True Response Rate Research Articles

An optimal three‐stage design for phase II clinical trials

A phase II clinical trial in cancer therapeutics is usually a single-arm study to determine whether an experimental treatment (E) holds sufficient promise to warrant further testing. When the criterion of treatment efficacy is a binary endpoint (response/no response) with probability of response p, we propose a three-stage optimal design for testing H0: p < or = p0 versus H1: p > or = p1, where p1 and p0 are response rates such that E does or does not merit further testing at given levels of statistical significance (alpha) and power (1--beta). The proposed design is essentially a combination of earlier proposals by Gehan and Simon. The design stops with rejection of H1 at stage 1 when there is an initial moderately long run of consecutive treatment failures; otherwise there is continuation to stage 2 and (possibly) stage 3 which have decision rules analogous to those in stages 1 and 2 of Simon's design. Thus, rejection of H1 is possible at any stage, but acceptance only at the final stage. The design is optimal in the sense that expected sample size is minimized when p = p0, subject to the practical constraint that the minimum stage 1 sample size is at least 5. The proposed design has greatest utility when the true response rate of E is small, it is desirable to stop early if there is a moderately long run of early treatment failures, and it is practical to implement a three-stage design. Compared to Simon's optimal two-stage design, the optimal three-stage design has the following features: stage 1 is the same size or smaller and has the possibility of stopping earlier when 0 successes are observed; the expected sample size under the null hypothesis is smaller; stages 1 and 2 generally have more patients than stage 1 of the two-stage design, but a higher probability of early termination under H0; and the total sample size and criteria for rejection of H1 at stage 3 are similar to the corresponding values at the end of stage 2 in the two-stage optimal design.

Phase IV trial of daily oral etoposide in the treatment of advanced soft-tissue sarcoma

Intravenous-bolus etoposide has modest activity in sarcomas when given daily for 3-5 days. Low frequent doses theoretically inhibit topoisomerase II activity over a longer duration and have been reported to have increased activity in small-cell lung cancer. A phase I trial of oral etoposide resulted in partial responses in two patients with soft-tissue sarcomas. To estimate more accurately the response rate for daily oral etoposide in sarcomas, we treated 25 patients with 50 mg/m2 per day by mouth for 21 days every 4 weeks. Treatment-related toxicity included > or = grade 2 neutropenia in 6 of the 25 patients and thrombocytopenia in 3. One brief partial response was observed (4%; 95% confidence interval for true response rate, 0-11%). Disease stabilized in five patients for periods ranging from 3 to 18 months. At this dose and on this schedule, daily oral etoposide appears to have little activity against soft-tissue sarcomas.

Transient increase in total serum alkaline phosphatase predicts radiological response to systemic therapy in breast cancer patients with osteolytic and mixed bone metastases.

Assessment of the response of bone metastases to endocrine or chemotherapy is difficult, and true response rate is probably underestimated by UICC criteria. Biochemical markers of osteoblast activity, which is linked with bone healing, could be useful for early detection of treatment response. We studied changes in osteoblast function, assessed by serial serum total alkaline phosphatase (tALP) at 0, 1, 2, 3 months from the start of systemic therapy, in 31 patients bearing bone metastases from advanced breast cancer. After 1 month of endocrine or cytotoxic treatment, all responding patients (7/31) showed a significant rise in tALP (mean increase: 351 IU/l, p < 0.05) followed by a gradual decrease over the subsequent months (tALP flare). Transient increase in tALP was also found in 2/16 patients with stable disease who benefited from therapy. 2/8 patients with progressive disease showed a rise indistinguishable from responders, but the subsequent decrease was not apparent. These observations suggest that serum tALP profile is an earlier predictor of response than X-rays.

Studies of interferons in the therapy of melanoma.

Melanoma does not respond meaningfully to systemic chemotherapy. No significant improvement in overall survival has been observed with any therapy in the setting of advanced disease, nor in the adjuvant setting. The most active single drugs achieve 14% to 22% response rates in larger phase II series, and drug combinations have not in general improved true response rates by 15% or more. Experience with recombinant interferon alpha-2 (rIFN alpha 2) administered by a variety of schedules and routes has demonstrated tumor response rates of 12% to 22% in advanced melanoma. Administered combined with chemotherapy, rIFN alpha 2 has improved response rates in some, but not all trials to date. On the basis of increased responsiveness noted to be inversely related to tumor size, IFN alpha has been explored over the past 7 years as an adjuvant to definitive surgery for melanoma. The North Central Cancer Treatment Group (NCCTG) and Eastern Cooperative Oncology Group (ECOG) have recently completed trials of 3 and 12 months' duration of maximal dosages of rIFN alpha 2 in subjects with high-risk resected deep primary or lymph node metastatic melanoma. These randomized controlled studies completed accrual in 1990. The ECOG trial EST 1684 has tested the effect of rIFN alpha 2b, given intravenously daily for 5 days per week for 4 weeks at 20 x 10(6) IU/m2/d, then subcutaneously three times a week at 10 x 10(6) IU/m2/d for 11 months. A series of three analyses is planned for the ECOG trial, and the first of these interim analyses was reported to the ECOG in June, 1990, revealing an encouraging divergence of survival curves that does not achieve statistical significance at this early time. A randomized controlled study of 3 months' duration of rIFN alpha 2a at 12 x 10(6) IU/m2/d intramuscularly three times a week performed by the NCCTG is also in too early a stage to allow definitive conclusions yet. The toxicity of IFN alpha administered at maximum tolerated doses has been significant in terms of constitutional symptoms and organ dysfunction. There have been two instances of fatal toxicity observed in the ECOG study (286 subjects). Consideration of lower, more tolerable dosage regimens has been derived from the desire to evaluate longer periods of IFN alpha 2 therapy, and long-term maintenance treatment with IFN alpha 2 in adjuvant melanoma therapy. In addition, immunologic studies suggest that dosages of 3 x 10(6) IU/m2/d may be more immunologically active in vivo.(ABSTRACT TRUNCATED AT 400 WORDS)

Phase II trial of trimetrexate in patients with advanced soft-tissue sarcoma

Trimetrexate, a lipophilic, 2,4-diaminoquinazoline derivative of methotrexate, enters cells by passive diffusion rather than via a transport system. Trimetrexate has shown promising activity in animal model systems. A total of 16 patients with metastatic soft-tissue sarcoma who had received only one prior chemotherapy regimen were treated with trimetrexate (8 mg/m2 given intravenously daily for 5 days) every 3 weeks. Treatment-related toxicity included greater than or equal to grade 2 neutropenia (8/16), thrombocytopenia (3/16), mucositis (4/16) and skin rash (3/16). No partial or complete responses were observed in 15 evaluable patients (95% confidence interval for true response rate, 0-22%) Six subjects showed stabilization of disease for periods ranging from 2 to 9 months. At this dose and on this schedule, trimetrexate appears to have little activity against refractory soft-tissue sarcomas.

A phase II trial of continuous-infusion 6-mercaptopurine for childhood solid tumors

A phase II pediatric trial of a continuous intravenous infusion of 6-mercaptopurine (6-MP) in patients with refractory solid tumors or lymphoma was performed. The dosing schedule of 50 mg/m2 per hour for 48 h was chosen to produce optimal cytotoxic concentrations of 6-MP. There were no complete or partial responses in the 40 patients entered in the trial. Accrual was sufficient for the conclusion to be drawn that there was greater than 95% probability that the true response rate was no greater than 22% and 26% in osteosarcoma and Ewing's sarcoma, respectively. Dose-limiting toxicity was observed in one-third of the patients and included reversible hepatotoxicity, myelosuppression, and mucositis. The excellent penetration of drug into the cerebrospinal fluid (CSF) suggests that future trials of this intravenous dosing schedule should be conducted on tumors of the CNS.

Chemotherapy with Tauromustine in Advanced Non-Small Cell Lung Cancer

Tauromustine (TCNU) is a newly developed nitrosourea compound. As a result of molecular modification, TCNU is more hydrophilic than BCNU and CCNU. In experimental data there was a high therapeutic index, especially in Walker 256 carcinosarcoma in rats, and in phase I trials antitumor activity was observed in NSCLC (10/33 remissions). There was also activity in melanoma, breast cancer, pleuramesotheliomas and ovarian cancer. To determine the effectiveness, duration of response and toxicity of TCNU the following phase II trial was performed. Patients received 130 mg/m2 TCNU every 35 days orally. Twenty-five patients were treated; 22 were evaluable. The female/male ratio was 18/4, 1 patient was stage III, 21 patients stage IV, the mean age was 62.3 years (range 32-70). Between 1 and 4 courses (mean 1.9) were administered. Histology was as follows: 6 squamous cell, 11 adenocarcinoma, 2 large cell and 3 polymorph cell carcinomas. No objective response (CR + PR) was observed; 6/18 patients had stable disease, 7/18 progression and 5/18 early progression. The median survival time is 4.9 months. The most severe side effect was thrombocytopenia (WHO grade 3 + 4, 4/22 patients). TCNU administered at this dose and schedule does not show substantial antitumor activity in patients with NSCLC. The fact that no objective tumor remission was observed suggests that the true response rate is less than 20% (p less than 0.05). It is improbable that TCNU has a relevant impact on the course of inoperable NSCLC.

Experience of the Belgian Society of Medical Oncology with single-administration 5 g/m2 ifosfamide with mesna as second- or third-line therapy in advanced breast cancer

In an ongoing phase II trial conducted in advanced breast cancer, we tested a therapy schedule consisting of continuous, 24-h infusion of 5 g/m2 ifosfamide (IFO) in 3 1 dextrose saline with mesna (MSN), repeated every 3 weeks until disease progression. Since September 1988, 16 heavily pretreated patients with advanced disease (11 with visceral lesions) considered refractory to standard chemotherapy (regimens always including cyclophosphamide) have been included. Objective partial remissions were observed in two cases (one in liver and one in soft-tissue and pleural lesions), and disease stabilization for at least 3 months occurred in four cases. No treatment-related death was recorded and tolerance was judged to be excellent (six cases) or acceptable in all instances. The haematological toxicity consisted mainly of transient leucopenia (nadirs evaluated by WHO scale as grade 3 in 43% and grade 4 in 29%), sometimes associated with thrombocytopenia (grade 3 in 7% and grade 4 in 7%). Other side effects included nausea and/or vomiting (grade 3-4 in 33%); worsening of preexisting alopecia (five cases); haemorrhagic cystitis (one case); mild, transient somnolence (two cases); and moderate fluid retention (two cases). We concluded that infusion of 5 g/m2 IFO over 24 h with MSN rescue might represent an acceptable second- or third-line salvage regimen. Close monitoring of haematological and renal function parameters is recommended. A larger number of patients will be treated in a continuation of this study to evaluate the true response rate within narrower confidence limits.

The Use of the Long-Acting Somatostatin Analogue, Octreotide Acetate, in Patients with Islet Cell Tumors

Octreotide lowers plasma concentrations of the marker peptide in the majority of patients with islet cell tumors. However, as described above the effect of octreotide on plasma concentrations of marker peptides is not necessarily related to the effect on symptoms. Nevertheless octreotide is capable of producing symptomatic relief in a large proportion of patients with islet cell tumor syndromes. The data on the effect of octreotide on the symptoms due to VIPoma and due to the carcinoid syndrome (presumably including some who have islet cell tumors) are strong and the drug has been approved for these indications by the Food and Drug Administration. With respect to the other islet cell tumor syndromes, the published data suggest that the utility of octreotide differs in the different syndromes. Insulinomas are usually single, benign, and can and should be removed surgically, resulting in cure. Octreotide therefore has no role to play in such patients, particularly since the response of insulinomas is variable. However in the 10 per cent of insulinomas that are malignant octreotide is certainly effective in at least a portion of cases, although as yet the true response rate and efficacy compared with diazoxide is not clear. Although octreotide is effective at reducing acid output, and thus improving symptoms in patients with Zollinger-Ellison syndrome, because of the effectiveness of histamine H2-receptor antagonists and omeprazole, there is no need for octreotide in this syndrome. For patients with glucagonoma, GHRHoma, Cushing's syndrome, and other rare islet cell tumor syndromes octreotide may well be of benefit and should be considered. The current data do not support the use of octreotide for an antitumor effect.

Phase II study of ifosfamide and mesna in patients with previously-treated carcinoma of the cervix

Thirty patients with advanced squamous carcinoma of the uterine cervix recurrent after radiotherapy or surgery and refractory to first-line chemotherapeutic agents were treated with ifosfamide in a dose of 1.2 grams/m2 IV daily for five days every four weeks and Mesna 300 mg/m2 IV every four hours for three doses daily for five days. One patient had an inadequate trial and two were inevaluable for response, leaving 27 patients evaluable for response. All but two patients had received prior radiotherapy and all but one prior cisplatin-based or cisplatin analog chemotherapy. Seventeen patients had prior surgery. All patients were Gynecologic Oncology Group performance status 0, 1, or 2. Partial responses were observed in three patients (11.1%), two with pelvic and one with extrapelvic disease. A 90% confidence interval for the true response rate is 4.5%-24.8%. Severe (grade 3 or 4) leukopenia and anemia were seen in nine and seven patients, respectively. Severe thrombocytopenia was not observed. Three patients had grade 3 or 4 neurotoxicity, and one had grade 3 renal impairment. Reversible alopecia was universal. This dose and schedule of ifosfamide and Mesna is active in patients with squamous carcinoma of the cervix failing platinum-based therapy. Phase II testing in untreated patients is currently underway.

Bayesian statistics for direct marketers

Decision makers involved in list selection and purchase for direct marketing campaigns typically use sample response rates as a barometer of future success for a rollout effort. In some instances, decision makers may be convinced that sample response rates are not indicative of the true response rates for a given mailing list. Bayesian statistics present a methodology for revising test sample results using prior assessments and opinions on the likelihood of a particular response rate for given lists. Bayes estimation for updating response probabilities and an illustration of Bayes’ technique in direct marketing are presented.

Phase II trial of oral 4-demethoxydaunorubicin in patients with non-small cell lung cancer.

4-Demethoxydaunorubicin (4-DMDR) is an orally active analog of daunorubicin that in preclinical testing has demonstrated greater antitumor activity and less cardiotoxicity than its parent compound. Thirty-two patients with metastatic non-small cell lung cancer received 4-DMDR at a dose of 40-50 mg/m2 orally every 21 days. Thirteen patients had received no prior chemotherapy. Among the 30 adequately treated patients, one major response lasting 5.2 months was observed. Leukopenia 10-14 days after treatment was the most commonly observed toxicity. With an overall observed major response rate of 3.3% in 30 patients, the predicted true response rate is less than or equal to 16% (p = 0.05). At the dose and schedule studied in this group of patients with non-small cell lung cancer, 4-DMDR had only marginal activity.

Phase II study of epirubicin in advanced malignant melanoma.

Twenty patients with advanced malignant melanoma refractory to conventional chemotherapy, were entered into a Phase II study of epirubicin, one of the new doxorubicin analogues. The drug was given at a dose of 90 mg/m2 IV every 3 weeks. One partial response and three disease stabilizations were observed. Nausea and vomiting and alopecia were common. Mild to moderate leukopenia occurred in 6 patients. Three cases of reversible ST-T changes were recorded. The observed response rate of 5% with a 39.2% probability of a true response rate greater than or equal to 10%, does not suggest that epirubicin, in the dose and schedule chosen, is active in metastatic malignant melanoma.

Charts for the early stopping of pilot studies.

Cooperative oncology groups usually run pilot studies of new agents or combinations concurrently with their major randomized clinical trials. A primary objective of these studies is to determine whether the new regimen should be tested further in a group-wide clinical trial. The accrual goals of such pilot studies are typically fixed in advance at between 30 and 40 patients, on the grounds that this number provides a reasonably tight confidence interval on the true response rate. Nevertheless early termination of pilot studies is often desirable either because the regimen appears inactive or because early results indicate extreme activity and justify immediate testing in a randomized study. Statistical charts are provided for early termination in both these situations. The charts are read by specifying the number of evaluable patients already accrued, the number of responses observed and the minimum true response rate, theta 0, at which the regimen would be considered active. The charts provide the posterior probability that the true response rate exceeds theta 0, that is, that the regimen is active. An additional chart that computes a 90% probability interval for the true response rate, based on the observed rate and sample size, is also provided. The use of the chart is illustrated with two examples from the Eastern Cooperative Oncology Group.

Phase II trial of epirubicin in advanced squamous, adeno- and large cell carcinoma of the lung

Epirubicin, a steroisomer of doxorubicin with suggested lower potential for cardiotoxicity in animal tumor systems, was evaluated in a disease-oriented phase II trial in non-small cell lung cancer. The drug was given as a direct i.v. injection of 90 mg/m 2 repeated every 3 weeks. Four partial remissions were observed among 75 evaluable patients. Forty-two of the 75 patients had received no prior chemotherapy. The predicted true response rate is equal to 5% (0.2–10%). Leucopenia (75% of patients), gastrointestinal disturbances (76% of patients) and alopecia (53% of patients) were common side-effects observed. Four patients had cardiac abnormalities after treatment with epirubicin (one sinustachycardia, two premature beats, one biopsy-proven cardiomyopathy with congestive heart failure). One patient developed a peripheral neuropathy possibly related to epirubicin. We conclude that epirubicin in the present dose and schedule is an inactive agent in patients with non-small cell lung cancer.

Sample sizes required for binomial trials when the true response rates are estimated

Binomial trial sample size specification depends upon the values of the unknown response rate parameters, as well as upon the size and power of the resulting test. In practice, the values assumed for these parameters are based upon the results of previous or pilot trials, or upon the investigator's prior knowledge or belief. In either case, there is some uncertainty associated with these values that should be taken into account if the sample sizes are to be specified realistically. This paper describes a procedure for incorporating this uncertainty explicitly into the sample size determination on the basis of joint confidence distributions obtained from the pilot or prior information.

Assessment of scintigram quality

The application of standard psychophysical techniques to the measurement of the quality of noisy images is shown using examples taken from clinical radionuclide imaging. In clinical radionuclide imaging the distribution of a radiopharmaceutical injected into a patient is mapped in vivo by using a scintillation detector to record the emitted gamma rays. Areas of above or below average radiopharmaceutical concentration may indicate clinical abnormalities, such as tumours. As the images have only a few hundred photons/cm2, random (Poisson) fluctuations in intensity are large and may mask changes in radiopharmaceutical concentration. The quality of these images is assessed by using either the method of constant stimulus or signal-detection theory to measure an observer&apos;s ability to detect small changes in image intensity. The method of constant stimulus is used to compare analogue with digital images. It is shown that smaller changes in intensity can be detected on digital images than on the analogue ones. Signal detection theory is used to measure the effect of filtering on image quality. For a given rate of false positive responses, the filtered images produce a higher true positive response rate than for the unfiltered ones.

The use of Chance Profiles for Detecting Carelessness: The Effect of Determining the True Response Rate from Items in Scales

The use of Chance Profiles for Detecting Carelessness: The Effect of Determining the True Response Rate from Items in Scales