Of 329 consecutive patients who underwent surgical resection of their primary PC, 88 (27%) survived 5 years, which to our knowledge is the highest actual survival rate reported (). We attribute this result to the use of objective criteria for the selection of patients for surgery, a standardized approach to the technical aspects of the operation (to minimize local recurrence), an institutional emphasis on multimodality therapy, and the frequent use of neoadjuvant treatment sequencing, which may result in avoiding surgery in patients most susceptible to early disease recurrence. However, it is important to note that patients included in this report were treated between 1990 and 2002 to allow for a minimum follow-up of 5 years; patients treated more recently may do even better with the progress (albeit modest) that has resulted from the development and use of systemic chemotherapy and the integration of systemic therapy, chemoradiation, and surgery into contemporary treatment schemas.
International series of long-term survivors after treatment for pancreatic adenocarcinoma
The selection of patients for surgery was influenced by the use of high-quality pretreatment cross-sectional imaging with CT, treatment sequencing that often involved neoadjuvant therapy, and the clinical assessment of patients by experienced oncology specialists. We used objective CT-based criteria to define the extent of disease as resectable, borderline resectable, locally advanced, or metastatic.29
Importantly, local tumor resectability was determined preoperatively, and surgery was considered only in patients with resectable or borderline resectable disease. In the absence of extrapancreatic metastatic disease, an aggressive approach was taken to venous resection and reconstruction when isolated venous involvement was the only impediment to an otherwise complete gross resection.18
In contrast, we did not attempt resection in patients with locally advanced, stage III disease in whom a gross (R0 or R1) resection was not possible. In patients who undergo an incomplete gross (R2) resection, length of survival is not improved in comparison to cases of stage III disease managed without surgery in patients who receive chemotherapy and/or chemoradiation.35
Indeed, among patients with advanced disease8–11,13
and among those who underwent a grossly incomplete (R2) resection11,13
who were explicitly included in prior reports of long-term survival after pancreatic resection, only a single 5-year survivor (reported to have had stage III disease) was identified.8
Accurate pretreatment staging and multidisciplinary consensus with regard to resectability (based on CT images) is something that can—and should—be performed at all medical centers that offer surgical treatment for PC.36
Such a practice will minimize the inappropriate use of surgery in patients with advanced disease and will ensure that all patients with resectable disease are considered for surgery, we hope as part of a multimodality treatment program.
Consensus is growing that chemotherapy with or without radiotherapy combined with surgery results in higher rates of survival in patients with resectable PC than surgery alone.2,3,15,37–39
In this report, 91% of patients received either neoadjuvant or adjuvant therapy, and most patients were enrolled onto a clinical trial. Importantly, neoadjuvant therapy was delivered to 77% of all patients. The cytotoxic effect of such induction therapy is likely responsible for the lower-than-expected rates of microscopically involved lymph nodes and positive resection margins observed in the surgical specimens.30,40
The administration of chemotherapy and/or chemoradiation before surgery also enriches the population of patients selected to undergo pancreatic resection with those most likely to have a favorable outcome compared with patients treated with surgery first. In our most recent two clinical trials of neoadjuvant therapy for patients with stage I and II PC, 30% of patients who began neoadjuvant therapy did not undergo PD as a result of disease progression, evolving medical comorbidities, or a decline in performance status.26,27
These patients, who had a median survival of <12 months, include those patients who would not have received a survival benefit from surgery as a result of the presence of metastatic disease that was radiographically occult at the time of pretreatment staging, and those with medical comorbidities that were also not readily apparent at the time of diagnosis. Neoadjuvant treatment sequencing accurately identified those patients who would otherwise have experienced early postoperative recurrence and those who may have an increased risk for perioperative complications; such patients did not undergo pancreatectomy. Surgery-last treatment sequencing benefits both the patients who undergo resection of their primary tumor and those who do not.
We recently reported our institutional experience with patients having borderline resectable pancreatic cancer, a prospectively identified subset of AJCC stage III disease, in whom a neoadjuvant strategy is particularly important.17,29
At our institution, three clearly defined groups of patients were classified as borderline resectable: (1) patients with strictly defined borderline resectable local tumor anatomy, predominantly arterial abutment, as described above; (2) patients with localized tumors who also had additional CT findings suspicious but indeterminate for metastatic disease; and (3) patients with a marginal but potentially recoverable performance status or extensive comorbidities requiring a prolonged evaluation that precluded immediate major abdominal surgery. In each of these three groups, we took advantage of the theoretical benefits of neoadjuvant treatment sequencing over a long time period (minimum of 4 months) of systemic chemotherapy and chemoradiation. Serial restaging evaluations at 2-month intervals selected patients for additional therapy and ultimately surgery; only patients with an acceptable performance status and no evidence of disease progression at the end of neoadjuvant therapy underwent surgery.
In our previously published series of 160 patients treated with this approach, 41% of patients completed all therapy, including surgery; 56% of resected specimens had a pathologic response to treatment characterized by <50% tumor viability, and 94% of resections resulted in microscopically negative (R0) margins. The 41% of patients who completed all therapy including surgery had a median survival of 40 months. Median survival was 13 months for the 59% of patients who developed disease progression or evolving medical comorbidities. Patients with borderline resectable disease are at high risk for having CT-occult distant metastases, likely are at higher risk for a positive resection margin than patients with stage I or II PC, and often require a larger, more complex, and higher-risk operation to remove their primary tumor. When the magnitude of the operation and the risk for recurrence are both increased, neoadjuvant treatment sequencing becomes more attractive as a strategy to more precisely select patients who will benefit from pancreatectomy.
Patients who did not receive neoadjuvant therapy were routinely encouraged to receive postoperative adjuvant therapy, either, typically as part of a clinical trial. However, a number of factors may delay or prohibit the administration of adjuvant therapy in the postoperative patient. Indeed, a recent investigation of national practice patterns for multimodality therapy use reported that <50% of patients who underwent pancreatectomy at high-volume centers received chemotherapy or chemoradiation, although the reasons for the low rate of multimodality therapy were unclear.15
These data are supported by two recently published large single-institution experiences in which adjuvant therapy was received by only 44% and 60% of eligible patients who had received a surgery-first treatment strategy for PC.41,42
In a previous study from our institution, we reported that 26% of patients who underwent PD without any prior treatment did not receive intended adjuvant therapy.21
Patients did not receive postoperative adjuvant therapy for reasons that could be classified into three categories: treatment related (surgical complications, delayed recovery), disease related (disease progression), and patient related (advanced age, marginal preoperative performance status, medical comorbidities, patient refusal). For those patients with an Eastern Cooperative Oncology Group (ECOG) performance status that we would consider of marginal acceptance for major surgery (in the lower range of ECOG 2), a surgery-first strategy is likely to be associated with both an increased risk for complications and a high likelihood of not receiving any additional oncologic treatment. An understanding of the complexity of delivering multimodality therapy to patients of advanced age who require a large cancer operation and often have marked medical comorbidities will become even more important as our systemic therapies for PC improve.
The present report failed to reveal an association between the administration of neoadjuvant or adjuvant therapy and long-term survival. However, this is not surprising, given the high rate of combined modality treatment among all patients, the relatively modest patient numbers, and the retrospective design of this study. Only 7% of patients did not receive systemic therapy and/or chemoradiation in addition to surgery.
The frequent use of neoadjuvant therapy and the standardized approach to surgery likely influenced the low rate of margin positivity (16%). In a previous report from our institution focusing specifically on the incidence of R1 resections and the implications of this pathologic finding, the frequency of a positive SMA margin was less in those patients who received preoperative chemoradiation (13%) compared with those patients taken directly to surgery (19%).19
This difference was not statistically significant but was clinically important, given the selection bias in favor of going straight to surgery, without neoadjuvant therapy, in patients with smaller tumors whose theoretical risk for an R1 resection was thought to be low. In fact, such carefully selected patients actually had a higher frequency of having a disease-positive SMA margin on final pathologic analysis of the PD specimen. This finding lends further support to the observation that PC can extend along visceral perineural fibers to the SMA and a positive microscopic margin can be found when the grossly visible tumor seems to be separate from the lateral wall of the SMA. Both multimodality therapy and proper surgical technique may be necessary to minimize the risk for a positive SMA margin and thereby reduce the risk of local recurrence. For example, all tissue to the right of the SMA should be removed with the PD specimen; the application of a stapling devise or a series of clamps without visible identification of the SMA should be avoided. In this report, local recurrence was seen radiographically in 42 (13%) of the 329 patients. Local control is clearly necessary (but not sufficient) for long-term survival, and as our systemic therapies improve, the importance of maximizing local disease control at the time of initial treatment may provide further enthusiasm for neoadjuvant chemoradiation.
In this report, factors adversely associated with long-term survival on multivariate analysis included the presence of metastatic disease in regional lymph nodes and a previous attempt at tumor resection before referral to our institution. Of the 88 five-year survivors, only five patients had undergone an unsuccessful attempt at tumor removal before referral. However, 48 patients had undergone laparotomy for planned pancreatectomy before referral; the effect of an unsuccessful prereferral laparotomy was profound and something not widely discussed in the literature. The importance of carefully selecting patients for PC surgery who are compatible with the skill set of the surgeon cannot be overstated.
Of the 88 five-year survivors, 32 (36%) were found to have pathologically involved lymph nodes. In fact, of the 157 node-positive patients, 32 (20%) survived 5 years. To what degree the favorable outcome in patients with N1 disease is related to the use of multimodality therapy cannot be accurately determined. One would assume that the selection bias introduced by neoadjuvant treatment sequencing combined with the frequent use of systemic chemotherapy is partly responsible for this encouraging result. In any event, the finding that 20% of node-positive patients were alive at 5 years after diagnosis would argue against routine lymph node biopsy at the time of surgery because node-positive disease does not seem to represent a contraindication to surgical resection of the primary tumor when performed as part of a multimodal treatment strategy.
Finally, the incidence and pattern of disease recurrence warrants further comment. As demonstrated in , most recurrences occurred early and developed in the abdomen (largely in the liver). In contrast, late recurrences developed predominantly in the lung. This pattern of recurrence supports the use of abdominal CT or magnetic resonance imaging for routine follow-up, particularly within the first 3 to 5 years after definitive treatment. Although not analyzed in this report, we found that serum levels of CA 19-9 are frequently also helpful, unless undetectable (indicative of individuals with the Lewis a–b blood group antigen who do not synthesize CA 19-9). In this report, the latest cancer recurrence was identified 6.7 years from diagnosis, and the latest cancer-related death occurred at 7.6 years. These findings support prior observations that 5-year survival does not always equate with cure for patients with this disease.9,13
However, the plateau of our disease-specific survival curve () does suggest that patients free of disease at 7 to 8 years after diagnosis are at very low risk for death from recurrent PC. For patients who died of recurrent disease within 5 years, death occurred at a median of 5.5 months (range, .1–36.5 months) after recurrence was identified. In contrast, of the 17 five-year survivors who died of recurrent PC, death occurred at a median of 15 months (range, .7–51 months) after the diagnosis of recurrence (). These data suggest that 5-year survivors who are not cured are characterized by an as-yet undefined tumor biology that includes a predisposition for pulmonary metastases and a more indolent form of disease progression.
In conclusion, we report a consecutive series of patients with resectable (stage I, II) and borderline resectable (stage III) PC who were treated with curative intent to include surgical resection of the primary tumor. The favorable long-term survival reported herein reflects what is possible when a well-selected group of patients are carefully staged with high-quality imaging and treated in a disease site-specific multidisciplinary program with state-of-the-art surgery, combination chemotherapy, and radiotherapy. Future progress in the treatment of patients with PC will emphasize both the optimization of our current technologies and treatments, as well as the development of novel and more effective systemic therapies.