Patients with resectable PC who undergo PD benefit from adjuvant therapy; current trials for resectable disease no longer have a control arm which receives surgery alone.12
Unfortunately, up to 56% of patients do not receive postoperative therapy when planned, due largely to delayed surgical recovery or early tumor recurrence.25
Neoadjuvant treatment sequencing ensures that all patients with resectable PC who undergo PD receive multimodality treatment. Neoadjuvant strategies also lead to lower than expected rates of lymphatic metastasis and positive surgical margins, enrich the population of patients who undergo PD with those most likely to benefit from surgery, and contribute to actual 5-year survival rates as high as 27%.28
Successful neoadjuvant treatment approaches require sequential staging evaluations to select those patients who will benefit from surgery—perhaps best considered as one of the earliest forms of personalized cancer care. We performed this analysis to determine whether CA 19-9 could prospectively identify those patients in whom radiographically occult advanced disease will preclude completion of a multidisciplinary strategy employing neoadjuvant therapy and PD.
An elevated CA 19-9 level at diagnosis in patients with radiographically resectable PC has been reported to signify occult disease that will prohibit primary resection.8
Our results suggest that this is not necessarily the case when surgery is preceded by induction therapy. Indeed, of 78 patients with an evaluable pretreatment CA 19-9 level above the normal range, 52 (67%) underwent PD, of whom 15 (22%) died of another cause or had not recurred at last follow-up. All patients in our study with an evaluable pretreatment CA 19-9 level greater than 1,125 U/ml either did not undergo PD or ultimately recurred after PD. However, although small patient numbers preclude rigorous statistical analysis, it is interesting that 9 of 16 (56%) patients with radiographically resectable disease and a pretreatment CA 19-9 level ≥ 1,000 U/ml underwent PD following neoadjuvant therapy, only 4 of these 9 patients recurred within 2 years, and the median overall survival of these resected patients approached 3 years. It may be that the antitumor effects of induction therapy alter the expected relationship between CA 19-9 and tumor burden over time. Our study assessed CA 19-9 only in the setting of normal bilirubin and included a more homogenous population of patients than prior studies, which also may have made differences between patient subgroups more subtle. Either way, these data support caution in the use of pretreatment CA 19-9 as an eligibility criterion for enrollment into clinical trials of neoadjuvant therapies for patients with resectable PC, as has been employed in trials of postoperative therapy (i.e., CONKO-001).12
Pretreatment CA 19-9 has also been reported to be a marker of overall prognosis for patients treated with initial surgery.8
In this analysis, pretreatment CA 19-9 within the normal range was associated with favorable overall survival. Our inability to demonstrate similar prognostic power when a cutoff of 37 U/ml was applied to the subgroup of patients who underwent PD may be due to the relatively small number of patients analyzed. Nonetheless, our data, combined with those of Berger et al., suggest that a normal CA 19-9 level upon diagnosis may indicate slightly more favorable tumor biology independent of the initial therapeutic approach.31
Response of CA 19-9 to surgical and adjuvant therapy has been reported to be a measure of therapeutic efficacy.8
Four analyses have examined the change in CA 19-9 over the course of nonoperative therapies prior to surgery. Three of these were small studies analyzing primarily patients with advanced, nonsurgical disease, who were treated in the absence of a defined plan for resection.16
The results of these studies suggested the possibility that CA 19-9 might be used as a crude measure of response to preoperative therapy. However, the heterogeneity of the patient populations studied makes this conclusion difficult to apply to individual patients with resectable disease who are being considered for neoadjuvant treatment prior to planned PD. Indeed, a recent prospective study of neoadjuvant chemoradiation prior to planned resection in 28 patients with resectable PC was unable to demonstrate any correlation between change in CA 19-9 and therapeutic response or ultimate resectability.15
Importantly, this study was small and did not take into account the effects of hyperbilirubinemia; the changes observed in CA 19-9 over the course of induction therapy may have been influenced by biliary decompression and not the anticancer therapy alone.
Data from the 82 patients in our study in whom both pretreatment and restaging CA 19-9 levels were evaluable affirm that both the restaging CA 19-9 level and the change in CA 19-9 over the course of neoadjuvant therapy are clinically relevant prognostic markers; in general, low restaging values are better than high values, and a decline in CA 19-9 following induction therapy is more favorable than a rise. However, four important caveats must be noted with regard to these observations. First, the PPV of the restaging CA 19-9 (86%) and the change in CA 19-9 (77%) for completing all therapy including PD were similar to that of the standard restaging evaluation (radiography and physical examination) alone (86%). Second, restaging CA 19-9 and its change from the pretreatment level were both associated with low NPV for competing PD; therefore, neither test effectively excluded radiographically occult metastatic disease at time of restaging. Third, although the number of patients analyzed was relatively small, the median survival of patients who underwent PD in the setting of restaging CA 19-9 higher than all cutoff values, or with stable or increased restaging CA 19-9, was similar to the median survival of patients who underwent PD in whom CA 19-9 levels were below each cutoff value or fell. Finally, we were unable to demonstrate any correlation between change in CA 19-9 level and response to treatment as assessed histopathologically.
This study has two potential limitations. The first is our inability to differentiate between patients with low but detectable level of CA 19-9 and patients with Lewisa-b-
blood type who do not secrete CA 19-9.22
The extent to which our results have been influenced by this is difficult to determine as few studies have examined the prognosis of Lewis antigen-negative patients. Available data suggest that Lewisa-b-
patients have a prognosis similar to, but perhaps even more favorable than, patients with CA 19-9 levels that are detectable but within the normal range or slightly elevated.11
Future trials are necessary to clearly define the cancer biology of this group of patients.
A second potential limitation of this study is the exclusion of significant numbers of patients from analysis due to elevation in serum bilirubin. This is particularly true in the pretreatment setting: 67 of 174 patients with an available pretreatment CA 19-9 level were excluded from analysis due to concomitant obstructive jaundice. Hyperbilirubinemia, however, can confound measurements of CA 19-9 levels and can introduce significant error into analyses in which CA 19-9 levels associated with both normal and elevated bilirubin levels are considered.7
Indeed, as we have argued, this represents a major limitation of other studies.10
Importantly, we found that the demographics, clinical factors, and outcomes of patients with and without an evaluable CA 19-9 at each time point were comparable, suggesting that the exclusion criteria used in this study actually strengthen our conclusions (as opposed to weaken them).
In summary, based upon these data, we offer the following conclusions with regard to use of CA 19-9 in the evaluation of patients with resectable PC treated with neoadjuvant therapy. Serum CA 19-9 levels within the normal range at diagnosis will most often remain normal after induction therapy, and patients with a normal pretreatment CA 19-9 level can be expected to have favorable prognosis compared with those with an elevated level. Nonetheless, the presence of an elevated pretreatment serum CA 19-9 level may not preclude completion of all therapy to include PD. Similarly, both a low restaging CA 19-9 level and a decline over the course of induction therapy are associated with undergoing successful PD; however, a persistently elevated CA 19-9 level at restaging does not reliably signify disease progression and may not preclude successful PD. Based upon these findings, we recommend that therapeutic decision-making with regard to use of neoadjuvant therapy and PD for patients with potentially resectable PC remain largely based on expert clinical assessment and high-quality radiographic staging.