National Estimates of the Participation of Patients With Cancer in Clinical Research Studies Based on Commission on Cancer Accreditation Data.

PURPOSE: National estimates of cancer clinical trial participation are nearly two decades old and have focused solely on enrollment to treatment trials, which does not reflect the willingness of patients to contribute to other elements of clinical research. We determined inclusive, contemporary estimates of clinical trial participation for adults with cancer using a national sample of data from the Commission on Cancer (CoC). METHODS: The data were obtained from accreditation information submitted by the 1,200 CoC programs, which represent more than 70% of all cancer cases diagnosed in the United States each year. Deidentified, institution-level aggregate counts of annual enrollment to treatment, biorepository, diagnostic, economic, genetic, prevention, quality-of-life (QOL), and registry studies were examined. Overall, study-type estimates for the period 2013-2017 were estimated. Multiple imputation by chained equations was used to account for missing data, with summary estimates calculated separately by type of program (eg, National Cancer Institute [NCI]-designated cancer centers) and pooled. RESULTS: The overall estimated patient participation rate to cancer treatment trials was 7.1%. Patients with cancer participated in a wide variety of other studies, including biorepository (12.9%), registry (7.3%), genetic (3.6%), QOL (2.8%), diagnostic (2.5%), and economic (2.4%) studies. Treatment trial enrollment was 21.6% at NCI-designated comprehensive cancer centers, 5.4% at academic (non-NCI-designated) comprehensive cancer programs, 5.7% at integrated network cancer programs, and 4.1% at community programs. One in five patients (21.9%) participated in one or more cancer clinical research studies. CONCLUSION: In a first-time use of national accreditation information from the CoC, enrollment to cancer treatment trials was 7.1%, higher than historical estimates of <5%. Patients participated in a diverse set of other study types. Contributions of adult patients with cancer to clinical research is more common than previously understood.

Overcoming Barriers to Discovery and Implementation of Equitable Pharmacogenomic Testing in Oncology.

Pharmacogenomics (PGx), the study of inherited genomic variation and drug response or safety, is a vital tool in precision medicine. In oncology, testing to identify PGx variants offers patients the opportunity for customized treatments that can minimize adverse effects and maximize the therapeutic benefits of drugs used for cancer treatment and supportive care. Because individuals of shared ancestry share specific genetic variants, PGx factors may contribute to outcome disparities across racial and ethnic categories when genetic ancestry is not taken into account or mischaracterized in PGx research, discovery, and application. Here, we examine how the current scientific understanding of the role of PGx in differential oncology safety and outcomes may be biased toward a greater understanding and more complete clinical implementation of PGx for individuals of European descent compared with other genetic ancestry groups. We discuss the implications of this bias for PGx discovery, access to care, drug labeling, and patient and provider understanding and use of PGx approaches. Testing for somatic genetic variants is now the standard of care in treatment of many solid tumors, but the integration of PGx into oncology care is still lacking despite demonstrated actionable findings from PGx testing, reduction in avoidable toxicity and death, and return on investment from testing. As the field of oncology is poised to expand and integrate germline genetic variant testing, it is vital that PGx discovery and application are equitable for all populations. Recommendations are introduced to address barriers to facilitate effective and equitable PGx application in cancer care.

Consensus recommendations for improving the cancer clinical trial matching environment.

Enrollment in cancer clinical trials cannot occur without first successfully identifying trials for which patients are a match based on their clinical characteristics. A lack of onsite matching trials has been identified as the single largest barrier preventing patients from participating in clinical trials. The site-agnostic cancer clinical trial matching environment is a mix of public and private tools and infrastructure that are not designed to work together to facilitate trial matching in an efficient manner. To identify policy and infrastructure solutions that could enable more effective and more frequent use of third-party site-agnostic matching, the American Cancer Society Cancer Action Network held a summit to examine challenges and propose consensus recommendations that could address those challenges. At this 2019 summit, stakeholders in this field examined these barriers and challenges and made a number of policy and infrastructure recommendations to improve the ability of this environment to work in a more coordinated and efficient manner.

Feasibility of institution-agnostic, EHR-integrated regional clinical trial matching.

BACKGROUND: A lack of onsite clinical trials is the largest barrier to participation of cancer patients in trials. Development of an automated process for regional trial eligibility screening first requires identification of patient electronic health record data that allows effective trial screening, and evidence that searching for trials regionally has a positive impact compared with site-specific searching. METHODS: To assess a screening framework that would support an automated regional search tool, a set of patient clinical variables was analyzed for prescreening clinical trials. The variables were used to assess regional compared with site-specific screening throughout the United States. RESULTS: Eight core variables from patient electronic health records were identified that yielded likely matches in a prescreen process. Assessment of the screening framework was performed using these variables to search for trials locally and regionally for an 84-patient cohort. The likelihood that a trial returned in this prescreen was a provisional trial match was 45.7%. Expanding the search radius to 20 miles led to a net 91% increase in matches across cancers within the tested cohort. In a U.S. regional analysis, for sparsely populated areas, searching a 100-mile radius using the prescreening framework was needed, whereas for urban areas a 20-mile radius was sufficient. CONCLUSION: A clinical trial screening framework was assessed that uses limited patient data to efficiently and effectively identify prescreen matches for clinical trials. This framework improves trial matching rates when searching regionally compared with locally, although the applicability of this framework may vary geographically depending on oncology practice density. PLAIN LANGUAGE SUMMARY: Clinical trials provide cancer patients the opportunity to participate in research and development of new drugs and treatment approaches. It can be difficult to find available clinical trials for which a patient is eligible. This article describes an approach to clinical trial matching using limited patient data to search for trials regionally, beyond just the patient's local care site. Feasibility testing shows that this process can lead to a net 91% increase in the number of potential clinical trial matches available within 20 miles of a patient. Based on these findings, a software tool based on this model is being developed that will automatically send limited, deidentified information from patient medical records to services that can identify possible clinical trials within a given region.

Provider motivations and barriers to cancer clinical trial screening, referral, and operations: Findings from a survey.

BACKGROUND: Provider and institutional practices have been shown to have a large impact on cancer clinical trial enrollment. Understanding provider perspectives on screening for trial eligibility is necessary to improve enrollment. METHODS: A questionnaire about incentives, barriers, process tools, and infrastructure related to opening trials and referring patients to onsite and offsite trials was administered to diverse stakeholders, including professional societies, advocacy organizations, and industry networks. Descriptive statistics were used to summarize findings. RESULTS: Overall, 693 responses were received, primarily from physicians (42.7%) and nurses (35.6%) employed at hospital health systems (43.7%) and academic centers (36.5%). Approximately half (49.2%) screened all patients for onsite clinical trials with screening typically done by manual chart review (81.9%). The greatest incentive reported for offering trials was providing the best treatment options for patients (67.7%). Contracting and paperwork (48.5%) were the greatest barriers to opening more onsite trials. Offsite referrals were rare. CONCLUSIONS: Screening for trial eligibility is a largely manual and ad hoc process, with screening and referral to offsite trials occurring infrequently. Administrative and infrastructure barriers commonly prevent sites from opening more onsite trials. These findings suggest that automated trial screening tools built into workflows that screen in a site-agnostic manner could result in more frequent trial eligibility screening, especially for offsite trials. With recent momentum, in part in response to the COVID-19 pandemic, to improve clinical trial efficiencies and broaden access and participant diversity, implementing tools to improve screening and referral processes is timely and essential. PLAIN LANGUAGE SUMMARY: There are many factors that contribute to low adult enrollment in cancer clinical trials, but previous research has indicated that provider and institutional barriers are the largest contributors to low cancer clinical trial enrollment. In this survey, we sought to gain insight into cancer clinical trial enrollment practices from the perspective of health care providers such as physicians and nurses. We found that only approximately half of respondents indicated their institution systematically screens their patients for clinical trials and this process is manual and time consuming. Furthermore, we found that providers infrequently search for and refer patients to clinical trials at other sites. Creating better screening methods could improve enrollment in clinical trials.

Association of Remote Technology Use and Other Decentralization Tools With Patient Likelihood to Enroll in Cancer Clinical Trials.

Importance: Logistical challenges such as travel time and distance to a clinical trial site can be a barrier to patient participation. The association of remote technology use and other decentralization tools that can reduce these barriers with likelihood to enroll in cancer trials is not well understood. Objective: To assess the association of remote technology and other decentralization tools used to reduce participation-related time and travel with the likelihood to enroll in cancer clinical trials. Design, Setting, and Participants: Between July 6 and September 8, 2021, a 41-question, cross-sectional, internet-based survey was administered to patients with cancer and survivors of cancer in the US who had been diagnosed with or treated for cancer in the past 7 years. Main Outcomes and Measures: Increase in self-reported likelihood to enroll in cancer clinical trials that use remote technology and other decentralization tools to decrease the need for travel to the trial site. Results: There were 1183 survey respondents, with a mean (SD) age of 58.2 (12.5) years. Respondents self-reported their gender, race and ethnicity, cancer type, and treatment status. Of the 1183 respondents, 848 (72%) were female, 296 (25%) were male, 8 (1%) were other/nonbinary, and 31 (3%) declined to answer. With regard to race, 28 respondents (3%) were American Indian or Alaska Native, 25 (2%) were Asian, 234 (20%) were Black or African American, 20 (2%) were Native Hawaiian or Other Pacific Islander, 825 (70%) were White, and 51 (4%) declined to answer. With regard to ethnicity, 115 respondents (10%) were Hispanic, Latino/Latina, or of Spanish origin, whereas 1017 (86%) were not and 51 (4%) declined to answer. Regarding cancer type and treatment status, 483 respondents (41%) either had or had survived breast cancer and 325 (28%) were being treated for cancer during the survey period. Individuals older than 55 years were more likely to say that they would only participate in trials no farther from their home than their regular care health care practitioner compared with younger respondents (26% vs 16%, respectively; P = .02). Higher-income earners (ie, those in households earning >$125 000/y) were significantly more likely than lower-income earners (ie, those in households earning <$70 000/y) to say they would participate in trials requiring additional effort (62% vs 41%, respectively; P = .03). If given the opportunity to enroll in a cancer clinical trial that required travel farther than their regular care, a majority of respondents (range, 60%-85%) indicated that they would be more likely to participate if the trial used remote technology and other tools to decrease the need for travel to a trial site. Conclusions and Relevance: In this cross-sectional study, the survey findings suggest that cancer clinical trials leveraging remote technology and decentralization tools to reduce patient time and travel burden associated with participation may increase the patient consent rate.

Strategies to Advance Equity in Cancer Clinical Trials.

Cancer clinical trials are critical for testing new treatments, yet less than 5% of patients with cancer enroll in these trials. Minority groups, elderly individuals, and rural populations are particularly underrepresented in cancer treatment trials. Strategies for advancing equity in cancer clinical trials for these populations include (1) optimizing clinical trial matching by broadening eligibility criteria, screening all patients for trial eligibility, expanding the number of trials against which patients are screened, and following up on all patient matches with an enrollment invitation; (2) conducting site self-assessments to identify clinical-, patient-, provider-, and system-level barriers that contribute to low rates of clinical trial screening and enrollment; (3) creating a quality improvement plan that addresses the barriers to enrollment and incorporates the use of tools and strategies such as clinical trial checklists; workforce development and trainings to improve cultural competence and reduce unconscious bias; guides to promote community education, outreach and engagement with cancer clinical trials; screening and accrual logs designed to measure participation by demographics; models of informed consent that improve understanding; clinical trial designs that reduce accessibility barriers; use of cancer clinical trial patient navigators; and programs to eliminate barriers to participation and out-of-pocket expenses; and (4) working with stakeholders to develop both protocols that are inclusive of diverse populations' geographic locations, and strategies to access those trials. These actions will support greater access for populations that have remained underrepresented in cancer clinical trials and thereby increase the generalizability and efficiency of cancer research.

Trends in Use of Next-Generation Sequencing in Patients With Solid Tumors by Race and Ethnicity After Implementation of the Medicare National Coverage Determination.

Importance: In March 2018, Medicare issued a national coverage determination (NCD) for next-generation sequencing (NGS) to facilitate access to NGS testing among Medicare beneficiaries. It is unknown whether the NCD affected health equity issues for Medicare beneficiaries and the overall population. Objective: To examine the association between the Medicare NCD and NGS use by insurance types and race and ethnicity. Design, Setting, and Participants: A retrospective cohort analysis was conducted using electronic health record data derived from a real-world database. Data originated from approximately 280 cancer clinics (approximately 800 sites of care) in the US. Patients with advanced non-small cell lung cancer (aNSCLC), metastatic colorectal cancer (mCRC), metastatic breast cancer (mBC), or advanced melanoma diagnosed from January 1, 2011, through March 31, 2020, were included. Exposure: Pre- vs post-NCD period. Main Outcomes and Measures: Patients were classified by insurance type and race and ethnicity to examine patterns in NGS testing less than or equal to 60 days after diagnosis. Difference-in-differences models examined changes in average NGS testing in the pre- and post-NCD periods by race and ethnicity, and interrupted time-series analysis examined whether trends over time varied by insurance type and race and ethnicity. Results: Among 92 687 patients with aNSCLC, mCRC, mBC, or advanced melanoma, mean (SD) age was 66.6 (11.2) years, 51 582 (55.7%) were women, and 63 864 (68.9%) were Medicare beneficiaries. The largest racial and ethnic categories according to the database used and further classification were Black or African American (8605 [9.3%]) and non-Hispanic White (59 806 [64.5%]). Compared with Medicare beneficiaries, changes in pre- to post-NCD NGS testing trends were similar in commercially insured patients (odds ratio [OR], 1.03; 95% CI, 0.98-1.08; P = .25). Pre- to post-NCD NGS testing trends increased at a slower rate among patients in assistance programs (OR, 0.93; 95% CI, 0.87-0.99; P = .03) compared with Medicare beneficiaries. The rate of increase for patients receiving Medicaid was not statistically significantly different compared with those receiving Medicare (OR, 0.92; 95% CI, 0.84-1.01; P = .07). The NCD was not associated with statistically significant changes in NGS use trends by racial and ethnic groups within Medicare beneficiaries alone or across all insurance types. Compared with non-Hispanic White individuals, increases in average NGS use from the pre-NCD to post-NCD period were 14% lower (OR, 0.86; 95% CI, 0.74-0.99; P = .04) among African American and 23% lower (OR, 0.77; 95% CI, 0.62-0.96; P = .02) among Hispanic/Latino individuals; increases among Asian individuals and those with other races and ethnicities were similar. Conclusions and Relevance: The findings of this study suggest that expansion of Medicare-covered benefits may not occur equally across insurance types, thereby further widening or maintaining disparities in NGS testing. Additional efforts beyond coverage policies are needed to ensure equitable access to the benefits of precision medicine.

Modernizing Clinical Trial Eligibility Criteria: Recommendations of the ASCO-Friends of Cancer Research Performance Status Work Group.

PURPOSE: Performance status (PS) is one of the most common eligibility criteria. Many trials are limited to patients with high-functioning PS, resulting in important differences between trial participants and patient populations with the disease. In addition, existing PS measures are subjective and susceptible to investigator bias. EXPERIMENTAL DESIGN: A multidisciplinary working group of the American Society of Clinical Oncology and Friends of Cancer Research evaluated how PS eligibility criteria could be more inclusive. The working group recommendations are based on a literature search, review of trials, simulation study, and multistakeholder consensus. The working group prioritized inclusiveness and access to investigational therapies, while balancing patient safety and study integrity. RESULTS: Broadening PS eligibility criteria may increase the number of potentially eligible patients for a given clinical trial, thus shortening accrual time. It may also result in greater participant diversity, potentially reduce trial participant and patient disparities, and enable clinicians to more readily translate trial results to patients with low-functioning PS. Potential impact on outcomes was explored through a simulation trial demonstrating that when the number of Eastern Cooperative Oncology Group PS2 participants was relatively small, the effect on the estimated HR and power was modest, even when PS2 patients did not derive a treatment benefit. CONCLUSIONS: Expanding PS eligibility criteria to be more inclusive may be justified in many cases and could result in faster accrual rates and more representative trial populations.See related commentary by Giantonio, p. 2369.

"When Offered to Participate": A Systematic Review and Meta-Analysis of Patient Agreement to Participate in Cancer Clinical Trials.

BACKGROUND: Patient participation in clinical trials is vital for knowledge advancement and outcomes improvement. Few adult cancer patients participate in trials. Although patient.decision-making about trial participation has been frequently examined, the participation rate for patients actually offered a trial is unknown. METHODS: A systematic review and meta-analysis using 3 major search engines was undertaken. We identified studies from January 1, 2000, to January 1, 2020, that examined clinical trial participation in the United States. Studies must have specified the numbers of patients offered a trial and the number enrolled. A random effects model of proportions was used. All statistical tests were 2-sided. RESULTS: We identified 35 studies (30 about treatment trials and 5 about cancer control trials) among which 9759 patients were offered trial participation. Overall, 55.0% (95% confidence interval [CI] = 49.4% to 60.5%) of patients agreed to enroll. Participation rates did not differ between treatment (55.0%, 95% CI = 48.9% to 60.9%) and cancer control trials (55.3%, 95% CI = 38.9% to 71.1%; P = .98). Black patients participated at similar rates (58.4%, 95% CI = 46.8% to 69.7%) compared with White patients (55.1%, 95% CI = 44.3% to 65.6%; P = .88). The main reasons for nonparticipation were treatment choice or lack of interest. CONCLUSIONS: More than half of all cancer patients offered a clinical trial do participate. These findings upend several conventional beliefs about cancer clinical trial participation, including that Black patients are less likely to agree to participate and that patient decision-making is the primary barrier to participation. Policies and interventions to improve clinical trial participation should focus more on modifiable systemic structural and clinical barriers, such as improving access to available trials and broadening eligibility criteria.

Feasibility of Cancer Clinical Trial Enrollment Goals Based on Cancer Incidence.

PURPOSE: More than 20% of US clinical trials fail to accrue sufficiently. Our purpose was to provide a benchmark for better understanding clinical trial enrollment feasibility and to assess relative levels of competition for patients by cancer diagnosis. METHODS: The Database for Aggregate Analysis of ClinicalTrials.gov, up to date as of September 3, 2017, was used to identify actively recruiting, interventional oncology trials with US sites. Observational studies were excluded because not all are registered. Trials were categorized through Medical Subject Headings or free-text condition terms and sorted by cancer diagnosis. Trials that included more than one cancer diagnosis were included in the overall cohort but excluded when evaluating enrollment by cancer type. Trial enrollment slot availability was estimated between September 1, 2017, and August 31, 2018. Availability was estimated from total anticipated enrollment and duration, assuming a constant recruitment rate. Estimates for studies with both foreign and domestic sites were then prorated to calculate available enrollment in the United States alone. Ratios of the number of newly diagnosed patients in the United States available per trial slot were estimated using the American Cancer Society cancer incidence estimates for 2017. RESULTS: A total of 4,598 interventional oncology trials were identified. Overall, the estimated ratio of newly diagnosed patients available per trial slot was 12.6. Estimated ratios of patients per trial slot for six cancer diagnoses with the highest potential of 12-month US enrollment were as follows: colorectal, 24.7; lung and bronchus, 20.1; prostate, 17.6; breast (female), 13.8; leukemia, 11.6; and brain and other nervous system, 6.0. CONCLUSION: For all cancers, successfully accruing trials currently open would require that more than one in every 13 recently diagnosed patients (7.9%) enroll. This ratio and relative difficulty of accrual varies among cancers examined.

Systematic Review and Meta-Analysis of the Magnitude of Structural, Clinical, and Physician and Patient Barriers to Cancer Clinical Trial Participation.

BACKGROUND: Barriers to cancer clinical trial participation have been the subject of frequent study, but the rate of trial participation has not changed substantially over time. Studies often emphasize patient-related barriers, but other types of barriers may have greater impact on trial participation. Our goal was to examine the magnitude of different domains of trial barriers by synthesizing prior research. METHODS: We conducted a systematic review and meta-analysis of studies that examined the trial decision-making pathway using a uniform framework to characterize and quantify structural (trial availability), clinical (eligibility), and patient/physician barrier domains. The systematic review utilized the PubMed, Google Scholar, Web of Science, and Ovid Medline search engines. We used random effects to estimate rates of different domains across studies, adjusting for academic vs community care settings. RESULTS: We identified 13 studies (nine in academic and four in community settings) with 8883 patients. A trial was unavailable for patients at their institution 55.6% of the time (95% confidence interval [CI] = 43.7% to 67.3%). Further, 21.5% (95% CI = 10.9% to 34.6%) of patients were ineligible for an available trial, 14.8% (95% CI = 9.0% to 21.7%) did not enroll, and 8.1% (95% CI = 6.3% to 10.0%) enrolled. Rates of trial enrollment in academic (15.9% [95% CI = 13.8% to 18.2%]) vs community (7.0% [95% CI = 5.1% to 9.1%]) settings differed, but not rates of trial unavailability, ineligibility, or non-enrollment. CONCLUSIONS: These findings emphasize the enormous need to address structural and clinical barriers to trial participation, which combined make trial participation unachievable for more than three of four cancer patients.

Association of Patient Comorbid Conditions With Cancer Clinical Trial Participation.

Importance: The American Society of Clinical Oncology (ASCO), Friends of Cancer Research, and the US Food and Drug Administration recently recommended modernizing criteria related to comorbidities routinely used to exclude patients from cancer clinical trials. The goal was to design clinical trial eligibility such that trial results better reflect real-world cancer patient populations, to improve clinical trial participation, and to increase patient access to new treatments in trials. Yet despite the assumed influence of comorbidities on trial participation, the relationship between patients' comorbidity profile at diagnosis and trial participation has not been explicitly examined using patient-level data. Objectives: To investigate the association between comorbidities, clinical trial decision-making, and clinical trial participation; and to estimate the potential impact of reducing comorbidity exclusion criteria on trial participation, to provide a benchmark for changing criteria. Design, Setting, and Participants: A national survey was embedded within a web-based cancer treatment-decision tool accessible on multiple cancer-oriented websites. Participants must have received a diagnosis of breast, lung, colorectal, or prostate cancer. In total, 5499 surveyed patients who made a treatment decision within the past 3 months were analyzed using logistic regression analysis and simulations. Exposures: Cancer diagnosis and 1 or more of 18 comorbidities. Main Outcomes and Measures: Patient discussion of a clinical trial with their physician (yes vs no); if a trial was discussed, the offer of trial participation (yes vs no); and, if trial participation was offered, trial participation (yes vs no). Results: Of the 5499 patients who participated in the survey, 3420 (62.6%) were women and 2079 (37.8%) were men (mean [SD] age, 56.63 [10.05] years). Most patients (65.6%; n = 3610) had 1 or more comorbidities. The most common comorbid condition was hypertension (35.0%; n = 1924). Compared with the absence of comorbidities, the presence of 1 or more comorbidities was associated with a decreased risk of trial discussions (44.1% vs 37.2%; OR, 0.86; 95% CI, 0.75-0.97; P = .02), trial offers (21.7% vs 15.7%; OR, 0.82; 95% CI, 0.70-0.96; P = .02), and trial participation (11.3% vs 7.8%; OR, 0.76; 95% CI, 0.61-0.94; P = .01). The removal of the ASCO-recommended comorbidity restrictions could generate up to 6317 additional patient trial registrations every year. Conclusions and Relevance: Independent of sociodemographic variables, the presence of comorbidities is adversely associated with trial discussions, trial offers, and trial participation itself. Updating trial eligibility criteria could provide an opportunity for several thousand more patients with well-managed comorbidities to participate in clinical trials each year.

Reducing tobacco-related cancer incidence and mortality: summary of an institute of medicine workshop.

Tobacco use remains a serious and persistent national problem. Recognizing that progress in combating cancer will never be fully achieved without addressing the tobacco problem, the National Cancer Policy Forum of the Institute of Medicine convened a public workshop exploring current issues in tobacco control, tobacco cessation, and implications for cancer patients. Workshop participants discussed potential policy, outreach, and treatment strategies to reduce tobacco-related cancer incidence and mortality, and highlighted a number of potential high-value action items to improve tobacco control policy, research, and advocacy.

Autologous chemotaxis as a mechanism of tumor cell homing to lymphatics via interstitial flow and autocrine CCR7 signaling.

CCR7 is implicated in lymph node metastasis of cancer, but its role is obscure. We report a mechanism explaining how interstitial flow caused by lymphatic drainage directs tumor cell migration by autocrine CCR7 signaling. Under static conditions, lymphatic endothelium induced CCR7-dependent chemotaxis of tumor cells through 3D matrices. However, interstitial flow induced strong increases in tumor cell migration that were also CCR7 dependent, but lymphatic independent. This autologous chemotaxis correlated with metastatic potential in four cell lines and was verified by visualizing directional polarization of cells in the flow direction. Computational modeling revealed that transcellular gradients of CCR7 ligand were created under flow to drive this response. This illustrates how tumor cells may be guided to lymphatics during metastasis.

Interstitial flow and its effects in soft tissues.

Interstitial flow plays important roles in the morphogenesis, function, and pathogenesis of tissues. To investigate these roles and exploit them for tissue engineering or to overcome barriers to drug delivery, a comprehensive consideration of the interstitial space and how it controls and affects such processes is critical. Here we attempt to review the many physical and mathematical correlations that describe fluid and mass transport in the tissue interstitium; the factors that control and affect them; and the importance of interstitial transport on cell biology, tissue morphogenesis, and tissue engineering. Finally, we end with some discussion of interstitial transport issues in drug delivery, cell mechanobiology, and cell homing toward draining lymphatics.