Kenneth Stanley

Impact of irradiation technique and tumor extent in tumor control and survival of patients with unresectable non-oat cell carcinoma of the lung. Report by the radiation therapy oncology group

An analysis of intrathoracic tumor control was carried out in 378 patients with histologically proven unresectable non‐oat cell carcinoma of the lung treated with definitive radiotherapy, randomized to one of four treatment regimens: 4000 rad split course (2000 rad in five fractions in one week, two weeks rest and additional 2000 rad in five fractions in one week) or 4000, 5000 or 6000 rad continuous courses, five fractions per week. Between 85 and 101 patients are analyzed in each treatment group. The complete plus partial response was 46–51% in the 4000 rad groups in contrast to 61–66% in the 5000 to 6000 rad groups (P = 0.008). The overall two year survival rate was 10–11% for the patients treated with 4000 rad split or continuous course, and 19% in the patients treated with 5000 to 6000 rad. The complete response in patients with tumors 3 cm or less in diameter was 16% when treated with 4000 rad in contrast to 20–31% in those treated with 5000–6000 rad. In the patients with lesions from 4 to 6 cm in diameter, complete and partial tumor regression was 48% in the 4000 rad group, 67% with 5000 rad, and 71% with 6000 rad. These differences are statistically significant (P = 0.033). Intrathoracic recurrences were correlated with the dose of irradiation given: 52% with 4000 rad, 41% with 5000 rad, and 30% with 6000 rad (P = 0.006). An analysis of protocol compliance was carried out in 301 patients with available data, irradiated at the primary site according to protocol instruction (none or minor variation). Median survival for patients treated to the ipsilateral or contralateral hilar lymph nodes according to the protocol varied from 46–50 weeks in contrast to 20–30 weeks for those with major protocol variations in nodal irradiation. Variations in ipsilateral and contralateral nodal irradiation correlated with significant reductions in tumor control (P = 0.02 and P = 0.009, respectively). In addition to patient and tumor characteristics, the technical factors of irradiation are critical parameters that affect tumor control and survival in patients with non‐oat cell bronchogenic carcinoma. Strict quality assurance criteria in radiotherapy are necessary to achieve optimal treatment results and a careful program to evaluate techniques of irradiation and protocol compliance should be maintained in cooperative group studies in order to enhance the validity of clinical trials.

Design of Randomized Controlled Trials

A major factor in the rapid advance of medical science over the past 50 years has been the development and refinement of the clinical research method known as the randomized controlled trial (RCT). A clinical trial is defined as a prospective scientific experiment that involves human subjects in whom treatment is initiated for the evaluation of a therapeutic intervention. In an RCT, each patient is assigned to receive a specific treatment intervention by a chance mechanism. Nothing more clearly indicates the key role of an RCT in modern clinical research than the placement of this specific research method at the top of the list of levels of evidence in evidence-based medicine.1 According to this classification, significant results of an RCT are more definitive than any other type of clinical research information. The purpose of this article is to present an overview of the design of RCTs. Some of the principles of a high-quality study, such as the use of randomization, placebos, and double-blind designs are well known. Other principles such as stratification, use of a decision-making structure, and statistical power are known by many investigators but are not universally recognized or fully understood. These features plus others that indicate the design of a high-quality RCT are discussed. A companion article on the conduct and evaluation of RCTs will appear in a future issue of this journal. One of the most easily recognized aspects of a well-designed and conducted clinical trial is the apparent clarity of the research mechanism evident in its published report. Alternatively, one of the more common problems with a published clinical trial is the apparent “design by committee” in which different members of a protocol team have different goals. Because a clinical trial is a resource-intensive undertaking, many investigators feel that the study should attempt to …

Patterns of tumor recurrence after definitive irradiation for inoperable non-oat cell carcinoma of the lung

Abstract Preliminary analysis was carried out on a prospective randomized cooperative group study involving 375 patients with histologically proven unresectable non-oat cell carcinoma of the lung who were treated with definitive radiotherapy. The patients were randomized to one of four treatment regimens: 4000 rad split course (2000 rad in five fractions one week, two weeks rest and an additional 2000 rad, five fractions in one week) or 4000, 5000 or 6000 rad continuous courses, five fractions per week. 84 to 100 patients were accessioned to each group. The one year survival rate was about 40%; the two year survival rate was 10% to 18%. The patients who were treated with the split course had the lowest survival (10% at two years) compared with the other groups (14% to 18%). Complete and partial local tumor regression was 48 % in patients who were treated with 4000 rad, 65 % in the 5000 rad and 61 % in the 6000 rad group. The rate of initial intrathoracic recurrence was 38 % in patients who were treated with 6000 rad; 45 % in those who received 5000 rad, 51 % and 64 % with 4000 rad split or continuous course, respectively. Patients who showed complete or partial regression of the tumor following irradiation exhibited an initial local recurrence rate of 42 % and 46 % respectively in contrast to 57 % for those without tumor regression. Patients with epidermoid carcinoma had an initial local failure rate of 53%, adenocarcinoma and large cell undifferentiated carcinoma 41 %. Distant metastases concurrent with or prior to intrathoracic failure were significantly higher in the patients with adenocarcinoma or large cell adenocarcinoma (63%) than in epidermoid carcinoma (33%). The present data strongly suggest that patients who were treated with 5000 or 6000 rad had a better response, tumor control and survival than those who were treated with lower doses. Additional follow-up of patients at risk in each group will be necessary before a final conclusion is drawn. Further investigations should determine the impact that a variety of prognostic factors may have in efficacy of irradiation in patients with bronchogenic carcinoma. This information will be extremely useful in the design of future therapy for these various subpopulations of patients with different manifestations of the disease.

Neuropsychological functioning and viral load in stable antiretroviral therapy-experienced HIV-infected children

Objective. Neuropsychological functioning and its correlation with viral load were investigated for previously treated HIV-infected children who underwent a change in treatment regimen. Methods. Thirteen age-appropriate measures of cognitive, neurologic, and behavioral functioning were administered to 489 HIV-infected children who were aged 4 months to 17 years and had been treated previously for at least 16 weeks with antiretroviral therapy. These clinically and immunologically stable children were randomized onto 1 of 7 drug treatment combinations, 6 of which included a protease inhibitor (PI), and evaluated prospectively for 48 weeks with respect to changes in neuropsychological performance and viral load. Results. Neuropsychological functioning was significantly poorer at baseline for the HIV-infected children as compared with established norms for their age. Children with higher viral load had poorer cognitive, both-hands fine-motor, and neurologic signs at baseline, but single-hand fine-motor and behavioral functioning were not correlated with viral load. After 48 weeks of treatment with PI-containing combination therapy, there was significant improvement in only the vocabulary score. Neuropsychological changes did not differ among the 6 PI-containing combination regimens. At week 48, even children with a viral load response below the level of detection (RNA ≤400 copies/mL) still showed poorer neuropsychological functioning compared with established norms. Conclusion. Poor neuropsychological functioning was seen for HIV-infected children and was worse for children with higher viral loads. Only 1 measure of neuropsychological functioning showed improvement after treatment with PI-containing combination therapy, and the extent of that improvement was relatively minor. Treatment strategies for children with HIV disease need to be reevaluated so that they consider restoration of neuropsychological functioning in addition to lowering the viral load.

Combination nucleoside analog reverse transcriptase inhibitor(s) plus nevirapine, nelfinavir, or ritonavir in stable antiretroviral therapy-experienced HIV-infected children : Week 24 results of a randomized controlled trial-PACTG 377

One hundred eighty-one antiretroviral-experienced, protease inhibitor-naive, clinically stable HIV-infected children between 4 months and 17 years of age were randomly assigned to receive one of four combination regimens to evaluate the change in plasma HIV RNA, safety, and tolerance when changing antiretroviral therapy to a protease inhibitor-containing combination regimen. All four regimens contained stavudine; in addition children received nevirapine plus ritonavir, lamivudine plus nelfinavir, nevirapine plus nelfinavir, or lamivudine plus nevirapine plus nelfinavir. Twelve additional children chose to receive stavudine plus lamivudine plus nelfinavir, with nelfinavir given bid, rather than tid as for the main regimens. Overall, 51% (89/176; 95% CI 43-58%) of the children on the randomized portion of the study had an HIV RNA response (< or =400 copies/ml) on at least two of the three HIV RNA determinations taken at Weeks 8, 12, and 16. At Week 24 the proportion of children with an HIV RNA response still on initial therapy was 47% (83/176; 95% CI 40-55%) and ranged from 41 to 61% for the four randomized treatment arms. Rash was frequently seen (27%) on the treatment arms containing nevirapine. At Week 24 64% (7/11, 95% CI 31-89%) of the children on the bid nelfinavir combination regimen were still on initial therapy with an HIV RNA response as compared with 46% (23/50; 95% CI 32-61%) on the corresponding tid nelfinavir combination regimen. A change in antiretroviral therapy to a protease inhibitor-containing regimen was associated with a virological response rate of approximately 50% for this patient population.

Growth of human immunodeficiency virus-infected children receiving highly active antiretroviral therapy.

Background: Weight and height growth of HIV-infected children tends to lag behind that of uninfected children of similar age. Previous reports of the effect of highly active antiretroviral therapy (HAART) on the growth of HIV-infected children have been contradictory. Methods: Age- and gender-adjusted height and weight z scores were studied for 192 HIV-infected children, 4 months to 17 years of age, who had been treated with antiretroviral therapy for at least 16 weeks. These children, in clinically and immunologically stable condition, were enrolled into one of 4 HAART regimens and evaluated for 96 weeks. Results: At baseline, these HIV-infected children were significantly shorter than uninfected children (mean z score, −0.57; 95% confidence interval, −0.73 to −0.41; P < 0.001). Children with greater viral loads at baseline were significantly shorter and lighter than children with smaller viral loads (both P < 0.001). Administration of HAART led to an increase in mean weight z scores to normal values (mean z score increase, from −0.16 to >0) by week 48 and an increase in mean height z scores of 72% toward normal values (mean z score increase, from −0.57 to −0.16) by week 96. Younger children gained height more rapidly (P < 0.001), and children with greater baseline viral loads gained weight more rapidly (P < 0.001). There was no evidence of differential height or weight changes in 48 weeks between children with different degrees of virologic control. Conclusions: HAART improved the average weight gain of HIV-infected children from subnormal to normal after 1 year and improved average height growth to nearly normal after 2 years.

Prophylactic cranial irradiation in patients with inoperable carcinoma of the lung. Preliminary report of a cooperative trial

In March 1975, the Veterans Administration Lung Cancer Group (VALG) initiated a study of whole brain irradiation for subclinical metastases in patients with inoperable or unresectable carcinoma of the lung still confined to the thorax. Patients (all with negative brain scans) are stratified by institution and performance status, then randomly assigned such that half receive 2000 rad in 2 weeks to the entire brain with supervoltage irradiation. A second objective of the study is to evaluate short course local irradiation (4200 rad in 3 weeks) versus the more standard intermediate course (5000 rad in 5 weeks). With 341 patients entered in the study, preliminary results confirm that local control of disease with either dose‐time regimen is highly correlated with survival (p = .001). Tumor control with the short course regimen seems equivalent to the intermediate course (NSD is the same by design), but morbidity from the short course may be somewhat greater. Patients with small cell carcinoma have a higher rate of intracranial failure and the prophylactic dose used does not seem to control micrometastases in the brain. Prophylactic brain irradiation, even with low doses, does decrease the appearance of brain metastases in patients with squamous, large cell, and adenocarcinoma (p = .054). Longer observation will determine whether this is delay of appearance or actual control of brain metastases.

Patterns of failure in patients with inoperable carcinoma of the lung

Patterns of failure were evaluated for 343 patients with inoperable bronchogenic carcinoma confined to one hemithorax. Patients with both small cell and non‐small cell carcinoma were treated with either chest irradiation or chest irradiation plus brain irradiation. The pattern of failure depended upon the histologic type. Patients with small cell carcinoma were most likely to exhibit disseminated disease (53%) prior to recurrence of local disease. Patients with adenocarcinoma and large cell carcinoma also had a similar tendency (40%), as opposed to patients with squamous cell carcinoma (20%). The occurrence of objective tumor regression improved survival but did not appear to alter the pattern of failure. Because of this tendency for local control to delay the overall disease process, therapy for these patients should concentrate on the local disease.

Immunologic response to combination nucleoside analogue plus protease inhibitor therapy in stable antiretroviral therapy-experienced human immunodeficiency virus-infected children.

The response of 40 immunologic parameters was studied for 147 clinically stable, protease inhibitor-naive, human immunodeficiency virus (HIV)-infected children aged 2-17 years when antiretroviral therapy was changed to either a dual nucleoside analogue regimen or a protease inhibitor-containing regimen. Immunologic response to therapy, as measured by lymphocyte subsets, 3-color flow cytometric measures, and lymphoproliferative assays, were investigated for changes in weeks 44 and 48. The most significant changes after baseline that were associated with the administration of a protease inhibitor-containing regimen were seen for percentages of CD8(+)/CD38(+)/HLA-DR(+), CD8(+)/CD95(+)/CD28(-), and CD8. The percentages of CD8(+)/CD38(+)/HLA-DR(+) and CD8(+)/CD95(+)/CD28(-) decreased from baseline medians of 33% and 46% to medians of 18% and 30% at week 44 (P<.0001 for both). Median CD4 cell count increased 168 cells/microL (from 694 cells/microL to 862 cells/microL; P=.02) by week 48 in this clinically stable population. Changes in lymphoproliferative responses to HIV antigens and recall antigens did not increase over time and between groups.

Small‐cell carcinoma of the lung—survival according to histologic subtype: A veterans administration lung group study

Six‐hundred‐twenty cases of small‐cell carcinoma of the lung entered into the Veterans Administration Lung Group protocols 9–15 were retrospectively subdivided into histologic subtype, as proposed by the WHO (1977). Medium survival was greater for subtype No. 21 (lymphocyte‐like) than for subtype No. 22 (intermediate) (17.2 vs. 12.6 weeks; P = 0.005). Patients with extensive disease survived longer with subtype No. 21 than subtype No. 22 (14.5 vs. 10.9 weeks; P = 0.026). However, no median survival difference was seen with limited disease. Survival for subtype 21 was greater than No. 22 (P = 0.016) for patients with poor initial performance status (IPS; Karnofsky 70 or less); for ambulatory patients (IPS 80‐100) a survival advantage was seen for subtype No. 21 compared with No. 22, but did not quite reach statistical significance (P = 0.09). Survival in subtype No. 21 was better than in subtype No. 22 (24.3 vs. 14.7 weeks; P = 0.001) when no weight loss (less than 10 pounds over the six‐month period prior to therapy) was documented. However, with weight loss (greater than 10 pounds) survival in each subtype was similar.