Recurrent disease detection after resection of pancreatic ductal adenocarcinoma using a standardized surveillance strategy - an international randomized controlled trial by the Dutch Pancreatic Cancer Group

Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer
related mortality in Europe for both men and women. For patients with
resectable localized disease, radical resection combined with (neo)adjuvant
chemotherapy offers the best chances for long-term survival. However, even
after radical resection, almost all patients will experience local and/or
distant disease recurrence after sufficient follow-up, mostly within 2 years.
Therefore, PDAC continues to be associated with a 5-year survival rate of only
12-27% postoperatively.

Optimal management of recurrent PDAC is less well established as it is for
other primary PDAC and exists of either palliative chemotherapy or best
supportive care in the Netherlands. The lack of evidence-based effective
therapeutic options for the significant group of patients with pancreatic
cancer recurrence, in terms of improved quality of life and/or survival, has
led to a hesitant attitude towards postoperative recurrence-focused follow-up.
In most European countries, including the Netherlands, a standardized approach
to follow-up after surgery for PDAC is lacking. Furthermore, current PDAC
guidelines regarding follow-up are based on expert opinion and other low-level
evidence, and a global controversy about surveillance strategies exists.

According to the current literature, a selected group of patients with
recurrent PDAC might benefit from additional therapy. Moreover, the emergence
of more potent treatments for PDAC, such as new chemotherapy (e.g. FOLFIRINOX)
and stereotactic body radiotherapy (SBRT), has led to a rising interest in
diagnosis of recurrent PDAC. Consequently, a standardized surveillance strategy
is increasingly recommended. To determine whether early detection of recurrence
can lead to improved survival and quality of life, further studies are
warranted.

The RADAR-PANC trial is designed to investigate whether a standardized
surveillance strategy with serial tumor marker testing and routine imaging
improves the overall survival in patients after radical resection for
pancreatic ductal adenocarcinoma (PDAC) in the Netherlands, compared to current
non-standardized follow-up. Furthermore, the consequences of a standardized
surveillance strategy on quality of life and additional (experimental)
treatment will be assessed within this study.

We hypothesize that patients in the standardized surveillance arm will be
diagnosed with PDAC recurrence at an earlier stage (i.e. localized disease and
a good performance status). Consequently, this will lead to a higher number of
patients eligible for additional (experimental) treatment for recurrence. The
eventual goal of standardized surveillance will therefore be to improve
survival.

The RADAR-PANC is a randomized controlled trial nested within the PACAP and
PACOPS-projects according to the Trials within Cohorts (TwiCs) design, in all
hospitals affiliated to the Dutch Pancreatic Cancer Group (DPCG) and the UK.
The TwiCs design has already gained positive experience within other national
cohorts as the Prospective Dutch colorectal cancer cohort (PLCRC, www.plcrc.nl,
registered at Clinicaltrials.gov under NCT02070146).

When participating in the PACAP or PACOPS-cohort, patients will be followed and
treated according to the current, non-standardized practice. To investigate
whether an standardized surveillance strategy improves survival rates,
subsequent randomization for follow-up method is performed within a subgroup of
eligible patients. This subgroup exists of all PACAP and PACOPS-participants
with histologically confirmed macroscopic radical resection (R0-R1) of PDAC.
Patients who participate in the PREOPANC-2 trial are excluded as these patients
are subjected to a study-specific follow-up. Participants are either randomized
for follow-up according to the current, non-standardized practice (50%), or
routine surveillance according to our study-protocol (50%). Only patients
randomized for the investigational arm are approached for participation;
patients randomized for the control arm are not further notified. Study-related
follow-up will be at 3, 6, 9, 12, 15, 18, 21 and 24 months postoperatively
during the first two years after surgery.

The follow-up scheme of this study is based on current surveillance guidelines
after resection for PDAC as recommended by the National Comprehensive Cancer
Network (NCCN). For the first two years after surgery, clinical evaluation,
serum CA 19-9 testing and contrast-enhanced CT imaging of chest and abdomen is
performed three-monthly. In case of suspicious findings on CT without elevated
tumor markers, a PET-CT scan can additionally be performed. Also, as part of
the Dutch Pancreatic Biobank (PancreasParel), extra blood samples are taken
each follow-up visit for further scientific research. Quality of Life is
assessed during each follow-up appointment, which is already standardly
performed by assessing Patient Reported Outcome measures (PROMs) as a part of
the current PACAP and PACOPS-projects of the Dutch Pancreatic Cancer Group
(DPCG) and UK.

In case recurrent disease is detected, *best supportive care* or subsequent
palliative therapy and type of additional treatment will be administered at the
discretion of the treating clinician in both trial arms, which is the current
standard practice. According to the concept of the TwiCs studydesign, however,
all participants with disease recurrence in the cohort can be offered to
participate in new investigational trials on management of recurrent pancreatic
cancer. In the Netherlands, within the DPCG, various radiotherapeutic and/or
oncologic intervention studies for recurrent pancreatic cancer are being
initiated.

For the first two years after surgery, clinical evaluation, serum CA 19-9
testing and contrast-enhanced CT imaging of chest and abdomen is performed
three-monthly.

No side-effects are expected due to the intervention, as the safety protocol of
the department of radiology will be followed. CT-scanning is associated with
radiation exposure. However, no harm is expected given the short
life-expectancy in our study-population. Furthermore, a standardized follow-up
carries the potential for harm in terms of decrease in quality of life, since
disease progression is diagnosed in the absence of symptoms and the impact on
survival is yet unknown. Also, participants could experience stress regarding
their follow-up appointments. We will inform patients who are randomized for a
standardized surveillance about these issues thoroughly, using a written
patient information form, so that they can make a deliberated choice to
participate in the intervention arm. This information will be designed in
collaboration with the Dutch pancreatic cancer patients* association Living
With Hope. Potential benefits may be the possibility to undergo adjuvant
(experimental) treatment, a prolonged survival, better symptom directed
clinical detection and management, and patient recruitment to investigational
studies for innovative diagnostic and treatment modalities of PDAC.