Impact of therapy With chlorambucil, fludarabine, or fludarabine plus chlorambucil on infections in patients with chronic lymphocytic leukemia: Intergroup Study Cancer and Leukemia Group B 9011.

PURPOSE: We sought to determine whether therapy with single-agent fludarabine compared with chlorambucil alone or the combination of both agents had an impact on the incidence and spectrum of infections among a series of previously untreated patients with B-cell chronic lymphocytic leukemia (CLL). PATIENTS AND METHODS: Five hundred fifty-four previously untreated CLL patients with intermediate/high-risk Rai-stage disease were enrolled onto an intergroup protocol. Patients were randomized to therapy with chlorambucil, fludarabine, or fludarabine plus chlorambucil. Data pertaining to infection were available on 518 patients. Differences in infections among treatment arms were tested with the Kruskal-Wallis, Wilcoxon, and chi(2) tests. RESULTS: A total of 1,107 infections (241 major infections) occurred in 518 patients over the infection follow-up period (interval from study entry until either reinstitution of initial therapy, therapy with a second agent, or death). Patients treated with fludarabine plus chlorambucil had more infections than those receiving either single agent (P <.0001). Comparing the two single-agent arms, there were more infections on the fludarabine arm (P =.055) per month of follow-up. Fludarabine therapy was associated with more major infections and more herpesvirus infections compared with chlorambucil (P =.008 and P =.004, respectively). Rai stage and best response to therapy were not associated with infection. A low serum immunoglobulin G was associated with number of infections (P =.02). Age was associated with incidence of major infection in the combination arm (P =.004). CONCLUSION: Combination therapy with fludarabine plus chlorambucil resulted in significantly more infections than treatment with either single agent. Patients receiving single-agent fludarabine had more major infections and herpesvirus infections compared with chlorambucil-treated patients.

Fluorouracil modulation in colorectal cancer: lack of improvement with N -phosphonoacetyl- l -aspartic acid or oral leucovorin or interferon, but enhanced therapeutic index with weekly 24-hour infusion schedule--an Eastern Cooperative Oncology Group/Cancer and Leukemia Group B Study.

PURPOSE: To investigate mechanism-directed regimens in maximizing the efficacy of fluorouracil (5-FU) in advanced colorected cancer. PATIENTS AND METHODS: Based on promising phase II data, a randomized comparison of various methods for the biochemical modulation of 5-FU was undertaken in patients with advanced colorectal cancer. The control group received single-agent 5-FU as a 24-hour infusion weekly. Patients (N = 1,120) with no prior chemotherapy for metastatic disease were randomized to one of the following arms: arm A, 5-FU 2,600 mg/m2 by 24-hour infusion, weekly; arm B, N-phosphonoacetyl-l-aspartic acid 250 mg/m2 day l, 5-FU 2,600 mg/m2 by 24-hour infusion day 2, weekly; arm C, 5-FU 600 mg/m2 with oral leucovorin (LV) 125 mg/m2 hourly for the preceding 4 hours, weekly; arm D, 5-FU 600 mg/m2 with intravenous (IV) LV 600 mg/m2, weekly; arm E, 5-FU 750 mg/m2/d IV by continuous infusion for 5 days, then 750 mg/m2 weekly, and recombinant interferon alfa-2a 9 million units subcutaneously three times weekly. Median follow-up was 4.8 years. RESULTS: Of the 1,098 assessable patients, 57% had measurable disease. The toxicity of all the regimens was tolerable. Grade 4 or worse toxicity occurred in 11%, 11%, 30%, 24%, and 22% on each arm, respectively; diarrhea was the most common adverse effect. These toxicity patterns favored significantly (P <.001) the 24-hour infusion arms. Median survival (months) by arm was A, 14.8; B, 11.9; C, 13.5; D, 13.6; and E, 15.2. These survival durations did not differ significantly. CONCLUSION: We conclude that a weekly infusion regimen of 5-FU is significantly less toxic than and as effective as 5-FU bolus regimens modulated by either LV or interferon in patients with metastatic colorectal cancer.

A compass for customer needs.

Baldor Electric uses a tool it calls the value formula to help teach its employees to look at their work through the eyes of the customer. In fact, the goal of the value improvement process is to focus everyone on customer value, and the employees, by going through five training courses, learn how improving quality and service and reducing cost and time lead to higher value for the customer.

Building stable customer relationships that stand the test of time.

This article shows how Baldor Electric Company is using training to build a foundation for improving service in all areas of the business. It covers the background that led to Baldor Electric's decision to develop service training in-house, the steps that Baldor took in putting the course together, and the actual principles taught in the Baldor service course. The Baldor service course teaches basic principles that can be used by all employees to improve customer service, no matter what job they do.

Time for a change!

Learn how one successful manufacturer uses in-house training to cut the time it takes to do things in all areas of the company. Learn basic principles that can be used by anyone to reduce time in their work, no matter what job they do.

Aggressive chemotherapy in the treatment of Burkitt's and non-Burkitt's undifferentiated lymphoma.

Because of the aggressive nature and frequent recurrence of malignant lymphomas of the undifferentiated type, we used a multi-drug induction chemotherapy regimen that has met with some success in children with similar type of histopathology followed by intensification and 8 cycles of consolidation chemotherapy in an attempt to prolong the duration of remission and survival in adult patients with this diagnosis. Fifty-one patients (median age 35 years) with undifferentiated malignant lymphoma were collected over a 4 year period (1984-1988) and entered into a phase III protocol done under the auspices of the Eastern Cooperative Oncology Group (ECOG). Six patients who had their diagnosis made at surgery and had resection of their tumor were excluded from analysis of response to therapy. Sixty percent of the patients had Stage IV disease. Sixteen patients had marrow involvement and five had central nervous system (CNS) disease. None of the patients received CNS radiation therapy. The 45 patients evaluated for response showed a response rate of 67% (30/45) and a complete response rate of 40% (18/45). Thirteen responders continue disease-free with a median follow-up of > 40 months and have an estimated 5 year survival of 80%. Only two treatment related deaths were reported for the entire group. Patients with undifferentiated non-Burkitt's lymphoma had a longer survival than those with undifferentiated Burkitt's. We concluded that adult patients with undifferentiated lymphomas could be treated successfully with an aggressive multi-drug chemotherapy regimen, consisting of multiple alternating cycles of non-crossed-resistant chemotherapy. Toxicity with this aggressive prolonged regimen was acceptable.

Discordant immunophenotype of chronic B-cell lymphoproliferative disorders in simultaneous specimens from bone marrow and peripheral sites.

This study consisted of 10 cases of chronic B-cell lymphoproliferative disorders that had simultaneous specimens obtained from both bone marrow and peripheral sites for flow cytometric immunophenotyping. The immunophenotyping results of peripheral sites from all 10 cases showed a monoclonal B-cell proliferation expressing monoclonal surface immunoglobulin, CD19, CD20, HLA-DR, and CD5 (except 1 case). Eight (80%) of the 10 cases, however, demonstrated discordant immunophenotypes with myeloid-associated marker expression (CD13, CD11b, and/or CD15) found only in the bone marrow. Patients with CD13 or CD11b marker expression in the bone marrow followed an aggressive clinical course with advanced Rai's stage and a diffuse or mixed bone marrow infiltration pattern or disease transformation. These results indicate that discordant immunophenotypes of malignant cells from different body sites occur in chronic B-cell lymphoproliferative disorders and are not uncommon. Additionally; myeloid-associated markers, which some investigators have described as being associated with an unfavorable clinical course, may be expressed only in bone marrow specimens in these disorders. Thus, bone marrow specimens may be preferential in determining myeloid-associated marker expression in chronic B-cell lymphoproliferative disorders.

Concurrent radiation therapy, 5-fluorouracil, and cisplatin for stage II, III, and IV, node-negative, squamous cell head and neck cancer. Results and surgical implications.

METHODS: Between 1983 and 1989, 42 patients with Stage II, III, and IV, node-negative, squamous cell head and neck cancer were treated with concurrent 5-fluorouracil, cisplatin, and radiation therapy. Two courses of chemotherapy with 30 Gy of concurrent radiation therapy were to be followed in all patients by definitive surgery and then an additional 30 Gy of radiation therapy and one to two courses of chemotherapy. The patients who achieved a complete response to the initial induction treatment, however, did not undergo surgery. RESULTS: After the completion of all therapy, 41 of the 42 patients (98%) were considered disease-free. Only 4 of these 41 had relapses, for a projected Kaplan-Meier disease-free survival rate of 86%. Treatment failure occurred in no patients with Stage II, 1 of 17 patients with Stage III, and 4 of 14 patients with Stage IV disease. Of the 42 patients, 23 (55%) did not require surgery after achieving a complete response to induction therapy, and only 1 of these 23 patients subsequently had a relapse. CONCLUSIONS: Although the value of adding chemotherapy to conventional treatment remains unproven in squamous cell head and neck cancer, this treatment schedule appears promising in node-negative disease. Randomized trials will be necessary, however, to validate the efficacy of this approach and confirm the suggestion by the authors that surgery can be avoided in most patients with N0 disease.

Varying intensity of postremission therapy in acute myeloid leukemia.

The Eastern Cooperative Oncology Group (ECOG) conducted a randomized trial in patients less than or equal to 65 years old (median, 44 years) to determine whether increasing the intensity of postremission therapy in acute myeloid leukemia (AML) would improve the outcome. After uniform induction therapy, patients in complete remission (CR) who were less than 41 years old and who had a histocompatible sibling underwent allogeneic bone marrow transplantation (alloBMT) (54 patients). The remainder of patients in CR were randomized to receive either 2 years of continuous outpatient maintenance therapy with cytarabine and 6-thioguanine (83 patients) or a single course of inpatient consolidation therapy consisting of 6 days of high-dose cytarabine plus 3 days of amsacrine (87 patients). The median duration of follow-up is now 4 years, and patients are included in the analyses of outcome regardless of whether they relapsed before starting the intended treatment. Four-year event-free survival (EFS) was 27% +/- 10% for consolidation therapy versus 16% +/- 8% for maintenance therapy (P = .068) and 28% +/- 11% versus 15% +/- 9% (P = .047) in patients less than 60 years old. The outcome for patients receiving alloBMT was compared with the subset of patients less than 41 years old who received consolidation therapy (N = 29) or maintenance therapy (N = 21). Four-year EFS was 42% +/- 13% for alloBMT, 30% +/- 17% for consolidation therapy, and 14% +/- 15% for maintenance therapy. AlloBMT had a significantly better EFS (P = .013) than maintenance therapy, but was not different from consolidation therapy. In patients less than 41 years old, 4-year survival after alloBMT (42% +/- 14%) did not differ from consolidation therapy (43% +/- 18%), but both were significantly better than maintenance therapy (19% +/- 17%), P = .047 and .043, respectively. The mortality rate for maintenance therapy was 0%, consolidation therapy, 21%; and alloBMT, 36%. Consolidation therapy caused an especially high mortality rate in the patients greater than or equal to 60 years old (8 of 14 or 57%). The toxicity of combined high-dose cytarabine and amsacrine is unacceptable, especially in older patients, and alternative approaches to consolidation therapy such as high-dose cytarabine alone need to be tested. In AML, a single course of consolidation therapy or alloBMT after initial CR produces better results than lengthy maintenance therapy. Although EFS and survival of alloBMT and consolidation therapy do not differ significantly, a larger number of patients need to be studied before concluding that they are equivalent.

Escalating the intensity of post-remission therapy improves the outcome in acute myeloid leukemia: the ECOG experience. The Eastern Cooperative Oncology Group.

These ECOG trials have demonstrated that progressive increments in the intensity of post-remission therapy result in improving long-term, disease-free survival in adults with AML. The median duration of disease-free survival and long-term outcome from different post-remission therapies are summarized in Table 4. [table: see text] Despite the suggestive evidence of the ordered increment in value of intensive consolidation therapy, allogeneic and autologous bone marrow transplantation, it remains to be proved that the differences observed in our preceding studies are statistically significant and clinically meaningful. These remaining questions led to the current ECOG study, EST 3489, a randomized intergroup study conducted with members of the Southwest Oncology Group. The study includes all patients with de novo AML up to age 55; the schema is shown in Figure 3. Induction therapy consists of idarubicin plus cytarabine instead of DAT. A modified short course of this induction therapy is repeated after CR. Patients who have a histocompatible sibling are offered allogeneic bone marrow transplantation. The remaining patients are randomized to receive either autologous bone marrow transplantation or a single course of high-dose cytarabine. Autologous bone marrow transplantation utilizes the previously described high-dose busulfan and cyclophosphamide regimen plus 4-HC purging of the bone marrow. The dosage of cytarabine in the intensive consolidation arm is 3 gm/M2/day IV on days 1-6. The results of this study should determine the relative merits of these different approaches to post-remission therapy. [table: see text] As mentioned earlier, demonstration of improved CR rates is limited by the morbidity and mortality from the myelosuppression that results from induction therapy. This is especially marked for older patients with AML. In patients, ages 55-70 years old, the ECOG is conducting a randomized trial (EST 1490) of conventional induction therapy +/- GM-CSF to determine if accelerated neutrophil recovery can reduce the mortality of induction therapy and thereby increase the remission rate. It may be that the application of GM-CSF and other colony-stimulating factors can increase the CR rate for all patients, increasing the number of patients potentially eligible for cure by post-remission therapy.

Quantitation of dihydrofolate reductase and thymidylate synthase mRNAs in vivo and in vitro by polymerase chain reaction.

Rapid and quantitative polymerase chain reaction (PCR) assays based upon the competitive template technique have been developed for human dihydrofolate reductase (DHFR; E.C.1.5.1.3) and thymidylate synthase (TS; E.C.2.1.1.45) mRNAs. In various tumor cell lines and clinical tumor biopsies, TS mRNA levels correlated with TS levels as determined by [3H]-fluorodeoxyuridylate binding. Levels of DHFR and TS mRNAs, determined by PCR, correlated with mRNA quantitation by conventional dot blot methodology. The ratio of TS/DHFR mRNAs in a number of human carcinoma cell lines varies from 0.4 to 9.9 but ranges from 1 to greater than 1.5 x 10(3) in a number of tumor samples. Differences in the TS/DHFR mRNA ratio in tumors as compared with cultured cells reflects low levels of DHFR mRNA in some tumors. In patients treated with a combination of 5-fluorouracil and leucovorin, mRNA levels for TS increased approximately an order of magnitude in tumor samples 4 and 24 hr after drug treatment, whereas TS levels decreased. These results have significance for the biochemical pharmacology of antifolates and fluorinated pyrimidines in vivo and the relevance of cell culture models for antifolate chemotherapy and drug resistance.

Diffuse well differentiated lymphocytic lymphoma: a clinical study of 22 patients.

An analysis is presented of the clinical and prognostic features of 22 patients diagnosed with diffuse well differentiated lymphocytic lymphoma at Cleveland Metropolitan General Hospital between 1974 and 1987. At presentation, the disease was usually advanced with 86% of patients having stage IV disease and 73% of patients exhibiting bone marrow involvement. Ten second malignancies were documented in 7 (32%) of our patients. The goal of treatment in our patients was palliation except in the 2 stage 1 patients. The response rate to initial treatment was 55% (15% complete), although 75% of patients ultimately responded to some form of therapy; and the mean survival was 58 months, a figure not different from historical controls. There were no differences in survival between patients given simple versus complex therapy at diagnosis or at any time during the course of their disease; and no differences in survival between complete, partial and nonresponders.

Long-term results after chemoradiotherapy for locally confined squamous-cell head and neck cancer.

The long-term results after simultaneous chemoradiotherapy in 54 patients with previously untreated or minimally treated, locally confined (M0) squamous-cell carcinoma of the head and neck are presented. Multiple concurrent courses of radiation therapy and chemotherapy with cisplatin and a four-day 5-fluorouracil infusion were given. Twenty-eight patients underwent definitive surgery and 26 were treated without surgical resection. Treatment-associated toxicity was significant, including mucositis, myelosuppression, and a mean 12% loss of initial body weight. Of the 54 patients, 51 were ultimately rendered disease free by this combined modality protocol. With a follow-up ranging from 42-68 months, the projected Kaplan-Meier relapse-free survival for the entire patient cohort is 70%, with all relapses occurring within 17 months of patient entry. The projected Kaplan-Meier relapse-free survival for patients with Stage IV disease is 62%. The durability of these remissions suggests that there is a significant likelihood of cure in all patients with locally confined disease, and justifies comparative trials with standard treatment.

Simultaneous versus sequential combined technique therapy for squamous cell head and neck cancer.

Forty-eight patients with locally confined (M0) squamous cell head and neck cancer were prospectively randomized to receive either simultaneous (SIM) or sequential (SEQ) combined technique therapy with a 5-fluorouracil infusion, a cisplatin bolus injection, and radiation therapy. Patients with residual resectable disease underwent surgery after induction therapy, whereas those achieving a complete response to induction did not require surgery. Patients on the two treatment arms were equivalent in all measured variables, including disease extent. Toxicities of the SIM and SEQ arms also were equivalent except for mucositis and the resultant weight loss, which were more severe on the SIM arm (P = 0.002). With a follow-up time ranging from 9 to 41 months, seven of the 24 SIM patients and 14 of the 24 SEQ patients are considered treatment failures. The relapse-free survival is significantly better on the SIM arm (P = 0.03), although an overall survival advantage has not yet been demonstrated (P = 0.13). The achievement of a complete response after induction therapy correlates with both the relapse-free (P = 0.0005) and overall (P = 0.05) survival, and the likelihood of an induction complete response also is significantly better for those treated with the SIM schedule (P = 0.02). Eighteen patients did not require surgery after achieving an induction complete response. Relapse-free survival does not appear to be compromised in this patient subset.

Efficacy of high-dose oral leucovorin and 5-fluorouracil in advanced colorectal carcinoma. Plasma and tissue pharmacokinetics.

Thirty-one evaluable patients with advanced colorectal cancer were treated with oral leucovorin (LV) 500 mg/m2, administered hourly in four divided doses weekly for 6 weeks. Six patients received intravenous 5-FU at 450 mg/m2 and the remainder at 600 mg/m2 weekly for 6 weeks. This schedule was repeated after a 2-week rest period without medication. None of the patients had received previous chemotherapy. The results of the study showed a overall complete remission (CR) and partial remission (PR) of 45%. All responding patients received the 600-mg/m2 dose of 5-FU. There were five CR and nine PR. An additional seven (23%) patients had stable disease. Two of the seven received the 450-mg/m2 dose of 5-FU and the remainder received 600 mg/m2. The median disease-free interval for CR patients exceeded 25 months, while the interval for PR patients was 11.8 months. The median survival for CR patients was over 26.7 months and 16.5 months for the PR patients. The median survival for stable patients was 9.5 months and 5.5 months for patients with progressive disease. Toxicity included diarrhea in 70% of patients, excess lacrimal secretion in 35%, and nausea and vomiting in 25% There were no treatment-related deaths in this group. The authors conclude from this Phase I study that the optimal 5-FU dose in 600 mg/m2 combined with high-dose oral leucovorin for the treatment of advanced colorectal carcinoma.

Long-term survival after chemoradiotherapy for locally advanced squamous cell carcinoma of the esophagus.

Seven patients with locally far-advanced, inoperable, squamous cell cancer of the esophagus were given two cycles of concurrent radiation and chemotherapy. Each cycle consisted of 5-fluorouracil 1,000 mg/m2/day given as a continuous intravenous infusion over 96 hours, cisplatin 75 mg/m2 given as an intravenous bolus on day 1, and methotrexate 40 mg/m2 given as an intravenous bolus on days 8 and 15. Three thousand rads of radiation were given in 15 fractions between days 1 and 19. Six patients are evaluable for response. Symptomatic relief was obtained by all six and was complete in 4. Five patients achieved a complete response, and two remain alive and disease free. Five of the six evaluable patients survived for at least 12 months. Aggressive chemoradiotherapy may result in significant survival prolongation and symptomatic palliation in this poor-prognosis subset of patients with esophageal cancer.

Thromboembolic events in patients with malignant superior vena cava syndrome and the role of anticoagulation.

In patients with superior vena caval obstruction resulting from malignancy, the importance of vena caval thrombosis and the role of anticoagulation are incompletely understood. The authors discuss this aspect of the management of 25 patients with malignant superior vena cava syndrome. Ten patients were retrospectively reviewed after having been clinically diagnosed without venography, and treated without anticoagulation. Five thromboembolic complications occurred, two of which proved fatal. Fifteen patients were prospectively evaluated by angiography and then treated with anticoagulants. Angiographic evidence of intraluminal subclavian vein or superior vena caval thrombosis was found in five of these patients, and no thromboembolic complications occurred. Of the 20 patients ultimately anticoagulated, two fatal intracranial hemorrhages developed. The authors suggest the need for randomized prospective trials if the role of venography and anticoagulation in this syndrome is to be determined.

Maintenance chemotherapy prolongs remission duration in adult acute nonlymphocytic leukemia.

The value of maintenance therapy after the achievement of complete remission in adult acute nonlymphocytic leukemia (ANLL) has never been clearly established. A randomized Eastern Cooperative Oncology Group (ECOG) study of postremission therapy compared outcomes in patients who received no further therapy to those administered long-term maintenance chemotherapy. Adverse results in the group administered no further therapy led to early termination of this trial after only 51 patients were randomized. Patients receiving no postremission therapy experienced significantly inferior remission durations (P = .002) compared with patients receiving maintenance therapy. All 26 patients in the group administered no postremission therapy have relapsed, with a median duration of remission of 4.1 months. In contrast, four of 25 patients (16%) who received maintenance therapy remain disease free, with a median duration of remission of 8.1 months.