neuroblastoma and peripheral neuroepithelioma (primitive neuroectodermal tumor [PNET]) and whether the use of growth factor would allow increased dose intensity. METHODS: Twenty-nine patients diagnosed with recurrent neuroblastoma or PNET were treated with a combination chemotherapy regimen of cisplatin, 160 mg/m(2)/96 hours; doxorubicin, 40 mg/m(2)/96 hours; and escalated doses of etoposide and ifosfamide. Granulocyte-macrophage-colony stimulating factor (GM-CSF) was administered beginning 24 hours after the completion of the chemotherapy. Courses were repeated at 28-day intervals. Once the maximum tolerated dose (MTD) was defined the interval between courses was shortened by administering the next course as soon as the patient's neutrophil and platelet counts had recovered to > 1500/microL and > 75,000/microL, respectively. RESULTS: Sixteen patients were treated at 3 dose levels. The MTD was defined as 10 g/m(2)/96 hours of ifosfamide and 800 mg/m(2)/96 hours of etoposide. Thirteen additional patients then were treated at 1 level below the MTD to try and decrease the interval between courses. A total of 12 of 29 patients developed a dose-limiting toxicity (DLT) after the first course of therapy. The most common DLT was gastrointestinal toxicity followed by hematologic toxicity. Twenty-seven patients developed standard National Cancer Institute criteria Grade 3 or 4 toxicity after the first course of treatment and 7 patients achieved a complete or partial response to the first course. The use of GM-CSF did not allow further dose intensification. CONCLUSIONS: This chemotherapy combination achieved a 31% overall response rate. A further increase in the dose intensity of this regimen may require supportive measures other than GM-CSF to decrease toxicity.     

A phase I study of gemcitabine/cisplatin/etoposide in the treatment of small-cell lung cancer

PURPOSE: To define the maximum tolerated dose and toxicity of combined cisplatin, etoposide, and gemcitabine in patients with small-cell lung cancer. METHODS: We undertook a phase I study in patients with either extensive small-cell lung cancer with or without prior chemotherapy, or limited disease who had progressed or recurred despite prior treatment. Patients received cisplatin 75 mg/m2 i.v. day 1, etoposide 50-100 mg/m2 i.v. day 1 followed by oral administration of 50-100 mg/m2 days 2 5, and gemcitabine at either 800 or 1000 mg/m2 i.v. days 1 and 8, on a 3 weekly cycle. RESULTS: We treated 20 patients, 14 at the 800 mg/m2 gemcitabine dose level, and six at the 1000 mg/m2 dose level. The protocol initially used an etoposide dose of 100 mg/m2 etoposide daily (i.v. day 1 and orally days 2-5), but the first two patients died of septic complications. With reduction of the etoposide dose to 50 mg/m2 daily x 5, the regimen was well tolerated. At this etoposide dose, neutropenia, mucositis, and gastrointestinal toxicity occurred in one patient at each of the two gemcitabine dose levels. In addition, one patient receiving gemcitabine at the 1000 mg/m2 level experienced a possible allergic reaction. The overall response rate was 54%. Patients on gemcitabine at the 800 mg/m2 level who had not received prior chemotherapy had the highest response rate, at 75%. CONCLUSION: The recommended phase II doses for this regimen are cisplatin 75 mg/m2 i.v. day 1, etoposide 50 mg/m2 i.v. day 1 and orally days 2-5, and gemcitabine 800 mg/m2 i.v. days 1 and 8. Future trials should further examine the optimal relative doses and schedule of gemcitabine and etoposide.     

Results of treatment with high intensity, brief duration chemotherapy in poor prognosis non-Hodgkin's lymphoma.

A novel chemotherapeutic approach was designed for the treatment of intermediate and high-grade histology non-Hodgkin's lymphoma using augmented (but subtransplantation) doses of chemotherapy administered at frequent intervals in the inpatient setting. For the initial evaluation of this regimen, poor prognosis patients were treated with a projected long-term survival rate of less than 25% in response to standard therapy. Between March 1982 and May 1988, 56 previously untreated patients were entered into this study; all patients had either high-grade histology (20 patients) or predominantly large cell lymphoma (36 patients). Median age was 41.5 years (range, 18 to 69 years). Poor prognosis features included: Stage IV, 71%; poor performance status (Eastern Cooperative Oncology Group scale, 2 to 4), 55%; multiple extranodal sites of disease, 52%; elevated lactic dehydrogenase (greater than 300 IU/l), 43%; and bulky (greater than 10 cm) tumor masses, 30%. Thirty-three of 56 patients (59%) were in Shipp's Category 3. During the 6-year study, the chemotherapy regimen was modified in an attempt to improve efficacy and reduce toxicity. However, most patients received a 2-month course of therapy as follows: cyclophosphamide 1500 mg/m2 intravenously (IV) on days 1, 2, and 29; etoposide 400 mg/m2 IV on days 1, 2, and 3 and 100 mg/m2 on days 29, 30, 31; doxorubicin 45 mg/m2 IV on days 29, 30; vincristine 1.4 mg/m2 IV on days 8, 22, 36, and 50; bleomycin 10 units/m2 IV on days 8, 22, 36, and 50; methotrexate 200 mg/m2 IV on days 15 and 43 followed 24 hours later by leucovorin 15 mg/m2 IV every 6 hours for six doses; and prednisone 60 mg/m2 orally on days 1 to 7 and 29 to 35. The complete response (CR) rate was 77% (95% confidence interval, 64% to 86%). There were ten relapses, only one of which occurred after 18 months of follow-up. Overall event-free survival (EFS) was 52% (95% confidence interval, 36% to 68%), with a median follow-up of 36 months. Eleven of 13 patients with small noncleaved lymphoma had CR; actuarial EFS in this subgroup was 61%. Myelosuppression occurred in all patients, with severe leukopenia (less than 1000/microliters) lasting a median of 12 days (range, 3 to 29 days); toxic deaths occurred in five patients (9%; 95% confidence interval, 4% to 19%). This intensive approach improved the response and survival of very poor risk non-Hodgkin's lymphoma patients.     

Study of paclitaxel, etoposide, and cisplatin chemotherapy combined with twice-daily thoracic radiotherapy for patients with limited-stage small-cell lung cancer: a Radiation Therapy Oncology Group 9609 phase II study.

PURPOSE: To determine the response rate, progression-free survival and overall survival, and toxicity of paclitaxel, etoposide, and cisplatin combined with accelerated hyperfractionated thoracic radiotherapy in patients with limited-disease (LD) small-cell lung cancer (SCLC). PATIENTS AND METHODS: LD-SCLC patients with measurable disease, Karnofsky performance score of > or = 70, and adequate organ function who were previously untreated were eligible for the study. Treatment was as follows. In cycle 1 of chemotherapy, concurrent thoracic radiation therapy was administered. In cycles 2 to 4, chemotherapy was administered alone. In cycle 1, chemotherapy consisted of paclitaxel 135 mg/m(2) intravenous over 3 hours on day 1, etoposide 60 mg/m(2) intravenous on day 1 and 80 mg/m(2) orally on days 2 and 3, and cisplatin 60 mg/m(2) intravenous on day 1. In cycles 2 to 4, the paclitaxel dose was increased to 175 mg/m(2), with the etoposide and cisplatin doses remaining the same as in cycle 1. The thoracic radiation therapy consisted of 1.5 Gy in 30 fractions (total dose, 45 Gy) administered 5 days a week for 3 weeks. RESULTS: Fifty-five patients were enrolled onto the study, and 53 were assessable. The major toxicities included grade 3 and 4 acute neutropenia (32% and 43%, respectively) and grade 3 and 4 esophagitis (32% and 4%, respectively). Two patients died as a result of therapy (one died of acute respiratory distress syndrome, and one died of sepsis). There was one late fatal pulmonary toxicity. The median survival time was 24.7 months. The 2-year survival rate was 54.7%. The median progression-free survival time was 13 months, with a 2-year progression-free survival rate of 26.4%. CONCLUSION: Although this therapeutic regimen is effective in the treatment of patients with LD-SCLC, it is unlikely that the three-drug combination with thoracic radiation therapy will improve the survival times compared with the etoposide plus cisplatin chemotherapy regimen with thoracic radiation therapy in LD-SCLC patients.     

Etoposide and Mitoxantrone as a Second Cycle of Consolidation Therapy Following High Dose Cytosine Arabinoside and Daunorubicin in Patients with Acute Non-Lymphocytic Leukemia in Remission: A Pilot Study

High dose cytosine arabinoside (ARA-C) has produced long term relapse free survival in 26% to 49% of patients when used as consolidation therapy of acute non-lymphocytic leukemia (ANLL) in first remission. However, the optimal consolidation regimen has not been defined. In this pilot study we attempted to confirm and extend our previous studies of high dose consolidation therapy by administering two cycles of consolidation chemotherapy to patients with ANLL in first remission. The first cycle was high dose ARA-C 3 gm/m² over 1 hour every 12 hours for 12 doses followed by daunorubicin 45 mg/m²/day for three days. The second cycle was etoposide 75 mg/m²/day for 10 days and mitoxantrone 12 mg/m²/day for three days.

Twenty-three patients received high dose consolidation chemotherapy, 13 of whom received the proposed two cycles. The major reason for not receiving the planned second consolidation cycle was life threatening toxicity, primarily fungal infection, during the first consolidation cycle. By actuarial estimate, 46% of patients receiving consolidation chemotherapy were projected to be relapse free at 36 months. There were no deaths during consolidation. Survival was not improved in patients receiving etoposide and mitoxantrone as the second cycle of consolidation therapy as compared to patients receiving only one cycle of consolidation therapy.     

异长春花碱加异环磷酰胺加顺铂联合化疗治疗晚期非小细胞肺癌

目的 评价异长春花碱加异环磷酰胺加顺铂（NIP）联合方案作为第一线化疗对晚期非小细胞肺癌病人的疗效及毒副作用。方法 化疗方案包括异长春花碱25mg/m^2 20min静脉输注第1d和第8d,异环磷酰胺1．2g/m^2 3h静脉输注第1－3d,美司纳400mg-800mg于0、4、8h静脉推注第2－3d,顺铂25mg/m^2 2h静脉输注第1－3d。每3周重复疗程。结果 共54例病人进行本项研究。51例可评价疗效,54例可评价毒性反应。总缓解率为53％,3例（6％）完全缓解,24例（47％）部分缓解。16例（31％）肿瘤稳定,8例（16％）肿瘤发展。中位缓解期7个月,全组中位生存期10个月。本化疗方案的剂量限制毒性为骨髓抑制,其中72％的病人发生3－4度中性粒细胞下降。结论 NIP是治疗晚期非小细胞肺癌有效的联合化疗方案,毒性反应能够耐受,值得进一步研究。     

Combined chemoradiotherapy for unresectable pancreatic cancer.

This study was undertaken to evaluate the efficacy of a regimen of combined chemoradiotherapy in patients with unresectable adenocarcinoma of the pancreas. An analysis was undertaken on 27 patients from January 1992 to May 1996. Patients had a median age of 70 years (range, 40-78) and Eastern Cooperative Oncology Group Performance Status of 0-2. Eighteen patients had locoregional disease (T2-T3, N0-N1, M0), and nine had metastatic disease. Chemotherapy consisted of four cycles of 5-fluorouracil 1 gm/m2/day as a continuous infusion over 110 hours, streptozotocin 300 mg/m2/day over 30 minutes on days 2-4, and cisplatin 100 mg/m2 over 2 hours on day 4 only, followed by a maintenance regimen of 5-fluorouracil and leucovorin every 2 weeks. The radiotherapy was administered as a split course concurrently with chemotherapy to a total dose of 6000 cGy. Toxicity was frequent, but there were no treatment-related deaths. Grade III and IV toxicity was primarily limited to myelosuppression, stomatitis, and gastrointestinal side effects. Fifteen patients (56%) were able to complete either three or four cycles of chemoradiotherapy. All patients were evaluable for toxicity, response, and survival. Nine patients (33%) had an objective response (four complete response 5 partial response), two remained stable, and 16 (59%) had disease progression. Median survival for the entire group was 19 weeks (2-139), and the median survival for overall responders was 56 weeks (15-139). No patient with localized disease underwent subsequent surgical resection. The authors conclude that those patients who are able to tolerate the entire treatment regimen may achieve a useful prolongation of time to tumor progression.     

Phase II trial of high-dose cisplatin plus etoposide plus vinblastine in non-small-cell lung cancer. A Hoosier Oncology Group study.

Fifty-one patients with advanced non-small-cell lung cancer were treated on a Hoosier Oncology Group protocol with an aggressive, high-dose cisplatin combination chemotherapy regimen. All patients had a Karnofsky performance status of 80% or higher and had no prior chemotherapy. The drug regimen consisted of cisplatin 30 mg/m2 days one through five, etoposide 40 mg/m2 days one through five, and vinblastine 5 mg/m2 day one. Therapy was given every three weeks for a total of three courses. Forty-five patients were evaluable for response and an objective response was seen in 15 patients (33%) with only one complete responder. The median duration of response was 16.5 weeks. The median survival for the entire group was 29.0 weeks. Toxicity was moderately severe with two treatment-related deaths (4%). Despite an aggressive chemotherapy regimen in a favorable patient population, there was no obvious evidence of a major therapeutic value.     

Comparison of survival and quality of life in advanced non-small-cell lung cancer patients treated with two dose levels of paclitaxel combined with cisplatin versus etoposide with cisplatin: results of an Eastern Cooperative Oncology Group trial.

PURPOSE: Treatment with cisplatin-based chemotherapy provides a modest survival advantage over supportive care alone in advanced non-small-cell lung cancer (NSCLC). To determine whether a new agent, paclitaxel, would further improve survival in NSCLC, the Eastern Cooperative Oncology Group conducted a randomized trial comparing paclitaxel plus cisplatin to a standard chemotherapy regimen consisting of cisplatin and etoposide. PATIENTS AND METHODS: The study was carried out by a multi-institutional cooperative group in chemotherapy-naive stage IIIB to IV NSCLC patients randomized to receive paclitaxel plus cisplatin or etoposide plus cisplatin. Paclitaxel was administered at two different dose levels (135 mg/m(2) and 250 mg/m(2)), and etoposide was given at a dose of 100 mg/m(2) daily on days 1 to 3. Each regimen was repeated every 21 days and each included cisplatin (75 mg/m(2)). RESULTS: The characteristics of the 599 patients were well-balanced across the three treatment groups. Superior survival was observed with the combined paclitaxel regimens (median survival time, 9.9 months; 1-year survival rate, 38.9%) compared with etoposide plus cisplatin (median survival time, 7.6 months; 1-year survival rate, 31.8%; P =. 048). Comparing survival for the two dose levels of paclitaxel revealed no significant difference. The median survival duration for the stage IIIB subgroup was 7.9 months for etoposide plus cisplatin patients versus 13.1 months for all paclitaxel patients (P =.152). For the stage IV subgroup, the median survival time for etoposide plus cisplatin was 7.6 months compared with 8.9 months for paclitaxel (P =.246). With the exceptions of increased granulocytopenia on the low-dose paclitaxel regimen and increased myalgias, neurotoxicity, and, possibly, increased treatment-related cardiac events with high-dose paclitaxel, toxicity was similar across all three arms. Quality of life (QOL) declined significantly over the 6 months. However, QOL scores were not significantly different among the regimens. CONCLUSION: As a result of these observations, paclitaxel (135 mg/m(2)) combined with cisplatin has replaced etoposide plus cisplatin as the reference regimen in our recently completed phase III trial.     

High-dose chemotherapy with autologous hematopoietic stem-cell transplantation for advanced soft tissue sarcoma in adults.

PURPOSE: Patients with metastatic or locally advanced, unresectable soft tissue sarcoma (ASTS) are seldom curable, with 5-year survival rates of less than 10% in all large series. The role of high-dose chemotherapy (HDCT) with hematopoietic stem-cell support in this disease is not established. PATIENTS AND METHODS: Between 1988 and 1994, 30 patients with ASTS who responded to a standard chemotherapy regimen were included in a prospective pilot study of HDCT as consolidation therapy using ifosfamide (12 g/m(2)), etoposide (800 mg/m(2)), and cisplatin (200 mg/m(2)) (VIC). RESULTS: The median duration of grade 4 neutropenia and thrombocytopenia was 14 and 10 days, respectively. Nineteen patients (63%) experienced grade 1 or higher renal toxicity. All eight patients in complete remission (CR) before HDCT were still in CR at day 60. Of the 22 patients in partial remission (PR) or with a minor response to conventional chemotherapy, CR, PR, and stable disease were achieved in four (18%), three (13%), and 12 patients (54%), respectively, by day 60, while three patients (14%) progressed. With a median follow-up of 94 months, overall and progression-free survival rates at 5 years after HDCT were 23% and 21%, respectively. Patients in CR before HDCT had a significantly superior 5-year overall survival rate compared with other patients (75% v 5%; P: =.001). CONCLUSION: Despite the toxicity of the VIC regimen, a high survival rate was observed in HDCT-treated patients who were in CR after conventional chemotherapy. A phase III randomized trial is required to establish the role of HDCT in ASTS.     

Determining carboplatin/etoposide dosage in extensive stage small-cell lung cancer (SCLC).

In order to define the maximum tolerance level of combined carboplatin/etoposide dosage, patients with extensive stage small-cell lung cancer (SCLC) were treated with a fixed dose of carboplatin (300 mg/m2 iv on day 1) and escalating doses of etoposide starting with 80 mg/m2 iv on days 1-3. Five patients were given this starting and every following dose level. The daily dose of etoposide was increased in increments of 20 mg/m2 iv until severe myelosuppression occurred in 3 of 5 patients. Leuko- or thrombocytopenia WHO grade 3 or 4 occurred in 0/5 of the patients at the dose levels of 80 and 100 mg/m2, in 1/4 of the patients at the level of 120 mg/m2, in 2/5 of the patients at a level of 140 mg/m2, and 3/5 patients at a level of 160 mg/m2. Thus, increase in dosage was stopped at an etoposide dose of 160 mg/m2. Other side effects were mild and consisted predominantly of nausea and vomiting in 14/25 of the patients. The overall response rate was 40% with a 12% complete remission rate, median survival was 9.3 months and median progression-free survival totalled 4.3 months. These results indicate that combined carboplatin/etoposide is a well tolerated regimen in extensive-stage SCLC, with response rates comparable to those of other standard protocols. Using treatment intervals of 4 weeks the recommended dose of etoposide in combination with 300 mg/m2 carboplatin was identified as 140 mg/m2 iv for 3 consecutive days.