Globalization of anti-cancer therapies

Based on short reviews of lung, gastric, colorectal, prostate, breast and ovarian cancer, there remain significant differences between Japan and the West in the therapeutic regimen for most cancers. Some of the differences are due to differences in stage of disease at diagnosis or historical factors affecting availability of products. In both Japan and the West, there are initiatives to prepare treatment guidelines based on published data. For Japan this initiative is limited by the lack of Japanese clinical trial data or even safety data. When guidelines are prepared from international data, many of the products have limited indications in Japan and therefore not reimbursed. Availability of the most appropriate therapies to Japanese patients will depend on a facilitation of clinical trials in both primary and additional indications. However, the experience in other countries is that, even where data and registration approval are available, guidelines are hard to agree and are not uniformly accepted by prescribers. The ICH E5 guideline on the use of bridging studies to interpolate Western data to Japanese regulatory dossiers provides an opportunity to accelerate availability of new medicines to Japanese prescribers and patients. The use of bridging studies has so far been limited for anti-cancer therapies. Where relevant pharmacodynamic endpoints can be measured, (e.g. aromatase inhibition) there can increase confidence in bridging. The newer types of agent which act to stabilise disease rather than tumour shrinkage present a special problem. In some cases surrogate markers can be valuable but in each case they need to be validated. As globalization continues, an alternative approach is to include a significant cohort of Japanese patients in Japanese patients but this depends on sufficient similarity in the patient population and background therapy. The most significant limitation to either large outcome studies in Japan or for Japanese centers to join international trials has been the environment for conduct of clinical trials. There have been some recent improvements and further progress is expected so that Japanese doctors can play a full role in the evaluation of new therapies.     

Participation to international registration trials--from the investigator's standpoint

Clinical developments of new anti-cancer drugs in Japan are far behind from the Western as well as Asian countries, which resulted in much delay for indicating them into Japanese patients. The causes of delay are considered to exist in regulatory authorities, pharmaceutical companies, and investigators, respectively. However, these delays have recently been improved by the revision of Japanese regulatory guidelines with an activity of committee for this issue. After overcoming various issues, two global registration studies involving Japanese institutions have already been initiated and additional global studies are now conducting in the field of gastrointestinal (GI) cancer in Japan. A Japan-Korea joint phase I study of new agent for gastric cancer is also now being conducted. It is time for Japanese GI investigators to recover the delay in new drug development and to make an effort for new evidence originated from Japan.     

Efficacy and toxicity differences in lung cancer populations in the era of clinical trials globalization: the ‘common arm’ approach

Historically, notable variability has been observed in clinical trial outcomes between different regions and populations worldwide, even when employing the same cytotoxic regimen in lung cancer. These divergent results underscore the inherent challenges in interpreting trials conducted abroad and raise questions regarding the general applicability of transnational clinical trials. Various reasons have been postulated to account for these differences in efficacy and toxicity, including trial design, eligibility criteria, patient demographics and, perhaps most intriguingly, population-related pharmacogenomics. However, without methodology to control for such variables, these hypotheses remain largely untested. The authors previously developed the ‘common arm’ approach in order to directly compare efficacy and toxicity results of trials simultaneously performed in different countries. By standardizing clinical trial-associated variables such as treatment regimens (dose, schedule, and so on), eligibility, staging, response and toxicity criteria, this approach has the potential to determine the underlying reasons for divergences in trial outcomes across countries, and whether population-associated polymorphisms contribute to these differences. In the past decade, Japanese and US investigators have applied the common arm analytic method to trials in both extensive-stage small-cell lung cancer (SCLC) and advanced nonSCLC. In the SCLC analysis, a comparison of the cisplatin/irinotecan arms from both trials revealed significant differences in response rates and overall survival. Significant differences were also observed in the distribution of gender and performance status. The common arm analysis in nonSCLC included two trials from Japan and one from the USA, each containing a ‘common’ carboplatin/paclitaxel arm. Clinical results were similar in the two Japanese trials, but were significantly different from the US trial with regard to survival, neutropenia, febrile neutropenia and anemia. The underlying basis for these divergent outcomes is discussed. The common arm methodology provides a template for identifying and interpreting patient outcome differences across populations, and is an instructive lesson in the burgeoning era of clinical trials globalization.     

Current status of gynecologic cancer in Japan

To make an overview of the current status of gynecologic cancer in Japan, we reviewed the recent incidence of cervical, endometrial, and ovarian cancer in Japanese women. The incidence of all three cancers has increased, but trends differ respectively. In age specific cancer site distribution data, the uterus and ovary are leading sites of high incidence among Japanese women younger than 40 years of age. Therefore, fertility sparing cancer treatment has received much attention. Several multicenter clinical trials have been done by Japanese groups, and some excellent evidence has been collected for endometrial and ovarian cancer. A promising international collaboration trial for ovarian clear cell carcinoma is also underway at the present time.     

Scoping to analyze oncology trial participation in Australia

Equity in oncology clinical trial participation has been declared a global priority. Australia is a key stakeholder in the global clinical trials sphere and managed to maintain high clinical trial activity during the COVID pandemic. Despite these successes, there is paucity of understanding about what influences clinical trial participation in Australia. In the international context, systematic reviews have highlighted that sociodemographic barriers, access to health care, clinical trial inclusion criteria, and attitudes of physicians and patients are factors which influence oncology trial participation. Exploring the factors in Australian health services which influence trial participation is now of significant importance. The lack of clear evidence directly highlights a need to assess the factors that influence oncology trial participation in Australia. We call for review of existing data to identify future directions in Australia which will potentially give deeper insights for the international clinical trial community.     

Adjuvant chemotherapy for gastric cancer in Japan: global and Japanese perspectives

Adjuvant therapy for gastric cancer after surgical resection has been under clinical investigation for decades. However, up until now, consistent and concrete evidence has not been generated either in Japan or other countries in favor of adjuvant therapy in terms of survival compared to surgery alone. Meta-analyses reported from Western countries have shown either no or borderline benefit for chemotherapy after surgical resection of gastric cancer. A recent trial showed significant benefit for chemoradiotherapy. However, Japanese specialists believe that their perspectives are different from those in the West due to the following: (1) gastric cancer incidence is several times higher in Japan; (2) more stringent screening programs are emphasized in Japan, thus baseline conditions of cancer patients are different; (3) specific operative techniques are used; and (4) Japanese surgeons have probably acquired additional experience in gastric cancer resection techniques. From the 1960s to the 1980s first mitomycin (MMC) and, later, a combination of oral fluorinated pyrimidines (o-FP) and MMC showed improved survival benefit in Japan compared to surgery alone. However, in the late 1980s, an expert group re-examined the results of previous trials, questioned them, and suggested fresh trials. Since then, the Japanese Clinical Oncology Group (JCOG) has conducted relevant trials to re-examine the effect of MMC and/or o-FP as adjuvant chemotherapy. The results of trials JCOG 8801 and JCOG 9206 have already been reported, and the accrual of patients for another trial (NSAS-GC trial) has just been completed. A pooled analysis of the two preceding trials showed a borderline survival benefit for o-FP compared to surgery alone. If o-FP treatment shows a 5% difference in survival benefit in the NSAS-GC trial, a meta-analysis of the three trials would probably reveal overall significant results. In conclusion, this therapy could become the standard adjuvant treatment regimen for gastric cancer patients after curative resection in Japan.     

Comparison the standard therapies of gastric cancer in Japan with those in the West

We compare Japanese practice guidelines for gastric cancer with those published from National Comprehensive Cancer Network (NCCN). In surgery, D1 dissection is referred as standard in NCCN, because mortality of D2 dissection was higher than that of D1 (10% vs 4%). However, Japanese investigators show lower mortality rate (0.8%) of D2 dissection, so D2 dissection is referred as standard for stage II/III disease in Japan. Chemoradiotherapy is chosen for residual disease or unresectable disease (M0) in NCCN, but these categories are required D2 dissection or extensive resection in Japan. Because Japanese D2 dissection has better optimized survival rate than chemoradiotherapy,chemoradiotherapy will not be introduced to Japan.In chemotherapy, ECF or taxanes (e.g., DCF) is referred as a prior therapy in NCCN, but 5-FU contain regimen (e.g., FP, LV/5-FU, S-1, or S-1/CDDP) as a prior therapy in Japan. Both ECF and DCF are too toxic regimen for Japanese patient to use. Difference of race seem to be relevant to difference of mortality or toxicities. From the results of ACTS-GC, we think that adjuvant chemotherapy is referred as standard in Japan. Future, results of JCOG 9912 and many other trials will be coming soon, so the guidelines will be changed.     

Chemotherapy for advanced gastric cancer: future perspective in Japan

Differences in clinical outcomes between advanced gastric cancer (AGC) in Asia and that in other regions have been discussed for a long time, although no major significant differences in molecular profiles have been reported. The anti-human epidermal growth factor receptor 2 antibody trastuzumab and the anti-vascular endothelial growth factor receptor 2 monoclonal antibody ramucirumab were both approved as a treatment for AGC on the basis of global phase 3 trials including Japan. In recent years, others new agents for treatment of AGC have been investigated in global or Asian studies. Randomized phase 2 trials in Japan showed a higher response rate to S-1 plus leucovorin and oxaliplatin than to standard S-1 plus cisplatin, which is the rationale for an ongoing phase 3 trial in Asia (SOLAR trial). A recent global phase 1 trial of the anti-programmed cell death 1 monoclonal antibody pembrolizumab showed similar efficacy results in Asian patients and non-Asian patients, which led to large global phase 2 and phase 3 studies. Although the perspective of treatment of AGC in the near future depends on the results of ongoing large clinical trials, individualized choice of treatment based on more detailed molecular information will become important.     

Barriers to participation in clinical trials of cancer: a meta-analysis and systematic review of patient-reported factors

BACKGROUND: Enrolling participants onto clinical trials of cancer presents an important challenge. We aimed to identify the concerns of patients with cancer about, and the barriers to, participation in clinical trials. METHODS: We did a systematic review to assess studies of barriers to participation in experimental trials and randomised trials for validity and content. We estimated the frequency with which patients identified particular issues by pooling across studies that presented data for barriers to participation in clinical trials as proportions. FINDINGS: We analysed 12 qualitative studies (n=722) and 21 quantitative studies (n=5452). Two qualitative studies inquired of patients who were currently enrolled onto clinical trials, and ten inquired of patients who were eligible for enrolment onto various clinical trials. Barriers to participation in clinical trials were protocol-related, patient-related, or physician-related. The most common reasons cited as barriers included: concerns with the trial setting; a dislike of randomisation; general discomfort with the research process; complexity and stringency of the protocol; presence of a placebo or no-treatment group; potential side-effects; being unaware of trial opportunities; the idea that clinical trials are not appropriate for serious diseases; fear that trial involvement would have a negative effect on the relationship with their physician; and their physician's attitudes towards the trial. Meta-analysis confirmed the findings of our systematic review. INTERPRETATION: The identification of such barriers to the participation in clinical trials should help trialists to develop strategies that will keep to a maximum participation and cooperation in cancer trials, while informing and protecting prospective participants adequately.     

Estimating the quality of life in a clinical trial of patients with metastatic lung cancer using the Karnofsky performance status and the Functional Living Index--Cancer

Serial assessments of Karnofsky performance status (KPS) and of the Functional Living Index--Cancer (FLIC) have been used to estimate the quality of life (QOL) of patients in a prospective, randomized trial of supportive care versus supportive care given with combination chemotherapy to patients with metastatic non-small cell lung cancer. There was a good correlation between KPS and FLIC scores at study entry, thus confirming results originally reported using the FLIC. However, a number of unexpected problems were encountered in data collection and quality control with this QOL assessment instrument. This made it impossible to look for differences in treatment effect on QOL in this clinical trial. It is believed that QOL assessment should be an integral part of cancer clinical trials; however, investigators must acknowledge the difficulties in collecting this type of data. The development of new instruments and the refinement of old ones will facilitate the collection of data for this important aspect of clinical trials research.     

Chemotherapy for advanced gastric cancer: future perspective in Japan

Differences in clinical outcomes between advanced gastric cancer (AGC) in Asia and that in other regions have been discussed for a long time, although no major significant differences in molecular profiles have been reported. The anti-human epidermal growth factor receptor 2 antibody trastuzumab and the anti-vascular endothelial growth factor receptor 2 monoclonal antibody ramucirumab were both approved as a treatment for AGC on the basis of global phase 3 trials including Japan. In recent years, others new agents for treatment of AGC have been investigated in global or Asian studies. Randomized phase 2 trials in Japan showed a higher response rate to S-1 plus leucovorin and oxaliplatin than to standard S-1 plus cisplatin, which is the rationale for an ongoing phase 3 trial in Asia (SOLAR trial). A recent global phase 1 trial of the anti-programmed cell death 1 monoclonal antibody pembrolizumab showed similar efficacy results in Asian patients and non-Asian patients, which led to large global phase 2 and phase 3 studies. Although the perspective of treatment of AGC in the near future depends on the results of ongoing large clinical trials, individualized choice of treatment based on more detailed molecular information will become important.

     

Ongoing Colorectal Cancer Adjuvant Trials in Japan

In Japan, oral fluoropyrimidines have been used widely as adjuvant therapy for colorectal cancers. The 2009 Japanese guideline recommends uracil-tegafur (UFT) and capecitabine, in addition to 5-fluorouracil (5-FU)/leucovorin (LV), as adjuvant therapy for colorectal cancer. At present, seven studies are being conducted in Japan; all are evaluating the efficacy of oral fluoropyrimidines. The SACURA and Japanese Foundation for Multidisciplinary Treatment of Cancer (JFMC)38-0901 trials are investigating the efficacy of UFT and UFT plus polysaccharide K compared with surgery alone for stage II colorectal cancer. The Japan Clinical Oncology Group (JCOG)-0205 trial is evaluating the equivalence of UFT/LV and infusional 5-FU/LV for the treatment of stage III colorectal cancer. The ACTS-CC trial is evaluating the noninferiority of S-1 compared with UFT/LV, whereas the JFMC35-C1 (ACTS-RC) trial is designed to evaluate the superiority of oral S-1 compared with UFT/LV in stage II and III rectal cancer patients. The JFMC37-0801 and JFMC33-0502 trials are evaluating the optimal duration of adjuvant chemotherapy with either capecitabine or UFT/LV.     

Participation of patients 65 years of age or older in cancer clinical trials.

PURPOSE: Although 61% of new cases of cancer occur among the elderly, recent studies indicate that the elderly comprise only 25% of participants in cancer clinical trials. Further investigation into the reasons for low elderly participation is warranted. Our objective was to evaluate the participation of the elderly in clinical trials sponsored by the National Cancer Institute (NCI) and assess the impact of protocol exclusion criteria on elderly participation. PATIENTS AND METHODS: We conducted a retrospective analysis using NCI data, analyzing patient and trial characteristics for 59,300 patients enrolled onto 495 NCI-sponsored, cooperative group trials, active from 1997 through 2000. Our main outcome measure was the proportion of elderly patients enrolled onto cancer clinical trials compared with the proportion of incident cancer patients who are elderly. RESULTS: Overall, 32% of participants in phase II and III clinical trials were elderly, compared with 61% of patients with incident cancers in the United States who are elderly. The degree of underrepresentation was more pronounced in trials for early-stage cancers than in trials for late-stage cancers (P <.001). Furthermore, protocol exclusion criteria on the basis of organ-system abnormalities and functional status limitations were associated with lower elderly participation. We estimate that if protocol exclusions were relaxed, elderly participation in cancer trials would be 60%. CONCLUSION: The elderly are underrepresented in cancer clinical trials relative to their disease burden. Older patients are more likely to have medical histories that make them ineligible for clinical trials because of protocol exclusions. Insurance coverage for clinical trials is one step toward improvement of elderly access to clinical trials. Without a change in study design or requirements, this step may not be sufficient.     

He's not going to talk about in vitro predictive assays again, is he?

It is difficult for anyone to determine why oncologists have not paid more attention to the use of in vitro predictive tests in the care of their patients. A review of already completed in vitro-in vivo correlative trials in 2,300 patients indicates percentages of 69 for true positives and 91 for true negatives from predictive assays. These percentages are as good as or better than those seen with already accepted tests, such as estrogen receptor assays or bacterial sensitivity testing systems. Results of a randomized trial of single-agent chemotherapy selections based on a capillary cloning assay versus a clinician's choice indicate the response rate is significantly higher when single-agent chemotherapy is selected by the cloning assay than when it is selected by a clinician (21% vs. 3%). An ongoing randomized trial in which investigators are attempting to corroborate these results in patients with previously untreated small cell lung cancer has been so slow to accrue patients that it is unlikely these trials and others will ever be completed. The usefulness, if any, of these assays and their potential to provide answers to important questions will never be determined unless attitudes are changed about participation in trials. A tool with potential for helping oncologists select patient therapy could be lost unless participation in these trials is obtained.     

What is the Japanese consensus on adjuvant chemotherapy in breast cancer?

The international conference of adjuvant therapy for primary breast cancer in St. Gallen and the National Institute of Health Consensus Conference for Breast Cancer Treatment have recommended appropriate treatment for individual subgroups by recurrence risk. However, evidence provided by Japanese clinical trials did not contribute to the consensus recommendations. To compare the risk of recurrence in breast cancer patients between Japan and western countries, a database of Japanese breast cancer patients was analyzed. From 1991 to 2001, approximately 12100 articles listed on MEDLINE were reviewed by abstract, and articles were then selected and reviewed by the authors. According to the AHPC (Agency for Health Care Policy and Research), quality assessment and strength for recommendation of the evidence from clinical trials were classified. Even though there are likely some unknown ethnic differences, we should provide Japanese patients with state of the art treatment for breast cancer in accordance with global standard therapies, which have been evaluated by breast cancer specialists in western countries.     

CRAFT—A Proposed Framework for Decentralized Clinical Trials Participation in Canada

Canada’s vast geography, and centralized delivery of cancer care and clinical trials create barriers for trial participation for patients in remote and rural settings. The development and implementation of a framework that enables safe and regulatory compliant trial participation through local healthcare providers would benefit Canadian patients, clinicians, trial sponsors and the health care system. To address this issue, representatives of Canada’s cancer clinical trial community met to identify key challenges and develop recommendations for remote patient participation in trials. A structured literature review identified remote/rural trial delivery models. A panel of expert stakeholders reviewed the models and participated in a workshop to assess health system readiness, identify needed processes, tools and mechanisms, and develop recommendations for a Canadian framework for decentralized clinical trial conduct. The Canadian Remote Access Framework for clinical Trials (CRAFT) represents a risk-based approach used by site investigators to delegate responsibilities for a given trial to satellite health centres within a hub-and-spoke “trial cluster”. The Framework includes specific recommendations to ensure research experience, capacity, regulatory compliance and patient safety. Canada’s cancer care and telemedicine systems can be leveraged to enable broader access to clinical trials for patients who are geographically remote from cancer centres. CRAFT’s risk-based framework is based on other successful models of remote trial patient management and is in the pilot implementation phase in Canada.     

Clinical Trials,Disparities, and Financial Burden: It's Time to Intervene

The additional financial burden of clinical trial participation and the lack of availability of trials at safety net facilities make it essentially impossible for underserved patients to participate. If allowed to continue, these trends will ensure that only affluent cancer patients will be able to participate in clinical trials. Interventions to better handle financial stresses and widespread policy change are necessary to optimize high-quality care for all patients with cancer.An overarching goal of the entire oncology community is to ensure access to the best-quality care for all patients with cancer, regardless of race and socioeconomic status. The best possible treatment option for many patients with cancer is participation in a clinical trial. Although clinical trials offer the most novel and promising therapies, minority participation in trials is abysmally low for many reasons. As cancer clinical trials become more complex in the current era of targeted therapy and immunotherapy, trial complexities threaten to further reduce access to these trials for cancer patients in underserved populations.This issue of The Oncologist addresses the important issues of clinical trials: cancer disparities and financial burden. Gerber et al. analyzed cancer clinical trials activated at an academic medical center and its satellite safety net site [1]. Their study revealed that, over time, a decreasing proportion of cancer clinical trials were available at the safety net site, thereby decreasing access to this underserved group. Primary reasons for this trend included increased clinical trial complexity and costs to the institution. Also in this issue, Nipp et al. describe the mounting evidence of financial burden experienced by cancer patients receiving standard treatments and the additional financial burden of clinical trial participation [2]. They document the heavy additional burden imposed by more frequent travel, the need for overnight accommodations, and the loss of work time imposed by clinical trial participation. These papers rightly call for effective interventions to ease the financial strain imposed by clinical trial participation.In the general cancer population, people with cancer are more than 2.5 times more likely to declare bankruptcy than people without cancer [3]. Cancer patients who file for bankruptcy are more likely to be younger, women, and not white. If these bankruptcy rates exist in the general cancer population, the additional financial burden of clinical trial participation and the lack of availability of trials at safety net facilities make it essentially impossible for underserved patients to participate.If allowed to continue, these trends will ensure that only affluent cancer patients will be able to participate in clinical trials. This will lead to the inability to generalize results to a general cancer population. More important, from a social justice perspective, cancer patients from minority and low-socioeconomic status populations will be denied access to some of the most promising therapies. Whether one can participate in a promising clinical trial should not be decided by the size of one’s wallet. The cost of complex clinical trial participation should not be placed on the shoulders of weary and financially strapped patients. Interventions to better handle these financial stresses and widespread policy change among important stakeholders, such as payors and industry sponsors, are necessary to optimize high-quality care for all patients with cancer.     

Evidence for Taxotere treatment with solid tumors

Evidence based medicine is essential to further develop the state of the art for cancer treatments. We introduce the levels of evidence for Taxotere treatment against various solid tumors. Most evidence for Taxotere therapy was produced in other countries. However, in Japan we have some data from phase II clinical trials for the approval of Taxotere. We review these domestic results, which reveal its usefulness and toxicity in Japanese patients. In addition, we analyze the evidence from the data of clinical trials of Taxotere conducted by investigators in the USA/Europe. Japanese physicians or academies must build a consensus for the application of Taxotere to Japanese patients with solid tumors.     

Second-line chemotherapy for gastric cancer: a new issue lies ahead in global trials

Chemotherapy for gastric cancer has been advancing fairly well. It has been indicated that not only advances in first-line chemotherapy but also those in second-line chemotherapy have contributed to the prolongation of overall survival. The Arbeitsgemeinschaft Internistische Onkologie (AIO) study supports the idea that second-line chemotherapy is appropriate in patients with a good general condition. Also, the Japan Clinical Oncology Group (JCOG) integral analysis suggests that advances have been made in second-line chemotherapy. However, most recently reported studies of second-line chemotherapy have been conducted as small-scale phase II or retrospective trials. No randomized control trial to establish standard treatment has been reported. Which regimen is the most appropriate as second-line therapy must be investigated in the future. Currently, molecularly targeted agents for gastric cancer are being developed and tested in global trials. As a new issue in global trials, second-line chemotherapy has been emphasized. In recent global trials, subset analysis showed regional differences in overall survival. This was possibly associated with the regional differences in second-line chemotherapy. When developing new molecularly targeted agents for first-line chemotherapy, we cannot ignore the result that the proportion of patients in whom treatment was switched to second-line chemotherapy was high in Asia. In planning a global trial, this new issue should be sufficiently discussed.     

Older adult participation in cancer clinical trials: A systematic review of barriers and interventions

Cancer is a disease of aging and, as the world's population ages, the number of older persons with cancer is increasing and will make up a growing share of the oncology population in virtually every country. Despite this, older patients remain vastly underrepresented in research that sets the standards for cancer treatments. Consequently, most of what we know about cancer therapeutics is based on clinical trials conducted in younger, healthier patients, and effective strategies to improve clinical trial participation of older adults with cancer remain sparse. For this systematic review, the authors evaluated published studies regarding barriers to participation and interventions to improve participation of older adults in cancer trials. The quality of the available evidence was low and, despite a literature describing multifaceted barriers, only one intervention study aimed to increase enrollment of older adults in trials. The findings starkly amplify the paucity of evidence-based, effective strategies to improve participation of this underrepresented population in cancer trials. Within these limitations, the authors provide their opinion on how the current cancer research infrastructure must be modified to accommodate the needs of older patients. Several underused solutions are offered to expand clinical trials to include older adults with cancer. However, as currently constructed, these recommendations alone will not solve the evidence gap in geriatric oncology, and efforts are needed to meet older and frail adults where they are by expanding clinical trials designed specifically for this population and leveraging real-world data.