Alex Yuang-Chi Chang

Double-blind, randomized study of primary hormonal treatment of stage D2 prostate carcinoma: flutamide versus diethylstilbestrol.

PURPOSE Patients with stage D2 prostate carcinoma are often treated initially with hormones to decrease endogenous testosterone. Therapy with diethylstilbestrol (DES), leuprolide, or bilateral orchiectomy has been reported to be equivalent. DES is the cheapest preparation, but has the potential for serious cardiovascular or thromboembolic complications. Flutamide is a novel antiandrogen with fewer side effects. PATIENTS AND METHODS The Eastern Cooperative Oncology Group (ECOG) conducted a double-blind, randomized study to compare the efficacy of flutamide (250 mg three times daily) to DES (1 mg three times daily) as the primary hormonal therapy for patients with stage D2 prostate cancer. Patients were stratified by performance status, disease sites, and history of cardiovascular disease at randomization. RESULTS Forty-eight patients received DES and 44 flutamide. Patient characteristics were evenly distributed between the two treatments. The overall response rate was similar (DES, 62%; flutamide, 50%). Grade III or worse cardiovascular or thromboembolic toxicity developed in 33.3% of patients on DES and in 17.6% on flutamide (P = .051). Other toxicities were similar between the two treatment arms. However, DES produced significantly longer time to treatment failure (26.4 v 9.7 months, P = .016) and longer survival than flutamide (43.2 v 28.5 months, P = .040). CONCLUSION As the primary hormonal therapy for stage D2 prostate cancer, DES caused more serious cardiovascular or thromboembolic complications than flutamide. Despite this, flutamide was not as active an initial agent as DES. However, the effectiveness of flutamide in conjunction with other agents compared with DES remains undetermined, and the optimal initial hormone therapy of stage D2 prostate cancer requires further studies.

Prospective evaluation of carcinoembryonic antigen levels and alternating chemotherapeutic regimens in metastatic breast cancer.

Ninety-seven eligible and evaluable women with metastatic breast cancer were placed on a prospective clinical protocol to evaluate the use of continuous cyclic therapy with dibromodulcitol, doxorubicin, vincristine, tamoxifen, and fluoxymesterone (DAVTH) v DAVTH alternating with cyclophosphamide, methotrexate, 5-fluorouracil, and prednisone (CMFP); and the use of pretreatment and serial carcinoembryonic antigen (CEA) levels in these patients. Continuous DAVTH and DAVTH/CMFP were equivalent therapies with respect to response rates, time to treatment failure (TTF), and survival. Pretreatment CEA levels were elevated (greater than 5 ng/mL) in 42/97 patients and less than 5 ng/mL in the remaining patients. Patients with elevated pretreatment CEA levels were more likely to be estrogen receptor (ER) positive (P = .006), to have prolonged disease-free intervals (P = .017), to have hepatic (P = .004) and/or osseous (P = .01) metastases, and to have multiple sites of metastatic disease (P = .004). Pretreatment CEA levels did not significantly predict for overall response rates, TTF, or survival; nonetheless, those patients with low pretreatment CEA levels had more complete responses (CRs) (16/55 v 4/42; P = .02). Serial CEA levels during therapy revealed a number of interesting patterns. During the first 4 months of treatment, serial CEA levels in responding patients either (1) progressively declined (15/29 women with elevated pretreatment CEA levels), or (2) initially rose significantly (mean, 243% of pretreatment value) and then declined (14/29 women with elevated pretreatment CEA levels). Peak CEA levels in the latter patients were seen 27 to 135 days following initiation of cytotoxic therapy. In some patients the initial increase in the CEA level was incorrectly interpreted as evidence of impending disease progression. CEA levels frequently increased around the time of clinical disease progression. However, rising CEA levels rarely provided a clinically meaningful lead time before the appearance of other clinical evidence of disease progression. These data suggest that routine pretreatment and monthly serial CEA levels in metastatic breast cancer patients have minimal use in clinical practice. Two further noteworthy findings were observed in this prospective study. First, patients with an unknown ER status had a prolonged median survival when compared with patients with ER positive or negative tumors; this appeared to be related to prolonged disease-free intervals in ER unknown patients. Second, two case of secondary acute leukemia were seen in patients treated with continuous DAVTH therapy.

Engineering a Human Bone Marrow Model: A Case Study on ex Vivo Erythropoiesis

Bone marrow, with its intricate, three-dimensional tissue structure facilitating cell-cell interactions, provides a microenvironment supporting the production of hundreds of billions of multilineal blood cells everyday. We have developed a three-dimensional bone marrow culture system in which marrow cells are cultured in a reactor packed with porous microspheres. The culture supports a three-dimensional growth configuration and multilineal hemopoiesis mimicking the bone marrow in vivo. We studied ex vivo human erythropoiesis using the three-dimensional culture system. The system sustained extensive erythropoiesis at low erythropoietin concentrations (0.2 U/mL), plus stem cell factor, interleukin-3, granulocyte-macrophage colony-stimulating factor, and insulin-like growth factor-I. Erythroid cell production lasted for more than 5 weeks, and the percentage of erythroid cells in the nonadherent cell population was approximately 60%. Flow cytometric analysis using cell surface markers specific for erythroid cells (CD71 and glycophorin-A) indicated that the culture produced early, intermediate, and late erythroid cells. As the culture progressed, the erythroid cell population shifted gradually toward mature cell types. When compared to the three-dimensional culture, the traditional flask cultures failed to support extensive erythropoiesis under the same conditions. This indicates that the three-dimensional bone marrow culture system provides a microenvironment conducive to erythropoiesis under more physiological conditions and is a better bone marrow model.

Alternating chemotherapy and twice-daily thoracic radiotherapy in limited-stage small-cell lung cancer: a pilot study of the Eastern Cooperative Oncology Group.

PURPOSE This pilot study was undertaken to determine the efficacy and feasibility of alternating cisplatin and etoposide with multiple daily fractions of thoracic radiotherapy (TRT) in patients with limited-stage small-cell lung cancer (SCLC). PATIENTS AND METHODS Thirty-four SCLC patients received four courses of cisplatin (30 mg/m2/d x 3) plus etoposide (120 mg/m2/d x 3) (PE) every 3 weeks. TRT was administered twice daily (1.5 Gy per fraction) for 5 consecutive days in the week after cycles 1, 2, and 3 of chemotherapy (total TRT dose, 45 Gy). Patients who achieved a complete response (CR) received one course of late-intensification (LI) treatment consisting of cyclophosphamide (4 g/m2) and etoposide (900 mg/m2). Prophylactic cranial irradiation (PCI) was optional. RESULTS Nineteen of 32 assessable patients achieved a CR (59%) and 12 had a partial response (38%), for an overall response rate of 97% (95% confidence interval [CI], 84% to 99%). Median survival was 18 months, while 2-year progression-free survival was 47%. Leukopenia < or = 1,000/microL occurred in 12% of induction treatment cycles. Severe esophagitis was uncommon. Pulmonary fibrosis that was asymptomatic or minimally symptomatic was observed in eight patients (25%). There was one episode of adult respiratory distress syndrome (ARDS) during LI chemotherapy. Life-threatening neutropenia (< or = 500/microL) developed in all patients who underwent LI chemotherapy, with a median duration of 10 days (range, 8 to 19). Two patients died of sepsis during LI chemotherapy. CONCLUSION Alternating PE and TRT as performed in this trial is an effective brief induction regimen for limited-stage SCLC. However, this particular regimen did not appear to be substantially different in terms of efficacy or toxicity compared with regimens using concurrent chemotherapy and standard-fraction TRT. LI chemotherapy was associated with unacceptable toxicity and did not appear to have a favorable impact on survival.

Combined betaseron R (recombinant human interferon beta) and radiation for inoperable non-small cell lung cancer

PURPOSE Based on in vitro evidence of radiosensitization by Betaseron (beta-IFN), a Phase I/II study was undertaken to determine toxicity and response using combined radiation (RT) and B-IFN in patients with unresectable Stage III and nonsmall cell lung cancer. METHODS AND MATERIALS Varying doses of beta-IFN(10 to 90 x 10(6) IU) were administered IV immediately preceding RT on the first three days of weeks 1, 3, and 5. The RT dose was 1.8 Gy/day, 5 days/week for a total of 54 or 59.4 Gy. RESULTS Thirty-nine patients were entered, 32 of whom were evaluable. The median follow-up time at time of analysis was 60 months. Responses were based on CT scan. The response rate for the total group was 81% with 44% achieving complete response. Seventy-eight percent of patients with complete response survived a minimum of 21 months. Twenty-six patients had Stage III A/B disease with a median tumor size of 6.5 cm. and median survival was 19.7 months. The 5-year actuarial survival for this group was 31%, with a plateau persisting after 3 years. There were no treatment related deaths nor any event of life threatening toxicity. Of eight patients surviving 3-5 years, no long-term toxicity has been observed. Karnofsky indices were 90-100 and respiratory symptoms were minimal. CONCLUSION beta-IFN is well-tolerated. Response and survival rates are sufficiently encouraging to warrant further investigation in a randomized trial which has been accepted as an RTOG study awaiting drug availability.

Pulmonary toxicity induced by mitomycin C is highly responsive to glucocorticoids

The authors have studied five cases of biopsy‐proven pulmonary toxicity caused by the administration of mitomycin C (M), vincristine, and cisplatin in 64 patients with advanced non‐small cell lung cancer. The clinical triad of progressive dyspnea, rales, and pulmonary infiltrates presented in all five cases. In addition, pulmonary function tests showed hypoxemia (four/five), reduced forced vital capacity (three/four), total lung capacity (two/three), and forced expiratory volume (FEV1) (three/four) and very profound reduction in diffusion capacity (three/three). Transbronchial biopsy for tissue examination was necessary to rule out other causes. Characteristics but nonspecific pathologic changes were documented in all five cases. All the patients responded quickly and dramatically to high‐dose glucocorticoids with improvement of hypoxia, dyspnea, exercise tolerance, and sense of well being. In three patients the pulmonary infiltrates cleared. However, abrupt stopping or early withdrawal of steroid resulted in aggravation of dyspnea and pulmonary infiltrate in three cases who improved subsequently with escalation of steroid doses. The authors conclude that the treatment of choice for pulmonary toxicity induced by M or M‐containing chemotherapy regimens is a high dose of glucocorticoid and discontinuation of M at once when suspicion is raised. Cancer 57:2285–2290, 1986.

Pulmonary changes induced by combined mouse β-interferon (rMuIFN-β) and irradiation in normal mice - toxic versus protective effects

This study in normal mice was undertaken to investigate possible enhancement of pulmonary toxicity by interferon-beta (IFN-beta) combined with single doses of irradiation. A pharmacokinetic study preceded the toxicity study to determine the optimal route and timing of IFN administration. Graded single doses of radiation were combined with graded doses of IFN. Pulmonary toxicity was determined using endpoints of alveolar surfactant and procollagen in lung lavage fluid at 7 days, breathing frequency, lethality and histology. Increased lethality was seen when IFN was combined with irradiation at 12.5 Gy vs. irradiation alone. This occurred between 20 and 30 weeks post treatment with no increased breathing frequency or surfactant release, suggesting independent mechanisms of injury. Increased breathing frequency after 40 weeks, usually associated with fibrosis, was less pronounced for IFN treated vs. irradiation only controls. Ultrastructural studies at 72 weeks suggest reduced fibrosis in lungs of IFN treated vs. irradiation only controls. Supporting this was the finding that Procollagen III, a biosynthetic precursor of collagen, was increased in the lavage fluid at 7 days for all radiation doses but decreased with the addition of IFN at 12.5 and 15 Gy. Interferons can act either as sensitizers or radioprotectors, depending on the biological system and type of interferon. Our study suggests that while IFN-beta may increase the acute effects of radiation in the mouse lung, some protection from radiation-induced fibrosis, possibly related to alteration of immune mechanisms, may exist.

Continuous intravenous infusion of 5-fluorouracil in the treatment of refractory breast cancer

Ten patients with metastatic breast cancer refractory to multiple chemotherapeutic regimens as well as hormonal therapy were treated with continuous intravenous infusion of 5-fluorouracil (5-FU) at 200–300 mg/m2/24 h through a Broviac catheter using a Cormed pump. The treatment was continued until toxicity developed and restarted after resolution of the toxicity. Most common dose-limiting toxicities were mucositis and diarrhea. No grade II or worse myelosuppression was documented. All the patients had received 5-FU by bolus injection before entering the study. We observed three partial responses and one improvement, with two patients continued on the study (396+ and 90+ days, respectively). We conclude that continuous infusion of 5-FU is safe and tolerable even by heavily pretreated patients with poor performance status and is not cross-resistant to bolus injection of 5-FU and other chemotherapeutic agents. Our report warrants further investigation.

Phase II trial of 6-diazo-5-oxo-L-norleucine versus aclacinomycin-A in advanced sarcomas and mesotheliomas

SummaryNinety-eight patients with previously-treated advanced soft tissue sarcoma, bone sarcoma, or mesothelioma were randomly assigned to one of two intravenous single-agent treatment regimens, either 6-diazo-5-oxo-l-norleucine (DON; brief infusions of 50 mg/m2/day for 5 consecutive days every 4 weeks) or aclacinomycinA (ACM-A, as 30-min infusions of 100 mg/m2 or 85 mg/m2, administered every 3 weeks). Of 43 patients who were evaluable for response, survival and toxicity, there were two responses (5%) produced by ACM-A; one in a male with mesothelioma, and one in a female with malignant fibrous histiocytoma. None of the 36 evaluable patients treated with DON developed an objective tumor response. Median survival was 4.8 months in the DON treatment arm, and 6.8 months in the ACM-A treatment arm. No patients on the DON arm experienced lethal or life-threatening toxicities, and severe toxicities resulting from this treatment included nausea and emesis (10%), stomatitis (2%), gastrointestinal toxicity (2%), and anemia (2%). Moderate toxicities included vomiting (24%), hematologic toxicity (24%), neurologic toxicity (7%), diarrhea (7%), mucositis (5%), fever (5%), palpitations (2%), hepatotoxicity (2%), bleeding (2%) and edema (2%). Fifteen percent experienced at least one severe reaction, and 63% experienced at least one moderate or greater toxicity. ACM-A was associated with four cases of life-threatening myelosuppression (7%); severe toxicities included myelosuppression (11%), neurologic toxicity (4%), diarrhea (2%), respiratory toxicity (2%), pain and muscle spasms (2%), edema (2%), and ulceration following extravasation (2%). Moderate toxicities included diarrhea (9%), mucositis (7%), hepatotoxicity (7%), infection (5%), fever (7%), gastrointestinal toxicity (4%), respiratory (2%), dehydration (2%), cardiac (2%), alopecia (2%), ulceration following extravasation (7%), and edema (2%). Thirty-eight percent of patients on the ACM-A arm developed one or more severe or worse toxicity, and 76% had at least one moderate or worse toxicity. Neither regimen produces useful clinical results in patients with advanced sarcomas or mesotheliomas.

Phase Ii Trial of Carboplatin in Patients with Metastatic Malignant Melanoma: A Report from the Eastern Cooperative Oncology Group

Thirty patients with pathologically proven, measurable metastatic melanoma without prior chemotherapy were treated with carboplatin 400 mg/m2 by intravenous infusion for 30 minutes every 4 weeks. Twenty-seven patients were evaluable for response and toxicity. Two complete responses and one partial response (3 of 27 = 11%, 90% confidence intervals: 3–26%) were documented. The median survival was 4.7 months. The most common toxicity was myelosuppression. One drug-related death was observed due to renal failure. Prior radiotherapy and liver metastasis were the poor prognostic indicators identified in our study. Carboplatin in the dose and schedule reported in our trial has only modest antitumor activity in patients with advanced malignant melanoma.