Administration of postoperative therapy is essential to providing optimal outcomes for PC patients who undergo R0 or R1 PD. Of equal importance, however, are the components of care delivered prior to adjuvant therapy. Precise clinical staging, appropriate patient selection for surgery, meticulous surgical dissection, and accurate pathologic examination of the surgical specimen all enable assessment of and, perhaps more importantly, modulate the risk for disease recurrence following therapy. Unfortunately, these components of care are typically performed prior to protocol enrollment and are therefore rarely subject to the same degree of scrutiny and standardization as the adjuvant treatments that follow. Thus, paradoxically, the primary component of multimodality therapy protocols—indeed, the only component proven to be potentially curative—is not quality controlled in any way. In this study, we confirmed an absence of standardization and quality control of these factors by rigorous review of the primary data sources of patients enrolled in a national trial of adjuvant therapy.
Variation in surgical quality has been demonstrated to influence rates of locoregional recurrence and long-term survival among patients with colorectal cancer.16–19
Such studies often focus on case volume as a surrogate marker of quality, but this metric is itself a surrogate marker of several technical variables.19,20
For patients with PC, one of the most important of these is the ability of the surgeon to achieve margin-negative resection. Rates of microscopically positive margins among PD specimens range between 16% and 85%, and margin status has been identified as an independent prognostic factor for survival in most series.1,2,15,21–24
As confirmed by this study, the soft tissue margin adjacent to the SMA is the most frequently positive margin after PD ().15
It has been suggested that microscopically incomplete resection at this margin is an exclusive reflection of aggressive tumor biology.5,6
However, given the fact that the medial edge of the tumor is often just millimeters away from the SMA, it stands to reason that medial retraction of the SMV and skeletonization of the lateral aspect of the SMA in thoroughly staged patients with potentially resectable disease can minimize rates of R1 resection ().25
FIG. 1 a Lateral retraction of the SMV and dissection along the adventitia of the SMA may enhance the potential for margin-negative resection; this technique is considered optimal. b Stapler dissection of the SMA margin and/or failure to retract the SMV laterally (more ...)
Despite the oncologic significance of the SMA margin and the importance of technical factors in maximizing the R0 resection rate, we found wide variability in the techniques used for SMA dissection in patients enrolled in ACOSOG Z5031. Indeed, a stapler was used to free the uncinate process from the retroperitoneum in 24% of patients in whom the technique of dissection was documented. Although efficient, use of a stapler may leave as much as 43% of the soft tissue between the uncinate process and the SMA in situ and may therefore increase the potential for R1 resection.26,27
Furthermore, irrespective of the technique used for SMA dissection, adequate skeletonization of the SMA was documented in only 25% of patients in this study, and the SMA margin was marked or inked by the surgeon in only 25%. Together, these findings demonstrate a lack of emphasis placed upon this crucial step of PD and illustrate one potential source of the wide variability of margin-positivity rates seen in published reports. It is also conceivable, or even likely, that suboptimal surgical technique contributed to the high local recurrence rate (46%) observed in ACOSOG Z5031.14
Although the method with which pathologic examination of the PD specimen is performed is also critical, a universally accepted approach to the analysis of the PD specimen is lacking.11,12,23,28–32
As affirmed in this study, a major source of inconsistency is the assessment, description, and documentation of the oncologic status of the retroperitoneal tissues. We found documentation of the “uncinate process margin,” “retroperitoneal margin,” “SMA margin,” “radial margin,” “deep margin,” and “posterior margin”—all referring to margins in the retroperitoneum. Even the AJCC and CAP guidelines appear to disagree on the designation and relative importance of tissues in this region. The AJCC places emphasis on the margin of divided tissue just lateral to the SMA (the descriptor for which has been changed to the “SMA margin” to differentiate it from the tissue between the posterior surface of the uncinate process and vena cava). In contrast, until October 2009 the CAP emphasized the oncologic significance of the deep radial posterior surface of the pancreatic head, and the newly updated guideliness still refer to the SMA margin tissue as the uncinate margin.12,13,15
Perhaps as a result of this inconsistency and ambiguity, the status of the tissue margin adjacent to the SMA was documented in only 47% of patients enrolled in this trial. This, combined with diversity among pathologists with regard to the methods used to ink, section, and analyze the SMA and other margins, also helps to explain the disparity in published rates of R1 resection.11,12,23,30–32
Significantly, although only 25% of patients enrolled in ACOSOG Z5031 were reported to have undergone R1 resection, we found at least one positive margin in 44% of the 36 patients in whom evaluation of all three AJCC-recommended margins was documented.
The importance of accurate perioperative staging must also be emphasized as a means both to predict prognosis and to accurately exclude or enroll patients in adjuvant therapy trials. Not surprisingly, we identified wide variation in the perioperative staging methods used to evaluate patients, along with deficiency in reporting of key staging indicators (). Although preoperative computed tomography scan was performed on all patients, the quality of these scans and the accuracy of their interpretation were not subject to central review, and a basic description of preoperative disease stage based on these scans was documented in a minority of operative reports. Furthermore, we found a description of a systematic intraoperative search for extrapancreatic disease absent in a surprising number of cases. Moreover, less than one-quarter of operative reports documented the absence of macroscopic residual disease after removal of the surgical specimen. Combined, these findings suggest further potential for clinical heterogeneity among patients enrolled in trials of postoperative therapy for PC.
Frequency with which critical surgical and pathologic factors were documented in operative and pathology reports of patients enrolled on ACOSOG Z5031
Like any retrospective study, ours is not without limitations. Clearly, our appraisal of the technical aspects of the staging, surgical, and pathologic methods utilized prior to enrollment in ACOSOG Z5031 is limited by the accuracy and comprehensiveness of the operative and pathology reports generated for these patients. It is possible that the surgical and pathologic documentation may have mis- or underrepresented clinical events or processes, particularly given the deficiencies identified in these reports (). However, all documents were authored and/or approved by the attending physician, minimizing this possibility. We further acknowledge that the retrospective evaluation of clinical events described in these reports is subject to interpretation by those gathering the data. We addressed this by requiring all data to be collected by two independent surgeons, with subsequent analysis by the complete panel of four surgeons. Indeed, a major strength of the analysis reported herein is the rigorous evaluation of primary data sources by experienced pancreatic surgeons as opposed to review of a large database by a trainee.
In summary, we found an overwhelming absence of consistency in perioperative staging, surgical treatment, and pathologic analysis for PC patients in this study. Although the independent influences of these factors and their documentation upon outcome are unknown, the overall effect could clearly result in heterogeneity among patients enrolled in clinical trials of adjuvant therapies, the potential for misinterpretation of the results of these trials, and unsatisfactory outcomes. Our data suggest critical areas for improvement in the design of multidisciplinary treatment protocols for patients with resectable PC.