High-dose etoposide and cyclophosphamide without bone marrow transplantation for resistant hematologic malignancy

Seventy-five patients with resistant acute leukemia or lymphoma received high-dose cyclophosphamide and etoposide to explore the activity of this combination in resistant hematologic malignancies, and to determine the maximum doses of these drugs that can be combined without bone marrow transplantation. Etoposide was administered over 29 to 69 hours by continuous infusion corresponding to total doses of 1.8 g/m2 to 4.8 g/m2. Cyclophosphamide, 50 mg/kg/d, was administered on 3 or 4 consecutive days total 150 to 200 mg/kg ideal body weight). At all dose levels myelosuppression was severe but reversible. Mucosal toxicity was dose-limiting with the maximum tolerated dose level combining etoposide 4.2 g/m2 with cyclophosphamide 200 mg/kg. Continuous etoposide infusion produced stable plasma levels that were lower than would be achieved after administration by short intravenous infusion, and this could explain our ability to escalate etoposide above the previously reported maximum tolerated dose. There were 28 complete (35%) and 12 partial (16%) responses. Median duration of complete response (CR) was 3.5 months (range 1.1 to 20+). Seventeen of 40 patients (42%) with acute myelogenous leukemia (AML) achieved CR, including 6 of 20 (30%) with high-dose cytosine arabinoside resistance. We conclude that bone marrow transplantation is not required after maximum tolerated doses of etoposide and cyclophosphamide. This regimen is active in resistant hematologic neoplasms, and the occurrence of CR in patients with high-dose cytosine arabinoside-resistant AML indicates a lack of complete cross-resistance between these regimens.     

A new concentrated perfluorochemical emulsion and carbogen breathing as an adjuvant to treatment with antitumor alkylating agents

Summary Many anticancer drugs require oxygen to be cytotoxic or are selectively cytotoxic toward cells under oxygenated conditions. The effects of the dilute perfluorochemical emuolsion Fluosol with a wide variety of chemotherapeutic agents have been explored; however, it has not been possbile to determine the optimal level of circulating perfluorochemical emulsion with anticancer drugs because the volume of Fluosol that may be administered is limiting. Using a new concentrated perfluorochemical emulsion, a wide range of perfluorochemical doses has been examined in combination with melphalan, cyclophosphamide and 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) in the FSaIIC fibrosarcoma. When the perfluorochemical emulsion was administered by injection i.v. just prior to the injection of melphalan (10 mg/kg), cyclophosphamide (150 mg/kg) or BCNU (50 mg/kg), the greatest tumor growth delays were obtained with dosage levels between 4 g and 12 g of the perfluorochemical perfluorooctyl bromide/kg. With each drug the greatest tumor growth delays were obtained when the drug was prepared in the emulsion and the combination injected i. v. In each case, each dose of drug was followed by 6 h of breathing carbogen. The addition of the perfluorochemical emulsion/carbogen breathing to treatment with melphalan, BCNU or cyclophosphamide resulted in significant increases in the killing of tumor cells by these drugs without a concomitant increase in toxicity to bone marrow granulocyte/macrophagecolony-forming units. In each case, preparing the drug in the perfluorochemical emulsion was most effective. These results indicate that clinical trial of this perfluorochemical emulsion/carbogen breathing in combination with cancer chemotherapy may be warranted.Abbreviations BCNU 1,3-bis(2-chloroethyl)-1-nitrosourea - CFUGM granulocyte/macrophage-colony-forming units This work was supported by a grant form Alliance Pharmaceutical Corporation, San Diego, Calif.     

Moderate to high dose cyclophosphamide and intercalated Corynebacterium parvum in patients with metastatic lung cancer

Thirty-nine patients with histologically proven widely metastatic bronchogenic carcinoma were treated with cyclophosphamide and Corynebacterium parvum. The dosage of cyclophosphamide was higher than conventional as previous work had indicated better results with increased dosage. Experimental work had suggested that the addition of Corynebacterium parvum would increase the antitumour effect and possibly reduce the cyclophosphamide induced granulocytopenia. A short treatment programme using three i.v. injections of cyclophosphamide, 1.5 g/m2, 2.5 g/m2 then 3.5 g/m2, at 3 week intervals were given. Four days after each cyclophosphamide injection, C. parvum 2 mg/m2 i.v. was administered. An overall 38% tumour response rate was observed, 18% for patients with non-small-cell carcinoma and 65% for small-cell carcinoma patients. The median survival for the 39 patients was 5 months (range 1-16+ months). These results, particularly for the non-small-cell patient group are comparable to those obtained with intensive combination chemotherapy regimens administered intermittently over much longer periods. An important consideration, objectively assessed in the present study, was the effect of treatment on quality of life and breathlessness. Improvement was noted not only in those patients with tumour response but also in a proportion of those who did not fulfil the criteria of response. Toxicity was also carefully assessed and, although the cyclophosphamide dosages were higher than conventionally used, no undue problems were noted. The addition of C. parvum did not have any noticeable beneficial effect. Cyclophosphamide given at dosages higher than is usual but which do not require bone marrow rescue is worthy of further study.     

Ablation of hemophilic FVIII inhibitors with FVIII priming, cyclophosphamide immune suppression, and rapid tapering of FVIII immune tolerance

The efficacy and toxicity of factor VIII (FVIII) priming, cyclophosphamide immune suppression, and rapid tapering of concurrent FVIII immune tolerance for subjects with hemophilic inhibitors were evaluated. Four subjects with hemophilic inhibitors were studied. Before treatment, inhibitors were present for a median of 8 months (mean 13 +/- 14.0 months). The median FVIII inhibitor titer was 16 BU/mL (mean 27.2 +/- 29.2 BU/mL). Following FVIII priming (80.0 +/- 70.2 U/kg), subjects received cyclophosphamide 1,418 +/- 636 mg/M2 i.v. q3 weeks for 4.4 +/- 1.7 courses. Subjects concurrently received a low (6 U/kg/day), moderate (30 U/kg/day), or high (100 U/kg/day) dose of FVIII followed by a rapid taper as the inhibitor titer decreased or resolved. During treatment, the inhibitor titer initially increased but then rapidly declined. Inhibitors resolved in 3.9 +/- 2.9 months. One inhibitor recurred at 2.8 years, but it was successfully re-treated. Effectiveness did not depend on the FVIII dose. Toxicity was minimal. Cyclophosphamide (1,400 mg/M2) administered after a priming dose of FVIII (80 U/kg) i.v. q3 weeks for 2-6 cycles with a rapid taper of concurrently administered daily FVIII as the inhibitor titer falls is an effective approach to hemophilic inhibitor ablation.     

IV melphalan in children

Forty children with multiply relapsed cancers received iv melphalan at three doses: 30 mg/m2, 45 mg/m2, and 60 mg/m2. The hematologic toxicity was severe and protracted at all dose levels, whether or not the bone marrow was involved with tumor. Of 39 evaluable patients, 37 had grade 3 or 4 hematologic toxicity. Nonhematologic toxic effects were infrequent and not severe. Two complete responses (Hodgkin's disease, rhabdomyosarcoma), eight partial responses, and 30 failures were seen. There appeared to be a very narrow margin between efficacy and toxicity. Further study of melphalan in pediatric tumors may be warranted in special circumstances: in higher doses (greater than 100 mg/m2) as cytoreduction therapy for specific cancers with marrow rescue, or as part of combination therapy in certain cancers (eg, lymphoma, sarcoma), possibly at doses of 20 to 30 mg/m2 every 4 weeks.     

ADOC regimen for unresectable advanced thymic cancer]

Between 1996 and 1998, we treated 6 patients with unresectable and advanced thymic cancer (stages IVa and IVb). All received 50 mg/m2 of cisplatin and 40 mg/m2 of doxorubicin intravenously (i.v.) on day 1,0.6 mg/m2 of vincristine i.v. on day 3, and 700 mg/m2 of cyclophosphamide i.v. on day 4; ADOC regimen, respectively at 3-4 week intervals. Four patients obtained a partial response (PR) after ADOC chemotherapy and the overall clinical response rate was 67%. No life-threatening side effects were noted. In 2 patients, cisplatin plus VP-16 chemotherapy failed to demonstrate any benefits prior to the ADOC regimen. Radiotherapy was initiated after the achievement of PR in the other 2 patients. ADOC chemotherapy appears to be an effective treatment for thymic cancer.     

Phase I study of thymidine plus 5-fluorouracil infusions in advanced colorectal carcinoma.

In order to determine the minimal toxic dose of a 5-day infusion of 5-fluorouracil (5--FU) in combination with an infusion of thymidine (TdR), 12 patients, received TdR at a dose of 8 g/m2/day for 5 1/2 days, beginning at the same time as a 5-day infusion of 5-FU at doses of 5--20 mg/kg/day. Myelosuppression was the dose-limiting toxicity, and the minimal toxic dose of 5--FU was found to be 7.5 mg/kg/day. Gastrointestinal toxicity was minimal to absent. In eight patients with carcinoma of the colon who had received no prior chemotherapy, there were two patients with partial responses (at doses of 5.0 and 7.5 mg/kg/day of 5--FU), two patients with stable disease, one patient with progressive disease, and three patients with early death (two drug-related deaths and one disease-related death). In four patients who had received prior 5--FU, one had stable disease, one had progressive disease, and two had early death (one drug-related death). We conclude that the addition of TdR to 5--FU infusions changes the dose-limiting toxicity from gastrointestinal toxicity to myelosuppression. The minimal toxic dose is decreased to approximately one third of that when 5--FU is administered alone.     

Phase-II clinical trial of 4′-epi-doxorubicin in metastatic solid tumors

4'-Epi-doxorubicin, one of the analogs of doxorubicin, was shown in experimental animal tumor models to have a wide spectrum of antitumor activity. In comparison, its toxic side effects were less prominent than those of doxorubicin. Results of the first phase-I and II clinical trials in human tumors have confirmed experimental data. The aim of our study was to carry out a broad phase-II clinical trial mainly in various types of primarily chemoresistant solid tumors to obtain further information on the antitumor activity spectrum and toxicity of 4'-epi-doxorubicin. Ninety-two patients, 55 males and 37 females aged from 32 to 75 with an average age of 51 years, were available for the study. Karnofsky performance status was not less than 50. Previous chemotherapy was recorded in 33 patients. The drug was administered at doses of 40 mg/m2 i.v. daily for 2 days in the first 25 patients and, in all other patients, the dosage was increased to 50 mg/m2 i.v. daily for 2 days (100 mg/m2/cycle). The overall response was registered in 18 (seven complete, 11 partial remissions) out of 92 patients (20%). Regarding tumor types, the response was observed in 2/15 lung, 4/15 stomach, 3/14 colorectal, and 5/13 breast cancers. No response was observed in 11 patients with melanoma and five with hypernephroma. Toxicity was mild (myelosuppression, gastrointestinal toxicity, cardiotoxicity) and tolerable for the patients. On the basis of these results, we could conclude that 4'-epi-doxorubicin is an active antitumorigenic agent in breast cancer and in stomach, rectal, and small-cell lung tumors. These results justify further clinical investigation of this compound especially in combination chemotherapy treatment.     

Nonablative allogeneic hematopoietic transplantation as adoptive immunotherapy for indolent lymphoma: low incidence of toxicity, acute graft-versus-host disease, and treatment-related mortality.

This study investigated the use of a nonablative conditioning regimen to decrease toxicity and achieve engraftment of an allogeneic blood stem cell transplant, allowing a graft-versus-malignancy effect to occur. All patients had follicular or small cell lymphocytic lymphoma after relapse from a prior response to conventional chemotherapy. Patients received a preparative regimen of fludarabine (25 mg/m(2) given daily for 5 days or 30 mg/m(2) daily for 3 days) and intravenous cyclophosphamide (1 g/m(2) given daily for 2 days or 750 mg/m(2) daily for 3 days). Nine patients received rituximab in addition to the chemotherapy. Tacrolimus and methotrexate were used for graft-versus-host disease (GVHD) prophylaxis. Twenty patients were studied; their median age was 51 years. Twelve were in complete remission (CR) at transplantation. All patients achieved engraftment of donor cells. The median number of days with severe neutropenia was 6. Only 2 patients required more than one platelet transfusion. The cumulative incidence of acute grade II to IV GVHD was 20%. Only one patient developed acute GVHD of greater than grade II. All patients achieved CR. None have had a relapse of disease, with a median follow-up period of 21 months. The actuarial probability of being alive and in remission at 2 years was 84% (95% confidence interval, 57%-94%). Nonablative chemotherapy with fludarabine/cyclophosphamide followed by allogeneic stem cell transplantation is a promising therapy for indolent lymphoma with minimal toxicity and myelosuppression. Further studies are warranted to compare nonablative allogeneic hematopoietic transplantation with alternative treatment strategies.     

Adjuvant treatment of osteogenic sarcoma with high-dose cyclophosphamide.

Six patients with osteosarcoma and no evidence of metastases received postoperative adjuvant chemotherapy with high-dose cyclophosphamide (25 mg/kg iv every other day for five doses). Three of these patients are alive without evidence of disease at 2 1/2, 3, and 5 years following diagnosis. The regimen was tolerable in terms of toxicity. Cyclophosphamide in high doses may be effective adjuvant therapy in some patients with osteosarcoma.     

Modulations of dose intensity of doxorubicin and cyclophosphamide in association with G-CSF and peripheral blood stem cells in adjuvant chemotherapy for breast cancer: comparative evaluation of completion and safety of three intensive regimens

The aim of this study was to evaluate and to compare in terms of toxicity the modulations of dose intensity of cyclophosphamide and doxorubicin in adjuvant chemotherapy for high-risk breast cancer. Four cycles of sequential high-dose chemotherapy with doxorubicin and cyclophosphamide (AC), supported with G-CSF and peripheral blood stem cells (PBSC) were administered to 81 women. Three successive cohorts were studied: doxorubicin (75 mg/m(2)) + cyclophosphamide (3000 mg/m(2)) every 21 days (group 1), doxorubicin (75 mg/m(2)) + cyclophosphamide (3000 mg/m(2)) every 15 days (group 2), and doxorubicin (75 mg/m(2)) + cyclophosphamide (6000 mg/m(2)) every 21 days (group 3). Seventy-five patients received four cycles of treatment with a total of 310 cycles administered. The received dose intensity of doxorubicin was higher in group 2 and that of cyclophosphamide was lower in group 1 than in the other two groups. Hematological and extra-hematological toxicities, as well as the number and duration of hospitalizations for toxicity, were significantly higher in group 3. We conclude that the group 3 regimen is associated with toxicities comparable to autologous transplantation. Increasing dose intensity of doxorubicin and cyclophosphamide is feasible in an outpatient setting and safe in groups 1 and 2 with the support of hematopoietic factor and PBSC.     

Isophosphamide therapy for hematologic malignancies in patients refractory to prior treatment.

Isophosphamide was administered to 27 patients with acute leukemia and to 15 patients with malignant lymphoma refractory to primary therapy. The starting dose of isophosphamide was 1200 mg/m2 administered as a daily continuous infusion x 5 days; the courses of treatment were repeated every 2-3 weeks. Of the 27 patients with acute leukemia, four achieved complete remission, two achieved partial remission, and two achieved hematologic improvement. However, no responses occurred in ten patients with acute myelogenous leukemia (AML). Thus, the response rate was 47% (eight responses among among 17 patients, in patients with acute lymphoblastic leukemia and acute undifferentiated leukemia. Seven of the 15 patients with malignant lymphoma responded. Most responses (five of six patients) occurred in patients with diffuse histiocytic lymphoma. Twenty-one of the 42 patients had received prior therapy with cyclophosphamide and 12 of these patients (two with leukemia and ten with lymphoma) responded, thus suggesting that as in the treatment of L1210 leukemia, isophosphamide is effective for tumors resistant to prior cyclophosphamide therapy. No significant genitourinary toxicity occurred; however, myelosuppression became the dose-limiting toxicity. Isophosphamide is active in malignant lymphomas and acute leukemias (except AML) and may have a role in combination regimens for such diseases.     

Dexamethasone, paclitaxel, etoposide, cyclophosphamide (d-TEC) and G-CSF for stem cell mobilisation in multiple myeloma

Forty-one patients with multiple myeloma were treated with a novel stem cell mobilisation regimen. The primary end points were adequate stem cell mobilising ability (>1% circulating CD34-positive cells) and collection (> or = 4 x 10(6) CD34-positive cells/kg), and safety. The secondary end point was activity against myeloma. The regimen (d-TEC) consisted of dexamethasone, paclitaxel 200 mg/m(2) i.v., etoposide 60 mg/kg i.v., cyclophosphamide 3 g/m(2) i.v., and G-CSF 5-10 microg/kg/day i.v. A total of 84 cycles were administered to these 41 individuals. Patient characteristics included a median age of 53 years, a median of five prior chemotherapy cycles, and a median interval of 10 months from diagnosis of myeloma to first cycle of d-TEC. Seventy-five percent of the patients had stage II or III disease, 50% had received carmustine and/or melphalan previously, and 25% had received prior radiation therapy. Eighty-eight percent of patients mobilised adequately after the first cycle of d-TEC and 91% mobilized adequately after the second cycle. An adequate number of stem cells were collected in 32 patients. Of the remaining nine patients, three mobilised, but stem cells were not collected, two mobilised but stem cell collection was < 4 x 10(6) CD34-positive cells/kg, three did not mobilise, and one died of disease progression. Major toxicities included pancytopenia, alopecia, fever and stomatitis. One patient died from multi-organ failure and progressive disease. Fifty percent of evaluable patients demonstrated a partial response and 28.6% of patients had a minor response. This novel dose-intense regimen was safe, capable of stem cell mobilisation and collection, even in heavily pre-treated patients, and active against the underlying myeloma.     

Phase I study of 5-fluorodeoxyuridine plus cytosine arabinoside infusions in patients with solid tumors.

A phase I trial was conducted in 30 patients with solid tumors, using infusions of 5-fluorodeoxyuridine (5-FUdR) plus cytosine arabinoside (ara-C). Doses of 5-FUdR administered over 2 hours daily X 5 ranged from 0.02 to 1.0 mg/kg, and these doses immediately preceded a 1-hour infusion of ara-C. These schedules were selected because 5-FUdR pretreatment had been shown to sensitize L5178Y cells in culture to acute cell death by ara-C. Dose-limiting toxicity was myelosuppression. Based upon results in this study, the recommended dose of 5-FUdR to be used in phase II trials of this combination is 0.04--0.05 mg/kg (1.6--2.0 mg/m2) given prior to ara-C at a dose of 100 mg/m2. Antitumor responses were seen in patients with head and neck cancer, breast carcinoma, and carcinoid syndrome.     

Anthracycline-carboplatin combination in metastatic breast cancer

Summary In a pilot study a carboplatinum, 250 mg/m² i.V., and 4-epidoxirubicin, 90 mg/m² i.v. or mitoxantrone, 10 mg/m² i.v., combination chemotherapy regimen was studied in a group of breast cancer patients with high-risk metastatic disease. All 11 patients had liver and/or lung metastases. Of the 11 patients, 9 had progressive disease and in 2 patients the disease had stabilised. The toxicity of both anthracycline-containing regimes was similar. Subjective toxicity was mild, but hematological toxicity was inacceptable. The tested carboplatinum-anthracycline combination regimes given in the administered doses are not useful in the treatment of metastatic breast cancer, mainly because of toxicity.     

Phase I clinical evaluation of cytarabine and cisplatin in patients with advanced cancer

Studies in cell culture systems and tumor-bearing animals have demonstrated synergistic cytotoxicity of cytarabine (ara-C) and cisplatin. We have conducted a phase I trial to assess the toxic effects and tolerable doses of these drugs in patients with advanced cancer. Forty-five such patients were treated with varying dosages of ara-C infused continuously during Days 1-3 of a 28-day cycle. Cisplatin at a dose of 100 mg/m2 was administered on Day 2 of the cycle. Using this schedule, the maximally tolerated dose of ara-C in previously untreated patients was 60 mg/m2/day (180 mg/m2). Hematologic toxicity was dose-limiting with median wbc and granulocyte count nadirs of 1800 and 168/mm3, respectively. Reduction of the cisplatin dose while maintaining the ara-C dose at 60 mg/m2/day resulted in less myelosuppression, suggesting that these drugs may have synergistic effects on the bone marrow. Objective responses were seen in six of 41 evaluable patients, including five of 12 patients with non-small cell lung cancer. The severe bone marrow toxicity observed at relatively low drug doses and the 42% response rate in patients with non-small cell lung cancer suggest that the combination of ara-C and cisplatin has substantial clinical activity. Phase II trials are warranted in non-small cell lung cancer and other tumors.     

I.V. busulfan in pediatrics: a novel dosing to improve safety/efficacy for hematopoietic progenitor cell transplantation recipients

A retrospective population pharmacokinetic (PPK) analysis was performed in 24 pediatric patients (PEDS) (0.45-16.7 years old) receiving i.v. busulfan/cyclophosphamide (i.v. Bu/Cy 4) regimen prior to allogeneic hematopoietic stem cell transplantation. I.V. Bu doses were given as a 2-hour infusion every 6 h over 4 days. Initial dosing of i.v. Bu was 1 mg/kg for children < or =4 years old and 0.8 mg/kg for patients >4 years old. Bu plasma concentrations at doses 1, 9 and 13 were analyzed through a multivariate NONMEM analysis. A close log-linear relationship between body weight (BW) and i.v. Bu clearance was demonstrated with no further age-dependency or gender effect. The interpatient coefficient of variation (CV) in Bu clearance significantly decreased from 56% (covariate-free model) to 19% (BW covariate model) and reproducible i.v. Bu exposure between doses was illustrated (intraindividual CV=9%). Based on the PPK model, a novel Bu dosing regimen (ie: doses in mg/kg adjusted to discrete weight categories) for a better AUC targeting was developed by simulation on 1000 patients. Age-based dosing was demonstrated not to be clinically relevant with i.v. Bu. Use of the new BW-based dosing appears to be more appropriate for the PEDS.     

Effect of a bovine hemoglobin preparation on the response of the FSaIIC fibrosarcoma to chemotherapeutic alkylating agents

Summary Polymerized bovine hemoglobin solutions (PBHS) are being actively investigated as blood substitutes. In studies analogous to those we conducted with perfluorochemical emulsions/carbogen, we have examined the effect of PBHS ± carbogen (95% O₂, 5% CO₂) breathing on the antitumor efficacy of melphalan, cyclophosphamide,N,N-bis(2-chloroethyl)-N-nitrosourea (BCNU) andcis-diamminedichloroplatinum(II) (cisplatin). The tumor growth delay of the FSaIIC fibrosarcoma treated with melphalan (10 mg/kg), cyclophosphamide (150 mg/kg), cisplatin (10 mg/kg) and BCNU (15 mg/kg) was increased about 2.2-fold, about 2.1-fold, about 1.2-fold and about 1.5-fold, respectively, when PBHS (12 mg/kg) was administered i.v. before each drug was injected i.p. The tumor growth delay produced by each drug was further increased when carbogen breathing for 6 h was allowed after administration of the drug and PBHS. In tumor cell survival experiments 24 h following drug treatment, the addition of PBHS increased the tumor cell killing of both melphalan and cyclophosphamide by about a factor of 10 at the lowest doses of each drug tested (10 mg/kg for melphalan and 100 mg/kg for cyclophosphamide) compared to the drug alone. However, at higher drug doses this effect was lost. The toxicity of each antitumor agent toward bone marrow (granulocyte/macrophage-colony-forming units) was increased 2- to 3-fold by the combined treatment. These results suggest that use of PBHS ± carbogen breathing may add significantly to the efficacy of antitumor alkylating agents, however, the in vivo/in vitro data suggest that there will be increased bone marrow toxicity with this approach. This needs to be taken into account in the design of clinical trials.Abbreviations PBHS polymerized bovine hemoglobin solution - BCNU N,N-bis(2-chloroethyl)-N-nitrosourea This work was supported by NIH grant PO1-19589 and a gift from Biopure Inc., Boston, Mass.     

5-FU in the treatment of small cell anaplastic carcinoma of the lung: a phase II trial

The effect of 5-FU as a single agent in small cell anaplastic carcinoma of the lung was evaluated in 26 patients. All patients had received prior chemotherapy. Ten patients were treated with 5-FU doses of 600 mg/m2 iv on Days 1--5, followed by 1000 mg/m2 iv on Day 22 and then every second week. Among eight evaluable patients, partial remissions of 42--45 days' duration were seen in three cases. However, toxic reactions, consisting of thrombocytopenia (less than 50,000/mm3) in five cases and leukopenia (less than 1000/mm3) with septicemia in two patients, were unacceptable. Therefore, the remaining 16 patients were treated with 400 mg/m2 iv daily for 5 days, while the maintenance dosage of 5-FU remained unchanged. With this dosage the hematologic toxicity was moderate, but no responses were observed. It is concluded that 5-FU has a low order of activity in previously treated patients with small cell anaplastic carcinoma of the lung.     

Non-haematological toxicity limiting the application of sequential high dose chemotherapy in patients with advanced breast cancer.

A programme of repeated high dose chemotherapy for advanced breast cancer was developed using (1) cyclophosphamide 4 g/m2 followed by autologous peripheral blood stem cell (PBSC) collection; (2) three cycles of conventional dose chemotherapy; (3) high dose cyclophosphamide, cisplatin, and carmustine with PBSC rescue; and (4) high dose etoposide and melphalan with PBSC rescue. Fifteen eligible patients had advanced poor prognosis breast cancer either at initial diagnosis (one patient) or at relapse (14 patients). During the course of the protocol, there were three treatment related deaths, two patient withdrawals due to debilitating toxicity, five patient withdrawals due to disease progression, and one patient withdrawal due to inadequate collection of PBSC. The remaining four patients did not complete the planned protocol as the programme was terminated because of the unacceptable morbidity and mortality. They were treated with an alternative high dose chemotherapy protocol which was well tolerated. This study highlights the significant problems associated with a complex sequential high dose chemotherapy regimen. Cyclophosphamide mobilized PBSC infused following high dose chemotherapy enables rapid haematological recovery. However the non-haematological toxicity following high dose chemotherapy regimens is often severe and may limit the application of certain sequential high dose chemotherapy combinations in patients with breast cancer.