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Recent trends in the management of lymphomas at M.D. Anderson Cancer Center.

The overall therapeutic strategy for the management of lymphomas at the M.D. Anderson Cancer Center consists of devising new drug combinations that are tested first in patients with relapsed lymphoma and, if successful, are then incorporated into first-line management. This article describes the preliminary results of the alternating triple therapy (ATT) first-line regimen for patients with M.D. Anderson stages B, C, and D of intermediate-grade lymphomas. This regimen is based on three non-cross-resistant combinations, two of which were originally developed as salvage therapy. Statistically significant improvement in the overall survival and failure-free survival at 1 year has already been seen for the stage D patients (high tumor burden and high lactate dehydrogenase levels). A new therapeutic strategy in current use for patients with Ann Arbor stages III and IV low-grade lymphoma is also described. This regimen consists of CHOP-Bleo (cyclophosphamide, doxorubicin, vincristine, prednisone-bleomycin) alternating with ESHAP (etoposide, Solu-medrol [methylprednisolone, Upjohn Company], Ara-C [cytarabine], platinum) and NOPP (Novantrone [mitoxantrone, American Cyanamid Company], Oncovin [vincristine Eli Lilly and Company], procarbazine, prednisone). Maintenance interferon (IFN) is also used for 1 year. Finally, the current salvage regimen in use at the M.D. Anderson Cancer Center is described. This MINE-ESHAP regimen consists of an induction with mesna, ifosfamide, Novantrone (mitoxantrone), and etoposide, which is administered until maximum response and followed by consolidation with 3 to 6 courses of ESHAP. The preliminary results of this regimen are encouraging, but more follow-up is required before any conclusions can be drawn.

Adult↗

M.D. Anderson Cancer Center continues award-winning style.

The University of Texas M.D. Anderson Cancer Center in Houston is an institution singularly committed to the highest standards of performance and achievement. Accordingly, its communications/public relations staff are expected to produce an outstanding annual report every year.

Annual Reports as Topic↗

Impact of clinical trial protocols on patient care systems at the University of Texas M.D. Anderson Cancer Center.

Clinical trial protocols represent a significant component of the research program at the University of Texas M.D. Anderson Cancer Center. Currently, there are nearly 800 active protocols using more than 150 investigational drugs. Sponsors of these trials include the National Cancer Institute, numerous pharmaceutical companies, and a variety of other funding sources. Because of our large patient base, however, routine participation in cooperative groups is limited. The impact of clinical trial protocols on patient care systems is a growing concern that is addressed primarily by the Surveillance Committee at M.D. Anderson. Like many institutional review boards, this committee reviews all protocols and must grant approval before the activation of any clinical trial. The issues of medical ethics, including a risk-benefit assessment for research subjects, equitable patient selection, safeguards for economically disadvantaged populations, and the general requirements for informed consent, also fall under the purview of this board. For any comprehensive cancer center to succeed, it must have strong research programs that enhance treatment options for patients. The crisis in financing health care significantly threatens the viability of cancer research. Reimbursement for the related costs of individuals participating in clinical trials has become a battle ground for third-party payers. The resulting economic risk is shared by health care providers and patients. As a consequence, many cancer centers, including M.D. Anderson, have initiated an economic-impact analysis for protocols as a component of the review process. This analysis includes an estimation of the patient care costs compared to the funding allocated to support the research. Future research will include pharmacoeconomic analysis and other ways to relate the costs and outcomes of treatment protocols. In the interim, we must monitor reimbursement trends for patients enrolled in clinical trials closely and amend the informed consent process to include a discussion of potential economic risk or hardship to patients if insurance claims are denied. Cancer care providers, third-party payers, the federal government, and society at large must work together to address the funding of cancer research and patient care.

Cancer Care Facilities↗

Age contrasts in patients with advanced epithelial ovarian cancer. The M.D. Anderson Cancer Center experience.

BACKGROUND: This study reviews the experience at the University of Texas M.D. Anderson Cancer Center with elderly patients treated for advanced epithelial ovarian cancer with cisplatin-based combination chemotherapy. METHODS: From 1978 through 1988, 215 patients with Stage III or IV, Grade 2 or 3 epithelial ovarian cancer were entered onto one of three consecutive trials involving cisplatin-based combination chemotherapy. The treatment plans were as follows: Trial 1: 12 cycles of cisplatin-melphalan (75 patients); Trial 2: 12 cycles of cisplatin-cyclophosphamide (49 patients); and Trial 3: 6 cycles of cisplatin-cyclophosphamide (91 patients). End-points of analysis included the effect of age on other prognostic factors, clinical response rate, surgical response rate, toxicity, progression-free survival, and survival. RESULTS: Of the entire study group, 57 patients (27%) were 65 years of age and older at diagnosis. There was no effect of age on FIGO stage or histologic grade distribution, but 61% of patients younger than 65 years of age had residual tumors less than or equal to 2 cm compared with only 33% of patients 65 years of age and older (P = 0.00027). There were no differences between the two age groups with respect to response rates, recurrence rate after negative second-look surgery, toxicity, or progression-free survival. Patients in the younger than 65 years of age group, however, had a significantly longer median survival time than those 65 years of age and older (30 versus 19 months, respectively) (P = 0.0038). CONCLUSIONS: This analysis suggests that elderly patients are more likely to begin chemotherapy with bulky residual disease and to have a significantly shorter survival time than their younger counterparts.

Adult↗

Measuring service quality at the University of Texas M.D. Anderson Cancer Center.

Evaluates the service quality of four clinics at the University of Texas M.D. Anderson Cancer Center using a questionnaire methodology. The SERVQUAL instrument was administered to patients of the Medical Breast, Leukemia, Medical Gastroenterology and Bone Marrow Aspiration clinics. Results show that, according to the service gap methodology of comparing expectations and perceptions, across all four clinics the issues of billing accuracy and waiting times are deemed by patients as significant problems. In comparing the individual clinics, the Medical Gastroenterology and Leukemia clinics are best performers and the Medical Breast clinic is the worst. However, these differences in performance are due to differences in patients' expectations of service quality, rather than differences in perceptions. Concludes that customer expectations can have a strong impact on a firm's evaluation of its service quality.

Bone Marrow Neoplasms↗

Update: the M.D. Anderson Cancer Center experience with paclitaxel in the management of breast carcinoma.

The first of three trials at M.D. Anderson Cancer Center investigating paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) in metastatic breast cancer was a phase II study involving 25 patients (297 courses) previously treated with only one chemotherapy regimen; the patients received paclitaxel 250 mg/m2 infused over 24 hours without granulocyte colony-stimulating factor (G-CSF). Complete (12%) and partial responses (44%) led to median durations of response and survival of 9 and 21 months, respectively. The median paclitaxel dose was 200 mg/m2. Despite profound neutropenia (median granulocyte count of 0.3 cells x 10(9)/L for the first three courses), infection occurred in 42% of patients but only 6% of courses. In a phase I trial of paclitaxel 125 mg/m2 over 24 hours followed by doxorubicin 60 mg/m2 using G-CSF at 5 micrograms/kg days 5 through 19, dose-limiting mucositis with neutropenic fever occurred at the starting dose, so the maximum tolerated dose was one dose lower: paclitaxel 125 mg/m2 (over 24 hours) followed by doxorubicin 48 mg/m2 over 48 hours. Among 10 patients, there was one complete response and seven partial responses (overall response, 80%). Suspecting a schedule-dependent interaction between drugs, a phase I trial of the reverse sequence yielded a maximum tolerated dose, defined by neutropenic fever without mucositis, of doxorubicin 60 mg/m2 (over 48 hours) followed by paclitaxel 150 mg/m2 (over 24 hours) in 21 patients. A pharmacokinetic study in which the sequence of administration of paclitaxel over 24 hours and doxorubicin over 48 hours was alternated in courses 1 and 2 indicated that when paclitaxel by 24-hour infusion is given first, doxorubicin plasma levels at the end of infusion were an average 70% higher and doxorubicin clearance was reduced approximately 30% compared with the reverse sequence. Similarly, the incidence of grade 2 or 3 mucositis was 70% with the paclitaxel/doxorubicin sequence versus only 10% with the reverse sequence. We concluded that paclitaxel slows doxorubicin metabolism and that when used together in this schedule, doxorubicin should precede paclitaxel. In the third trial paclitaxel without G-CSF was administered to two groups of heavily pretreated patients: (1) those with only two prior chemotherapy regimens (inclusive of adjuvant therapy) received paclitaxel 175 mg/m2 over 24 hours and (2) those with three or more prior regimens received paclitaxel 150 mg/m2 over 24 hours. Response rates in both regimens were approximately 20%. We conclude that paclitaxel has significant antitumor activity in metastatic breast cancer, especially in patients with limited prior therapy, without need for G-CSF.(ABSTRACT TRUNCATED AT 400 WORDS)

Adult↗

Adult acute megakaryocytic leukemia: an analysis of 37 patients treated at M.D. Anderson Cancer Center.

To characterize acute megakaryocytic leukemia (FAB M7 AML), we identified 37 patients with M7 AML treated at M.D. Anderson Cancer Center between 1987 and 2003 and compared them with 1800 patients with non-M7, non-M3 AML treated during the same period. The median age of the M7 AML group was 56 years (range, 21-78 years); 22 patients (59%) had an antecedent hematologic disorder or myelodysplastic syndrome or both, and 7 patients (19%) had previously received chemotherapy for other malignancies. Extensive bone marrow fibrosis was found in 23 patients (62%). Poor cytogenetic characteristics were observed in 49% of patients with M7 AML versus 33% of others (P < .001). Complete remission rates were 43% with M7 AML and 57% with non-M7 AML (P = .089). Median overall survival (OS) was 23 and 38 weeks, respectively (P = .006). Median disease-free survivals were 23 versus 52 weeks, respectively (P < .001). By multivariate analysis, M7 AML was an independent adverse prognostic factor for OS, independent of other factors including cytogenetic abnormalities (hazard ratio 1.51, P = .049). These results confirm the poor prognosis of M7 AML and indicate that other biologic characteristics beyond cytogenetic abnormalities likely play a role in this disease.

Adult↗

Community respiratory virus infections in bone marrow transplant recipients: the M.D. Anderson Cancer Center experience.

Community respiratory virus (CRV) infections are common among bone marrow transplant (BMT) recipients during community outbreaks. At M.D. Anderson Cancer Center (MDACC), experience with CRV infection in this population over the past decade suggests that BMT recipients in the preengraftment phase are at special risk of progression of upper respiratory tract infection (URTI) to pneumonia. After pneumonia is established, no currently available therapy substantially reduces mortality. For BMT recipients with respiratory syncytial virus URTIs, treatment with ribavirin and intravenous immunoglobulin may be helpful in preventing progression to pneumonia and thus in reducing mortality, but this approach requires confirmation in controlled clinical trials. Prevention of CRV infection in this vulnerable patient population is crucial to reducing morbidity and mortality. Aggressive infection control precautions, which have been in effect at MDACC since 1994, have reduced nosocomial transmission of these potentially lethal infections.

Antiviral Agents↗

Paclitaxel in the treatment of metastatic breast cancer: M.D. Anderson Cancer Center experience.

Paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) 250 mg/m2 by 24-hour infusion at 21-day intervals was evaluated at M.D. Anderson Cancer Center as a single agent in patients who had received one prior chemotherapy regimen either as adjuvant therapy or for metastatic disease. Of 25 patients treated, 12% had a complete remission and 44% had a partial response. The median time to progression was 9 months (range, 1 to 20 months). In the next phase of development, a phase I trial evaluated sequentially administered paclitaxel and doxorubicin as initial therapy for metastatic disease. Granulocyte colony-stimulating factor also was administered in each cycle. The dose-limiting toxicity was either stomatitis or neutropenic fever. The maximum tolerated dose (MTD) was 125 mg/m2 for paclitaxel and 48 mg/m2 for doxorubicin. Because of much lower than anticipated MTDs of both drugs in this schedule, it was hypothesized that there may be a schedule-dependent toxicity; therefore, in the second phase I study the schedule of administration was reversed (ie, doxorubicin followed by paclitaxel infusion). The MTDs of this schedule were 60 mg/m2 and 150 mg/m2 for doxorubicin and paclitaxel, respectively. Pharmacokinetic studies subsequently have confirmed that administration of paclitaxel before doxorubicin impairs the elimination of doxorubicin by some unknown mechanism. In an ongoing phase II study, paclitaxel is being evaluated in patients who have received three or more treatments with chemotherapy. Paclitaxel is administered at doses of 135 and 150 mg/m2 (for poor- and good-risk patients, respectively) without granulocyte colony-stimulating factor. Six patients (19%) have shown objective partial responses. Our initial phase II study showed significant antitumor activity for paclitaxel in patients who had received limited prior chemotherapy. Our phase I studies established that initial administration of paclitaxel alters the pharmacokinetics of doxorubicin and increases morbidity. The reverse sequence of administration was associated with better tolerance and a higher MTD. In heavily treated patients this drug also has significant antitumor activity.

Antineoplastic Combined Chemotherapy Protocols↗

Supraglottic laryngectomy for intermediate-stage cancer: U.T. M.D. Anderson Cancer Center experience with combined therapy.

We reviewed the records of all patients with previously untreated squamous cell carcinomas of the supraglottic larynx who presented to The University of Texas M.D. Anderson Cancer Center from 1974 to 1987. Of 404 patients, 60 (15%) underwent supraglottic laryngectomy and functional anterior neck dissection as a primary modality of therapy; these patients were studied. Fifty of the 60 patients (83%) received adjunctive postoperative radiotherapy. Tumor-free survival was 96% at 2 years and 91% at 5 years. There were no local failures, 4 regional failures, and 3 distant metastases. Second cancers, mostly of the lung, occurred in 9 patients (15%). Three patients required completion laryngectomies for intractable aspiration. Analysis of deglutition and tracheal decannulation rehabilitation revealed a higher incidence of complications in patients who underwent arytenoidectomies.

Algorithms↗

Multidisciplinary approach to cancer treatment: a model for breast cancer treatment at the M.D. Anderson Cancer Center.

Despite that fact that a multidisciplinary approach is important for cancer treatment, this approach is not widely used in Japan. The M.D. Anderson Cancer Center (MDACC) is one of the most well-established cancer institutes in the world, and has implemented a unique multidisciplinary team management approach for the treatment of breast cancer. The efforts of MDACC to eliminate cancer have been ongoing for more than 60 years. Here, we describe the multidisciplinary approach used at MDACC for the treatment for breast cancer. We focus on the background of the institute, in terms of establishing its treatment model and educational system, and compare its multidisciplinary approach with the current approach used in Japan, in the hopes of influencing future directions in cancer therapy in Japan.

Breast Neoplasms↗

The University of Texas M.D. Anderson Cancer Center experience with paclitaxel in breast cancer.

The first phase II study of paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) in breast cancer was completed at M.D. Anderson Cancer Center, and included 25 patients with metastatic breast cancer who had been previously treated with one chemotherapy regimen. Fourteen of these patients achieved a major objective response; the median response duration was 9 months, and the median survival time, 20 months. Additional trials showed that paclitaxel maintained its antitumor efficacy in patients with two and three prior chemotherapy regimens, including patients with anthracycline-resistant breast cancer. Combination therapy with doxorubicin showed that this combination was effective, although with the long infusion duration used for both agents, sequence-dependent toxic interactions were encountered. In combination with vinorelbine, dose-limiting toxicity included neutropenic fever and neuropathy. High-dose single-agent paclitaxel is currently being explored in the management of inflammatory breast cancer and as part of neoadjuvant chemotherapy for stages II and III operable disease.

Antineoplastic Combined Chemotherapy Protocols↗

Spinal myxopapillary ependymoma outcomes in patients treated with surgery and radiotherapy at M.D. Anderson Cancer Center.

This study was undertaken to determine the disease outcomes in patients treated with surgery alone or surgery and adjuvant radiotherapy (RT) for myxopapillary ependymoma (MPE) of the spine. The medical records of 35 patients with MPE treated at The University of Texas M.D. Anderson Cancer Center between December 1968 and July 2002 were reviewed. The endpoints analyzed were progression-free survival (PFS), overall survival, and local control. The median age of patients was 35 years (range, 14-63 years), and the male to female ratio was 2.5:1. In total, 21 (60%) patients underwent a gross total resection, 13 (37%) a subtotal resection, and 1 (3%) a biopsy only; 22 of them (63%) also received adjuvant RT. The median follow-up was 10.7 years. The 10-year overall survival, PFS, and local control rates for the entire group were 97%, 62%, and 72%, respectively. Of 11 patients 5 (45%) who had undergone gross total resection alone had recurrence. A total of 12 (34%) patients had disease recurrence, all in the neural axis; 8 of them had treatment failure at the primary site only, 3 in the distant neural axis only, and 1 at the primary site and in the distant neural axis. Patient age (> 35 years; P = 0.002) and adjuvant RT (P = 0.04) significantly affected PFS. The long-term patient survival duration for MPE managed with surgery and adjuvant RT is favorable. Regardless of the extent of resection, adjuvant RT appears to significantly reduce the rate of tumor progression. Failures occurred exclusively in the neural axis, mainly at the primary site.

Adolescent↗

Long-term cardiac tolerability of trastuzumab in metastatic breast cancer: the M.D. Anderson Cancer Center experience.

PURPOSE: To evaluate the cardiac safety of long-term trastuzumab therapy in patients with human epidermal growth receptor 2 (HER2) -overexpressing metastatic breast cancer (MBC) treated at The University of Texas M.D. Anderson Cancer Center (Houston, TX). PATIENTS AND METHODS: Among 218 MBC patients treated with trastuzumab-based therapy for at least 1 year, 173 patients were assessable for cardiac toxicity. Cardiac events (CEs) were defined as follows: asymptomatic decrease of left ventricular ejection fraction (LVEF) below 50%; decrease of 20 percentage points in LVEF compared with the baseline; or signs or symptoms of congestive heart failure (CHF). RESULTS: The median cumulative time for trastuzumab administration was 21.3 months. The median follow-up was 32.6 months (range, 11.8 to 79.0 months). Forty-nine patients (28%) experienced a CE: three patients (1.7%) had an asymptomatic decrease in the LVEF of 20 percentage points, 27 patients (15.6%) experienced grade 2 cardiac toxicity, and 19 patients (10.9%) experienced grade 3 cardiac toxicity. All but three patients had improved LVEF or symptoms of CHF with trastuzumab discontinuation and appropriate therapy. There was one cardiac-related death (0.5%). Baseline LVEF was significantly associated with CE (hazard ratio, 0.94; P = .001). The hazard of a CE among patients taking concomitant taxanes was higher early in the follow-up period but declined during the course of follow-up. CONCLUSION: The risk of cardiac toxicity of long-term trastuzumab-based therapy is acceptable in this population, and this toxicity is reversible in the majority of the patients. In patients who have experienced a CE, additional treatment with trastuzumab can be considered after recovery of cardiac function.

Adult↗

Survival and recurrence factors in adult medulloblastoma: the M.D. Anderson Cancer Center experience from 1978 to 1998.

Medulloblastoma is a rare adult primary brain tumor for which limited retrospective studies are available to elucidate natural history or to guide therapy. A retrospective chart and imaging review of adult patients (aged >18 years) with medulloblastoma was performed to identify survival and prognostic factors. Fifty-seven patients were evaluated at the University of Texas M.D. Anderson Cancer Center from 1978-1998. Statistical analysis of prognostic factors and overall survival was performed for a subgroup of 28 patients who were followed exclusively at our institution from the time of diagnosis until death or last follow-up. These 28 patients had an overall survival of 91% at 3 years and 84% at 5 years, whereas median survival was not reached after a median follow-up of 168 weeks (range, 9-602 weeks). Progression-free survival for all patients was 68% at 3 years and 62% at 5 years, and was not statistically different between poor- and standard-risk patients. Univariate analysis of clinical features, such as age, sex, extent of local disease, extent of resection, and use of adjuvant chemotherapy, did not identify any prognostic variables for survival among the 28 patients. Patterns of recurrence revealed that the posterior fossa was the most common site (56%), followed by bone marrow (25%). Adult medulloblastoma appears to have a favorable prognosis after treatment with maximally surgically feasible resection followed by craniospinal irradiation. Optimal treatment remains to be clarified, as both standard-risk and poor-risk patients have prolonged disease-free survival. The marked difference between survival and progression-free survival suggests that salvage therapy, usually with combination chemotherapy in this cohort of patients, is of benefit. More formal analysis of the survival benefit was not possible, however, because of the small number of patients treated at recurrence with any one therapeutic regimen.

Adult↗

Clinical course of breast cancer patients with metastases confined to the lungs treated with chemotherapy. The University of Texas M.D. Anderson Cancer Center experience and review of the literature.

PURPOSE: To evaluate the clinical course of patients with a metastatic breast cancer (MBC) confined to the lungs and treated with doxorubicin/cyclophosphamide-containing chemotherapy (DC-CT). PATIENTS AND METHODS: Between 1973 and 1985, 1581 patients with MBC were treated with DC-CT at M.D. Anderson Cancer Center. Data for 88 patients (5.6%) with metastases confined to the lungs were reviewed to correlate various clinical characteristics with response to treatment and survival. RESULTS: The overall response rate was 76% with 33% achieving complete response (CR). The median overall survival time was 22 months (range 1-210). The 10-year survival rate was 9%. The overall response and CR rates were higher for the patients with metastases confined to the lungs (76% and 33%. respectively) than for the remainder of MBC patients (64% and 14%; P < 0.01). The 10-year survival rate was also higher (9% versus 3%, P < 0.01), but there were no differences in median overall survival rate. CONCLUSIONS: This retrospective analysis demonstrated that patients with metastases confined to the lungs treated with DC-CT had a high objective response rate, especially high CR rates, and a median survival comparable to that of our entire population of MBC patients. A small but clinically significant percentage of patients had prolonged survival. Therefore, not all visceral sites are indicators of poor prognosis.

Adult↗

Phase I/II trial of high dose mitoxantrone in metastatic breast cancer: the M.D. Anderson Cancer Center experience.

Anthracyclines are among the most active agents in metastatic breast cancer. Mitoxantrone demonstrated a different toxicity profile when compared to doxorubicin. We performed a phase I/II study of single-agent high-dose mitoxantrone therapy for advanced breast cancer. Nineteen patients who had a diagnosis of metastatic breast cancer received treatment at the M.D. Anderson Cancer Center between June 1986 and December 1987. The patients received escalating doses of mitoxantrone until a maximum tolerated dose (MTD), defined as grade 3 or 4 nonhematologic toxicity or infection, was obtained. The starting dose of 25 mg/m2, given by short intravenous infusion, was escalated by 25% in each five-patient cohort if each patient in the previous cohort tolerated the initial course and 2 or fewer patients reached the MTD. The median cumulative dose of mitoxantrone was 93 mg/m2 (range, 25-205) and the maximum single dose was 39 mg/m2. Myelosuppression was the dose limiting toxicity. The median duration of granulocyte count < or = 250/microl was 5-7 days. Four patients (22%) had infections that required hospitalization, 3 patients (17%) had cardiac toxicity. One patient (6%) achieved a complete response, and 3 (17%) had a partial response, with an overall response rate of 22.3%. No apparent dose-response relationship was observed in our study. The mitoxantrone dosage recommended for phase II studies is 25 mg/m2 every 3-4 weeks. We conclude that high-dose mitoxantrone therapy for metastatic breast cancer was relatively well tolerated but was not associated with a higher response rate than that of standard dose mitoxantrone.

Adult↗