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Pancreatic Cancer pp 1105-1130 | Cite as

Treatment of Recurrent Pancreatic Cancer After Surgery

  • Oliver Strobel
  • Willem Niesen
  • Markus W. Büchler
Reference work entry

Abstract

The majority of patients with pancreatic cancer eventually develop and die from recurrence even after successful surgical resection and adjuvant therapy. Pancreatic cancer recurrence and its treatment are, therefore, very relevant clinical concerns. For several reasons there is a striking lack of knowledge and evidence with respect to the incidence and pattern, the detection, and the management of pancreatic cancer recurrence. This chapter summarizes available data on the incidence, timing, and pattern of recurrence, discusses the need for and the potential of structured surveillance programs, and provides an overview of treatment options for pancreatic cancer recurrence. While most patients will eventually die from systemic recurrences, a relevant subgroup of 20–30% of patients at first present with isolated local recurrence. For systemic recurrences chemotherapy is the only treatment option. However, data from observational cohort studies suggest that treatment strategies that include local approaches may be associated with prolonged survival patients with isolated local recurrences. In order to improve the treatment of both local and systemic recurrence of pancreatic cancer and to enable clinical trials, it will be important to establish surveillance programs after resection and to address treatment options for recurrence in future guidelines.

Keywords

Pancreatic cancer Resection Surveillance Recurrence Isolated local recurrence Systemic recurrence Re-resection Outcome Survival 

Abbreviations

CA 19-9

Carbohydrate antigen 19-9

CT

Computed tomography

PDAC

Pancreatic ductal adenocarcinoma

PET

Positron emission tomography

RCT

Randomized controlled trial

Introduction

Management of pancreatic ductal adenocarcinoma (PDAC) recurrence is a very relevant topic because even after successful resection and administration of adjuvant therapy, PDAC recurs in the majority of cases. Most patients eventually succumb to local, metastatic, or combined tumor recurrences resulting in a median survival of only 20–25 months and 5-year survival rates around 20% [1, 2]. Three main reasons contribute to the high recurrence rate and poor prognosis of PDAC:
  1. (i)

    An obvious reason for local recurrences is insufficient resection margin clearance reflected by the high rate of R1 resections identified by stringent margin assessment [3, 4, 5, 6]. The high rates of R1 resection are not caused by inappropriate surgical technique but explained by the tumor biology of PDAC with extrapancreatic and extratumoral perineural spread toward the arteries identified in 60–70% of cases [7].

     
  2. (ii)

    Even more importantly most patients die from early metastatic recurrence. Undetectable micrometastatic disease at the time of resection is thought to be the main reason for this systemic failure. While this provides a clear rational for the administration of systemic therapies in the adjuvant or neoadjuvant settings (see chapters “ Adjuvant Chemotherapy in Pancreatic Cancer” and “ Neoadjuvant Chemotherapy in Pancreatic Cancer”), the follow-up data derived from randomized controlled trials on adjuvant therapy show that the tested therapy regimens can significantly delay but not prevent recurrence (see Table 1) [8, 9, 10, 11, 12, 13, 14, 15, 16, 17].

     
  3. (iii)

    The aggressive tumor biology and high chemoresistance of PDAC are thought to be main reasons for the failure of available regimens for adjuvant therapy to achieve a sustained local and systemic control [2].

     
Table 1

Incidence, timing, and pattern of recurrence after resection for pancreatic cancer in selected RCTs on adjuvant therapy

Reference and name of study

Study arms

n

Overall survival (median and survival rates)

Disease-free survival (median and survival rates)

Incidence and pattern of recurrence

Follow-up (median)

Neoptolemos et al. (2004) [8]

ESPAC-1

4 × 4 factorial design:

    

Survivors: 47 months

CRT (20Gy + FU)

73

13.9 months, 5YSR: 7%

Chemotherapy: 15.3 months

Local only: 35%

Chemotherapy: FU

75

21.6 months, 5YSR: 29%

Local and systemic: 27%

Chemotherapy + CRT

72

19.9 months, 5YSR: 13%

No chemotherapy: 9.4 months

Systemic only: 34%

Observation

69

16.9 months, 5YSR: 11%

Smeenk et al. 2007a [9]

EORTC 40891 (long-term results)

CRT (40Gy + FU)

110

21.6 months

18 months

Total: 68%

Overall: 11.7 years

5YSR: 25%, 10YSR: 17%

5YSR: 21%, 10YSR: 16%

Initially local only: 20%

Observation

108

19.2 months

14.4 months

Local and systemic: 29%

Survivors: 9.8 years

5YSR: 22%, 10YSR: 18%

Initially systemic: 48%

5YSR: 20%, 10YSR: 17%

Total: 70%

Initially local only: 21%

Local and systemic: 30%

Initially systemic: 46%

Oettle et al. (2007) [10]

CONKO-001

Gemcitabine

179

22.1 months

13.4 months

Total: 74.3%

53 months

2YSR: 47.5%, 5YSR: 22.5%

2YSR: 30.5%, 5YSR: 16.5%

Local ± systemic: 34%

Observation

175

20.2 months

6.9 months

Systemic only: 56%

2YSR: 42%, 5YSR: 11.5%

2YSR: 14.5%, 5YSR: 5.5%

Total: 92.0%

Regine et al. (2008) [11]

RTOG 97-04

FU – CRT (FU, 50.4 Gy) – FU

230

16.9 months, 3YSR: 22%

NA

Total: 85.7%

Overall: 1.5 years

Local: 28%, regional: 8%,

systemic: 71%

Gemcitabine – CRT (FU, 50.4Gy) – Gemcitabine

221

20.5 months, 3YSR: 31%

NA

Total: 83.3%

Survivors: 4.7 years

Local: 23%, regional: 7%

Systemic: 71%

Ueno et al. (2009) [12]

JSAP-02

Gemcitabine

58

22.3 months

11.4 months

Total: 76%

60.4 months

2YSR: 48.3%, 5YSR: 23.9

2YSR: 27.2%

Local: 23%

Systemic: liver 30%, peritoneal 18%, other 27%

Observation

60

18.4 months

5.0 months

Total: 88%

Local: 32%

Systemic: liver 30%, peritoneal 13%, other 23%

2YSR: 40.0%, 5YSR: 10.6%

2YSR: 16.7%

Neoptolemos et al. (2010) [13]

ESPAC-3

FU + folinic acid

551

23.0 months, 2YSR: 48.1%

14.1 months, 2YSR: 30.7%

Total: 63% (local, systemic or both)

Survivors: 34.2 months

Gemcitabine

537

23.6 months, 2YSR: 49.1%

14.3 months, 2YSR: 29.6%

Van Laethem et al. (2010)b [14]

EORTC-40013-22012/FFCD-9203/GERCOR

Gemcitabine (4 cycles)

45

24.4 months, 2YSR: 50.2%

10.9 months

Local only: 24%

33.3 months

Local and systemic: 13%

Systemic only: 40%

Gemcitabine, (2 cycles) + Gem-based CRT

45

24.3 months, 2YSR: 50.6%

11.8 months

Local only: 11%

30.7 months

Local and systemic: 20%

Systemic only: 42%

Schmidt et al. (2012) [15]

CapRI

Chemoradioimmunotherapy (FU, cisplatin, interferon, 50 Gy)

64

32.1 months

15.2 months

Total: 67% (local, systemic or both)

Overall: 42.7 months

FU + folinic acid

68

28.5 months

11.5 months

Uesaka et al. (2016) [16]

JASPAC 01

Gemcitabine

190

25.5 months

11.3 months

Total: 67%

82.3 months

3YSR: 38.4%,

3YSR: 22.6%,

Local: 26%

5YSR: 24.4%

5YSR: 16.8%

Systemic: liver 29%, peritoneal 16%, other 32%

S1

187

46.5 months

22.9 months

Total: 66%

79.3 months

3YSR: 59.0%, 5YSR: 43.6%

3YSR: 39.2%, 5YSR: 33.3%

Local: 19%

Systemic: liver 19%, peritoneal 12%, other 33%

Updated from Strobel and Büchler [17]

ESPAC European Study Group for Pancreatic Cancer, EORTC European Organization for Research and Treatment of Cancer, CONKO Charite Onkologie, RTOG Radiation Therapy Oncology Group, YSR year survival rate, FU fluorouracil, NA data not available, JASPAC Japan Adjuvant Study Group on Pancreatic Cancer

aOnly T1/2, N0-1a pancreatic orT1–3, N0-1a periampullary cancers included

bOnly R0-resections included

With significant improvements in the surgical therapy and in accompanying (neoadjuvant or adjuvant) systemic treatment options, the long-lasting controversy on the role of surgery in resectable PDAC has been resolved [1]. High-volume centers have reported actuarial 5-year survival rates after resection of 20% overall and of up to 60% in patient subgroups with a favorable combination of prognostic factors [6, 18, 19, 20]. More recently, the JASPAC-1 study has marked a significant advance in adjuvant treatment with S1 resulting in a 5-year survival rate of 44% [16]. Today it is undisputed that surgical resection in combination with systemic treatment remains the only chance of long-term survival or cure in patients with primary PDAC.

In contrast, although PDAC recurrence is a pressing problem affecting the majority of resected patients, its management is poorly studied and highly controversial. A part of the underlying problem is a certain therapeutic nihilism toward PDAC recurrence that is reflected by the fact that most current treatment guidelines do not recommend structured surveillance programs after resection due to a lack of evidence for effective treatment options for recurrence or lack of a survival benefit by regular follow-up exams (see Table 2) [21, 22, 23, 24, 25, 26]. Of note, some current guidelines do not even address the problem of PDAC recurrence and its management.
Table 2

Recommendations on surveillance after resection for pancreatic cancer in selected recent clinical guidelines

Guideline

Recommendation

Level of recommendation

Level of evidence

AWMF Germany 2013 [22]

9.33:

A

5

Structured surveillance programs for PDAC are not recommended as there are no available data that regular staging examinations are associated with a survival benefit

Consistent level 1 studies

Expert opinion without explicit appraisal or based on physiology, bench research, or “first principles”

According to Oxford Centre for Evidence-Based Medicine

NCCN USA (2016) [21]

MS-43/PANC-6:

Category 2B

Lower level

 History and physical examination for symptom assessment, CA 19-9 testing, and follow-up CT scans every 3–6 months, then every 6–12 months

Based upon lower-level evidence, there is NCCN consensus that the intervention is appropriate

 Are category 2B recommendations, because data are not available to show that earlier treatment of recurrences leads to better patient outcomes

ASCO USA (2016) [23]

6.1:

Moderate

Low

 In the absence of RCT evidence, the panel recommends that patients who have completed treatment of potentially curable pancreatic cancer and have no evidence of disease be monitored for recovery of treatment-related toxicities and recurrence. Visits may be offered at 3- to 6-month intervals; the role of serial cross-sectional imaging, the extent to which surveillance intervals should be prolonged over time, and the duration of recommended surveillance are all undefined

Informal consensus, benefits outweigh harms

Low confidence that the available evidence reflects the true magnitude and direction of the net effect. Further research may change either the magnitude and/or direction this net effect

The available evidence was deemed insufficient to inform a recommendation to guide clinical practice. The recommendation is considered the best current guidance for practice, based on informal consensus of the expert panel

ESMO Europe (2015) [24]

There is no evidence that regular follow-up after initial therapy with curative intent is useful

D

IV

Moderate evidence against efficacy or for adverse outcome, generally not recommended

Retrospective cohort studies or case-control studies

NCI USA (2016) [25]

Not addressed

NA

NA

IAP and EPC consensus review of guidelines (2015) [26]

Not addressed

NA

NA

AWMF Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgemeinschaften e.V. (Version 1.0 October 2013), NCCN National Comprehensive Cancer Network (Version 2.2016), ASCO American Society of Clinical Oncology (2016), ESMO European Society for Medical Oncology (2015), NCI National Cancer Institute, IAP International Association of Pancreatology, EPC European Pancreatic Club

This chapter aims to provide an overview of current treatment options for PDAC recurrence with a special focus on isolated local recurrence . The chapter also addresses several aspects that are relevant in the context of PDAC recurrence, including incidence and pattern of recurrence after resection, and the potential value of structured surveillance after resection.

Incidence and Pattern of Recurrence

The knowledge about the incidence, timing, and pattern of recurrence is vague as surveillance programs are not generally recommended in current clinical guidelines resulting in a lack of follow-up data from large patient cohorts. The best information on clinically detected recurrence is probably available from randomized controlled trials on resection and adjuvant therapy (Table 1 [8, 9, 10, 11, 12, 13, 14, 15, 16]) with some additional data available from the few observational studies dedicated to the topic of recurrence [27]. A few available autopsy series provide important data on the pathological pattern of recurrence after resection [28, 29, 30].

Data from randomized controlled trials (RCTs) provide the best indication of the “clinical” pattern of recurrence detectable by structured follow-up programs with assessment of patient history, physical examination, cross-sectional imaging (usually contrast-enhanced computed tomography (CT)), and serum values of tumor markers, especially of carbohydrate antigen 19-9 (CA 19-9). The follow-up results of selected RCTs on resection and adjuvant therapy are summarized in Table 1. These data allow several important conclusions on incidence, timing, and pattern of recurrence after resection for PDAC. Data on disease-free survival from RCTs comparing adjuvant therapy versus observation show that without adjuvant therapy 50% of patients develop clinically detectable cancer recurrence within 5–10 months [8, 10, 12]. Adjuvant chemotherapy with gemcitabine or 5-fluorouracil [5-FU] monotherapy cannot prevent but delay recurrence to 11–15 months. With patient selection based on known prognostic factors, recurrence is observed later, at 14.4 months without and at 18 months with adjuvant therapy [9]. Even in the more recent RCTs, the median disease-free survival remains at 12–15 months [13, 15]. Up to 90% of patients without and about 70% with adjuvant therapy develop PDAC recurrence within a follow-up time of 30–50 months. More recently, the JASPAC-1 study marked an exceptional advance, at least for Asian patients, with a median disease-free survival of 22.9 months and 5-year disease-free survival rate of 33.3% after resection and adjuvant therapy with S1 [16].

While the reporting on the pattern of recurrence in different RCTs is rather heterogeneous and the majority of patients presents with systemic progression, 20–30% of patients are consistently found to primarily present with isolated local recurrence (Table 1). In summary, the data on recurrence from RCTs demonstrate that even with adjuvant therapy, most patients develop recurrence within 1.5 years after resection. The data also suggests that based on structured surveillance programs, it may be possible to identify a subgroup of 20–30% of patients who first develop isolated local recurrence (as detectable by current imaging technology).

A multicenter observational study in 1130 patients undergoing resection between 2000 and 2010 reported a median actuarial overall survival of 25.9 months (median follow-up 18 months) [27]. Based on radiographic evidence, pathologic confirmation, and/or tumor marker elevation, the local recurrence rate in this study was 22%, and metastatic recurrence was detected in 41% of patients, confirming the clinically detectable recurrence patterns observed in RCTs. The identification of positive lymph node status as most relevant risk factor for local recurrence [27] suggests that many patients with “local recurrence” may in fact have progression of preexisting lymph node metastases and may be good candidates for re-resection .

Only the few available autopsy series can demonstrate the “true” pathological pattern of recurrence and the relevance of the sites of recurrence for death. In an autopsy study in 24 patients who died after resection of pancreatic cancer, 75% of patients had local recurrence, 75% had distant metastases, and the local recurrence was the cause of death in 17% of patients [28]. Another autopsy study in patients with PDAC included 22 patients after resection [29]. At autopsy, two patients (9%) had died of unrelated causes and had no evidence of recurrence, three (14%) had isolated local recurrence , four (18%) had only metastatic recurrence, and 13 (59%) had both local and systemic recurrence. In this study, expression of DPC4 in the tumor was highly correlated with metastatic but not with localized disease [29]. These autopsy studies confirm that after resection and adjuvant therapy for pancreatic cancer, most patients die from systemic disease, but a subgroup of patients develop and die from isolated local recurrence, and molecular properties of the tumor appear to contribute to the pattern of recurrence.

It will be interesting to see how the neoadjuvant or adjuvant administration of more aggressive chemotherapy regimens such as S1 [16] and FOLFIRINOX [31, 32, 33] and advances in radiation oncology will affect incidence, timing, and pattern of PDAC recurrence. Translational studies characterizing the molecular properties of PDAC in the context of the pattern of disease may identify biomarkers associated with systemic progression that may become useful for personalized decision-making in the management of PDAC recurrence.

Surveillance After Resection for Pancreatic Cancer

The effectiveness of surveillance after PDAC resection is highly controversial, and in most countries structured surveillance programs are not established. While some of the available treatment guidelines for PDAC do not even address this relevant topic, several “evidence-based” guidelines give out different recommendations with respect to follow-up after potentially curative surgery (Table 2). Based on very similar literature, the German S3 guidelines do not recommend structured surveillance programs for PDAC due to a lack of evidence of positive effects of surveillance on prolonging survival after the completion of adjuvant chemotherapy [22], while the North American NCCN guidelines acknowledge the lack of evidence but still recommend CA 19-9 examination and cross-sectional imaging every 3–6 months for the first 2 years. The latter recommendation was based on the consensus that earlier detection of recurrence may facilitate patient eligibility for investigational studies or other forms of treatment [21]. However, a cost-effectiveness analysis revealed higher costs without any survival benefit from a regular follow-up program that included abdominal imaging [34].

On the one hand, it should be acknowledged that clinical guidelines have to be based on current evidence and have to include socioeconomic considerations and that there is at present little evidence for the benefit of surveillance. On the other hand, structured surveillance programs are needed to enable studies investigating the potential survival benefit from early detection and timely therapy of PDAC recurrence.

Although regular surveillance is not generally recommended and usually not paid by the health insurances, some centers offer a structured follow-up with physical examination, blood tests (including CA 19-9 levels), and abdominal imaging to all patients who undergo PDAC resection. In a recent analysis of 940 postoperative follow-up visits performed in 618 pancreatic patients over a 1-year period, recurrences were detected in 74 (40%) of 184 patients in follow-up after PDAC resection, of whom only 26% had symptoms [35]. In all of these patients, a cancer-directed therapy was initiated. Importantly, 12 (75%) of 16 patients with isolated local recurrence were without symptoms and 11 were referred for re-resection [35]. The comparison of sequential follow-up CT scans allows for early detection of local recurrences by identification of subtle but progressive changes at typical predilection sites for local recurrences (Fig. 1) [36]. The value of CT scans in the early detection of local recurrence was recently confirmed in an independent series [37].
Fig. 1

Typical findings of local recurrence in sequential CT scans for surveillance after resection for pancreatic adenocarcinoma. (a) Perivascular recurrence at different time points after pancreatoduodenectomy for pT3pN1R1 ductal adenocarcinoma in a 64-year-old patient. Unsuspicious findings at 20 months. At 27 months increase of dense tissue between the superior mesenteric artery and vein with further increase and hypodense changes after 31 months. The patient underwent successful re-resection with intraoperative radiation therapy (IORT). (b) Local tumor recurrence involving the pancreatic remnant after pancreatoduodenectomy for pT3N1R1 ductal adenocarcinoma. Unsuspicious findings until 18 months after resection. Hypodens changes in the pancreatic remnant at 24 months with increase after 36 months. The patient underwent re-resection with completion pancreatectomy and adrenalectomy

These data have important implications, because they show that most recurrences are at first asymptomatic and will be detected earlier with regular surveillance including cross-sectional imaging, and this offers the opportunity for earlier initiation of cancer-directed therapy. While it appears logical that earlier detection of recurrence and initiation of therapy may result in better outcomes, future studies will have to assess how the treatment options discussed below affect survival and quality of life of patients with PDAC recurrence.

The development of tools for screening of risk populations and for early detection of PDAC is an area of intensive research. Novel analytic targets such as exosomal markers and cell-free DNA that are currently being evaluated for early detection of PDAC may also be promising tools for post-resection surveillance [38, 39]. The potential of structured surveillance programs after resection will have to be redefined in the future as better diagnostic tools, and more effective systemic therapies will hopefully become available.

Treatment of Recurrence of Pancreatic Cancer

The treatment of pancreatic cancer recurrence is based on very limited evidence. The available literature is restricted to mostly small retrospective studies in selected patients and/or multiple case reports, suggesting a considerable publication bias.

While several of the current treatment guidelines do not even address the topic of treatment of PDAC recurrence, the German S3 [22] and the NCCN guidelines [21] mention several treatment options dependent on the pattern of recurrence including local therapy for local recurrences (Table 3) [21, 22, 23, 24, 25, 26]. Based on common sense rather than on actual evidence, the pattern of recurrence defines the potential benefit of additional local versus merely systemic treatment. The appropriate treatment options further depend on multiple parameters including the exact localization of recurrence, the clinical performance status and comorbidity of the patient, previous cancer-directed treatment (i.e., neoadjuvant and/or adjuvant treatment regimens), and timing of recurrence (i.e., interval between resection and recurrence and timing in relation to adjuvant therapy).
Table 3

Recommendations on treatment of recurrent pancreatic cancer in selected recent clinical guidelines

Guideline

Recommendation

Level of recommendation

Level of evidence

AWMF Germany (2013) [22]

7.13:

GCP – strong consensus

NA

Local recurrence: In case of isolated local recurrence for pancreatic cancer, all possibilities for local therapy should be considered

Systemic recurrence: Not specifically addressed

NCCN USA (2016) [21]

MS-44/PANC-10:

Category 2B

Lower level

Confirmatory biopsy

All cases of recurrent disease

Category 2A

Based upon lower-level evidence, there is uniform NCCN consensus that the intervention is appropriate

➔ Clinical trial is preferred option

➔ Palliative and best supportive care without additional therapy should also be an option

Local recurrence:

 Chemoradiation can be considered in patients with local disease recurrence only, if not previously administered

 An alternative chemotherapy regimen can be given

 Surgical resection may be considered in select cases (i.e., good performance status, location of recurrence is favorable), though there is currently no evidence to support this recommendation

Systemic recurrence:

 <6 months after adjuvant therapy → alternative chemotherapy

 6 months after adjuvant therapy → systemic therapy as previously administered or an alternative systemic regimen

 Previous adjuvant treatment and good performance status → gemcitabine/nab-paclitaxel and FOLFIRINOX

ASCO USA (2016) [23]

Not addressed

NA

NA

ESMO Europe (2016) [24]

Not addressed

NA

NA

NCI USA (2016) [25]

Local recurrence: Not addressed

NA

NA

Systemic recurrence:

 Palliative chemotherapy

 Chemotherapy: fluorouracil or gemcitabine

 Treatment options under clinical evaluation (refers to clinical trials)

IAP and EPC consensus review of guidelines (2015) [26]

Not addressed

NA

NA

AWMF Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgemeinschaften e.V. (Version 1.0 October 2013), NCCN National Comprehensive Cancer Network (Version 2.2016), ASCO American Society of Clinical Oncology (2016), ESMO European Society for Medical Oncology (2015), NCI National Cancer Institute, IAP International Association of Pancreatology, EPC European Pancreatic Club, GCP good clinical practice

Available treatment options described in the literature are summarized in Table 4 in the context of the pattern of recurrence The following paragraphs address treatment options for systemic recurrence and isolated local recurrence separately.
Table 4

Cancer-directed treatment options for recurrent pancreatic cancer

Type of recurrence

Possible treatment

Intention

Comments

Isolated local recurrence

Chemotherapy

Palliation

Considered the standard therapy for any kind of recurrence without curative intention

Data based on cohort studies

Chemoradiation

Palliation/local control/pain therapy

Considered by many as only alternative treatment option that includes a local therapy

Data based on cohort studies (see Table 5)

Re-resection in combination with chemotherapy or chemoradiation

Potential cure/medium- to long-term control

Re-resection in a multimodal setting in combination with chemotherapy/chemoradiation is the only potentially curative treatment option. Performed in highly specialized surgical centers

Data based on cohort studies (see Table 6)

Locally ablative therapies in combination with chemotherapy

Palliation/local control

Experimental treatment options (including irreversible electroporation, radiofrequency ablation, etc.). Data mainly extrapolated from cohort studies in unresectable disease. Only case reports in the setting of isolated local recurrence

Oligometastatic systemic recurrence

Chemotherapy

Palliation

Standard treatment for metastatic recurrence

Data based on cohort studies in recurrence. Preferred regimens mainly extrapolated from studies on second-line treatments for primarily unresectable/metastatic disease

Metastasectomy in combination with chemotherapy

Medium- to long-term control

May be appropriate for selected patients

Limited data from small retrospective cohort studies. Best data for pulmonary metastases

Locally ablative therapies in combination with chemotherapy

Medium- to long-term control

May be appropriate for selected patients

Data restricted to case reports

Systemic recurrence

Chemotherapy

Palliation

Standard treatment for metastatic recurrence

Data based on cohort studies in recurrence. Preferred regimens mainly extrapolated from data on second-line treatments for primarily unresectable/metastatic disease

Treatment of Systemic Recurrence

As discussed above, the majority of patients with recurrence after PDAC resection present with systemic disease. Clearly, systemic chemotherapy is the appropriate cancer-directed therapy for the majority of these patients. There is little evidence from the literature as to the best regimen in this situation. However, this is a palliative situation, and depending on the timing of recurrence (during or after adjuvant therapy), the regimen used for neoadjuvant and/or adjuvant therapy, and the performance status of the patients, the same principles as outlined for second-line chemotherapy in advanced disease and for palliative treatment may be recommended (see chapters  “Palliative Management of Pancreatic Cancer” and  “Chemotherapy for Advanced Pancreatic Cancer”). Among current treatment guidelines, the NCCN guidelines provide the most detailed recommendations adjusted to the possible clinical scenarios (Table 4) [21]. With respect to quality of life, adequate pain therapy, management of cancer complications, and supportive care are very important aspects of palliative therapy in patients with PDAC recurrence (see chapter  “Palliative Management of Pancreatic Cancer”).

Oligometastatic Recurrence

None of the current guidelines specifically address the situation of oligometastatic recurrence of PDAC in their main recommendations, because the evidence on the management of this condition is limited to small case series and case reports of oligometastatic recurrence in the liver and lungs. Metastasectomy for both initially systemic disease and systemic PDAC recurrence is highly controversial. However, recent reports suggest that such operations are increasingly performed [40, 41, 42, 43]. Data on resection of metachronous liver metastases is limited to case reports and subgroup analyses of small series. The few available series on resection for liver metastases of PDAC mainly analyze synchronous resection and resection in patients with good response to chemotherapy, and the median survival of 14–15 months is not very encouraging [40, 41]. In 23 patients who underwent resection for metachronous metastases of PDAC, the median survival after diagnosis of liver metastases was 14.5 months (unpublished data) in line with the published series.

In contrast, favorable survival has consistently been reported after resection of the rare event of isolated lung metastases including metastatic pulmonary recurrences [42, 44, 45, 46, 47]. PDAC with isolated pulmonary metastases appears to identify a subgroup with favorable prognosis, probably explained by unique molecular properties of these tumors [43, 48, 49]. The favorable survival observed after resection of pulmonary metastases may, thus, at least in part be explained by a selection bias.

While there is no evidence for a survival benefit of local therapies for metastatic disease, metastasectomy may be considered in selected patients with oligometastatic hepatic and particularly pulmonary recurrences, especially in patients with good performance status and a long interval between resection and diagnosis of the metastatic recurrence. Other local treatment options such as locally ablative therapies or radiation therapy may also be considered.

Treatment of Isolated Local Recurrence

The evidence on treatment of isolated local recurrence of PDAC is limited, but there are promising results from several retrospective cohort studies or case series for multimodal concepts including chemoradiation and surgical re-resection (Tables 5 and 6) [46, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61]. The use of local ablation therapies such as irreversible electroporation and radiofrequency ablation may represent another strategy worth testing for isolated local recurrences (Table 4). However, as data on local ablation therapies are restricted to case reports, the following paragraphs will focus on radiation therapy and surgical re-resection.
Table 5

Retrospective series of radiation therapy for local recurrence of pancreatic cancer

Author

Year

N included

Radiotherapy

Chemotherapy

Oncologic outcome

Wilkowski [50]

2006

18

45 Gy

5-FU (n = 4)

OS: 17.5 months

5-FU, Gem (n = 6)

PFS: 14.7 months

Cis, Gem (n = 8)

CR: n = 6 (33%)

Wild [51]

2013

18a

SBRT 25 (20–27) Gy

28% (n = 5)

OS: 8.8 months

Habermehl [52]

2013

41

39.6–54 Gy + IORT (15 Gy) in n = 15

Gem (90%)

OS: 16.1 months

5-FU or Cap (10%)

PFS: 6.9 months

CR: n = 6 (15%)

Nakamura [53]

2014

30

54 (39–60) Gy

Gem (n = 18)

OS: 15.9 months

S1 (n = 7)

PFS: 6.9 months

Zeng [54]

2016

24 (n = 5 additional metastases)

SBRT 45 (42–50) Gy

Reported in n = 3

OS: 12.2. months

PFS: NA

CR: n = 5 (21%)

Included are studies with >5 patients undergoing chemoradiation

SBRT stereotactic body radiation therapy, OS overall survival, PFS progression-free survival, CR complete response (clinical). Updated from Strobel and Büchler [17]

aStudy includes n = 3 patients after definitive chemoradiation (no resection) for locally advanced disease

Table 6

Retrospective series of re-resection for local recurrence of pancreatic cancer

Author

Year

N operated

N resected

Resection rate

Mortality

Other cancer-directed therapy

Oncologic outcome

Kleeffa [55]

2007

30

15

50%

1 (7%)

Chemoradiation: n = 7

Re-resection:

OS: 17.0 months

Radiation: n = 1

Chemotherapy: n = 9

Exploration:

2nd re-resection: n = 6

OS: 9.4 months

None: n = 4

NA: n = 9

Lavu [56]

2011

NA

8

NA

0

NA

OS: 17.5 months

Thomasb [46]

2012

NA

7

NA

0

NAb

OS: NAb

DFS: 9 months

Strobela [57]

2013

97

41

42.3%

1 (1.8%)

In cases with re-resection:

Re-resection:

OS: 26.0 months

Chemoradiation: n = 22

IORT: n = 22

Chemotherapy: n = 21

Exploration (ILR):

NA: n = 4

OS: 10.8 months

Exploration (M1):

OS: 9.4 months

Booneb [58]

2014

NA

10

NA

0

NA

OS: 31.8 months

Miyazaki [59]

2014

NA

11

NA

0

Chemotherapy: n = 8

Re-resection:

OS: 25.0 months

None: n = 3

No re-resection:

OS: 9.3 months

Shima [60]

2015

NA

6

NA

0

Chemotherapy: n = 1

OS: 27.5 months

Chang [61]

2016

NA

7 PDAC

NA

0

NA

Re-resection:

OS: 8.9 months

Exploration:

OS: 5.8 months

Included are studies with >5 patients undergoing re-resection

OS overall survival, DFS disease-free survival, ILR isolated local recurrence without evidence of systemic disease confirmed by surgical exploration. Updated from Strobel and Büchler [17]

aThe cohort by Kleeff et al. is from the same center and included in the follow-up study by Strobel et al.

bMixed cohort of local and distant recurrence. Only data of patients with local recurrence included here

Only two of the analyzed guidelines specifically address the treatment of isolated local recurrence (Table 3). The current German S3 guidelines recommend the evaluation of available local therapies and mention the options of re-resection and chemoradiation in the supporting discussion [22]. The NCCN guidelines are more specific and recommend first inclusion in clinical trials (preferred), the administration of chemoradiation (if not previously done), a change of the regimen of systemic chemotherapy, or palliative and best supportive care. In their 2/2016 version, the NCCN guidelines for the first time mention the option of surgical re-resection in the supporting discussion, but continue with the statement that “there is currently no evidence to support this recommendation” [21].

Given the available data on radiation therapy and re-resection discussed below and summarized in Tables 5 and 6, this preference of chemoradiation over re-resection is somewhat startling and may point to a certain dominance of radiooncologists in the guideline panels.

Rational for Local Therapy

Undisputedly, most pancreatic cancer patients will eventually die from metastatic spread even after potentially curative resection. However, it has been generally accepted that in primary pancreatic cancer, surgical resection in combination with systemic chemotherapy (or chemoradiation) is currently the only therapy option offering long-term survival and, in rare cases, even cure [2].

With advances in both safety and radicality, the limits of surgical resection are today being pushed toward extended resections [62] or resections after aggressive neoadjuvant therapies for locally advanced PDAC [31, 32] with promising results. Strategies of neoadjuvant treatment offer the advantage to select patients without progression for surgical resection, while patients with early systemic progression are selected out. Similarly, an isolated local recurrence may identify patients with tumors of a less aggressive phenotype resulting in slower systemic progression and better prognosis [29, 57]. This notion provides a good rational to test localized treatments such as re-resection and chemoradiation in this selected subgroup of patients with a localized disease pattern. However, the majority of patients presenting with suspected isolated local recurrence may also have occult systemic disease and may develop systemic progression later in the course of their disease. Therefore, as for primary pancreatic cancer, local therapies for recurrence must always be embedded in multimodal treatment strategies that include systemic chemotherapy.

Radiation Therapy for Isolated Local Recurrence

Radiation therapy/chemoradiation is often discussed as the main alternative to merely palliative chemotherapy for treatment of local recurrence [21]. The evidence for chemoradiation is based on only few retrospective series of limited size (Table 5) [50, 51, 52, 53, 54]. The actuarial overall median survival reported for different radiation therapy protocols ranges between 8.8 and 17.5 months. The three series using chemoradiation report longer median survival around 15.9–17.6 [50, 52, 53] compared to the two series on stereotactic body radiation therapy (SBRT, 8.8 and 12.2 months) [51, 54], probably because fewer patients received additional systemic chemotherapy in the latter two studies. Data on progression-free survival, local control rates, toxicity, and symptom relief are all inconsistently reported among the available studies. It should be noted that three studies report complete radiologic response rates of 15–33% [50, 52, 54].

With clear evidence for local efficacy in all studies and overall survival rates of up to 18 months, treatment strategies that include radiation therapy to improve local control should be further tested in patients with isolated local recurrence after resection of PDAC. However, the data also suggest that local radiation has to be accompanied by systemic chemotherapy to achieve adequate progression-free and overall survival.

Re-resection for Isolated Local Recurrence

Very similar to the situation described for radiotherapy, the evidence for re-resection for isolated local PDAC recurrence is based on retrospective series of limited sample size (Table 6) [46, 55, 56, 57, 58, 59, 60, 61]. However, the reported outcome with median overall survival rates of 25 to >30 months after re-resection in four of the more recent series [57, 58, 59, 60] is superior to the outcome reported after chemoradiation. These differences can in part be explained by bias due to the exclusion of patients with radiologically undetectable metastatic disease in the resected subgroups. While most series did not report on resection rates, the series from Heidelberg initially reported a resection rate of 50%, which dropped to 42.3% in the larger follow-up study, mainly due to intraoperative diagnosis of metastases [55, 57]. Overall, the available series clearly show that re-resection for isolated local recurrence is feasible and safe (low mortality rates of 0–2%) and associated with encouraging survival results. However, it should be emphasized that these results are based on cohorts of highly selected patients treated in specialized referral centers for pancreatic surgery and may not be commonly applicable.

The initial experience with re-resection at Heidelberg University Hospital was reported in 2007 [55], and the so far largest series on re-resection for isolated local PDAC recurrence was published in 2013 [57]. Of 97 patients with preoperatively suspected isolated local recurrence and histologic proof of recurrence, 57 (59%) had isolated local recurrence by surgical exploration, while distant metastases were identified in 40 (41%) patients. This highlights the necessity of better diagnostic tools to detect small metastatic deposits, a problem known from staging of primary PDAC. Of 57 isolated local recurrences, 41 (72%) were resected (Fig. 2), while 16 (28%) were locally unresectable. Median postoperative survival was 16.4 months in confirmed isolated local recurrence versus 9.4 months in metastatic recurrence, confirming the better prognosis associated with localized disease pattern observed in other studies [63]. Importantly, median survival in isolated local recurrence was significantly longer after re-resection compared to locally unresectable recurrences (26.0 vs. 10.8 months). This observation in surgically confirmed isolated local recurrence clearly points to a potential survival benefit from re-resection. R0 re-resection in 18 patients was associated with a favorable median survival of 30.5 months [57]. While a true benefit of re-resection can only be demonstrated by RCTs, these results suggest that selected patients with suspected isolated local PDAC recurrence may benefit from re-resection.
Fig. 2

Intraoperative findings in a patient with isolated locoregional recurrence in a typical predilection site after resection for adenocarcinoma of the pancreatic head, interaortocaval lymph nodes below the left renal vein. (a) Location of the recurrence (*) after exposure and dissection. (b) Operative site after tumor removal and retroperitoneal lymphadenectomy. A abdominal aorta, IVC inferior caval vein, LRV left renal vein

Only one study [61] that did not report on administration of systemic therapy reports a sobering median survival of 8.9 months after re-resection for PDAC recurrence. This again points toward the need to embed re-resection in a multimodal treatment strategy that includes systemic chemotherapy in order to achieve long-term survival.

Overall, the available series on re-resection clearly demonstrate that this concept is promising and should be tested in selected patients. A direct comparison of survival outcomes reported for radiation therapy and re-resection is not scientifically sound and should not be made. However, it is very clear that the available evidence for re-resection is at least equal, if not superior, to the evidence on radiation therapy in terms of the numbers and sample size of studies as well as with respect to reported survival outcomes.

Selection of Patients for Local Therapy

The identification and selection of patients that benefit from a treatment that includes local therapy are very relevant in the context of PDAC recurrence. Clearly, patients with a localized disease pattern without systemic progression, in whom the local recurrence may define prognosis, are the most likely to benefit from local therapy.

To identify these patients, early detection of the local recurrence by adequate surveillance and a thorough diagnostic workup to minimize the risk of occult metastatic disease are necessary. However, as discussed above, the rate of undetected metastatic disease is high [57]. While PET-CT is a currently available technology which holds promise in detection of local and distant PDAC recurrence and warrants further investigation [64], better tools for detection of metastatic disease are needed in the future.

The larger available series on treatment of local PDAC recurrence analyzed parameters that are associated with survival and may be useful for patient selection. The interval between primary tumor resection and detection of recurrence [46, 53, 55, 58] and CA 19-9 serum levels [57] are two parameters that may be useful, but the available data do not yet allow to determine cutoff values to support decision-making. In the absence of clear evidence, patients with a long interval between primary tumor resection and detection of local recurrence, low tumor markers, good performance status, and low comorbidity are probably the best candidates for local therapies based on common sense.

There is accumulating evidence that molecular properties of the primary tumor define the pattern of localized versus metastatic disease and even the distribution of metastatic disease between organs (e.g., liver and lung) [29, 48, 49]. Recently, several distinct molecular subtypes of pancreatic cancer that are associated with treatment response and prognosis have been identified [65, 66, 67, 68]. Similar studies may allow for identification of molecular signatures associated with localized disease or systemic progression and serve as new powerful tools for patient selection in the future.

Conclusions

Pancreatic cancer recurrence is a pressing problem that affects the vast majority of patients even after successful resection and completion of adjuvant chemotherapy. It is, therefore, surprising how little evidence there is with respect to the management of pancreatic cancer recurrence, and it is concerning that this important topic is still missing in many current clinical practice guidelines for pancreatic cancer. While the majority of patients develop metastatic recurrence, a significant subgroup of 20–30% of patients first develop isolated local recurrence. These patients appear to have tumors of less aggressive subtypes with slower systemic progression and may benefit from local therapy. As most recurrences are at first asymptomatic, structured follow-up programs are needed for earlier detection and timely initiation of therapy. However, in the absence of evidence, structured surveillance programs are currently not recommended. Although the literature provides little evidence with respect to the management of isolated PDAC recurrence, both chemoradiation and surgical re-resection appear to be safe and effective based on several retrospective series. The best “standard” management for isolated PDAC recurrence can only be determined based on RCTs which are unlikely to be conducted for this indication. More likely, the therapy for PDAC recurrence will remain a matter of interdisciplinary, personalized decision-making. Novel biomarkers for early detection of PDAC and the development of more effective systemic treatments will hopefully also advance surveillance after PDAC resection and treatment of PDAC recurrence.

Cross-References

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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Oliver Strobel
    • 1
  • Willem Niesen
    • 1
  • Markus W. Büchler
    • 1
  1. 1.Department of General, Visceral and Transplantation SurgeryHeidelberg University HospitalHeidelbergGermany

Section editors and affiliations

  • James L. Abbruzzese
    • 1
  • Raul A. Urrutia
    • 2
  • John Neoptolemos
    • 3
  • Markus W. Büchler
    • 4
  1. 1.Duke University Medical CenterDurhamUSA
  2. 2.Mayo Clinic Cancer CenterMayo ClinicRochesterUSA
  3. 3.Division of Surgery and OncologyUniversity of LiverpoolLiverpoolUK
  4. 4.Department of General, Visceral and Transplantation SurgeryUniversity of HeidelbergHeidelbergGermany

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