Phase I/II trial of dose-reduced capecitabine in elderly patients with advanced colorectal cancer.

BACKGROUND: Combination chemotherapy is associated with improved outcomes in trials of selected fit patients with advanced colorectal cancer (acrc). For older or less-fit patients, combination chemotherapy is associated with greater toxicity and less benefit. Capecitabine monotherapy is a reasonable option for those patients, but the optimal dose remains controversial. METHODS: A multicentre phase i/ii trial of reduced-dose capecitabine (2000 mg/m2, days 1-14 every 21 days) was conducted in 221 patients representing one or more of the following subsets: age greater than 65 years (n = 167), Eastern Cooperative Oncology Group (ecog) performance status of 1 or greater (n = 139), elevated lactate dehydrogenase (ldh) (n = 105), or prior pelvic radiation (n = 54). Based on phase i results, patients with prior pelvic radiation received capecitabine 750 mg/m2 twice daily. The goal was to ascertain efficacy in a design that was unlikely to cause high levels of toxicity. RESULTS: Median age in the patient cohort was 72 years. A median of 5 and a mean of 8 capecitabine cycles were given (range: 0-50 cycles). Grade 3 or 4 toxicity occurred in 25% of patients during the first 3 cycles (8.1% hand-foot syndrome, 7.7% diarrhea). The response rate was 13.6%, with a 69.7% disease control rate. Median progression-free survival (pfs) was 5.6 months. Post progression, 56 patients received further capecitabine monotherapy (median of 4 additional cycles). Median overall survival duration for the patients was 14.3 months. Median survival was significantly higher for those who, at baseline, had an ecog performance status of 0 (compared with 1 or more) and normal ldh (compared with elevated ldh). CONCLUSIONS: Toxicity is less with dose-reduced capecitabine than with historical full-dose capecitabine, with only a small trade-off in efficacy, seen as a lower objective response rate. The improved tolerability could lead to an increased number of cycles of therapy, and pfs appears to be consistently higher at the lower dose. Those observations should, in the absence of a head-to-head clinical trial, be viewed as compelling evidence that 1000 mg/m2, or even 750 mg/m2, twice daily is an appropriate dose in elderly or frail patients with acrc.

Clinical, radiological, histological and molecular characteristics of paediatric epithelioid glioblastoma.

AIMS: A few case series in adults have described the characteristics of epithelioid glioblastoma (e-GB), one of the rarest variants of this cancer. We evaluated clinical, radiological, histological and molecular characteristics in the largest series to date of paediatric e-GB. METHODS: Review of clinical characteristics and therapy, imaging studies and histology was performed in patients younger than 22 years with e-GB seen at our institution over 15 years. Sequencing of hotspot mutations and fluorescence in situ hybridization of relevant genes were undertaken. RESULTS: Median age at diagnosis of six patients was 7.6 years. Tumours originated in the cerebral cortex (n = 2) or diencephalon (n = 4). Three patients presented with acute, massive haemorrhage and three had leptomeningeal dissemination at diagnosis. Paediatric e-GB had the typical histological characteristics seen in adult tumours. Universal immunoreactivity for INI1 and lack of diverse protein expression were seen in all cases. One tumour had a chromosome 22q loss. Three tumours (50%) harboured a BRAF: p.V600E. One thalamic tumour had an H3F3A p.K27M. All patients received radiation therapy with (n = 3) or without chemotherapy (n = 3). All patients experienced tumour progression with a median survival of 169 days. One patient with nonmetastatic disease had early leptomeningeal progression. Two patients had symptomatic tumour spread outside the central nervous system (CNS) through a ventriculoperitoneal shunt. One additional patient had widespread metastases outside the CNS identified at autopsy. CONCLUSIONS: Paediatric e-GBs are rare cancers with an aggressive behaviour that share histological and genetic characteristics with their adult counterparts. BRAF inhibition is a potential treatment for these tumours.

Anatomic Neuroimaging Characteristics of Posterior Fossa Type A Ependymoma Subgroups.

BACKGROUND AND PURPOSE: Posterior fossa type A (PFA) ependymomas have 2 molecular subgroups (PFA-1 and PFA-2) and 9 subtypes. Gene expression profiling suggests that PFA-1 and PFA-2 tumors have distinct developmental origins at different rostrocaudal levels of the brainstem. We, therefore, tested the hypothesis that PFA-1 and PFA-2 ependymomas have different anatomic MR imaging characteristics at presentation. MATERIALS AND METHODS: Two neuroradiologists reviewed the preoperative MR imaging examinations of 122 patients with PFA ependymomas and identified several anatomic characteristics, including extension through the fourth ventricular foramina and encasement of major arteries and tumor type (midfloor, roof, or lateral). Deoxyribonucleic acid methylation profiling assigned ependymomas to PFA-1 or PFA-2. Information on PFA subtype from an earlier study was also available for a subset of tumors. Associations between imaging variables and subgroup or subtype were evaluated. RESULTS: No anatomic imaging variable was significantly associated with the PFA subgroup, but 5 PFA-2c subtype ependymomas in the cohort had a more circumscribed appearance and showed less tendency to extend through the fourth ventricular foramina or encase blood vessels, compared with other PFA subtypes. CONCLUSIONS: PFA-1 and PFA-2 ependymomas did not have different anatomic MR imaging characteristics, and these results do not support the hypothesis that they have distinct anatomic origins. PFA-2c ependymomas appear to have a more anatomically circumscribed MR imaging appearance than the other PFA subtypes; however, this needs to be confirmed in a larger study.

Is it an E lesion or stage IV? An unsettled issue in Hodgkin's disease staging.

To determine whether recognized experts in the area of Hodgkin's disease would agree on the determination of stage when various types of extranodal disease are present, we asked senior investigators at 15 major centers to assign a stage to four different patients. In general, these experts agreed in cases representing the extremes of difference between localized and distant extranodal disease. However, when presented with patients with nearby but not contiguous extranodal disease of lung or bone, one half of the experts classified this as an E lesion and one half as stage IV. This disagreement in stage assignment has implications not only for individual patient treatment, but also for reporting of clinical trials. Over-assignment of stage IV has the practical result of "improving" the results of treatment of both low stage (by removing higher risk patients) and advanced stage patients (by including better risk patients). Papers reporting the results of treatment of Hodgkin's disease should include information concerning how patients with extranodal disease were separated into those with E lesions and those with stage IV disease.

MOPP/ABV hybrid program: combination chemotherapy based on early introduction of seven effective drugs for advanced Hodgkin's disease.

Seventy patients with advanced Hodgkin's disease, 54 with new disease, and 16 in first relapse after initial radiotherapy, have been treated with a seven-drug, 8-month program: MOPP (nitrogen mustard, vincristine, procarbazine, prednisone)/ABV (Adriamycin [Adria Laboratories of Canada, Mississauga, Ontario], bleomycin, vinblastine) hybrid. A single involved field of radiotherapy was given to selected partial responders after 6 months of chemotherapy. Forty-six of the 52 (88%) evaluable new-disease patients and 14 of the 16 (87%) evaluable patients with relapsing disease reached a complete response. The actuarial overall survival at 49 months for the patients with new disease was 90% (median follow-up from diagnosis was 27 months). For the patients with relapsing disease, the actuarial survival at 54 months was 79% (median follow-up from diagnosis was 27 months). The actuarial relapse-free survival at 41 months for complete responders was 93% for patients with new disease (median follow-up after treatment was 20 months) and 80% for those with relapsing disease (median follow-up after treatment was 27 months). Toxicity was moderate, with two treatment-related deaths and eight episodes of serious infection. These results compare favorably with the best results reported in the literature. Furthermore, they were achieved with a moderate level of toxicity, high drug delivery rates, and a relatively short duration of treatment. The efficacy and toxicity data of the MOPP/ABV hybrid program will now be evaluated in a prospectively randomized multicenter study.

Testicular lymphoma: improved outcome with early brief chemotherapy.

We investigated the impact of early brief chemotherapy on the natural history of primary testicular lymphoma. We compared the outcome for patients seen before 1980--a group primarily managed with orchiectomy and regional radiation--with those seen from 1980 to 1986--a prospectively and consecutively gathered group who were offered brief chemotherapy in addition to standard orchiectomy and irradiation. The historical and study groups were similar in clinical characteristics. However, the chemotherapy group had a better relapse-free survival, 93% v 50% (P less than .02), and overall survival, 93% v 50% (P less than .02). With a median follow-up of 44 months in the chemotherapy group, it is clear that the use of early, brief chemotherapy strongly alters the natural history of testicular lymphoma by preventing relapses, the large majority of which occur early after regional therapy. We conclude that a program incorporating orchiectomy, early brief chemotherapy, and involved-field radiation therapy confers the following benefits on patients with primary testicular lymphoma: (1) laparotomy is not needed for staging; (2) relapses, including those in the opposite testicle and CNS, are largely prevented; and (3) toxicity can be kept to a modest level acceptable in elderly patients.

Low-dose ACOP-B and VABE: weekly chemotherapy for elderly patients with advanced-stage diffuse large-cell lymphoma.

Elderly patients with advanced-stage diffuse large-cell lymphomas (DLCLs) are either excluded from or under-represented in most clinical trials of combination chemotherapy regimens because they tolerate treatment poorly and usually have a worse outcome. We report two brief weekly chemotherapy regimens designed specifically for elderly patients. Eligible patients were aged 65 to 85 years, had advanced-stage DLCL (diffuse mixed, diffuse large-cleaved or noncleaved, immunoblastic, or diffuse large-cell not otherwise specified). Advanced stage was defined as Ann Arbor stage III or IV or stage I or II with a mass greater than 10 cm or B symptoms. Low-dose doxorubicin, cyclophosphamide, vincristine, bleomycin, and prednisone (LD-ACOP-B) accrued 40 patients between March 1983 and September 1985; 65% achieved a complete response (CR), there were two toxic deaths, the actuarial failure-free survival (FFS) is 19%, disease-specific survival (DSS) 30%, and overall survival (OS) 28%, with a maximum follow-up of 6 years. The regimen of etoposide, doxorubicin, vincristine, bleomycin, and prednisone (VABE) accrued 32 patients between July 1985 and June 1987; 63% achieved a CR, there were two toxic deaths, and the actuarial FFS is 34%, DSS 45%, and OS 36%, with a maximum follow-up of 4 years. There is no difference in FFS, DSS, or OS between these two regimens. VABE caused more myelosuppression and infectious complications, although the toxic death rates were similar. We prefer LD-ACOP-B because follow-up is longer and toxicity is less.

Late relapse in patients with diffuse large-cell lymphoma treated with MACOP-B.

PURPOSE: To examine the clinical course of patients who experienced a late relapse after initial curative chemotherapy for advanced-stage diffuse large-cell lymphoma. PATIENTS AND METHODS: Between April 1981 and June 1986, 127 patients with de novo advanced-stage diffuse large-cell lymphoma were treated with a 12-week chemotherapy program (methotrexate, doxorubicin, cyclophosphamide, vincristine, prednisone, and bleomycin [MACOP-B]). The overall survival rate at 10 years is 52%. One hundred six patients (83%) entered a complete remission (CR) and 43 of them relapsed. With a median follow-up duration of 146 months, 26 patients relapsed early and 17 relapsed late, ie, after a continuous CR (cCR) of greater than 24 months. All late relapses occurred in patients with B-cell lymphoma. RESULTS: After 24 months from diagnosis, the rate of late relapse averaged 2.2% per year and reached a projected 22% actuarial risk of late relapse after 10 years. The median time to late relapse was 69 months (range, 38 to 141). Ten patients relapsed with aggressive histologic subtypes and were treated with curative intent using anthracycline-based chemotherapy. Four remain in second CR, one is alive with disease, and five died of disease or while on treatment. The 6-year overall survival rate from the time of relapse (SFR) for these 10 patients is 42%. Six patients relapsed with low-grade follicular lymphoma. These patients received various treatments intended to control, but not necessarily cure disease. One is in second CR, one is alive with disease, and four died of disease or while on treatment. The 6-year overall SFR rate for these six patients is 40%. bcl-2 translocation and Bcl-2 protein expression at diagnosis did not predict for the type of late relapse. One patient did not undergo repeat biopsy at relapse and died 9 months later despite aggressive therapy. CONCLUSION: Curative therapy should be attempted in patients who relapse late with aggressive-histology lymphoma and those who relapse with follicular histology may benefit from palliative treatment. The behavior of late-relapse lymphoma is similar to de novo lymphoma, with outcome dictated by the histologic subtype at relapse.

Prognostic variables in patients with diffuse large-cell lymphoma treated with MACOP-B.

One hundred twenty-six patients with diffuse large-cell lymphoma were treated with methotrexate with leucovorin, doxorubicin, cyclophosphamide, vincristine, prednisone, and bleomycin (MACOP-B) between April 1981 and June 1986. Univariate and multivariate analyses were performed using overall survival as of September 1989 as the end point. Four independent negative predictors of survival were identified: presence of B symptoms; more than two involved lymph node sites; more than one extranodal site (variables related to tumor burden), and age older than 60, a variable related to the patient's ability to tolerate treatment. Each variable contributed the same relative risk of dying and, accordingly, this simple predictive formula was developed empirically: (4-N) x 30 = the approximate percentage of chance of survival at 5 years. "N" is the number of predictive variables present. The same four predictors were also found to be significant by multivariate analysis when only those patients achieving a complete response were analyzed.

In search of an optimal regimen for elderly patients with advanced-stage diffuse large-cell lymphoma: results of a phase II study of P/DOCE chemotherapy.

PURPOSE: The results of a prospective, phase II trial of an 8-week treatment program consisting of epirubicin or doxorubicin, vincristine, cyclophosphamide, etoposide, and prednisone (P/DOCE) for elderly patients with advanced large-cell lymphoma are reported and compared with previous phase II studies conducted in similar patients at the same institution. PATIENTS AND METHODS: Between March 1988 and September 1991, 63 previously untreated patients aged 65 to 85 years (median, 75) with advanced-stage diffuse large-cell lymphoma, defined as Ann Arbor stage III or IV or stage I or II with B symptoms or bulky disease, were enrolled on a brief, 8-week protocol consisting of five outpatient chemotherapy treatments. RESULTS: The complete response (CR) rate was 62%. The treatment-related mortality rate was 8%, the actuarial 4-year failure-free survival (FFS) rate was 41%, and the overall survival (OS) rate was 45%. These results were compared with two earlier, 12-week protocols, low-dose doxorubicin, cyclophosphamide, vincristine, bleomycin, and prednisone (LD-ACOB-B) and etoposide, doxorubicin, bleomycin, and prednisone (VABE), performed at the same center. There was no difference in outcome among the three regimens. If all 133 patients treated on any one of these three specially designed regimen for elderly patients are combined, the projected 5-year OS rate is 38%. CONCLUSION: The 8-week P/DOCE chemotherapy regimen is equal in efficacy and similar in toxicity to 3 months of chemotherapy administered on a weekly schedule and similar to the results reported in the literature for longer, anthracycline-based chemotherapy treatments. There does not appear to be any improvement in outcome from more protracted treatment programs compared with the 8-week P/DOCE protocol.