The measurement of symptoms in children with cancer.

The purpose of this study was to determine symptom prevalence, characteristics, and distress in children with cancer. The Memorial Symptom Assessment Scale (MSAS) 10-18, a 30-item patient-rated instrument adapted from a previously validated adult version, provided multidimensional information about the symptoms experienced by children with cancer. This instrument was administered to 160 children with cancer aged 10-18 (45 inpatients, 115 outpatients). To confirm the instrument's reliability and validity, additional data about symptoms were collected from both the parents and the medical charts, and retesting was performed on a subgroup of inpatients. Patients could easily complete the scale in a mean of 11 minutes. The analyses supported the reliability and validity of the MSAS 10-18 subscale scores as measures of physical, psychological, and global symptom distress, respectively. Symptom prevalence ranged from 49.7% for lack of energy to 6.3% for problems with urination. The mean (+/- SD) number of symptoms per inpatient was 12.7 +/- 4.9 (range, 4-26), significantly more than the mean 6.5 +/- 5.7 (range, 0-28) symptoms per outpatient. Patients who had recently received chemotherapy had significantly more symptoms than patients who had not received chemotherapy for more than 4 months (11.6 +/- 6.0 vs. 5. 2 +/- 5.1), and those patients with solid tumors had significantly more symptoms than patients with either leukemia, lymphoma, or central nervous system malignancies (9.9 +/- 7.0 vs. 6.8 +/- 5.5 vs. 6.8 +/- 5.0 vs. 8.0 +/- 6.1). The most common symptoms (prevalence > 35%) were lack of energy, pain, drowsiness, nausea, cough, lack of appetite, and psychological symptoms (feeling sad, feeling nervous, worrying, feeling irritable). Of the symptoms with prevalence rates > 35%, those that caused high distress in more than one-third of patients were feeling sad, pain, nausea, lack of appetite, and feeling irritable. Subscale scores demonstrated large variability in symptom distress and could identify subgroups with high distress. The prevalence, characteristics, and distress associated with physical and psychological symptoms could be quantified in older children with cancer. The data confirm a high prevalence of symptoms overall and the existence of subgroups with high distress associated with one or multiple symptoms. Symptom distress is relatively higher among inpatients, children with solid tumors, and children who are undergoing antineoplastic treatment. Systematic symptom assessment may be useful in future epidemiological studies of symptoms and in clinical chemotherapeutic trials. Symptom epidemiology may also provide a focus for future clinical trials related to symptom management in children with cancer.

Large cell non-Hodgkin lymphoma of childhood: Analysis of 78 consecutive patients enrolled in 2 consecutive protocols at the Memorial Sloan-Kettering Cancer Center.

BACKGROUND: The authors report a study of pediatric patients with advanced diffuse large cell lymphoma (DLCL) who were treated with 2 consecutive regimens, LSA2-L2 and LSA4, over a 25-year-period at the Memorial Sloan-Kettering Cancer Center. They also describe a comparative analysis of two subgroups retrospectively identified as having CD30 positive (+) anaplastic large cell lymphoma (ALCL) and CD30 negative (-) DLCL. To the authors' knowledge, this study represents the longest follow-up on the largest series of uniformly treated pediatric DLCL patients reported to date. METHODS: A total of 78 consecutive patients were treated for Stage III/IV DLCL. Immunophenotypic data were obtained retrospectively for 52 patients using a panel of monoclonal antibodies against CD30, CD15, CD45, CD45Ro, CD43, epithelial membrane antigen, CD5, BCL-2, cyclin-D, and p53. RESULTS: A disease free survival rate of 72% in patients with advanced stage DLCL using the LSA2-L2 and LSA4 regimens. Of the 78 treated patients, 56 are alive and without evidence of disease with a median follow-up of 120 months (range, 24-312 months). The recurrence rate was significantly higher in the CD30+ ALCL subgroup (33%) than in the CD30- DLCL group (0.04%). Of 52 patients for whom immunophenotypic data were available, 28 had disease of B-cell lineage, 24 had disease of T-cell/null phenotype, 19 were CD30+ (36. 5%), 18 had disease of T-cell phenotype, and 1 had disease of B-cell lineage. CONCLUSIONS: The CD30- DLCL cases mostly were of B-cell lineage, had a small risk of treatment failure, and did not develop a recurrence off therapy. A distinct clinical pattern was identified for the CD30+ ALCL group; although these tumors were of T-cell lineage and had a significantly higher rate of late recurrences (median follow-up of 24 months) they all were salvageable. Based on the findings of the current study, the authors propose that T-cell CD30+ ALCL be addressed in the future according to equal dose intensity regimens in induction therapy, as is done for B-cell lymphomas; prolonged periods of maintenance chemotherapy, as is done for T-cell lymphoblastic lymphomas; and no central nervous system prophylaxis beyond the induction period unless other recognized risk factors are present.

High risk of leukemia after short-term dose-intensive chemotherapy in young patients with solid tumors.

PURPOSE: To help fill the gap in knowledge about the risk of leukemia from repetitive high-dose use of alkylating agents and topoisomerase-II inhibitors in young patients with solid tumors. METHODS: Poor-risk solid tumors were treated with four courses of cyclophosphamide (4,200 mg/m2)/ doxorubicin (75 mg/m2), and three courses of ifosfamide (9,000 mg/m2)/etoposide (500 mg/m2). The cumulative incidence of treatment-related myelodysplasia/ leukemia (t-AML) was calculated using the method of competing risks. The expected number of leukemic events was calculated by applying national incidence rates to person-years classified by age and sex. RESULTS: Among 86 patients (median age, 17 years) monitored for 6 to 88 months (median, 24), five cases of t-AML were detected at 10 to 37 months (median, 17). The expected number of leukemic events in this cohort was .001. Clinical and cytogenetic findings implicated prior alkylator therapy in three cases and prior treatment with topoisomerase-II inhibitors in two. At 40 months, the cumulative incidence of t-AML was 8% (SE 7%). CONCLUSION: Repetitive high-dose use of alkylating agents given with topoisomerase-II inhibitors is strongly leukemogenic, even with modest cumulative doses of each drug. This finding is notable for the following reasons: (1) it undermines predictions that limited use of high-dose chemotherapy might be minimally leukemogenic, and (2) it contrasts strikingly with the previously reported low risk of t-AML following treatment of pediatric solid tumors with chemotherapy lacking the alkylator dose-intensity and prominence of etoposide that are hallmarks of current regimens.

Quality of life and survival: the role of multidimensional symptom assessment.

BACKGROUND: Recent data from clinical trials suggest that quality-of-life (QOL) measurements may independently predict survival. The relation between survival and QOL measurements was tested among 122 inpatients and 96 outpatients with malignancies at one of four sites (colon, breast, ovary, or prostate) who participated in a cross-sectional validation study of the Memorial Symptom Assessment Scale (MSAS), a measure of the frequency of, severity of, and distress caused by physical symptoms. METHODS: The relation between MSAS summary scores and survival was evaluated in a multivariate analysis that adjusted concurrently for other important covariates, such as age, site and extent of disease, inpatient status, Karnofsky performance status (KPS), and other QOL measurements. RESULTS: In the multivariate analysis, extent of disease (P < 0.0001), inpatient status (P=0.014), higher MSAS physical symptom subscale score (P=0.004), and lower KPS score (P=0.009) independently predicted decreased survival. Other QOL measurements did not contribute significantly to the model. CONCLUSIONS: The MSAS physical symptom subscale score significantly predicts survival and adds to the prognostic information provided by KPS and extent of disease. Patients may be under-assessed regarding both the number and the severity of symptoms. Measurements of physical symptoms and related distress offer additional prognostic information concerning the survival of patients with cancer and may account for the predictive value of QOL scores.

Abdominoperineal resection via total mesorectal excision and autonomic nerve preservation for low rectal cancer.

We have examined the results of abdominoperineal resection (APR) for primary cancer of the rectum performed in accordance with the principles of total mesorectal excision (TME) and autonomic nerve preservation (ANP). TME is defined as sharp pelvic dissection under direct vision between the parietal and visceral planes of the pelvic fascia. TME results in the resection of all mesorectal disease with intact, negative lateral or circumferential margins of resection. Statistical analysis was done of survival, local recurrence, and both sexual and urinary functions in a prospective database of consecutive patients. Operative mortality was 2% (3/148) due to cardiac disease. Overall survival was 60%, significantly worse than consecutive patients from the same database who were able to undergo sphincter preservation (81%) (p = 0.0003). Poorer survival was statistically related to the presence of positive lymph nodes (p = 0.0009). Overall, local recurrence rates were 5% (8/148) in patients without distant metastases, and 15% to 21% in patients with positive nodes. Positive lymph nodes, N2 disease, lymphatic vascular invasion, and perineural invasion were independent significant risk factors for local recurrence. Sexual function was preserved in approximately 57% of patients undergoing APR versus 85% of patients undergoing sphincter preservation. No significant urinary morbidity was encountered. Low rectal cancer requiring APR seems to be a disease with more locally advanced disease and adverse pathologic features than are seen with mid-rectal cancers treatable by low anterior resection. APR when performed in accordance with the principles of TME and ANP ensures the greatest likelihood of resecting all regional disease while preserving both sexual and urinary functions. Preoperative combined modality treatment may be warranted in all T3 or greater low rectal cancers.

Immune reconstitution following T-cell depleted bone marrow transplantation: effect of age and posttransplant graft rejection prophylaxis.

Transplantation of T-cell depleted bone marrow has been associated with an increased risk of graft failure, requiring additional immunosuppression to prevent this complication. To determine the effect of graft rejection prophylaxis with posttransplant anti-thymocyte globulin and methylprednisolone on immune reconstitution, the lymphoid phenotype, function, and infectious complications of 170 recipients of a T-cell depleted bone marrow transplantation, 57 of whom received prophylaxis, were analyzed. Neutrophil recovery and normalization of T-cell numbers were more rapid in patients given anti-thymocyte globulin and methylprednisolone. Adults given graft rejection prophylaxis had prolonged inversion of their CD4/CD8 ratio, increased numbers of CD8+ CD11b+, HLA-DR+, CD57+, CD28- T cells, and delayed recovery of T-cell mitogen responses when compared to adults not given ATG and steroids. Even without posttransplant immunosuppression to prevent graft failure, adults experienced delayed recovery of total and CD45RA+ CD4+ cells, prolonged inversion of the CD4/CD8 ratio, and delayed recovery of T-cell mitogen responses when compared to children. During the first posttransplant year, Epstein-Barr Virus-Associated Lymphoproliferative disorders and opportunistic infections were increased in patients given prophylaxis. Patients who developed an opportunistic infection or EBV-LPD had significantly fewer circulating CD4+ T cells than those who did not. This study demonstrates that older age and graft rejection prophylaxis, rather than T-cell depletion alone, are associated with delayed immune reconstitution. In addition, it suggests that CD4 cell counts may be useful in predicting which patients are at increased risk of developing opportunistic infections following successful engraftment.

Detailed quality of life assessment in patients treated with primary radiotherapy for squamous cell cancer of the base of the tongue.

BACKGROUND: This study was conducted to evaluate quality of life in patients treated with primary radiotherapy (RT) for cancer of the base of tongue. METHODS: From 1981 to 1990, 36 patients with primary squamous cell cancer of the base of tongue were managed with primary radiotherapy. Ages ranged from 35 to 71 years (median, 58 years), T Stage was: T1, n = 11; T2, n = 14; T3, n = 10; T4, n = 1. Thirty-one patients (86%) had palpable cervical lymph node metastases at initial examination (N1, n = 16; N2, n = 11; N3, n = 4). Patients received external beam RT to their primary site and necks, followed by a brachytherapy boost to the tongue. Those with neck nodes also had a neck dissection. The median follow-up is 5 years (minimum, 3 years). Actuarial 5-year local control was 85%; regional control was 96%; distant metastases-free survival was 87.5%; and overall survival, 85%. Twenty-nine of the 30 long-term survivors completed (1) Memorial Symptom Assessment Scale (MSAS), (2) Functional Assessment of Cancer Therapy (FACT), (3) Performance Status Scale for Head and Neck Cancer (PSS), and (4) a sociodemographic and economic questionnaire. At the time of cancer diagnosis, 62% were employed full-time, and 21% were employed part-time; 83% were earning > $20,000/year, and 59% were earning > $60,000/year. RESULTS: At follow-up, annual incomes were similar to those at initial examination. Of those who had been working full-time, 72% were still in full-time work, and of those who had been working part-time, 83% were still in part-time work. Average PSS scores were 90 for eating in public, 96 for understandability of speech, and 68 for normalcy of diet. On the MSAS, the following symptoms had prevalence: > 30% xerostomia, difficulty swallowing, decreased energy, pain, worrying, insomnia, cough, drowsy, change in taste, and irritability. Scores on the FACT exceeded published values collected for a mixed cancer population. CONCLUSIONS: The overwhelming majority of patients achieved excellent functional status and quality of life and could maintain their prediagnosis earning potential and employment status after primary radiation for advanced base of tongue cancer.

All-trans retinoic acid significantly increases 5-year survival in patients with acute promyelocytic leukemia: long-term follow-up of the New York study.

All-trans retinoic acid (ATRA) induces a high incidence of complete remission (CR) in patients with acute promyelocytic leukemia (APL); however, the magnitude of this agent's contribution to increased rates of cure of this disease has not yet been established. From 1990 to 1995 we used RA as remission induction therapy in 103 APL patients (73 newly diagnosed and 30 previously treated) who were retinoid-naive and were treated on the basis of initial morphology. Patients whose diagnosis was changed on the basis of the results of molecular testing (n = 13) were withdrawn from RA treatment and given chemotherapy alone. After achieving a CR, previously untreated patients received several cycles of consolidation chemotherapy, usually with idarubicin and cytosine arabinoside. Among individuals whose diagnosis was molecularly confirmed, 54 of 65 new patients (83%) and 25 of 30 previously treated patients (83%) achieved a CR. All induction failures in molecularly diagnosed cases were due either to early death or to premature withdrawal. Median disease-free and overall survival rates recorded for all newly diagnosed patients are currently > 40+ and > 43+ months, respectively. We subsequently examined a subset of 27 newly diagnosed patients treated during the first 2 years of this program whose actual median follow-up period is now > 5 years. Median disease-free and overall survival rates recorded for this group are > 57+ and > 58+ months, respectively; 56% of these patients are alive in first remission. These results significantly exceed those achieved using chemotherapy alone in a historical control group of 80 patients consecutively treated at this center from 1975 to 1990, whose median disease-free and overall survival rates were 11 and 19 months, respectively; only 22% of these patients were alive in first remission at 5 years. Although a high proportion of previously treated patients also achieved a CR after RA treatment, median disease-free and overall survival rates noted for that group were markedly lower (i.e., 7.5 and 10.9 months, respectively). Thus, data from patients whose median follow-up period is now > 5 years have confirmed earlier projections and indicate that the use of RA for remission induction yields an approximately 2.5-fold increase in the proportion of patients who have presumably been cured of this disease.

Total mesorectal excision in the operative treatment of carcinoma of the rectum.

BACKGROUND: Total mesorectal excision (TME) is reported to reduce local recurrence and improve survival rates in patients with carcinoma of the rectum. STUDY DESIGN: Two hundred forty-six consecutive patients with Dukes' B (T3, N0, M0) and C (T(any), N1-2, M0) primary rectal carcinomas underwent operation according to the principle of TME. Kaplan-Meier estimates of survival and pelvic recurrence rates were calculated from a database of patients followed prospectively. RESULTS: The operative mortality rate was 0.8 percent (two of 246). The Kaplan-Meier five-year survival rate for patients with stages B and C was 74.2 percent; for patients with stage T3, N0, M0, 86.7 percent; for patients with stage T(any), N1-2, M0, 64.0 percent; and for patients with substage T3, N1-2, M0, 68.0 percent. Pelvic recurrences were observed in a total of 18 patients (7.3 percent) with or without metastases. In the 246 patients with Dukes' stages B and C, pelvic recurrence rates were 4.0 and 8.1 percent, respectively, in the presence or absence of distant metastases, and 3.0 and 5.8 percent, respectively, in the absence of distant spread. Statistically significant risk factors for pelvic recurrence were N2 disease and perineural invasion. Adjuvant radiation therapy was of no statistical benefit in preventing local recurrences. CONCLUSIONS: Total mesorectal excision cures carcinoma of the rectum and provides excellent local control through resection of the entire unit of regional spread that is excised, intact and with negative circumferential margins. Total mesorectal excision is compatible with autonomic nerve preservation and with sphincter preservation. The current role of combined modality adjuvant therapy, which is standard therapy following conventional surgery, should be reconsidered in patients who have undergone resection in accordance with TME.

Screening for lung cancer. The Mayo Lung Project revisited.

BACKGROUND: The Mayo Lung Project (MLP) reported lung cancer incidence and mortality in a population offered chest radiographs and sputum cytologic screening examinations every 4 months and a population offered only the Mayo Clinic advice to undergo annual examination. No mortality benefit attributable to screening was observed after 6 years of observation and at least 1 year of follow-up. METHODS: The authors describe a simulation study designed to estimate from Mayo data the parameters in a mathematical model of the natural history of lung cancer and to estimate the potential benefit associated with periodic screening of high-risk people starting at 45 years of age. RESULTS: It was found that the mean duration of Stage I non-small cell lung cancer is at least 4 years and that rates of Stage I detectability and curability are less than 25% and 35%, respectively. CONCLUSIONS: A trial of the magnitude, duration, and contamination of the MLP would have a less than 20% probability of showing significant benefit from screening; however, long-term annual screening might result in a modest decrease in lung cancer mortality, ranging from 0% to 13%. A greater benefit would accrue from improved detection and treatment.