Table 3.

Multivariate Analyses Of Delayed Care Associations In Pancreatic Cancer

Study	Analyzed Population	Outcome Parameter	Findings In Multivariate Analyses	Potential Sources Of Confounding, And/Or Adjustment For Intermediate Outcomes
17	Pancreatic cancer	Time from first symptom to first consultation >30 days	Presence of metastasis: OR 1.2 (95% CI 0.8–1.8). Adjusted for age, sex, and type of initial symptoms#.	Not controlled for histology type and time from first consultation to metastasis status assessment.
		Time from first consultation to first treatment >29 days	Presence of metastasis: OR 0.5 (95% CI 0.3–0.9)#§. Treatment type: medical bypass OR 0.7 (95% CI 0.3–1.7), chemo- or radiotherapy OR 2.1 (95% CI 1.0–4.4). Adjusted for age, sex, Charlson comorbidity index, type of initial symptoms#, type of first practitioner (GP/gastroenterologist/emergency room#/other), and socioeconomic quintiles.	Not controlled for histology type and time from first symptom to first consultation. Wait time paradox; length bias (untreated patients excluded).
Overall survival	Time from first symptom to first consultation >30 days: HR 1.09 (95% CI 0.74–1.63); Time from first consultation to treatment ≥29 days: HR 0.73 (95% CI 0.51–1.06); Both periods above the thresholds: HR 0.84 (95% CI 0.60–1.17). Adjusted for age#, sex, socioeconomic quintiles, and stage/radicality of surgery (M0 with R0/M0 without R0/M1)#.	Not controlled for histology type, and for location within the pancreas or type of initial symptoms. Adjusted for intermediate outcomes (complete resection and presence of distant metastasis). Wait time paradox; length bias (untreated patients excluded).
18	Periampullary cancers of any histology, serum total bilirubin 2.3–14.6 mg/dL, no CT evidence of locoregional irresectable or metastatic disease, all patients who underwent surgery	Overall survival	Time from randomization to surgery in weeks: HR 0.91 (95% CI 0.84–0.99)#§. Adjusted for age, sex, bilirubin quartiles at randomization#, resection of tumor, intraoperative blood transfusion, and surgery complications.	Adjustment by design (RCT) was imperfect, imbalance in sex and in BMI. Not controlled for histology in the analyses. Adjusted for an intermediate outcome (tumor resectability at surgical exploration). Length bias (patients not undergoing surgery were excluded).
Subgroup undergoing resection surgery	Time from randomization to surgery in weeks: HR 0.85 (95% CI 0.75–0.96)#§. Adjusted for age, sex, histology (PDAC/other)#, nodal status#, microscopically residual disease (R1)#, bilirubin quartiles at randomization#, and surgery complications#.	Adjustment by design (RCT) was imperfect, imbalance in sex and BMI. Adjusted for intermediate outcomes (nodal status and microscopically residual disease). Length bias (patients not undergoing resection surgery were excluded).
19	All solid organ cancers	Presence of metastasis at diagnosis	Time from first symptom to first visit in months: OR 0.97 (95% CI 0.96–0.99)#§. Adjusted for age groups# and sex#.	Not controlled for primary organ, histology type, location within the pancreas or type of initial symptoms, and delay from first visit to diagnosis. Wait time paradox.
29	Surgical candidates with PDAC deemed resectable by imaging	Presence of unresectable disease	Time from imaging to resection ≤32 days: OR* 0.35 (95% CI 0.14–0.90)#. Adjusted for preoperative tumor size (<30 mm)# and preoperatively assessed vascular involvement (no or minor)#.	Not controlled for age, sex, location within the pancreas or type of initial symptoms. No adjustment for intermediate outcomes. Controlled for length bias and for the wait time paradox.
32	Pancreatic cancer, stratified by chemotherapy	Overall survival	Time from symptoms to diagnosis in weeks: HR 1.0240 (95% CI 1.0117–1.0365)#. Adjusted for age, sex, location within the pancreas (head/other), histology (PDAC/other), stage (I+II/III+IV), size#§, and surgery type (radical resection/other)#.	Adjusted for an intermediate outcome (radical resection). Tumor size and stage could also be intermediate outcomes if determined after diagnosis from surgery specimens. Wait time paradox; length bias (patients with incomplete diagnostics were excluded).
35	PDAC; all periampullary tumors excluded	Overall survival	Time from symptoms to referral in days: HR 1.001, 95% CI 1.000–1.002, p=0.010)#; time from referral to treatment: NS, HR not reported. Adjusted for age, sex, type of initial symptoms, operability, resectability#.	Adjusted for intermediate outcomes (operability and resectability). Wait time paradox; length bias (patients not receiving treatment were excluded). Risk of lead time bias in sensitivity analysis of a 143-day threshold for patient delay.
38	Pancreatic cancer patients undergoing definitive surgery	Overall survival	Time from diagnosis to definitive treatment >31 days: HR 1.23 (95% CI 1.07–1.41)#. Adjusted for age, sex, Charlson comorbidity score, hospital type, insurance, radiotherapy after definitive surgery, chemotherapy after definitive surgery, type of medical care institution, hospital volume#, and year of diagnosis. (No information on the significance of covariates except for hospital volume).	Not controlled for histology and for location within the pancreas or type of initial symptoms. Adjusted for intermediate outcomes (having radiotherapy and chemotherapy after definitive surgery, probably due to incomplete resection). Wait time paradox; length bias (patients not receiving treatment were excluded).

Notes: # statistically significant association; § paradoxical association; * Reported as HR but is most likely OR based on the study methods.

Abbreviations: CI, confidence interval; HR, hazard ratio; OR, odds ratio; PDAC, pancreatic ductal adenocarcinoma.