Multi-Specialty Physician Perspectives on Barriers and Facilitators to the Use of Neoadjuvant Therapy for Pancreatic Ductal Adenocarcinoma

Abstract

Introduction

Neoadjuvant therapy (NT) is increasingly utilized for patients with localized pancreatic ductal adenocarcinoma (PDAC). Given the importance of completing multimodality therapy, the purpose of this qualitative study was to characterize physician perspectives on barriers and facilitators to delivering NT.

Methods

A purposive sample of surgical, medical, and radiation oncologists participated in semi-structured interviews. Interviews were transcribed and coded by 3 independent researchers, iteratively identifying themes until saturation was achieved.

Results

Participants (n=27) were heterogeneous in specialty, years of experience, practice setting, gender, and geography. The most commonly cited advantage of NT was the ability to downstage patients. The most commonly cited barriers included lack of access and limited evidence. Patient preference for immediate surgery was frequently cited as a barrier, but most participants felt that patients eventually understood the treatment recommendation after informed discussion. Recommendations to enhance the delivery of NT included improved patient education, communication, and better evidence.

Discussion

In this qualitative study, indications for, barriers to, and opportunities to improve the delivery of NT for localized PDAC were identified. These results highlight the need for better evidence and protocol standardization for NT as well as methods of improving care coordination, communication, and education to improve patient-centered outcomes.

Introduction

Surgical resection is generally considered necessary but not sufficient for curative-intent treatment of pancreatic ductal adenocarcinoma (PDAC). The delivery of chemotherapy and/or chemoradiation therapy prior to surgery, known as neoadjuvant therapy (NT), is increasingly utilized for patients with localized PDAC as it is for other cancer types as well.^1,2 NT improves margin-negative resection rates, increases the receipt of multimodality therapy since a substantial proportion of patients undergoing pancreatectomy will be unable to initiate adjuvant chemotherapy, and based on emerging evidence from randomized controlled trials, leads to improved overall survival.^3–9 For these reasons, NT is now the recommended approach for borderline resectable (BR) and locally advanced (LA) cancers and an acceptable option for potentially resectable (PR) cancers according to national guidelines.^9–11

The delivery of NT is inherently complex and requires an experienced multi-disciplinary team to facilitate completion of all intended therapy and receipt of surgical resection.¹² Unfortunately, recent prospective trials have shown that nearly 30% of patients with PR cancers are unable to complete NT and undergo resection,^13–15 most often because of disease progression but also due to toxicity from treatment, performance status decline, or personal preference. The odds of successfully completing NT and undergoing resection are even worse among patients with more advanced disease or coexisting health conditions. Nevertheless, there is a limited understanding of barriers and facilitators to the effective initiation and delivery of NT for PDAC which will be necessary for designing innovative methods of improving outcomes for patients with localized PDAC.

The purpose of this qualitative study was to explore multi-specialty perspectives on barriers and facilitators to the delivery of NT for PDAC. We hypothesized that physicians from different specialties have unique perspectives on barriers and potential facilitators to delivering NT more effectively.

Methods

Study Design and Population

An equal sample of surgical, medical, and radiation oncologists who care for patients with PDAC in the state of Ohio were recruited to participate in this qualitative study. A sample size of 8-10 participants from each specialty was decided a priori as prior research has suggested that theme saturation typically occurs following 15-25 interviews.^16,17 A purposive sampling strategy was used to balance physician demographics, including age, gender, geographic location, years of experience, and practice setting (academic vs non-academic). Interviewees were identified via the researchers’ prior professional relationships and/or referrals from colleagues. The researchers reached out to all potential participants by phone, informed consent was obtained, and a semi-structured interview was scheduled at the participant’s convenience.

Interview Guide and Process

The interview script was developed using evidence synthesis, stakeholder engagement, and data from preliminary surveys (n=20) administered to PDAC physicians at The Ohio State University Wexner Medical Center (OSUWMC). Content of the interviews focused on perceived advantages and disadvantages of, current indications for, and barriers and facilitators to the use of NT for PDAC. Questions were open-ended, prompting additional questions depending on the responses of the interviewees. This type of interview method was selected due to the descriptive nature of the research. Semi-structured interviews allow researchers to discuss topics of interest more in detail by elaborating on emerging themes and asking probing questions.¹⁸ A nominal gift card was given to participants for their participation. This study was approved by the Institutional Review Board of The Ohio State University.

Data Analysis

All interviews were transcribed verbatim using an automatic transcription service (Wreally, California). Transcripts were then uploaded to NVivo12 (QSR International, Australia) for data extraction, synthesis, and analysis purposes.¹⁹ Data extraction followed an integrated approach, which includes both an inductive and deductive coding methodology. The following preliminary codes were developed before a more in-depth, inductive coding process took place: advantages and disadvantages, physician decision making, barriers and challenges, solutions and facilitators, and patient perspectives. Three researchers independently coded the transcripts for sub-themes in an iterative fashion until thematic saturation was achieved. All discrepancies were discussed at team meetings until a consensus was reached. Demographic data from participants were summarized and illustrative quotes from each theme were selected. Less frequently discussed themes are listed in table footnotes.

Results

Participant Characteristics

A total of 27 radiation, surgical, and medical oncologists (n=9 each) from the state of Ohio were interviewed (Figure 1). On average, physicians had 9.1 years of experience, ranging from 1 to 25 years. Physician practice settings were academic medical centers (n=11), private practice (n=11), hybrid (defined as a hospital either affiliated with an academic medical center or with a residency training program) (n=3), and community centers (n=2). Complete participant characteristics are reported in Table 1.

Figure 1:

Geographical location of primary work site throughout state of Ohio of participating physicians classified by specialty.

Table 1:

Characteristics of Physician Participants Grouped by Specialty

	Surgical Oncologist (n=9)	Medical Oncologist (n=9)	Radiation Oncologist (n=9)	All (n=27)
Gender
Male	7	5	6	18
Female	2	4	3	9
Race
White	6	5	6	17
Black	0	1	0	1
Asian	3	3	3	9
Practice Setting
Academic	5	3	3	11
Private	1	5	5	11
Hybrid	3	0	0	3
Community Center	0	1	1	2
Years of Experience
Mean	8.9	9.3	9.2	9.1
Range	1-17	3-25	2-25	1-25
Pancreas Cancer Patients Treated per Year
Mean	66	19	12	32
Range	10-125	2.5-50	2.5-40	2.5-125

Advantages and Indications for Neoadjuvant Therapy

Numerous potential advantages were raised by participants (Table 2). The most commonly cited advantage of NT overall was the ability to downstage patients with advanced disease to resectable (n=17), followed by improved rates of multimodality therapy (n=16) and patient selection for surgery (n=15). Whereas surgical oncologists frequently cited the ability to deliver multimodality therapy (n=7 of 9) and improved patient selection for surgery (n=7 of 9) as advantages of NT, radiation oncologists emphasized the importance of downstaging (n=8 of 9). Interestingly, a minority of physicians felt that improved overall survival (n=6) or that assessing patients’ physical response (n=5) or tumor response (n=4) were important advantages of NT.

Table 2:

Proposed Advantages of Neoadjuvant Therapy for Pancreatic Cancer

Theme	Frequency				Definition	Representative Quote
	All	SO1	MO2	RO3
Downstaging	17	4	5	8	Improving the odds of surgical resection	“the main advantages of neoadjuvant therapy are to help do tumor down staging, shrink the tumor, help to potentially make the surgery go better”
Multimodality Therapy	16	7	5	4	Increase the odds of receiving all intended therapy	“most patients that undergo these big surgeries, a majority of them do not get to [adjuvant] chemotherapy. So giving it up front, you know, pretty much guarantees that they will get it”
Patient Selection	15	7	3	5	Ensuring that the cancer biology is appropriate for surgery	“preoperative chemotherapy allows us to only do these operations on people that are truly going to benefit from them; that is to say people that rapidly progress while on chemotherapy are spared an unnecessary operation”
Margin-negative	14	3	6	5	Increasing the likelihood of achieving R0 margins	“if somebody is considered potentially to be a rough resectable case or someone that somebody’s worried about margins or fascial planes, doing the neoadjuvant therapy increases the likelihood that you’re going to have an R0 surgery, an R0 surgery meaning complete, everything’s taken out”
Control of Micro-metastatic Disease	10	2	3	5	Treating presumed micro-metastatic	“would allow them to have systemic chemotherapy that hopefully would reduce the chance of the micro-metastatic disease becoming to metastatic disease.”
Survival Benefit	6	2	3	1	Improved overall survival	“[even if] they have a small tumor, I usually do try to push them towards doing neoadjuvant because …. the literature that is out there saying that if you do it, you’ll increase their overall and disease-free survival”
Evaluating Patients’ Physical Response	5	2	3	0	Determining patients’ functional capacity for surgery	“if a patient is struggling from a performance status, not able to thrive during neoadjuvant chemotherapy, then I think I would think long and hard about performing a Whipple or pancreas resection on them”
Evaluating Tumor Response	4	2	1	1	Determining in vivo response to treatment	“It can kind of declare what the disease is like, you know, if it’s going to respond you kind of know the better prognostic indicator versus if it doesn’t respond”
Improved Tolerability	4	0	2	2	Fewer toxicities of therapy prior to surgery	“most people tolerate both chemotherapy and radiation better when it’s done neoadjuvantly”

Less frequently discussed themes: improved local control (n=2), more effective therapies can be used (n=2), opportunity for prehabilitation (n=1), patients can continue work (n=1)

¹Surgical Oncologist,

²Medical Oncologist,

³Radiation Oncologist

When asked about current indications for NT, the most common response was that NT was indicated when achieving a margin-negative resection was in doubt (n=17), followed by the belief that NT is indicated for all patients (n=12). Among surgical oncologists, the belief that NT was indicated for all patients was the most common response (n=7 of 9) whereas questionable resectability was the most common response among radiation and medical oncologists (n=14 of 18). Physicians commonly discussed factors that influenced their practice preferences regarding NT. The most commonly mentioned factor was their training, education, and/or background (n=21), followed by emerging data from the literature (n=10), as well as guidelines and protocols (n=10). While some depended on input from their multidisciplinary tumor board (n=5), non-surgeons often deferred the decision on NT to the surgical oncologist’s recommendation (n=5 of 18).

Disadvantages and Barriers to Neoadjuvant Therapy

Multiple disadvantages and potential barriers to the use of NT were mentioned (Table 3). The most commonly cited disadvantage of NT was toxicity from treatment (n=21). Challenges with care delivery were also frequently mentioned: limited access (e.g., access to physician specialists, challenges with travel, adequate health insurance, etc. (n=14)); care coordination (n=12), and communication among providers (n=8). Tumor progression was not uniformly felt to be a disadvantage as many had highlighted that this typically represented aggressive tumor biology and was a method of patient selection before surgery. Finally, limited evidence and/or data (n=8) and conflicting opinions on treatment approach (n=8) were felt to be barriers to utilizing NT.

Table 3:

Proposed Disadvantages of & Barriers to Neoadjuvant Therapy for Pancreatic Cancer

Theme	Frequency				Definition	Representative Quote
	All	SO1	MO2	RO3
Toxicity	21	7	7	7	Adverse effects of chemotherapy or radiation	“The chemotherapy we want to give in the neoadjuvant setting could make someone very sick”
Access	14	3	5	6	Accessibility, affordability, and availability of services	“I work in a small center…We don’t have any hepatobiliary surgeons here, for example”
Care Coordination	12	2	5	5	Coordinating multidisciplinary cancer care	“one of our challenges is just having to coordinate with physicians at another center, requires a little bit more work because we’re in different hospital systems.”
Progression and Tumor Spread	10	1	3	6	Tumor progression precluding surgical resection	“We’ve had patients…where they started neoadjuvant treatments and then we realize that the cancer has spread and now they’re not a surgical candidate”
Communication	8	2	5	1	Communication among providers	“You know, a lot of times I have to request the records each time they come to get an update about what’s going on because we’re not necessarily automatically included in that circle of communication”
Conflicting Opinions	8	4	3	1	Inconsistent treatment recommendations from different physicians	“they were confused because I spent all this time with him the night before talking about neoadjuvant…and the [other physician] comes in, we hadn’t gotten our story straight, and said, yeah get surgery first.”
Lack of Data	8	3	2	3	Inadequate evidence to support practice	“it’s harder to justify because we don’t have strong data supporting it”
Delayed Surgery	5	0	3	2	Surgery delayed	“if you had someone who you thought was a great surgical candidate and someone who’s going to do great through therapy and then for whatever reason they just have extremely hard time with neoadjuvant chemo and then surgery gets delayed.”
Inability to Predict Response	4	2	2	0	Lack of biomarkers to predict responders to NT	“We just can’t predict when those disadvantages will become clinically relevant or when they will not be.”

Less frequently discussed themes: Referring institutions inexperienced delivering NT (n=3), technical challenges (n=3), losing patients to other institutions/providers (n=2), may make surgery more difficult (n=2), ongoing symptoms of tumor (n=2), no protocols (n=2), need for patient trust (n=2), no disadvantages (n=2), time intensive to educate patients (n=1)

¹Surgical Oncologist,

²Medical Oncologist,

³Radiation Oncologist

Compared to radiation and medical oncologists, fewer surgical oncologists reported concern with disease progression (n=1 of 9), access to care (n=3 of 9), or challenges associated with care coordination (n=2 of 9). Medical oncologists cited communication among providers as a challenge (n=5 of 9) and radiation oncologists were especially concerned with the potential for local or distant progression (n=6 of 9).

Solutions and Facilitators to Delivering Neoadjuvant Therapy

Several facilitators and potential solutions were discussed to potentially improve the delivery of NT for patients with PDAC (Table 4). The most commonly cited facilitator to enhancing the delivery of NT was to better educate patients about expectations, advantages, and disadvantages of NT as well as help navigate them through the process of initiating NT (n=18). Many participants discussed the need for better evidence (n=15) as well as protocol standardization (n=8). In addition, better communication among providers (n=12) and with patients (n=10) were highlighted.

Table 4:

Proposed Solutions and Facilitators for Neoadjuvant Therapy for Pancreatic Cancer

Theme	Frequency				Definition	Representative Quote
	All	SO1	MO2	RO3
Patient education and navigation	18	3	8	7	Educating and assisting patients on initiating and undergoing treatment	“right now, I’m sort of acting as my own patient navigator, but it would certainly be nice to have a well-trained nurse or some sort of navigator position who was familiar with the different chemotherapy regimens, familiar enough with the surgery that she could explain any additional questions they may have you know when they leave our initial clinic visit.”
Evidence and data for treatment plans	15	4	3	8	Improved evidence to support use of NT	“There needs to be compelling outcome data showing that it’s advantageous. If that’s the case, then the paradigm will switch pretty easily … they just need data to support it.”
Communication between providers	12	2	5	5	Communication between providers about patients	“Adequate communication between treatment teams I think is very important. If there’s discordance, that could be very challenging as far as the role of and why chemotherapy. Having consistent messaging…”
Communication with patients	10	2	3	5	Communication with patients	“I try very very hard to explain things usually two or three different ways when I’m talking with them and then before the end of the visit make sure I reiterate”
Protocol standardization	8	3	2	3	Establishing treatment algorithms	“I’m definitely a believer in protocols. I like it where, you know, we have a preset plan of this is how it’s going to be, and this is how it’s going to be pretty much for everybody that has this kind of cancer because it allows people to know their role”
Logistics and scheduling	6	2	1	3	Improving logistics of delivering NT	“I think that keeping the ball rolling, so to speak is important…. trying to do things in parallel not one after the other is important because that gets things done more quickly and certainly would remove any hesitation or concern that a patient may have about a delay in start of treatment”
Ancillary Services	5	1	1	3	The use of services such as nutrition, physical therapy, social work, and others to assist patients	“having patients seen by ancillary services like dietitians early in the course of treatment, you know, understanding that weight loss can be very detrimental” can be very helpful
Treatment efficacy	4	2	1	1	The development of less toxic, more targeted and/or more effective systemic therapies	“we always want to be able to find something that is better than what we standardly have to offer for patients”
Multidisciplinary clinics	4	2	1	1	Clinics with multi-specialty providers	“so [patients] know that all the treating team clinicians are on the same page but also minimizes the number of visits they need and sort of gets everything done in one comprehensive visit, maybe something that could make the process more efficient”

Less frequently discussed themes: multidisciplinary treatment teams (n=3), social support (n=2)

¹Surgical Oncologist,

²Medical Oncologist,

³Radiation Oncologist

Physician Perspectives on Patient Experience

Physician perspectives on the patient experience were also assessed. Patient preference for immediate surgery was frequently cited (n=22) as a barrier to NT. Additionally, patient anxiety, fear, and stress was discussed as potential barriers to NT (n=10), as well as financial concerns associated with receiving this type of treatment (n=9). On the other hand, while patient fear and anxiety were often perceived by physicians, most participants felt that patients eventually understood the rationale for recommending NT after informed discussion (n=26) and ultimately placed their trust in their health care providers regarding their treatment decisions (n=16).

Discussion

While initially pioneered at a few institutions, advances in systemic therapies, expanding evidence of its safety and efficacy, and its incorporation into national guidelines has led to an increase in the use of NT for localized PDAC.²⁰ Nevertheless, the current indications for, the duration and components of treatment, and suitable endpoints to define treatment response are poorly established. At the same time, the delivery of NT is complex and research on barriers and facilitators to the effective initiation and delivery of NT for PDAC is scarce. In this qualitative study of multi-specialty physicians from diverse practice settings, numerous barriers and challenges of NT were identified including toxicity associated with treatment, access to care, care coordination, and patient psychosocial stress and preference for immediate surgery. In addition to better evidence and protocol standardization, improved patient education, communication, and care coordination were identified as factors necessary to enhance the delivery of NT.

Several rationales have been proposed for the use of NT in the past. The current study suggests that most physicians prioritize the use of NT to improve the chances of a margin-negative resection whether through downstaging BR/LA cancers or to decrease microscopically positive margins among resected patients. This concept coincides with patient expectations in which surgery is highly prioritized and that the strongest justification for NT is if it improves the odds of undergoing surgical resection (unpublished data).²¹ Interestingly, potential differences were observed in our study based on specialty. Surgical oncologists frequently emphasized improved multimodality therapy and patient selection as advantages of NT and that NT should be considered for all cases of localized PDAC. It is possible that surgeons’ viewpoints are influenced by prior patients’ difficulty in initiating adjuvant therapy or developing early recurrence after surgery. Notably, a number of factors were also mentioned less frequently, which underscores the wide range of perspectives on the current indications and expectations for NT.

It is unsurprising that toxicity was the single most frequently cited disadvantage of NT, since side effects of aggressive chemotherapy and radiation are common. While these therapies may be better tolerated prior to (rather than immediately following) a major operation, toxicities are still common and occasionally severe enough to preclude surgery.¹³ This highlights the need for more efficacious and less toxic therapies for PDAC as well as strategies to support patients receiving NT. However, other barriers to the successful initiation and delivery of NT are notable. For example, lack of access was frequently cited and examples from participants included underinsurance, lack of available specialty physicians (e.g. pancreatic surgeon) and travel burdens. Challenges in care coordination and communication were also commonly mentioned. NT is inherently complex and multi-disciplinary, requiring coordination among a team of expert specialists and providers. These challenges may be even greater when care is fragmented across multiple hospitals or clinics.²²

Despite the perceived barriers and challenges, multiple potential solutions to improving the delivery of NT were offered. The most commonly cited facilitator to enhancing the delivery of NT was to better educate patients about NT. Along the same lines, the need for better communication with patients was highlighted. These findings align with previous research stating that providing patients with information about their disease and treatment plan can positively impact patients’ anxiety levels and aid in managing the disease.^23,24

An important domain that evolved throughout the study was physician perspectives on the patient experience. In fact, most physicians felt that patients, in general, had an innate preference for immediate surgery (i.e. “just get the tumor out”). On the other hand, most physicians also felt that after an informed discussion, most patients eventually understood the rationale for recommending NT. Additional research on patient preferences and optimal methods of communication to enhance shared-decision making are needed. In addition, patient anxiety, fear, and stress were commonly mentioned by physicians as barriers to NT. While limited evidence suggests that patient quality of life is preserved during NT for PDAC,²⁵ little information is available on the patient experience while undergoing NT. Since evidence suggests that screening for and addressing psychosocial distress improves patient outcomes during cancer treatment;^26,27 additional research on patient emotional health and the role of psychosocial distress screening during NT is needed.

Several limitations of the current study should be acknowledged. First, when conducting qualitative research, there is always a risk of implicit researcher bias. To minimize this bias, the interview script was developed using a standardized validated approach. Second, a diverse sample of multi-specialty physicians was recruited from heterogeneous practice settings and locations. Nevertheless, it is possible that our findings are not generalizable to the larger population of pancreatic cancer physicians. Future research may employ different methodologies to ascertain a more representative national perspective.

In conclusion, this is the first qualitative study to characterize physician perspectives on the indications for, barriers to, and opportunities to improve the delivery of NT for localized PDAC. These study results highlight the need for better evidence and protocol standardization for NT as well as methods of improving care coordination, communication, and education to improve patient-centered outcomes of those undergoing NT for PDAC.