Recombinant human erythropoietin therapy for anemic cancer patients on combination chemotherapy.

BACKGROUND: Patients with advanced cancer frequently experience clinically significant anemia, which is often exacerbated by myelosuppressive chemotherapy. Consistent with the anemia of chronic disease, studies have documented serum erythropoietin levels that are inappropriately low for the degree of anemia in cancer patients. Myelosuppressive chemotherapy impairs erythropoiesis, which may not fully recover between treatment cycles. Recombinant human erythropoietin (rHuEPO) has been used safely and effectively to treat anemia in AIDS patients receiving zidovudine (AZT) and in patients with chronic renal failure. PURPOSE: This study was designed to evaluate the clinical role of rHuEPO in reducing symptomatic anemia in patients with advanced cancer who were receiving myelosuppressive chemotherapy (excluding cisplatin). METHODS: We studied 153 anemic cancer patients receiving cyclic combination chemotherapy in a prospective multicenter, double-blind, placebo-controlled trial. The patients were randomly assigned to receive either rHuEPO (150 U/kg) or placebo subcutaneously three times a week for a maximum of 12 weeks or until the hematocrit level increased to 38%-40%. If the hematocrit reached this target level before 12 weeks, the rHuEPO dose could be reduced to maintain the hematocrit at that level for the duration of the study. Response to rHuEPO therapy was assessed by measuring changes in hematocrit level, transfusion requirements, and quality of life. Quality-of-life assessment was based on patients' responses to questionnaires before and after the courses of therapy. RESULTS: The increase in hematocrit in the rHuEPO-treated group compared with hematocrit in the placebo-treated group was statistically significant (P = .0001) as measured by percentage point of change from baseline to final evaluation, by an increase in hematocrit level of six percentage points or more unrelated to transfusion, and by a rise in hematocrit level to 38% or more unrelated to transfusion. There was a trend toward the reduction in mean units of blood transfused per patient during months 2 and 3 of therapy combined in rHuEPO-treated patients compared with placebo-treated patients (0.91 U versus 1.65 U; P = .056). In addition, rHuEPO-treated patients experienced a statistically significant improvement in energy level and ability to perform daily activities (P < or = .05). The two treatment groups showed no statistically significant differences in toxic effects except for increased incidence of diaphoresis (P < .05) and diarrhea (P = .05) in the rHuEPO-treated group. CONCLUSIONS: We conclude that rHuEPO is safe and effective for reversing anemia related to advanced cancer or to chemotherapy for cancer.

Cytologically negative pericardial effusion complicating combined modality therapy for localized small-cell carcinoma of the lung.

A 17% frequency of cytologically negative pericardial effusion (CNPE), accompanied in some cases by tamponade, occurred a median of 12.6 months from the onset of treatment for localized small-cell carcinoma of the lung. CNPE was apparently caused by toxicity of radiation/chemotherapy treatment rather than recurrent cancer. The occurrence of CNPE does not appear to represent enhanced toxicity of immediate (as opposed to delayed) concurrent chemoradiotherapy, but may be a consequence of the superior survival status of patients treated in this way. The onset of chest pain and/or dyspnea associated with increase in cardiac silhouette and positive echocardiogram allowed accurate diagnosis. Each instance was relatively easily managed by catheter drainage, and, for some patients, with the addition of nonsteroidal antiinflammatory drugs. It is important to recognize the possibility that a radiation/chemotherapy-related syndrome of pericardial effusion/tamponade may occur so that early diagnosis can be made and the risk of fatal tamponade avoided.

Preoperative chemotherapy followed by surgery with possible postoperative radiotherapy in squamous cell carcinoma of the esophagus: evaluation of the chemotherapy component.

Twenty-four patients with squamous cell cancer of the esophagus were entered into a treatment protocol consisting of preoperative chemotherapy (CT), surgical resection (SR), and possible postoperative CT or radiation therapy (RT) beginning August 1981. CT consisted of two cycles of 5-fluorouracil, 1,000 mg/m2, by continuous intravenous infusion for 4 days and cisplatin, 100 mg/m2, on day 4 with mannitol-induced diuresis at 4-week intervals. Postoperatively, RT was administered when resection margins were minimal or if paraesophageal nodes were abnormal; the RT consisted of 5,000 to 5,400 cGy to the tumor area plus a 800- to 1,200-cGy boost to known abnormal tumor margins. Nineteen of 24 patients were resectable (79%). There was one SR death (5%). One of 22 had a normal barium swallow post-CT, no visible tumor at SR, and no pathologic evidence of any residual disease. There was complete radiologic and gross clinical disappearance of tumor post-CT or post-SR in ten of 22 patients (45%). Four of 22 (18%) had greater than or equal to 50% regression, and five of 22 (23%) had no response. Toxicity of CT was mild. Eight of 19 patients (42%) received RT, and six of 19 (32%) received CT postoperatively. Sixteen of 24 (67%) are alive with a median duration of observation of 9.5 months. Eight of 24 (33%) are dead, five of whom had not responded to preoperative CT. Ten of 14 responders are alive and disease free. The mean survival time for nonresponders was 6.70 months and for responders, 20.40 months, with the longest survivor disease free at 45 months.

A phase II trial of cyclophosphamide, etoposide, and cisplatin with combined chest and brain radiotherapy in limited small-cell lung cancer: a Cancer and Leukemia Group B Study.

Limited-extent small-cell lung carcinoma (SCLC) remains a therapeutic problem with little improvement in complete response (CR) rates and long-term survival in the past 5 years. From June 1984 through January 1985, 56 patients with limited-extent SCLC were enrolled in a Cancer and Leukemia Group B (CALGB) phase II study using five cycles of cyclophosphamide (500 mg/m2 intravenously [IV] day 1), etoposide (80 mg/m2 IV days 1 to 3), and cisplatin (33 mg/m2 IV days 1 to 3) administered at 3-week intervals (CEP), with radiation therapy (50 Gy to chest and 30 Gy to brain) administered concomitant with cycles 4 and 5, followed by three cycles of cyclophosphamide (500 mg/m2 IV day 1), etoposide (80 mg/m2 IV days 1 to 3), and doxorubicin (50 mg/m2 IV day 1). Of 49 patients evaluable for response, the overall response rate was 88%, with 57% CRs. The median overall survival was 14 months; the median duration of CR was 10 months, and nine CRs remain disease free at a median follow-up of 23 months. Toxicity was significant: 56% patients experienced WBC less than 1,000 microL, 32% platelets less than 25,000 microL and 10% hemoglobin less than 7 g/dL. There was one treatment-related septic death. These results are as good as the best previous CALGB study of SCLC, despite a reduction in duration of treatment from 18 to 5 months. We are currently using a variant of this multimodality treatment approach as our standard management for patients with limited-extent SCLC.

Phase I study to determine the maximum-tolerated dose of radiation in standard daily and hyperfractionated-accelerated twice-daily radiation schedules with concurrent chemotherapy for limited-stage small-cell lung cancer.

PURPOSE: An improvement in radiation dose schedule is necessary to increase local tumor control and survival in limited-stage small-cell lung cancer. The goal of this study was to determine the maximum-tolerated dose (MTD) of radiation (RT) in both standard daily and hyperfractionated-accelerated (HA) twice-daily RT schedules in concurrent chemoradiation. METHODS: The study design consisted of a sequential dose escalation in both daily and HA twice-daily RT regimens. RT dose to the initial volume was kept at 40 to 40.5 Gy, while it was gradually increased to the boost volume by adding a 7% to 11 % increment of total dose to subsequent cohorts. The MTD was defined as the radiation dose level at one cohort below that which resulted in more than 33% of patients experiencing grade > or = 4 acute esophagitis and/or grade > or = 3 pulmonary toxicity. The study plan included nine cohorts, five on HA twice-daily and four on daily regimens for the dose escalation. Chemotherapy consisted of three cycles of cisplatin 33 mg/m2/d on days 1 to 3 over 30 minutes, cyclophosphamide 500 mg/m2 on day 1 intravenously (IV) over 1 hour, and etoposide 80 mg/m2/d on days 1 to 3 over 1 hour every 3 weeks (PCE) and two cycles of PE. RT was started at the initiation of the fourth cycle of chemotherapy. RESULTS: Fifty patients were enrolled onto the study. The median age was 60 years (range, 38-79), sex ratio 2.3:1 for male to female, weight loss less than 5% in 73%, and performance score 0 to 1 in 94% and 2 in 6% of patients. In HA twice-daily RT, grade > or = 4 acute esophagitis was noted in two of five (40%), two of seven (29%), four of six (67%), and five of six patients (86%) at 50 (1.25 Gy twice daily), 45, 50, and 55.5 Gy in 1.5 Gy twice daily, 5 d/wk, respectively. Grade > or = 3 pulmonary toxicity was not seen in any of these 24 patients. Therefore, the MTD for HA twice-daily RT was judged to be 45 Gy in 30 fractions over 3 weeks. In daily RT, grade > or = 4 acute esophagitis was noted in zero of four, zero of four, one of five (20%), and two of six patients (33%) at 56, 60, 66, and 70 Gy on a schedule of 2 Gy per fraction per day, five fractions per week. Grade > or = 3 pneumonitis was not observed in any of the 19 patients. Thus, the MTD for daily RT was judged to be at least 70 Gy in 35 fractions over 7 weeks. Grade 4 granulocytopenia and thrombocytopenia were observed in 53% and 6% of patients, respectively, during the first three cycles of PCE. During chemotherapy cycles 4 to 5, grade 4 granulocytopenia and thrombocytopenia were noted in 43% and 29% of patients at 45 Gy in 30 fractions over 3 weeks (MTD) by HA twice-daily RT and 50% and 17% at 70 Gy in 35 fractions over 7 weeks (MTD) by daily RT, respectively. The overall tumor response consisted of complete remission (CR) in 51% (24 of 47), partial remission (PR) in 38% (1 8 of 47), and stable disease in 2% (one of 47). The median survival time of all patients was 24.4 months and 2- and 3-year survival rates were 53% and 28%, respectively. With regard to the different radiation schedules, 2- and 3-year survival rates were 52% and 25% for the HA twice-daily and 54% and 35% for the daily RT cohorts. CONCLUSION: The MTD of HA twice-daily RT was determined to be 45 Gy in 30 fractions over 3 weeks, while it was judged to be at least 70 Gy in 35 fractions over 7 weeks for daily RT. A phase III randomized trial to compare standard daily RT with HA twice-daily RT at their MTD for local tumor control and survival would be a sensible research in searching for a more effective RT dose-schedule than those that are being used currently.

Neoadjuvant chemotherapy and radiotherapy followed by surgery in stage IIIA non-small-cell carcinoma of the lung: report of a Cancer and Leukemia Group B phase II study.

PURPOSE: This phase II trial was designed to evaluate the feasibility, toxicity, response rates, and survival for neoadjuvant chemotherapy and radiotherapy (RT) followed by surgical resection in newly diagnosed patients with surgically staged IIIA non-small-cell lung carcinoma (NSCLC). PATIENTS AND METHODS: Previously untreated patients with NSCLC underwent bronchoscopy, chest and abdominal computed tomography (CT), bone scan, and surgical staging of the mediastinum. Neoadjuvant treatment consisted of concurrent chemotherapy and RT. Patients then underwent surgical resection, which was followed in turn by additional chemotherapy and RT. Chemotherapy included cisplatin 100 mg/m2 on days 1 and 29, vinblastine 3 mg/m2 on days 1 and 3 and 29 and 31, and fluorouracil (5-FU) 30 mg/kg/d by infusion on days 1 to 3 and 29 to 31 (FVP). RT began on day 1 and included 3,000 cGy in 15 fractions. Surgery took place on day 55, and one more cycle of chemotherapy and an additional 3,000 cGy of RT began on day 85. RESULTS: Forty-one eligible patients (median follow-up, 53 months) were studied. N2 disease was present in 80%, whereas 20% had T3N0 or T3N1 lesions. Response to neoadjuvant chemotherapy and RT included no complete responses (CR), 21 (51%) partial responses (PR) or regressions, 19 (46%) stable disease (SD), and one (2%) progressive disease (PD). Thirty-one patients underwent surgery, and 25 were resected. In four of the 25 resection specimens, no viable tumor was present, whereas in three of the six unresectable patients, extensive biopsy results demonstrated only necrotic tumor. The maximum response achieved using all protocol treatment was 27 (66%) CRs, seven (17%) PRs or regression, six (15%) SDs, and one (2%) PD. Toxicity was substantial and primarily hematologic. There were six (15%) treatment-related deaths, which included three perioperative deaths and three chemotherapy-related toxicity deaths. The Kaplan-Meier curve indicated a 1-year survival of 58% and a median survival of 15.5 months. Nine patients (22%) remain disease-free. CONCLUSIONS: There was a reasonably high rate of PR associated with concurrent neoadjuvant chemotherapy and RT, and a high percentage of patients who ultimately were rendered completely disease-free. However, treatment-related morbidity and mortality was common. Median survival seemed to be only modestly improved beyond that achieved with less intensive means of treatment. However, a group has emerged of patients who enjoy prolonged disease-free survival and possible cure.

Potential impact on survival of improved tumor downstaging and resection rate by preoperative twice-daily radiation and concurrent chemotherapy in stage IIIA non-small-cell lung cancer.

PURPOSE: The main objectives of this study were (a) to ascertain the feasibility and toxicity of preoperative twice-daily radiation therapy and concurrent chemotherapy, surgery, and postoperative therapy in stage IIIA (N2) non-small-cell lung cancer (NSCLC), and (b) to evaluate tumor response, resection rate, pathologic tumor downstaging, and survival. METHODS: Eligibility included biopsy-proven N2 lesion (stage IIIA) by mediastinoscopy, Karnofsky performance score > or = 70, and weight loss less than 5% in the 3 months before diagnosis. The treatment program consisted of two courses of preoperative cisplatin, vinblastine, and fluorouracil (5-FU); 42 Gy concurrent radiation at 1.5 Gy per fraction in two fractions per day; surgery on day 57; and one more course of postoperative chemotherapy and 12 to 18 Gy of concurrent twice-daily radiation. RESULTS: Forty-two patients with stage IIIA (N2) NSCLC (27 men and 15 women, age 38 to 77 years) were enrolled onto this prospective study. Forty of 42 patients tolerated the intended dose (42 Gy) of preoperative radiation and 37 of 39 resected patients received prescribed postoperative radiation. The intended dose of chemotherapy was given in 100%, 70%, and 60% of patients for the first, second, and third courses of chemotherapy. Marked dysphagia that required intravenous hydration was noted in 14% of patients (six of 42). Myelotoxicities included grade > or = 3 granulocytopenia in 23% and thrombocytopenia in 6% of 113 chemotherapy courses. Febrile neutropenia that required hospital admission was noted in 9% of 113 chemotherapy courses. Surgical resection was performed in 93% of patients. Treatment-related mortality was noted in 7% of patients. The overall survival rates by the Kaplan-Meier method were 66%, 37%, and 37% at 2,3, and 5 years, respectively, with a median follow-up time of 48 months. Pathologic examination of the surgical specimen showed a downward shift in tumor extent from stage IIIA (N2) to stage II (N1) in 33%, to stage I (NO) in 24% (10 of 42), and to stage 0 (TONO) in 9.5%, for a total of 67%. The degree of tumor downstaging was also translated into a survival benefit: 5-year survival rates from the time of surgery were 79%, 42%, and 18% for postoperative tumor stages 0 and I, II, and III, respectively (P = .04). CONCLUSION: Concurrent chemoradiotherapy using twice-daily radiation is an effective induction regimen that resulted in 67% tumor downstaging, and an encouraging 37% 5-year survival rate. The degree of tumor downstaging may be a useful intermediate end point for survival benefit in stage IIIA (N2) NSCLC.

Combination chemotherapy with mastectomy or radiotherapy for stage III breast carcinoma: a Cancer and Leukemia Group B study.

One hundred thirteen evaluable patients with previously untreated stage III breast carcinoma were treated with three monthly cycles of cyclophosphamide (CYC), doxorubicin (DOX), 5-fluorouracil (5-FU), vincristine (VCR), and prednisone (PRED) (CAFVP). Subsequently, 91 (81%) were deemed operable. Patients were then randomized to receive surgery or radiotherapy (RT) to determine which of these modalities afforded better local tumor control. All patients also received 2 additional years of CAFVP in a further attempt to eradicate local disease and systemic micrometastases. Forty-one of the randomized patients have relapsed. Approximately half of the initial relapses in each arm were local. The overall duration of disease control was similar following either modality, with a median of 29.2 months for surgery patients and 24.4 months for RT patients. Similarly, there was no major difference in survival related to randomized treatment with an overall median of 39 months (median follow-up 37 months). Pre- or perimenopausal status and inflammatory disease were associated with shorter disease control and survival. Treatment was generally well tolerated and toxicity was acceptable. This study demonstrates that prolonged control of stage III breast carcinoma can be achieved with combined modality therapy in which cytotoxic chemotherapy precedes and follows treatment directly primarily at the breast tumor, using either surgery or RT. Nevertheless, new regimens must be designed if significant advances that may lead to the cure of this disease are to be achieved.

Randomized trial of chemotherapy and radiation therapy with or without warfarin for limited-stage small-cell lung cancer: a Cancer and Leukemia Group B study.

PURPOSE: Studies by the Veterans Administration Cooperative Studies Program and Cancer and Leukemia Group B (CALGB) suggested that the addition of warfarin to chemotherapy might enhance response and/or survival in small-cell lung cancer (SCLC). This randomized study evaluated the effect of warfarin with chemotherapy and radiation therapy in limited-stage SCLC. PATIENTS AND METHODS: Patients were randomized to receive warfarin or no warfarin. All patients received three cycles of doxorubicin, cyclophosphamide, and etoposide (ACE). Cycles 4 and 5 (cisplatin, cyclophosphamide, and etoposide [PCE]) were given concurrently with radiation therapy. Three cycles of ACE were given after chemoradiation therapy, but were discontinued due to a high rate of pulmonary toxicity. RESULTS: There were no significant differences in response rates, survival, failure-free survival, disease-free survival, or patterns of relapse between the warfarin-treated and control groups. In patients treated according to the initial design, an increase in failure-free survival seen with warfarin treatment approached significance (P = .07). Preamendment results, while not significant, did not have superimposable treatment survival curves. A landmark analysis at 8 months showed a median survival time after the landmark for complete responders of 33 months with warfarin treatment compared with < or = 13.75 months for complete or partial responders not treated with warfarin (P = .05). Differences between the complete responders in this preamendment population were not significant (P = .103). CONCLUSION: Warfarin does not appear to improve outcome significantly in limited-stage SCLC. However, the differences in some variables between populations before the protocol amendment correspond to the favorable effects of anticoagulants observed in previous studies.

Postsurgical adjuvant chemotherapy of stage II breast carcinoma with or without crossover to a non-cross-resistant regimen: a Cancer and Leukemia Group B study.

PURPOSE: To compare two cyclophosphamide, methotrexate, fluorouracil, vincristine, and prednisone (CMFVP) regimens with a doxorubicin-based regimen--vinblastine, doxorubicin, thiotepa, and Halotestin (Upjohn, Kalamazoo, MI) (VATH)--in patients with stage II node-positive breast carcinoma. METHODS: Nine hundred forty-five women were treated with a 6-week induction course of CMFVP. They were then randomized to receive one of two consolidation CMFVP regimens: 6-week courses or 2-week courses. Following completion of CMFVP consolidation, patients were again randomized to either continue the CMFVP regimen or to receive six escalating doses of VATH. RESULTS: Among all patients, with a median follow-up time of 11.5 years, there is no statistically significant difference in disease-free survival (DFS) between the two consolidation CMFVP regimens. VATH intensification treatment is statistically significantly superior to CMFVP in terms of DFS (P = .0040). For patients with one to three involved nodes, there is currently no significant difference between VATH and CMFVP; however, among those with four or more positive lymph nodes, there is a significant difference in favor of VATH (P = .0037). There is also improved overall survival with VATH (P = .043; median, > 14 years v 10 years). This difference is also statistically significant in patients with four or more involved lymph nodes, among postmenopausal patients, and among postmenopausal estrogen receptor-positive patients. CONCLUSION: Chemotherapy with crossover to escalating doses of VATH following CMFVP was well tolerated and effective. Inauguration of VATH as a treatment intensification at the eighth month produced a major increase in relapse-free and overall survival. The observation that sensitivity to VATH is retained so long after mastectomy raises questions about the proper duration of adjuvant chemotherapy and lends support to further investigation of cross-over designs in future trials to postoperative adjuvant chemotherapy regimens.

Effects of treatment with 5-azacytidine on the in vivo and in vitro hematopoiesis in patients with myelodysplastic syndromes.

The myelodysplastic syndrome (MDS) comprises a group of clonal hematopoietic disorders derived from an abnormality affecting a multipotent hematopoietic stem cell. Despite trials testing numerous agents in patients with MDS, no single drug has yet emerged as the accepted standard of treatment. Observation and supportive care with blood products and antibiotics, when necessary, continue to be the mainstays of therapy. We administered 5-azacytidine, a cell-cycle specific ring analog of the pyrimidine nucleoside cytosine, as a continuous intravenous infusion, 75 mg/m2 per day for 7 days every 4 weeks. Patients had refractory anemia with excess blasts (RAEB) or refractory anemia with excess blasts in transformation (RAEB-T). Responses were seen in 21 (49%) of 43 evaluable patients: five (12%) in complete remission (CR, complete normalization of bone marrow and peripheral blood counts); 11 (25%) in partial remission (PR, > or = 50% restoration of the deficit from normal of all three peripheral blood cell lines, elimination of transfusion requirements, and a decrease in percentage bone marrow blasts by > or = 50% from prestudy values); five (12%) improved (> or = 50% restoration in the deficit from normal of one or more peripheral blood cell lines and/or a > or = 50% decrease in transfusion requirements). A trilineage improvement (CR and PR) occurred in 37% of the patients. The median survival for all patients was 13.3 months and the median duration of remission for those with CR and PR was 14.7 months. Mild to moderate nausea and/or vomiting was the most common side effect (63%). Myelosuppression, either bone marrow hypoplasia or drug related cytopenias requiring a reduction in the dose of azacitidine, occurred in only 33% of the patients. Prior to treatment, bone marrow erythroid progenitor cells were assayed in vitro. Colonies derived from erythroid burst-forming units (BFU-e) were undetectable in one patient and reduced in two. The number of colonies derived from erythroid colony-forming units (CFU-e)) were also reduced in two of the three patients. In the two patients with detectable colony growth prior to treatment, colony number decreased by day 8 of the first cycle, followed by a subsequent increase. Continued treatment with azacitidine led to normalization of the number of CFU-e derived colonies as well as an increase in the number of BFU-e derived colonies. This improvement in erythroid colony number correlated with the spontaneous rise in hemoglobin levels and red cell transfusion independence.(ABSTRACT TRUNCATED AT 400 WORDS)

Idiopathic thrombocytopenic purpura complicating chronic lymphocytic leukemia.

Three patients had severe, symptomatic idiopathic thrombocytopenic purpura (ITP) complicating chronic lymphocytic leukemia (CLL) that was refractory to prednisone treatment but that responded to splenectomy alone or in addition to immunosuppressive-cytotoxic treatment. Evidence of high titer of an antiplatelet factor, most likely an antibody, was corroborated in one case by the 14C-platelet serotonin release assay. This experience suggests that the treatment of ITP complicating CLL is similar to that of ITP not associated with lymphoproliferative disorders.

A phase I study of ifosfamide/carboplatin/etoposide/paclitaxel in advanced lung cancer.

A phase I study was conducted to define the maximally tolerated dose and toxicity profile of the ifosfamide/carboplatin/etoposide/paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) (ICE-T) regimen in advanced lung cancer. This chemotherapy program uses paclitaxel given as a 24-hour continuous infusion in conjunction with full-dose ICE chemotherapy with growth factor support. The dosage of paclitaxel was escalated from 75 to 225 mg/m2. Thirty-four patients have been accrued to date onto this study. Because hematologic dose-limiting toxicity was defined in terms of neutropenia and/or thrombocytopenia exceeding 7 days' duration, no patient demonstrated what was defined by the protocol as dose-limiting toxicity. Nonetheless, substantial hematologic toxicity was observed. Overall, 26% had fever and neutropenia, 56% had grade 4 neutropenia, and 26% had grade 4 thrombocytopenia. In all cases, hematologic toxicity was short term and reversible. While grade 3 and 4 myelosuppression was frequently observed, it was not dose related (in terms of paclitaxel dosage). Nonhematologic toxicity also was not dose related and, with only a few exceptions, was not clinically significant. Among 27 patients evaluable for response, 41% achieved an objective response, including 15% with a complete response. All of five patients with small cell lung cancer responded (including two with a complete response). Among 22 patients with non-small cell lung cancer, 27% achieved an objective response (also including two with a complete response). The results of this study suggest that with growth factor support, it is possible to safely administer full-dose, single-agent paclitaxel in conjunction with full-dose ICE chemotherapy. We will soon be initiating a phase II study of the ICE-T regimen using paclitaxel at 225 mg/m2 as a 24-hour continuous infusion in advanced lung cancer. We will also conduct a phase I study of ICE-T, with paclitaxel administered as a 3-hour continuous infusion.

Ifosfamide/carboplatin/etoposide/paclitaxel in advanced lung cancer: update and preliminary survival analysis.

The primary objective of this study was to define the maximum tolerated dose and toxicity profile of paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ), given as a 24-hour infusion, in conjunction with ifosfamide/carboplatin/etoposide (ICE) chemotherapy in patients with advanced lung cancer. Paclitaxel was escalated from 75 to 225 mg/m2 in 25-mg/m2 increments. All patients received granulocyte colony-stimulating factor 5 microg/kg/d from day 4 until the neutrophil count was > or = 10,000/microL. The study population consisted of 41 patients with a median age of 60 years and a median follow-up of 20.7 months. Stage distribution included 5% stage IIIA, 46% stage IIIB, and 49% stage IV. Histology consisted of 61% adenocarcinoma, 12% squamous cell carcinoma, 10% large cell carcinoma, 15% small cell carcinoma, and 2% mixed. The predominant toxicity was hematologic; 63% of patients experienced grade 4 neutropenia and 49% developed grade 4 thrombocytopenia. Fever and neutropenia occurred in 34% of patients. Hematologic toxicity was, in all cases, short-term and reversible and was not dose related. With few exceptions, nonhematologic toxicity was not clinically important. Among 39 patients evaluable for response, 36% achieved a remission (8% complete, 28% partial, 41% had stable disease, and 23% experienced disease progression). Among 33 patients with non-small cell lung cancer, the response rate was 27% (one complete response, eight partial responses, 15 had stable disease, and nine had progressive disease). Among six patients with small cell carcinoma, the response rate was 83% (two complete responses, three partial responses, and one had stable disease). The median survival of all 41 patients was 13.6 months. Survival was almost identical between stage IIIA and stage IV subsets. We conclude that it is possible to safely administer full-dose single-agent paclitaxel with granulocyte colony-stimulating factor support in conjunction with full-dose ifosfamide/carboplatin/etoposide chemotherapy. While response rates observed were not particularly notable, median survival is considerably longer than that usually achieved with combination chemotherapy in advanced lung cancer.

Carcinocythemia (carcinoma cell leukemia). An acute leukemia-like picture due to metastatic carcinoma cells.

Observation of a unique population of cells on a Wright-stained blood smear of a patient with metastatic breast carcinoma prompted a study to determine their origin. The primary carcinoma contained a marker, the presence of "signet cells." These were demonstrated in direct peripheral smears and buffy coat preparation of peripheral blood and confirmed histochemically by showing positive periodic acid-Schiff, alpha-napthol and beta-glucuronidase reactions. "Carcinocythemia" is suggested as a name for this unusual process observed over a six month period. Studies of the patient's immunocompetence, of circulating cell surface immunoglobulins and karyotype analysis were made. Postmortem examination revealed retroperitoneal fibrosis, splenic atrophy and extensive metastatic carcinoma but no evidence of leukemia. The cells will be contrasted to those seen in a second patient who appeared to have acute myelocytic leukemia complicating extensive cancer involving the bone marrow. The observations suggest that a leukemia-like blood picture due to circulating cancer cells may occur during the course of metastatic breast carcinoma.

Mediastinal irradiation for chronic lymphocytic leukemia.

Thirty-one patients with chronic lymphocytic leukemia were treated with mediastinal radiation. In none of the patients was complete remission achieved; either partial remission or clinical improvement was achieved in 52 per cent, but the duration of response was short. The response rate was 77 per cent for the patients receiving a total radiation dose greater than 3,000 rads and 45 per cent for those receiving less than 3,000 rads. Severe life-threatening toxicity was noted in 11 patients and seven of these patients died; two patients died with progressive disease. Severe toxicity was manifested by one or more of the following: bone marrow aplasia, pancytopenia, gram-negative sepsis, generalized herpes zoster and severe esophagitis. Neither the total dose of radiation nor the dose per week correlated withe the severity of reaction or death.

Importance of radiation dose in achieving improved loco-regional tumor control in limited stage small-cell lung carcinoma: an update.

Between 1974 and 1986, 576 patients (284 limited and 292 extensive stages) were treated at this institution. To keep multiagent chemotherapy (CT) at a uniform intensity, patients who received (a) combined modality approach of both multiagent chemotherapy and thoracic radiotherapy (RT) and (b) greater than or equal to 3 cycles of multiagent chemotherapy (greater than or equal to 3 drugs), were chosen for this analysis. Out of 284 patients with limited Stage small-cell lung carcinoma, there were 154 such patients who met these strict criteria, and the treatment methods for the remaining 130 patients were as follows: (a) chemotherapy alone with radiotherapy reserved for local failure (47 pts); (b) radiotherapy alone (20 pts); (c) surgery +/- adjuvant chemotherapy or radiotherapy (37 pts); (d) modified chemotherapy plus radiotherapy (26 pts). During the 12-year period, the therapeutic factors have evolved. Radiation-dose was increased from 30-40 Gy (time dose fractionation 49-66) in 1974-1977 to 44-52 Gy (time dose fractionation 73-86) in 1978-1986. The target volume for radiotherapy included the primary lesion with a 2-cm margin of normal lung and the mediastinum. Chemotherapy program also evolved from COP, CAV (1974-1977) to MACC, VCE-VCA, PCE-ACE (1978-1986). Fifty of 154 patients (32%) developed loco-regional recurrence (infield failure) and 98% (49/50) of these patients exhibited this by 2.5 years. Survival data of 154 patients were as follows: (a) Median survival time (MST) was 12 M; (b) actuarial survival rates at 2 and 5 years were 21% and 8%, respectively. Fifty percent of these patients died within 12 months (MST 12 M) and were not exposed to the full length of the risk period for loco-regional failure. To take into account the duration of exposure to the risk period, actuarial method was employed to measure the probability of loco-regional failure. Loco-regional failure rates at 2.5 years were 37%, 39%, 49%, 79%, and 84% for 50 Gy, 45 Gy, 40 Gy, 35 Gy, and 30 Gy, respectively. The difference between the recurrence rates of 37% and 79% by 50 Gy and 35 Gy was statistically significant, p less than 0.05. Although the recurrence rates of 37% and 49% by 50 Gy and 40 Gy were not statistically different, there was a strong trend of a better control rate of loco-regional carcinoma by higher radiation doses. The time to recurrence seems also shorter with lower radiation-dose than that of higher radiation doses.(ABSTRACT TRUNCATED AT 400 WORDS)

Combined modality treatment of gastric cancer.

In a series of 46 patients with localized gastric cancer treated at Massachusetts General Hospital, problems with excessive acute or chronic toxicity due to combination treatment with irradiation (XRT) and chemotherapy (CT) were not seen. Forty of the 46 received combined treatment with 2 regimens: 1) Irradiation plus concomitant 3 days of 5-FU followed by maintenance 5-FU or combined drugs--26 patients; 2) In the other 14 patients, the sequence of irradiation and chemotherapy was altered. A single course of combined drug chemotherapy was given prior to irradiation and 5-6 additional courses were administered after completion of XRT (CT-XRT-CT). The drug combination was initially 5-FU-BCNU but this was changed to FAM (5-FU, Adriamycin, Mitomycin C). Irradiation was delivered to tightly contoured portals using shaped blocks to spare as much small bowel, kidney and marrow as possible while giving 4500-5200 rad in 25 to 29 fractions over 5 to 6 weeks. In this series, there were no cases of septicemia or any deaths related to treatment. A 3 year survival rate of about 20% was achieved for the total group of patients and 43% in the group with resection but at high risk for later failure. Our inability to improve these numbers is undoubtedly a result of dose limitations with external beam irradiation combined with a systemic failure problem. When irradiation is combined with surgical resection of all or a majority of tumor, both survival and local control appear to be better than in the unresected patient group. Only 4 of 29 patients (14%) with curative resection, or resection but residual disease, had later evidence of failure within the irradiation field as opposed to 6 of 9 or 66% in the group with unresectable disease.

Stage III thymoma: pattern of failure after surgery and postoperative radiotherapy and its implication for future study.

PURPOSE: With the conventional approach of surgery and postoperative radiotherapy for patients with Masaoka Stage III thymoma, progress has been slow for an improvement in the long-term survival rate over the past 20 years. The objective of this study was to evaluate the pattern of failure and survival after surgery and postoperative radiotherapy in Stage III thymoma and search for a new direction for better therapy outcome. METHODS AND MATERIALS: Between 1975 and 1993, 111 patients with thymoma were treated at Massachusetts General Hospital. Of these, 32 patients were determined to have Masaoka Stage III thymoma. The initial treatment included surgery for clinically resectable disease in 25 patients and preoperative therapy for unresectable disease in 7 patients. Surgical procedure consisted of thymectomy plus resection of involved tissues. For postoperative radiotherapy (n = 23), radiation dose consisted of 45-50 Gy for close resection margins, 54 Gy for microscopically positive resection margins, and 60 Gy for grossly positive margins administered in 1.8 to 2.0 Gy of daily dose fractions, 5 fractions a week, over a period of 5 to 6.6 weeks. In preoperative radiotherapy, a dose of 40 Gy was administered in 2.0 Gy of daily dose fractions, 5 days a week. For patients with large tumor requiring more than 30% of total lung volume included in the target volume (n = 3), a preoperative radiation dose of 30 Gy was administered and an additional dose of 24-30 Gy was given to the tumor bed region after surgery for positive resection margins. RESULTS: Patients with Stage III thymoma accounted for 29% (32/111 patients) of all patients. The median age was 57 years with a range from 27 to 81 years; gender ratio was 10:22 for male to female. The median follow-up time was 6 years. Histologic subtypes included well-differentiated thymic carcinoma in 19 (59%), high-grade carcinoma in 6 (19%), organoid thymoma in 4 (13%), and cortical thymoma in 3 (9%) according to the Marino and Müller-Hermelink classification. The overall survival rates were 71% and 54% at 5 and 10 years, respectively. Ten of the 25 patients who were subjected to surgery as initial treatment were found to have incomplete resection by histopathologic evaluation. The 5- and 10-year survival rates were 86% and 69% for patients (n = 15) with clear resection margins as compared with 28% and 14% for those (n = 10) with incomplete resection margins even after postoperative therapy, p = 0.002. Survival rates at 5 and 10 years were 100% and 67% for those with unresectable disease treated with preoperative radiation (n = 6) and subsequent surgery (n = 3). Recurrence was noted in 12 of 32 patients and 11 of these died of recurrent thymoma. Recurrences at pleura and tumor bed accounted for 77% of all relapses, and all pleural recurrences were observed among the patients who were treated with surgery initially. CONCLUSION: Incomplete resection leads to poor results even with postoperative radiotherapy or chemoradiotherapy in Stage III thymoma. Pleural recurrence is also observed more often among patients treated with surgery first. These findings suggest that preoperative radiotherapy or chemoradiotherapy may result in an increase in survival by improving the rate of complete resection and reducing local and pleural recurrences.

The cost of surviving thrombotic thrombocytopenic purpura: case report.

The neuropsychiatric sequelae of thrombotic thrombocytopenic purpura (TTP) have not been discussed previously since most patients did not survive. The affective disorder, personality change, and cognitive deficits which resulted from TTP in a 55-year-old man who had already survived stage IIIB Hodgkin's disease are described. The neurologic and psychiatric residua did not indicate a chronic form of the disease.