Stephen L. George

Hyperfractionated Irradiation with or without Concurrent Chemotherapy for Locally Advanced Head and Neck Cancer

BACKGROUND Radiotherapy is often the primary treatment for advanced head and neck cancer, but the rates of locoregional recurrence are high and survival is poor. We investigated whether hyperfractionated irradiation plus concurrent chemotherapy (combined treatment) is superior to hyperfractionated irradiation alone. METHODS Patients with advanced head and neck cancer who were treated only with hyperfractionated irradiation received 125 cGy twice daily, for a total of 7500 cGy. Patients in the combined-treatment group received 125 cGy twice daily, for a total of 7000 cGy, and five days of treatment with 12 mg of cisplatin per square meter of body-surface area per day and 600 mg of fluorouracil per square meter per day during weeks 1 and 6 of irradiation. Two cycles of cisplatin and fluorouracil were given to most patients after the completion of radiotherapy. RESULTS Of 122 patients who underwent randomization, 116 were included in the analysis. Most patients in both treatment groups had unresectable disease. The median follow-up was 41 months (range, 19 to 86). At three years the rate of overall survival was 55 percent in the combined-therapy group and 34 percent in the hyperfractionation group (P=0.07). The relapse-free survival rate was higher in the combined-treatment group (61 percent vs. 41 percent, P=0.08). The rate of locoregional control of disease at three years was 70 percent in the combined-treatment group and 44 percent in the hyperfractionation group (P=0.01). Confluent mucositis developed in 77 percent and 75 percent of the two groups, respectively. Severe complications occurred in three patients in the hyperfractionation group and five patients in the combined-treatment group. CONCLUSIONS Combined treatment for advanced head and neck cancer is more efficacious and not more toxic than hyperfractionated irradiation alone.

Successful chemoprophylaxis for Pneumocystis carinii pneumonitis.

In a randomized, double-blind, placebocontrolled study to evaluate the efficacy of trimethoprim-sulfamethoxazole for the prevention of Pneumocystis carinii pneumonia, we studied 160 patients with cancer who were at high risk for this pneumonia over a two-year period. Seventeen of the 80 patients receiving a placebo acquired P. carinii pneumonitis, whereas none of the 80 given 150 mg of trimethoprim and 750 mg of sulfamethoxazole per square meter per day had the infection P less than 0.01). Bacterial sepsis, pneumonia other than that caused by P. carinii, acute otitis media, upper-respiratory-tract infections, sinusitis and cellulitis occurred less frequently in recipients of the drug than in the placebo group (P less than 0.01 in each case). Oral candidiasis was the only adverse effect ecountered from trimethoprim-sulfamethoxazole administration. The study shows the combination to be highly effective in the prevention of P. carinii pneumonitis.

Granulocyte–Macrophage Colony-Stimulating Factor after Initial Chemotherapy for Elderly Patients with Primary Acute Myelogenous Leukemia

Background Elderly patients with primary acute myelogenous leukemia (AML) are less likely to enter remission than younger adults, in part because of a higher mortality rate related to severe myelosuppression. Granulocyte–macrophage colony-stimulating factor (GM-CSF) has been shown to shorten the duration of neutropenia and decrease infectious complications when administered after chemotherapy to patients with lymphomas and solid tumors. Methods We randomly assigned 388 patients 60 years of age or older who had newly diagnosed primary AML to receive placebo or GM-CSF (5 μg per kilogram of body weight per day intravenously) in a double-blind manner, beginning the day after the completion of three days of daunorubicin and seven days of cytarabine. If leukemic cells persisted in the marrow three weeks after the initiation of chemotherapy, further daunorubicin (two days) and cytarabine (five days) were administered. GM-CSF or placebo was given daily until the neutrophil count was at least 1000 per cubic millim...

Surgery for colorectal cancer in elderly patients: a systematic review

BACKGROUND The effectiveness of surgery for colorectal cancer depends on it being carried out safely, which allows most patients to return to productive lives, with an improved postoperative life expectancy, or at least one that is not diminished by the surgery. Because colorectal cancer is a major cause of morbidity and mortality in elderly people, we have examined how the outcomes of surgery in elderly patients differ from those in younger patients. METHODS We did a systematic review of published and aggregate data provided by investigators. Studies were identified by computerised and manual searches of published and unpublished reports, scanning references, and contacting investigators. Within each study, outcomes for patients aged 65-74 years, 75-84 years, and 85+ years were expressed in relation to those aged less than 65 years. FINDINGS From 28 independent studies, and a total of 34,194 patients, we found that elderly patients had an increased frequency of comorbid conditions, were more likely to present with later-stage disease and undergo emergency surgery, and less likely to have curative surgery than younger patients. The incidence of postoperative morbidity and mortality increased progressively with advancing age. Overall survival was reduced in elderly patients, but for cancer specific survival age-related differences were much less striking. INTERPRETATION The relation between age and outcomes from colorectal cancer surgery is complex and may be confounded by differences in stage at presentation, tumour site, pre-existing comorbidities, and type of treatment received. However, selected elderly patients benefit from surgery since a large proportion survive for 2 or more years, irrespective of their age.

Secondary Acute Myeloid Leukemia in Children Treated for Acute Lymphoid Leukemia

We studied the risk of the development of acute myeloid leukemia (AML) during initial remission in 733 consecutive children with acute lymphoid leukemia (ALL) who were treated with intensive chemotherapy. This complication was identified according to standard morphologic and cytochemical criteria in 13 patients 1.2 to 6 years (median, 3.0) after the diagnosis of ALL. At three years of follow-up, the cumulative risk of secondary AML during the first bone marrow remission was 1.6 percent (95 percent confidence limits, 0.7 and 3.5 percent); at six years, it was 4.7 percent (2 and 10 percent). The development of secondary AML was much more likely among patients with a T-cell than a non-T-cell immunophenotype (cumulative risk, 19.1 percent [6 and 47 percent] at six years). Sequential cytogenetic studies in 10 patients revealed entirely different karyotypes in 9, suggesting the induction of a second neoplasm. In eight of these patients, the blast cells had abnormalities of the 11q23 chromosomal region, which has been associated with malignant transformation of a pluripotential stem cell. There was no evidence of loss of DNA from chromosome 5 or 7, a karyotypic change commonly observed in cases of AML secondary to treatment with alkylating agents, irradiation, or both. We conclude that there is a substantial risk of AML in patients who receive intensive treatment for ALL, especially in those with a T-cell immunophenotype, and that 11q23 chromosomal abnormalities may be important in the pathogenesis of this complication.

Planning the size and duration of a clinical trial studying the time to some critical event

Abstract This paper considers the dual problem of planning the size (i.e. the required number of patients) and the required duration of trial for a fixed sample size clinical trial comparing the length of time to some critical event (such as death or relapse) in two treatment regimens (‘treatment’ and ‘control’). The required number of patients is derived from the exact distribution of the usual test statistic and a comparison is made with two normal approximations. The required duration of the trial is derived assuming that the patient entry into the study is a process in continuous time, and that the time to failure is exponential. This approach may be considered to be a generalization of the approach in [4]. The principal results may be summarized as follows: 1. (1) The required number of patients (2d), based on the exact distribution of the test statistic, is uniformly lower than the required number, based on the approach which assumes that the difference in means is approximately normal. However, the approximation d = [ 2(k α + k β ) 2 ( ln Δ) 2 ] , based on the logarithmic transformation is, found to be quite accurate. 2. (2) A solution to the problem of finding the minimum required duration of study is found by expressing the accumulated number of patient-years in the time interval (0, t) as a filtered Poisson process and may be considered to be the analogue of the discrete patient entry model in [4]. For a given formulation, the required duration of study is found by solving a non-linear equation by iterative techniques. However, a very good lower bound is T ≈ 2d a , the expected number of years necessary to enter the required 2d patients. 3. (3) The implicit assumption in [4] that the optimal duration of study requires no follow-up time is given a theoretical justification by proving that it follows directly from the approach adopted in this paper. 4. (4) One table is given from which the required number of patients may be read and another table is given, which illustrates the results obtained for the required duration of study. Computer programs that compute these quantities for any given specification are available. 5. (5) Although perhaps preferable on theoretical grounds, the required duration of study T, as determined by the methods of this paper, is quite similar to the T determined by the methods in [4]. However, in several instances, the T determined in [4] is even less than the expected time necessary to enter the required 2d patients. Also, every T in [4] that satisfied the lower bound for the required T derived in this paper was larger than necessary to achieve the desired power.

Sensitivity of hyperthermia trial outcomes to temperature and time: Implications for thermal goals of treatment

PURPOSE In previous work we have found that the cumulative minutes of treatment for which 90% of measured intratumoral temperatures (T90) exceeded 39.5 degrees C was highly associated with complete response of superficial tumors. Similarly, the cumulative time for which 50% of intratumoral temperatures (T50) exceeded 41.5 degrees C was highly associated with the presence of > 80% necrosis in soft tissue sarcomas resected after radiotherapy and hyperthermia. In the present work we have calculated the time for isoeffective treatments with T90 = 43 degrees C and T50 = 43 degrees C, respectively, using published thermal isoeffective dose formulae. The purpose of these calculations was to determine the sensitivity of treatment outcome to variations in thermal isoeffective dose. METHODS AND MATERIALS The basis for the calculations were the thermal parameters and treatment outcomes in three patient populations: 44 patients with moderate or high grade soft tissue sarcoma treated preoperatively with hyperthermia and radiation; 105 patients with superficial tumors treated with hyperthermia and radiation, and 59 patients with deep tumors treated with hyperthermia and radiation. RESULTS The thermal dose values calculated are strongly associated with outcome in multivariate logistic regression analysis. Simple dose-response equations result from the analysis, and we use these equations to assess the sensitivity of outcome upon variations in thermal dose. This information, in turn, allows us to estimate the number of patients required in Phase II and III trials of hyperthermia and radiation therapy. CONCLUSIONS For regimens of 5 to 10 hyperthermia treatments, improvements in median T90 (superficial tumors) and T50 (deep tumors) parameters by 1.2-1.5 degrees C could result in response rates high enough (compared to radiotherapy alone) to justify Phase III trials. A similar improvement in response rates would require an increase in overall duration of treatment by a factor of 3 to 5. This would be difficult to achieve while also avoiding thermal tolerance induction. Achieving these temperature goals may be possible with improvements in hyperthermia technology. Alternatively, there may be ways to increase the sensitivity of cells to temperatures that can be achieved currently, such as pH reduction or chemosensitization.

A Screening Questionnaire for mother-infant bonding disorders

SummaryBackground: There is a need in primary care for an easily administered instrument to give early indications of disorders in mother-infant relationships. Methods: An 84 item questionnaire was administered to 104 subjects, including normal mothers, depressed mothers with a normal mother-infant relationship and mothers with bonding disorders. A principle component analysis was used to select items for scale construction. Scale scores were compared with interview data. Reliability, sensitivity and specificity of the scales were measured. Findings: 4 factors of clinical relevance were obtained and used to construct 4 scales. The questionnaire was reduced to 25 questions. Scale 1 (impaired bonding) had a sensitivity of 0.93 in detecting mothers with bonding disorder. Scale 2 (rejection and anger) specifically identified mothers with severe disorders. Scale 3 may be useful in anxious mothers. Scale 4 signalled the presence of incipient abuse, requiring urgent intervention. Interpretation: This questionnaire can be used, with the Edinburgh Postnatal Depression Scale, by midwives and health visitors, for the early diagnosis of mother-infant bonding disorders.

Development of a Disease Specific Quality of Life (QoL) Questionnaire Module to Supplement the EORTC Core Cancer QoL Questionnaire, the QLQ-C30 in Patients with Pancreatic Cancer

There is overwhelming consensus that quality of life assessment is urgently required in pancreatic cancer, yet little research has been conducted. We report on the development of a disease specific questionnaire module to supplement the EORTC core cancer module, the QLQ-C30 in patients with pancreatic cancer, using EORTC quality of life study group guidelines for module development. Relevant QoL issues were generated from literature searches and interviews with health professionals and patients with pancreatic cancer. Issues were constructed into items and provisionally translated. The provisional module was pretested in patients in 8 European centres. The resulting module the QLQ-PAN26 includes 26 items related to disease symptoms, treatment side-effects and emotional issues specific to pancreatic cancer. This should ensure that the module will be sensitive to assess the small but important disease and treatment related QoL changes in pancreatic cancer. The use of the QLQ-C30 and QLQ-PAN26 will provide a comprehensive system of QoL assessment in international trials of pancreatic cancer.

Dose Escalation Studies of Cytarabine, Daunorubicin, and Etoposide With and Without Multidrug Resistance Modulation With PSC-833 in Untreated Adults With Acute Myeloid Leukemia Younger Than 60 Years: Final Induction Results of Cancer and Leukemia Group B Study 9621

PURPOSE P-glycoprotein (Pgp) is strongly inhibited by PSC-833. A chemotherapy dose-escalation study was performed with PSC-833 in patients younger than 60 years with untreated acute myeloid leukemia. Clinical rather than pharmacokinetic end points were used to develop two induction therapies containing drugs susceptible to Pgp-mediated efflux and associated with comparable toxicities at the maximum-tolerated doses. PATIENTS AND METHODS A total of 410 patients were enrolled. Fifteen induction regimens containing variable doses of daunorubicin (DNR) and etoposide (ETOP) and fixed doses of cytarabine were evaluated with (ADEP) or without (ADE) a fixed dose of PSC-833. RESULTS Doses selected for phase III testing were DNR 90 mg/m(2) and ETOP 100 mg/m(2) in ADE, and DNR and ETOP each 40 mg/m(2) in ADEP. Intolerable mucosal toxicity occurred at higher doses of ADEP. Although the design of this study precludes direct comparisons, there was an apparent advantage for receiving ADEP with respect to disease-free and overall survival in patients < or = 45 years old, despite the significantly lower doses of DNR and ETOP given in ADEP compared with ADE. CONCLUSION A large clinical data set was used to develop induction regimens containing two drugs susceptible to Pgp-mediated efflux, with and without an inhibitor of Pgp function. The chosen doses have comparable antileukemia activity and toxicity, making them suitable for use in a phase III comparative study of induction chemotherapy for patients with acute myeloid leukemia younger than 60 years. That trial will also clarify whether patients < or = 45 years old are especially likely to benefit from Pgp inhibition during induction therapy.