Randomised Phase 1 clinical trials in oncology

The aims of Phase 1 trials in oncology have broadened considerably from simply demonstrating that the agent/regimen of interest is well tolerated in a relatively heterogeneous patient population to addressing multiple objectives under the heading of early-phase trials and, if possible, obtaining reliable evidence regarding clinical activity to lead to drug approvals via the Accelerated Approval approach or Breakthrough Therapy designation in cases where the tumours are rare, prognosis is poor or where there might be an unmet therapeutic need. Constructing a Phase 1 design that can address multiple objectives within the context of a single trial is not simple. Randomisation can play an important role, but carrying out such randomisation according to the principles of equipoise is a significant challenge in the Phase 1 setting. If the emerging data are not sufficient to definitively address the aims early on, then a proper design can reduce biases, enhance interpretability, and maximise information so that the Phase 1 data can be more compelling. This article outlines objectives and design considerations that need to be adhered to in order to respect ethical and scientific principles required for research in human subjects in early phase clinical trials.Subject terms: Drug safety, Cancer therapy     

Breakthrough Drugs and Turtle Soup

The U.S. Food and Drug Administration (FDA) category of Breakthrough Therapy drugs was established in 2012, fostered by collaboration between legislators, researchers, industry representatives, and cancer research advocates. This category allows the FDA to designate certain lifesaving drugs for expedited review, and it has been successful in speeding the approval of several new drugs.Open in a separate windowBruce A. Chabner, M.D.The common public perception of doing business in Washington, D.C., has been that success requires a heavy dose of partisan politics, lobbying, and trading favors for votes. A different side of the story is portrayed in the recent book The Georgetown Set [1], which tells of the profound influence of correspondents Joseph and Stewart Alsop on international relations and Cold War strategies over three decades (1940–1970). The Alsops exerted their influence through their friendships and through weekend dinners with State Department, Central Intelligence Agency, and Cabinet officials, and even the presidents, including their distant relative, Franklin D. Roosevelt. Joe Alsop’s famous turtle soup became the most effective libation for turning minds and setting foreign policy. To no small degree did those dinners lead to American support of Britain in the early days of World War II, U.S. containment policy toward the Soviet Union after the war, and U.S. commitment to both the Korean and Vietnam engagements.In the same manner, the war on cancer has been advanced by unofficial Washington, D.C. In particular, the recent, remarkable change in policy regarding drug approval—the Breakthrough Therapy designation for lifesaving therapies—is a case in point. For those of us accustomed to dealing with a skeptical and, at times, intransigent U.S. Food and Drug Administration (FDA) decades ago, the current activism of the FDA in rapidly approving new cancer drugs is, at times, breathtaking. In the period from 1970 to 1995, when the National Cancer Institute was the major source of new, mostly cytotoxic, drugs, one to two new drugs were approved each year. The average time in clinical trials prior to approval was 7 to 10 years, and approval usually required a lengthy phase III trial. The intellectual turning point was, undoubtedly, the 1992 introduction of Accelerated Approval (AA), a result of the pressure to approve new AIDS drugs [2]. AA provided a mechanism for early review of valuable new drugs. The second major event, and perhaps the cultural turning point in drug approval, was Congress’s passage of Breakthrough Therapy legislation in June 2012 [3]. This action followed on the heels of the rapidly evolving understanding of the molecular basis for malignant transformation and the discovery of “targets” for new drug development [4].A multitude of new drugs resulted from the explosion in biotechnology; 1,000 new drugs are in various stages of preapproval development at this time. The number of new chemical entities that have been approved each year for the past 5 years for cancer averages about 12, and promises to increase significantly with the entry of immunotherapies. Some of these new drugs are now approved after a single phase I trial, an event unimaginable 20 years ago.The regulatory turning point can be traced to legislation in July 2012 that established a new category: Breakthrough Therapy. It allowed the FDA to designate certain lifesaving drugs for expedited review, and gave the FDA the mandate to becoming actively involved with industry in each step of the way toward approval. Since 2013, 88 drugs have received breakthrough designation (43% of them in the cancer field) and 23 have been approved, including 8 cancer drugs [5]. How did this happen?The key player in initiating the idea of a Breakthrough designation was Ellen Sigal, the founder and chairperson of Friends of Cancer Research (FCR). FCR was founded in 2002 as a not-for-profit alliance of advocates, researchers, and policy interest groups in Washington, D.C. Sigal and her friends were personally frustrated by the lack of a sense of urgency for approval of new drugs and they became the private force behind efforts to “modernize” the approval process. Among their early achievements was legislation that provided user fees for the FDA, allowing the FDA workforce to expand to meet the rising productivity and pressures of industry. Sigal’s unofficial army of supporters and her inside advisors from the FDA in crafting the specific breakthrough proposal were Rick Pazdur, the director for oncologic drugs at the FDA and an experienced and highly respected medical oncologist in his own right, and Janet Woodcock, the eminent director of the FDA’s Center for Drug Evaluation and Research. To get the idea through Congress, Sigal needed allies in the Senate, and she found them in three senators, who dined at the Irish Embassy on the Irish version of turtle soup (i.e., soda bread, corned beef, and cabbage) on Valentine’s Day, February 14, 2012.The occasion was an invitation from Ireland’s ambassador to the U.S., Michael Collins, who wanted to acquaint them with Élan Corporation, Ireland’s largest domestic pharmaceutical company. At the dinner were U.S. Senators Orrin Hatch (R-Utah), Richard Burr (R-North Carolina), and Michael Bennet (D-Colorado). Hatch had a long history of active bipartisan engagement (with the late Senator Ted Kennedy) and support for NIH, FDA, and for health-care policy legislation (Fig. 1). Burr, the senior senator from North Carolina, had a special interest in FDA and NIH, based on the importance of these government institutions to industry, and to the Research Triangle Park and academic centers in his state. Bennet was a freshman senator and a close friend of the irrepressible Murphy brothers of Colorado Springs, Colorado. Marty Murphy, a cancer research scientist and executive editor of this journal, has long been an advocate for cancer drug development. His brother Chuck Murphy, a prominent Colorado Democrat, supported Bennet’s gubernatorial appointment to the Senate to fill the seat vacated by Ken Salazar when he became Secretary of the Interior (January 2009). To add to the Murphy passion for cancer drug approvals, Marty and Chuck’s brother John, a lawyer and developer, was one of the first patients to experience a long-term remission from metastatic melanoma on targeted therapy. Marty and Chuck were dining at the Embassy at the invitation of Ambassador Collins, and pressed the case for Breakthrough Therapy.Open in a separate windowFigure 1.Chuck Murphy and Senator Orrin Hatch.All three senators were members of the key Senate Health, Education, Labor, and Pensions Committee involved with FDA legislation. The three were implored by others at the dinner, including Marty and Chuck Murphy, and their friend Bob Ingram (then Élan’s chairman), to consider what they could do, in a bipartisan way, to speed approval for lifesaving drugs and, specifically, to consider Breakthrough Therapy legislation. At Marty Murphy’s suggestion, Bennet, a Democrat, and Burr, a Republican (Fig. 2), shared a ride home and agreed to back the proposal along with Hatch, a Republican.Open in a separate windowFigure 2.Senator Richard Burr and Senator Michael Bennet.The rest is history. A dozen drugs per year are approved in the U.S., many after phase II or even phase I trials. There are risks to early drug approval [6]. Given the limited experience with these agents, there are concerns about toxicities, drug interactions, and optimal dosing. Yet the benefits are remarkable, as witnessed by the early approval of the breakthrough immune checkpoint inhibitors. The advantages of early approval to industry—a proactive FDA, rapid entry of new drugs to market, longer periods of exclusivity, surrogate endpoints for trials—are also notable and important in generating interest in the cancer field. Ellen Sigal’s dream became a reality.Serious issues lie ahead. Drug approval is only the first step. Actually paying for these new breakthrough drugs is another challenge. The high cost of these drugs may become an additional burden on an already beleaguered health-care system, and the same agents may be essentially unaffordable for the majority of cancer patients in the developing world. Clearly we need more bipartisanship, and more turtle soup, to address these and other issues in the rapidly evolving story of “personalizing” cancer treatment.     

The evidence base of US Food and Drug Administration approvals of novel cancer therapies from 2000 to 2020

Concerns have been raised that regulatory programs to accelerate approval of cancer drugs in cancer may increase uncertainty about benefits and harms for survival and quality of life (QoL). We analyzed all pivotal clinical trials and all non-pivotal randomized controlled trials (RCTs) for all cancer drugs approved for the first time by the FDA between 2000 and 2020. We report regulatory and trial characteristics. Effects on overall survival (OS), progression-free survival and tumor response were summarized in meta-analyses. Effects on QoL were qualitatively summarized. Between 2000 and 2020, the FDA approved 145 novel cancer drugs for 156 indications based on 190 clinical trials. Half of indications (49%) were approved without RCT evidence; 82% had a single clinical trial only. OS was primary endpoint in 14% of trials and QoL data were available from 25%. The median OS benefit was 2.55 months (IQR, 1.33-4.28) with a mean hazard ratio for OS of 0.75 (95%CI, 0.72-0.79, I² = 42). Improvement for QoL was reported for 7 (4%) of 156 indications. Over time, priority review was used increasingly and the mean number of trials per indication decreased from 1.45 to 1.12. More trials reported results on QoL (19% in 2000-2005; 41% in 2016-2020). For 21 years, novel cancer drugs have typically been approved based on one single, often uncontrolled, clinical trial, measuring surrogate endpoints. This leaves cancer patients without solid evidence that novel drugs improve their survival or QoL and there is no indication towards improvement.     

Clinical staging of prostate cancer: reproducibility and clarification of issues.

The American Joint Committee on Cancer (AJCC) staging system for prostate cancer adopted in 1992 is based on tumor-node-metastasis (TNM) designations. It has been widely accepted for use in local and advanced disease. The purpose of this study was to assess reproducibility of staging among observers and to help clarify staging issues. Twelve prostate cancer cases were sent to 20 physicians with special expertise in prostate cancer including eight urologists, eight radiation oncologists, and four medical oncologists. Physicians were asked to assign a stage based on the 1992 AJCC clinical staging. The most frequently reported stage assigned to each case was taken to be the consensus. Agreement was the percentage of physicians who reported that particular stage. Seventy-five percent of the physicians responded. The overall agreement for assignment of T stage was 63.9%. Differences were found by specialty for inclusion of available information in designating a T stage. The overall agreement for N stage was 73.8%. The most common designation was Nx regardless of availability of a computed tomography scan. The overall agreement for M stage was 76.6%. Without a bone scan the most common designation was Mx regardless of Gleason grade or prostate-specific antigen (PSA). A frequent comment was that PSA was more indicative of disease extent than current clinical staging. The reproducibility of the 1992 clinical AJCC staging is poor even among experts in the field. This problem arises primarily from disagreement regarding which studies are included in assigning a stage. Some of these difficulties are addressed in the 1997 revision. However, the clinical staging does not address the true biological significance of disease in many instances.     

Fentanyl buccal tablet: faster rescue analgesia for breakthrough pain?

Breakthrough pain (BTP) is an unmet clinical need that is still poorly diagnosed, evaluated and inadequately treated. The prevalence of BTP has been estimated to affect at least 64% of cancer patients. Two pain-relief strategies were proposed: preventive and active ('rescue'). Oral short-acting opioid seems to be the most popular approach for BTP treatment, however, it is likely to be inadequate for a substantial proportion of patients as a result of the slow-onset of most available opioid preparations. Fentanyl buccal tablet (FBT) is a novel delivery system for fentanyl citrate. FBT utilizes OraVescent technology to improve bioavailability and speed of drug delivery. Recent studies have demonstrated superior pharmacokinetic profiles when compared with other available transmucosal opioids (OTFC), however, pharmacodynamic data are still somewhat limited.     

Overestimation of the effect size in group sequential trials

Group sequential designs (GSD), which provide for interim monitoring of efficacy data and allow potential early trial termination while preserving the type I error rate, have become commonplace in oncology clinical trials. Although ethically appealing, GSDs tend to overestimate the true treatment effect size at early interim analyses. Overestimation of the treatment effect may exaggerate the benefit of a drug and provide imprecise information for physicians and their patients about a drug's true effect. The cause and effect of such a phenomenon are generally not well understood by many in clinical trial practice. In this article, we provide a graphical explanation for why the phenomenon of overestimation in GSDs occurs. The potential overestimation of the magnitude of the treatment effect is of particular concern in oncology, in which the more subjective endpoint of progression-free survival has increasingly been adopted as the primary endpoint in pivotal phase III trials. Clin Cancer Res; 18(18); 4872-6. ?2012 AACR.     

Eventual success rate and predictors of success for oncology drugs tested in phase I trials

Previous estimates of the likelihood of a drug tested in phase I trials obtaining FDA clearance are out of date. In the intervening years, newer pharmaceuticals have been developed, resulting in new delivery systems and lines of therapies. We sought to explore and update these estimates by comprehensively searching drugs tested in phase I trials and to determine the factors associated with later receiving FDA approval. In a cross-sectional analysis, we searched for anti-tumor drugs tested in phase I trials and published in scientific journals or presented at hematology/oncology conferences. For each drug, we searched PubMed for phase II and phase III studies testing the drug for the same indication tested in phase I studies. We found 51 drug approvals; four were withdrawn. The probability of a drug tested in 2015 being approved by 2021 was 6.2%. Drugs tested as monotherapy were more likely to receive approval than drugs tested in combination, and monoclonal antibodies were more likely to receive approval than drugs of other mechanisms. In adjusted models, response rates higher than 40% in phase I studies, demonstrating an improvement in overall survival (OS) in phase III studies, and drugs tested as monotherapy were associated with receiving FDA approval. When looking at all drugs tested during a single year, most drugs were not approved, and among those that are approved, almost 8% are withdrawn. Response rates higher than 40%, testing a drug as monotherapy, and demonstrating an improvement in OS were associated with receiving FDA approval.     

When are "positive" clinical trials in oncology truly positive?

The approval of a new drug for cancer treatment by the regulatory authorities, such as the United States Food and Drug Administration or European Medicines Agency, is usually based on the positive results of one or more randomized phase III clinical trials comparing the investigational treatment with the standard treatment. A clinical trial is presented as positive if the new drug tested on an experimental group shows a statistically significant difference with the control group (P < .05) in the primary endpoint, which is usually a time-to-event endpoint (overall survival or progression-free survival). Such apparently positive clinical trials disregard whether the final value of the difference in the primary endpoints between the experimental and control groups (δ) meets the criterion that was predefined in the protocol. Currently, the trend is to design large trials that may detect statistically significant, but often trivial, differences in survival endpoints. However, recent appeals have been made in the oncology literature for the design of smaller clinical trials to detect or exclude only larger, clinically important, values of δ. Here, we have evaluated 18 randomized phase III clinical trials that were used for the approval of molecular-targeted anticancer drugs by the United States Food and Drug Administration. Results showed that in some of the articles the magnitude of the reported values of δ were lower than the values predefined in the protocol. We suggest that trials should not be declared positive based only on a statistically significant P value, but should also require detection of a difference in survival outcome that equals or exceeds a clinically important value that is specified in the protocol.     

Defining breakthrough invasive fungal infection–Position paper of the mycoses study group education and research consortium and the European Confederation of Medical Mycology

Breakthrough invasive fungal infections (IFIs) have emerged as a significant problem in patients receiving systemic antifungals; however, consensus criteria for defining breakthrough IFI are missing. This position paper establishes broadly applicable definitions of breakthrough IFI for clinical research. Representatives of the Mycoses Study Group Education and Research Consortium (MSG‐ERC) and the European Confederation of Medical Mycology (ECMM) reviewed the relevant English literature for definitions applied and published through 2018. A draft proposal for definitions was developed and circulated to all members of the two organisations for comment and suggestions. The authors addressed comments received and circulated the updated document for approval. Breakthrough IFI was defined as any IFI occurring during exposure to an antifungal drug, including fungi outside the spectrum of activity of an antifungal. The time of breakthrough IFI was defined as the first attributable clinical sign or symptom, mycological finding or radiological feature. The period defining breakthrough IFI depends on pharmacokinetic properties and extends at least until one dosing interval after drug discontinuation. Persistent IFI describes IFI that is unchanged/stable since treatment initiation with ongoing need for antifungal therapy. It is distinct from refractory IFI, defined as progression of disease and therefore similar to non‐response to treatment. Relapsed IFI occurs after treatment and is caused by the same pathogen at the same site, although dissemination can occur. These proposed definitions are intended to support the design of future clinical trials and epidemiological research in clinical mycology, with the ultimate goal of increasing the comparability of clinical trial results.     

The 2nd conference on Asian trends in prostate cancer hormone therapy

Among the aims of the 2nd Conference on Asian Trends in Prostate Cancer Hormone Therapy, Hong Kong, December 7-8, 2002, was to lay the groundwork for eventually having cooperative or collaborative studies of prostate cancer specifically in Asian patients. The conference was divided into 2 sessions. In the first session, entitled "Current Status of Therapy for Prostate Cancer in Asian Countries," the results of analysis of 100 patients with prostate cancer enrolled in the Patients Registration System is each of the 6 participating Asian countries were discussed. The Patients Registration System is a database template established by the Japanese Urological Association that allows physicians to compare prostate cancer therapy in the different Asian countries. Session 2 was devoted to a "Roundtable Discussion on the Establishment of Asian Guidelines for Prostate Cancer." This session included 2 lively discussions, on whether Asian physicians can apply Western clinical data to Asian patients, and the need for Asian clinical data and developing clinical trials in the region, respectively.     

Complete remission sustained 3 years from treatment initiation is a powerful surrogate for extended survival in multiple myeloma

BACKGROUND: Complete response (CR) has been considered a necessary although not sufficient early clinical endpoint for extended survival in multiple myeloma. METHODS: By using Total Therapy 2 (TT2) clinical outcome data in 668 patients, whether sustained CR (SUS-CR) was potentially a superior surrogate for survival than attaining CR status per se was evaluated. RESULTS: Compared with not achieving CR (NON-CR) and especially achieving and subsequently losing CR status (LOS-CR) within a 3-year landmark from treatment initiation, SUS-CR was associated with highly superior postlandmark survival (P < .0001). These results were validated in 231 untreated patients enrolled in the predecessor trial, TT1 (hazard ratio [HR] = 0.54, P = .013) and in 1103 previously treated patients on other transplant protocols (HR = 0.49; P < .001). CONCLUSIONS: In all 3 trial settings the survival benefit of SUS-CR was independent of metaphase abnormalities as a dominant adverse parameter. Given its bleak prognosis despite high CR rates, SUS-CR should be evaluated as a primary trial endpoint in high-risk myeloma.     

Assessment of quality of life as an endpoint of cancer treatment

In order to evaluate the efficacy of cancer therapy, it is important to assess quality of life (QOL) as an endpoint in addition to tumor size reduction and survival. Thus, assessment of QOL has been included in many clinical trials of cancer therapy. These studies use various multiple QOL scales. We have translated the English version of the FACT-BL (Functional Assessment of Cancer Therapy for Bladder Cancer) questionnaire into Japanese. In the process, we performed a comparative study simultaneously using this questionnaire and EORTC QLQ-C30J which is generally used for various cancer patients. We found that FACT-BL provides a more sensitive assessment of the QOL of patients with advanced bladder cancer than EORTC QLQ-C30J. This means that we should carefully choose a questionnaire which is directly related to disease site, symptoms and treatment and can be conducted clinically. In the future, the assessment of QOL will have an important role as an endpoint of cancer treatment if the methodology and infrastructure, such as coordinators and data centers, are established in Japan.     

Ten years of marketing approvals of anticancer drugs in Europe: regulatory policy and guidance documents need to find a balance between different pressures

Despite important progress in understanding the molecular factors underlying the development of cancer and the improvement in response rates with new drugs, long-term survival is still disappointing for most common solid tumours. This might be because very little of the modest gain for patients is the result of the new compounds discovered and marketed recently. An assessment of the regulatory agencies' performance may suggest improvements. The present analysis summarizes and evaluates the type of studies and end points used by the EMEA to approve new anticancer drugs, and discusses the application of current regulations. This report is based on the information available on the EMEA web site. We identified current regulatory requirements for anticancer drugs promulgated by the agency and retrieved them in the relevant directory; information about empirical evidence supporting the approval of drugs for solid cancers through the centralised procedure were retrieved from the European Public Assessment Report (EPAR). We surveyed documents for drug applications and later extensions from January 1995, when EMEA was set up, to December 2004. We identified 14 anticancer drugs for 27 different indications (14 new applications and 13 extensions). Overall, 48 clinical studies were used as the basis for approval; randomised comparative (clinical) trial (RCT) and Response Rate were the study design and end points most frequently adopted (respectively, 25 out of 48 and 30 out of 48). In 13 cases, the EPAR explicitly reported differences between arms in terms of survival: the range was 0-3.7 months, and the mean and median differences were 1.5 and 1.2 months. The majority of studies (13 out of 27, 48%) involved the evaluation of complete and/or partial tumour responses, with regard to the end points supporting the 27 indications. Despite the recommendations of the current EMEA guidance documents, new anticancer agents are still often approved on the basis of small single arm trials that do not allow any assessment of an 'acceptable and extensively documented toxicity profile' and of end points such as response rate, time to progression or progression-free survival which at best can be considered indicators of anticancer activity and are not 'justified surrogate markers for clinical benefit'. Anticipating an earlier than ideal point along the drug approval path and the use of not fully validated surrogate end points in nonrandomised trials looks like a dangerous shortcut that might jeopardise consumers' health, leading to unsafe and ineffective drugs being marketed and prescribed. The present Note for Guidance for new anticancer agents needs revising. Drugs must be rapidly released for patients who need them but not be at the expense of adequate knowledge about the real benefit of the drugs.     

Prognostic factors in brain metastases: should patients be selected for aggressive treatment according to recursive partitioning analysis (RPA) classes?

PURPOSE: To determine whether or not Radiation Therapy Oncology Group (RTOG) recursive partitioning analysis (RPA) derived prognostic classes for patients with brain metastases are generally applicable and can be recommended as rational strategy for patient selection for future clinical trials. Inclusion of time to non-CNS death as additional endpoint besides death from any cause might result in further valuable information, as survival limitation due to uncontrolled extracranial disease can be explored. METHODS: We performed a retrospective analysis of prognostic factors for survival and time to non-CNS death in 528 patients treated at a single institution with radiotherapy or surgery plus radiotherapy for brain metastases. For this purpose, patients were divided into groups with Karnofsky performance status (KPS) <70% and KPS > or =70%, as proposed by the RTOG. RESULTS: Median overall survival was 2.9 months (2.0 months for patients with KPS <70% and 3.6 months for patients with KPS > or =70%, p < 0.001). We did not find other variables splitting patients with KPS <70% in different prognostic groups. However, advanced age, multiple brain metastases, presence of extracranial metastases, and uncontrolled primary tumor each predicted shorter survival in patients with KPS > or =70%. When grouped into the original RTOG RPA classes, our data set split into three subgroups with different prognosis and median survival times of 10.5, 3.5, and 2 months, respectively (p < 0.05). Only 3% of patients fell into the most favorable group. Median time to non-CNS death was 4.1 months (12.9 months in RPA class I, 4.9 months in RPA class II, and 3.8 months in RPA class III, respectively, p > 0.05 for RPA class II versus III). However, it was 8.5 months in RPA class II patients with controlled primary tumor, which was found to be the only prognostic factor for time to non-CNS death in patients with KPS > or =70%. In patients with KPS <70%, no statistically significant prognostic factors were identified for this endpoint. CONCLUSIONS: Despite some differences, this analysis essentially confirmed the value of RPA-derived prognostic classes, as published by the RTOG, when survival was chosen as endpoint. RPA class I patients seem to be most likely to profit from aggressive treatment strategies and should be included in appropriate clinical trials. However, their number appears to be very limited. Considering time to non-CNS death, our results suggest that certain patients in RPA class II also might benefit from increased local control of brain metastases.     

Breast cancer screening among Cambodian American women

Our aim was to describe and identify factors associated with breast cancer screening among Cambodian American women. We conducted a cross-sectional survey of 1,365 households using bilingual and bicultural interviewers. We found that low proportions of Cambodian American women were up to date on their clinical breast examinations (CBE; 42%) and mammograms (40%). More than 80% of women with female physicians have had at least one prior screening, and 52% have had the tests recently. Women with male Asian American physicians were less likely to have had screening as compared to women with female non-Asian physicians: ever had CBE (odds ratio [OR], 0.26); recent CBE (OR, 0.39); ever had mammogram (OR, 0.36); and recent mammogram (OR, 0.22). Breast cancer screening among Cambodian American women lags behind the general U.S. population. Tailored promotion efforts should address barriers and promote cancer screening by physicians, staff, and organizations serving this population.     

A population-based study of the prevalence and influence of gifts to radiation oncologists from pharmaceutical companies and medical equipment manufacturers

PURPOSE: Hospital-based physicians are responsible for the purchase of expensive equipment. Little is known about the influence of gift giving on their behavior. We wanted to ascertain the prevalence of gift giving from the pharmaceutical industry and medical equipment manufacturers to radiation oncologists and determine whether or not the size of accepted gifts influences their opinions regarding gifts. METHODS AND MATERIALS: A population-based survey of hospital-based physicians conducted between 2002 and 2003. The study population consisted of all radiation oncologists who were members of the American Society of Therapeutic Radiology and Oncology between 2000 and 2001. A random number generator was used to identify 20% of the population. This group was invited by e-mail and conventional mail to complete a Likert scale questionnaire. Those asked to complete the questionnaire electronically were directed to a specially designed web site. RESULTS: Of 640 individuals who were asked to participate, 241 (38%) completed the questionnaire. 96% admitted accepting gifts. The most commonly accepted low value gifts were: pen or pencil (78%), drug samples for patient's use (70%), meal (66%), and a note pad (59%). The most commonly accepted high value gifts were trips to "equipment-users meetings" (15%), honoraria for speaking at a conference (10%), and participation in a conference call (9%). Only 5% of radiation oncologists agreed with the statement "my prescribing practices are affected" by gifts; however, 33% agreed with the statement "I believe that other physicians prescribing practices are affected." Similarly, although only 4% felt that their recommendations concerning purchases of medical equipment are affected by gifts, 19% felt that other physicians would be influenced. A test of the hypothesis that physicians believe that their conduct is less affected than those of their colleagues (i.e., "I am not influenced by gifts but someone else is" was strongly affirmed by a correlation statistic) (p < 0.0001). Of the radiation oncologists surveyed, 74% felt that they should be free to accept gifts of small value, 31% felt they should be free to accept meals or gifts of any type, 16% felt that residency programs should ban free meals provided by companies, 13% felt professional associations should discourage companies from hosting parties at the annual meeting, 17% felt that gift giving should stop, and 66% agreed that clinical information provided by companies provides a useful continuing medical education service. Those who accepted larger gifts were far more likely to disagree with statements such as "professional societies should actively discourage companies from hosting parties and providing free meals and giving gifts to physicians attending the annual meeting" (p = 0.0003) and "the practice of gift giving by companies should stop" (p = 0.0017); they were slightly more likely to agree with statements such as "clinical information provided to radiation oncologists by companies provides a useful continuing medical education service." CONCLUSIONS: To our knowledge, this study represents the first large-scale population based study of a hospital-based specialty and gift giving. This study demonstrates that: (1) Gift giving in radiation oncology is endemic. (2) Although each physician is likely to consider himself or herself immune from being influenced by gift giving, he or she is suspicious that the "next person" is influenced. (3) There is a correlation between the willingness of individual physician to accept gifts of high value and their sympathy toward this practice.     

Attitudes of Canadian Oncology Practitioners Toward Psychosocial Interventions in Clinical and Research Settings in Women With Breast Cancer

The aim of this study was to survey Canadian oncology practitioners' attitudes toward psychosocial concerns and issues in women with breast cancer. Surveys were mailed to 351 medical, radiation and surgical oncologists and 375 oncology nurses. Standard questionnaires assessed attitudes towards psychosocial issues in women with primary and metastatic breast cancer and evaluated the practitioners' willingness to refer women to psychosocial intervention trials in the presence and absence of competing drug trials. Responses were obtained from 74% of those surveyed. Respondents reported being aware of the common occurrence of psychosocial problems in women with metastatic breast cancer, however, physicians were less likely than nurses to offer these women psychosocial support on a prophylactic basis (p < 0.0001) and they expressed greater concern than nurses about scientific validity of (p = 0.0003), and potential psychological damage from (p = 0.005), psychosocial support groups. Nurses were more likely than physicians to favour a study investigating group psychosocial support over competing drug studies (p ≤ 0.003) in the metastatic setting. Physicians were less likely than nurses to deal with weight problems prophylactically in women with primary breast cancer (p = 0.0009) and they expressed greater concern over scientific validity of psychosocial interventions addressing weight than nurses (p = 0.0008); nurses were more concerned about excessive expectations of patients regarding potential benefits of such interventions (p < 0.0001). Regardless, nurses were more likely than physicians to favour a psychosocial intervention study focused on weight management over drug studies in pre- (p = 0.0006) and postmenopausal women (p = 0.05) with primary breast cancer. Canadian oncology practitioners are aware of the common occurrence of psychosocial distress in women with breast cancer. Physicians and nurses assigned differing priorities to psychosocial interventions in both clinical and research situations. © 1997 John Wiley & Sons, Ltd.     

Of mice and men: values and liabilities of the athymic nude mouse model in anticancer drug development

Human tumour xenografts implanted subcutaneously (s.c.) into immunosuppressed mice have played a significant role in preclinical anticancer drug development for the past 25 years. Their use as a predictive indicator of probable clinical activity has been validated for cytotoxics. A retrospective analysis for 39 compounds where both extensive xenograft testing and Phase II clinical data were available, performed by the National Cancer Institute (NCI), has shown that 15/33 agents (45%) with activity in more than one-third of xenografts showed clinical activity (P=0.04). However, with the exception of non-small cell lung cancer, activity within a particular histological type of the xenograft generally did not predict for clinical activity in the same tumour. Today, the question (largely unanswered) is how useful is the xenograft model (particularly the traditional s.c. model) in contemporary cancer drug discovery? There are many variables when conducting xenograft experiments which impact on outcome; viz, site of implantation, growth properties of the xenograft and size when treatment is initiated, agent formulation, scheduling, route of administration and dose and the selected endpoint for assessing activity. The xenograft model remains of value in current preclinical cancer drug development, especially when such studies give due consideration to the above variables and are based on sound mechanistic (e.g. status of the selected target in the chosen model) and pharmacological (e.g. use of formulated agent) principles. Dependent upon the drug target, a slowing of xenograft tumour growth (cytostatic effect) rather than tumour shrinkage might be the major observed effect. Human tumour xenografts are also particularly useful in determining pharmacodynamic markers of response for subsequent clinical application. Nevertheless, it needs to be kept in mind that the use of xenografts is relatively time-consuming and expensive, raises animal ethical issues and there are instances where the model is inappropriate as a likely predictor of clinical outcome (e.g. inhibitors of the metastatic process and anti-angiogenic strategies as the vasculature is of murine origin).