Strahlentherapie und Onkologie
Original Article
Maintenance Chemotherapy after Chemoradiation Improves Survival of Patients with Locally Advanced Pancreatic Carcinoma A Retrospective Analysis of Prospectively Recruited Patients Thomas B. Brunner1*, Dominik Tinkl1*, Gerhard G. Grabenbauer1, Thomas Meyer2, Wolfgang M. Brueckl3, Rolf Sauer1
Background and Purpose: Currently, there is no treatment standard for patients with locally advanced pancreatic cancer (PaCa) after chemoradiation. The aim of the present study was to retrospectively assess overall survival and toxicity of chemotherapy in addition to chemoradiation in this patient group. Patients and Methods: Three-dimensional conformal irradiation to the primary tumor (55.8 Gy) and the lymphatics (50.4 Gy) was combined with 5-fluorouracil- or gemcitabine-based chemotherapy followed by additional chemotherapy with gemcitabine until progression or no further treatment. Decision for chemotherapy was taken at the discretion of the attending physician considering the patient’s desire. Results: A total of 172 patients were addressed to the local tumor board. Patients with (neo)adjuvant treatment or metastatic disease were excluded (n = 90). 82 patients were treated with chemoradiation and had additional chemotherapy (n = 40) or no further treatment (n = 42). Characteristics of the two groups were equally distributed. Patients with chemotherapy had significantly longer overall survival as compared to patients without (13 months vs. 8 months; p < 0.0001; median survival = 10.7 months for all patients). Acute toxicity of maintenance chemotherapy was relatively mild. Conclusion: Maintenance chemotherapy after chemoradiation for patients with locally advanced PaCa may significantly increase survival rates without severe side effects and is therefore recommended as standard treatment following chemoradiation. Key Words: Pancreatic carcinoma · Chemoradiation · Additive · Chemotherapy · Gemcitabine Strahlenther Onkol 2006;182:210–5 DOI 10.1007/s00066-006-1524-x Erhaltungschemotherapie nach Radiochemotherapie verlängert die Überlebenszeit von Patienten mit lokal fortgeschrittenem Pankreaskarzinom. Eine retrospektive Analyse prospektiv rekrutierter Patienten Hintergrund und Ziel: Derzeit gibt es keine Standardbehandlung für Patienten, die eine Radiochemotherapie wegen eines lokal fortgeschrittenen Pankreaskarzinoms erhalten haben. Die Gesamtüberlebenszeit und die Toxizität einer additiven Chemotherapie nach Radiochemotherapie wurden bei dieser Patientengruppe untersucht. Patienten und Methodik: Eine dreidimensional geplante konformale Bestrahlung des Primärtumors (55,8 Gy) und der Lymphabflusswege (50,4 Gy) wurde mit 5-Fluorouracil- oder Gemcitabin-haltiger Chemotherapie kombiniert. Dieser folgte eine zusätzliche Chemotherapie mit Gemcitabin bis zum Progress oder keine weitere Behandlung. Die Entscheidung für eine Chemotherapie wurde unter Berücksichtigung des Patientenwunsches vom weiterbehandelnden Arzt getroffen. Ergebnisse: Dem lokalen Tumorboard wurden insgesamt 172 Patienten zugewiesen. Patienten mit neoadjuvanter und adjuvanter Behandlung oder Fernmetastasen wurden ausgeschlossen (n = 90). 82 Patienten wurden einer Radiochemotherapie und anschließenden Chemotherapie unterzogen (n = 40) oder erhielten keine weitere Behandlung (n = 42). Die Patientencharakteristika zwischen den beiden Gruppen waren ausgeglichen verteilt. Patienten mit additiver Chemotherapie überlebten signifikant länger im Vergleich zu solchen ohne weitere Therapie (13 Monate vs. 8 Monate; p < 0,0001; mediane Überlebenszeit = 10,7 Monate für alle Patienten). Die Akuttoxizität der Erhaltungschemotherapie war relativ gering. *Both authors contributed equally to the paper. 1
Department of Radiation Oncology, Friedrich Alexander University of Erlangen-Nuremberg, Erlangen, Germany, Department of Abdominal Surgery, Friedrich Alexander University of Erlangen-Nuremberg, Erlangen, Germany, 3 Department of Internal Medicine I, Friedrich Alexander University of Erlangen-Nuremberg, Erlangen, Germany. 2
Received: October 4, 2005; accepted: January 25, 2006
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Brunner TB, et al. Cx after CRT in Advanced Pancreatic Cancer
Schlussfolgerung: Eine Erhaltungschemotherapie nach Radiochemotherapie für Patienten mit lokal fortgeschrittenem Pankreaskarzinom steigert deren Überlebensraten signifikant, ohne schwere Nebenwirkungen zu verursachen, und wird daher als Standardbehandlung für diese Patienten empfohlen. Schlüsselwörter: Pankreaskarzinom · Radiochemotherapie · Additiv · Chemotherapie · Gemcitabin
Introduction with ductal pancreatic adenocarcinoma without distant meDespite considerable progress in the field of oncology during tastasis were eligible (clinical stages I–IVA; UICC 1997; Figthe past 2 decades including discovery of targeted therapy ure 1). Two of the 82 patients had paraaortic lymph nodes approaches [3], the dismal prognosis of patients with ductal ≥ 1 cm in CT scans which is regarded as metastatic spread. pancreatic carcinoma (PaCa) did not experience significant Resectability was assessed according to the criteria of Lu et improvements in survival over time. PaCa remains the fourth al. [19]. Patients with previous tumor-specific treatment were leading cause of cancer-related death in the USA and in Eunot included in this analysis. rope [26]. More than 80% of the patients are not resectable at diagnosis. Of these, about 50% present without distant metasMethods of Assessment and Treatment tasis and chemoradiation (CRT) is regarded as standard treatPretherapeutic staging included complete history, clinical ment [22]. The introduction of gemcitabine into palliative cheevaluation, complete blood count, clinical chemistry analysis, motherapy resulted first of all in an improvement of quality of blood coagulation analysis, and tumor markers CA 19-9 and life and to a much lower degree in a survival gain [6]. After CEA (carcinoembryonic antigen); furthermore, a chest discovery of the radiation-sensitizing properties of gemcitabiX-ray, an abdominal CT scan, and a spiral CT scan of the panne (reviewed in [21]), CRT schedules with concurrent use of creatic region (slice = 3 mm). Histological confirmation was this drug have been established and are currently investigated obtained by CT- or ultrasound-guided fine-needle biopsy. in randomized phase II trials [36]. Treatment planning was based on a CT scan with oral and i.v. Treatment failure in patients with locally advanced PaCa contrast with 3 mm slice thickness. The delineation of the occurs with about equal frequency locally and at distance. CRT planning target volume for three-dimensional conformal rais locally very active but not sufficiently effective against disdiotherapy was performed as outlined in detail elsewhere [4]. tant spread of disease. The need for systemic treatment in PaCa The primary tumor and the regional lymphatics were treated is comparable with patients treated for rectal cancer where with 1.8 Gy/day and five fractions per week up to a total dose additional chemotherapy now is regarded as an integral part of 50.4 Gy. The boost volume included the primary tumor and of CRT schedules [33, 37]. Recently, there is accumulating involved lymph nodes up to a total dose of 55.8 Gy. Concurevidence for PaCa as for other diseases of the upper gastrointestinal tract [17] N = 172; Presented that intensified therapies may be able to to tumor board achieve at least some prolongation of N = 32; Cx/Rx for distant metastasis N = 15; CRT for positive margins survival for the patients with a good perN = 1; Patient refused CRT N = 2; CRT for local relapse formance status [12, 25, 27, 28, 31]. N = 9; Histology other than ductal With continued interest in the use of N = 113; Patients with CRT CRT in PaCa, we are able to present data N = 31 of patients with locally advanced disease Neoadjuvant treatment and compared two groups who either received additive chemotherapy after CRT N = 82; Definitve RCT or not. The primary objective of this study was to analyze the impact of additional chemotherapy on survival supplemented with an analysis of toxicity. Patients and Methods Selection of Patients Between July 1995 and October 2003, 172 patients with PaCa were registered for evaluation and possible treatment at our department. Of these, 82 patients
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N = 42 CRT only
N =40 CRT and Chemo
Figure 1. Algorithm of the patients referred to the tumor board and their selection process for definitive chemoradiation. CRT: chemoradiation; Cx: chemotherapy; Rx: radiotherapy. Abbildung 1. Flussdiagramm der Patienten, die dem Tumorboard zugewiesen wurden, und deren Selektionsprozess für die definitive Radiochemotherapie. CRT: Radiochemotherapie; Cx: Chemotherapie; Rx: Radiotherapie.
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Table 1. Patient characteristics. CRT: chemoradiation; ECOG-PS: Eastern Cooperative Oncology Group performance status scale; f: female; 5-FU: 5-fluorouracil; Gem: gemcitabine; m: male; mtnc Cx: maintainance chemotherapy; n: number of patients.
100
80
Tabelle 1. Patientencharakteristika. CRT: Radiochemotherapie; ECOGPS: Skala der Eastern Cooperative Oncology Group für den Allgemeinzustand; f: weiblich; 5-FU: 5-Fluorouracil; Gem: Gemcitabin; m: männlich; mtnc Cx: Erhaltungschemotherapie; n: Anzahl der Patienten.
60
All patients n (%) 40
20
0 0 at risk: 82
10
20
30
46
9
3
Figure 2. Kaplan-Meier plot of survival for all patients with chemoradiation (n = 82). Median survival time = 10.7 months; 1-year survival = 43%; 2-year survival = 9%; 3-year survival = 5%. Abbildung 2. Kaplan-Meier-Überlebensanalyse für alle Patienten mit Radiochemotherapie (n = 82). Mediane Überlebenszeit = 10,7 Monate; 1-Jahres-Überlebensrate = 43%; 2-Jahres-Überlebensrate = 9%; 3-Jahres-Überlebensrate = 5%.
Patients 82 (100) Median age (range) 66 years (35–78 years) Gender (m : f) 48 : 34 (59 : 41) UICC 1997 • Ia 4 (5) • IIa 11 (13) • III 16 (20) • IVA 49 (60) • IVBb 2 (2) 5-FU-based 25 (30) Gem-based 57 (70) ECOG-PS •1 47 (57) •2 23 (28) •3 12 (15)
Definitive CRT, no mtnc Cx n (%)
Definitive CRT, with mtnc Cx n (%)
42 (51) 66 years (35–78 years) 22 : 20 (52 : 48)
40 (49) 64 years (37–76 years) 26 : 14 (65 : 35)
3 (7) 5 (12) 5 (12) 27 (64) 2 (5) 15 (36) 27 (64)
1 (3) 6 (15) 11 (28) 22 (55) 0 10 (25) 30 (75)
23 (55) 11 (26) 8 (19)
24 (60) 12 (30) 4 (10)
a
2
rent chemotherapy consisted of 5-fluorouracil (1 g/m /d c.i.v. d1–5, d29–33) and mitomycin C (10 mg/m2 bolus i.v., d1, 29) in 25 patients [2] or of gemcitabine (300 mg/m2 in 30 min i.v. d1, 8, 22, 29) and cisplatin (30 mg/m2 in 30 min i.v. d1, 8, 22, 29) in 57 patients [5, 36]. Since there is no evidence-based consensus if maintenance chemotherapy after CRT is of benefit for patients with locally advanced PaCa, the choice for additive chemotherapy was at the discretion of the treating physician. In line with accumulating data favoring chemotherapy for locally advanced and metastatic PaCa (reviewed in [35]), tendency to use chemotherapy showed a continual rise over the years of the reported time interval. Maintenance chemotherapy consisted of gemcitabine alone in 34 patients (1,000 mg/m2 d1, 8, 15 q21d), of gemcitabine (1,000 mg/m2 d1, 15 q28d) and cisplatin in three patients (50 mg/m2 d1, 15 q28d), of gemcitabine/5-fluorouracil in two patients, and of adriblastin in one patient. Statistical Methods and Toxicity Criteria Statistical data analysis was performed using the computer software Statistical Package for the Social Sciences®, version 11.0. For analysis of survival the Kaplan-Meier plot was calculated. The pairwise log-rank test served for comparison of the differences in survival in subgroups of patients. Classification of acute and chronic treatment-related side effects was performed according to the RTOG toxicity criteria [8],
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All patients grouped into UICC 1997 stages I and II had tumors with contact to the superior mesenterial vein ≥ 180° of the circumference and were therefore deemed to be nonresectable b grouped UICC IVB because of a paraaortic lymph node > 1 cm, respectively, at the level of the posterior pancreaticoduodenal nodes
the LENT-SOMA criteria [32] (side effects of radiotherapy) and the CTCAE v3.0 toxicity criteria of the NCI (hematologic side effects). Results Between August 1995 and October 2003, 82 patients with locally advanced ductal PaCa without distant metastasis were treated. Patients with neoadjuvant treatment or adjuvant treatment were excluded from analysis (Figure 1). At the time of the analysis in May 2005, 79 events had occurred. The type of chemotherapy given simultaneously to irradiation had no influence on overall survival (p = 0.40 at Kaplan-Meier analysis). Median overall survival time for all 82 patients was 10.7 months (Figure 2). A total of 40 patients received additional chemotherapy after CRT compared to 42 patients without further treatment. Table 1 shows equal distribution of patients’ characteristics for the two treatment groups. Of note, there was no difference in the distribution of ECOG performance status which is a known prognostic factor for survival of patients with PaCa after chemotherapy [12, 31]. ECOG performance status did not differ significantly between patients receiving additive
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Figure 3. Kaplan-Meier plot of survival after CRT ± maintenance chemotherapy. Solid line represents patients with maintenance chemotherapy (n = 40) and broken line without maintenance chemotherapy (n = 42) after CRT. Median survival time = 13.5 versus 7.6 months; 1-year survival rate = 65% versus 21%; 2-year survival rate = 14% versus 5%; 3-year survival rate = 6% versus 5%; p = 0.0001 by the log-rank method.
100 p = 0.0001 80
Abbildung 3. Kaplan-Meier-Überlebensanalyse nach Radiochemotherapie ± Erhaltungschemotherapie. Die durchgezogene Linie repräsentiert Patienten mit Erhaltungschemotherapie (n = 40) und die gestrichelte Linie Patienten ohne Erhaltungschemotherapie (n = 42) nach Radiochemotherapie. Mediane Überlebenszeit = 13,5 versus 7,6 Monate; 1-Jahres-Überlebensrate = 65% versus 21%; 2-Jahres-Überlebensrate = 14% versus 5%; 3-Jahres-Überlebensrate = 6% versus 5%; p = 0,0001 nach der Log-Rank-Methode.
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40 CRT + mtc Cx
20 CRT only
chemotherapy or patients without further tumor-specific treatment. A median of seven courses of maintenance chemotherapy was administered (range, two to 14). Actuarial Kaplan-Meier analysis showed a statistically highly significant (p = 0.0001) prolongation of overall survival for patients who received additional chemotherapy after completion of CRT as compared to CRT alone (median survival 13.5 vs. 7.6 months; Figure 3). Higher-grade toxicity (grade 3 or 4) was exclusively hematologic (Table 2). The most important toxicity was leukocytopenia, which was observed at a frequency of 25%. One fatal toxicity due to duodenal bleeding was experienced 4 months after CRT without thrombopenia. The patient received gemcitabine chemotherapy without gastric acid control medication. Discussion Since the introduction of newer chemotherapeutic agents in the mid-1990s [6], the question arose whether patients with locally advanced PaCa should be treated with CRT which was standard in the era of 5-fluorouracil treatment or with chemotherapy alone (reviewed in [35]). Many chemotherapeutic trials included patients with both metastatic and locally advanced disease. However, only studies with a subgroup analysis for locally advanced patients allow a comparison with the results of trials using CRT. There are four randomized phase III trials providing such data [1, 7, 15, 20] and their median survival results are rather disappointing with a median survival of about 6 months and a 12-month survival rate of only 15%. Newer CRT trials [9, 14, 16, 23, 34] reported median survival times of 10–11 months and 1-year survival rates of about 40%. These results confirm the role of CRT for nonmetastastic, unresectable PaCa. The median survival time of 10.7 months of the patients treated in this study is in line with the above-quoted CRT data. Distant failure occurs in about half of the patients after CRT for locally advanced PaCa [10]. For this reason, additional chemotherapy has already been used in the early randomized trials for PaCa [11, 24]. However, there is no consen-
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0
at risk:
0
10
20
30
40 42
31 14
7 2
2 2
sus whether to use or not to use additive chemotherapy [18]. Most recent data for patients with locally advanced PaCa indicate a prolongation of overall survival when chemotherapy was intensified at least for the subgroup of patients with good performance status [12, 25, 27, 28, 31]. The rationale of adding chemotherapy to definitive CRT is to exert a stronger effect on systemic disease in comparison to the more local effect of CRT. The dose intensity of concurrent combination of gemcitabine/cisplatin used within CRT trials has to be regarded as relatively ineffective against systemic disease and justifies further systemic treatment. Currently, to our knowledge, there are no published trials comparing CRT alone with CRT and sequential chemotherapy for patients with locally advanced PaCa. However, a recent meeting report did focus on this question [13]. In a retrospective analysis of the GERCOR study group, 128/181 Table 2. Acute toxicity of maintenance chemotherapy (n = 40). n: number of patients with observed toxicity. Tabelle 2. Akuttoxizität der Erhaltungschemotherapie (n = 40). n: Anzahl der Patienten mit der beobachteten Toxizität Toxicity
Grade 0–2 n (%)
Leukopenia Thrombopenia Anemia Gastrointestinal Recall radiation dermatitis
30 (75) 38 (95) 36 (90) 39 (98) 1 (2)b
a b
Grade 3 n (%) 9 (23) 2 (5) 4 (10) 0
Grade 4 n (%) 1 (2) 0 0 1 (2)a
One patient died of upper gastrointestinal bleeding 4 months after completion of CRT with gemcitabine chemotherapy and without gastric mucosal protection Recall radiation grade 1 was observed in one patient
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(70.3%) patients without disease progression after chemotherapy in prospective phases II and III were either treated with CRT (72/128; 56%) or continued to receive chemotherapy alone (56/128; 44%). Additional CRT prolonged median overall survival time to 15 months as compared to 11.7 months with chemotherapy alone (p = 0.0009). The longer median survival time of this report in comparison to our study probably results from a positive patient selection of the responding group to chemotherapy. This means that patients with biologically more aggressive tumors did develop distant metastasis during initial chemotherapy and thus were not eligible for CRT. By contrast, patients with early metastasis after initiation of CRT were included in this trial. The choice for additive chemotherapy was at the discretion of the treating physician. To exclude a selection bias, factors that may have influenced the decision for further chemotherapy were compared between both groups. However, neither age, UICC stages, nor ECOG performance status were significantly imbalanced between both groups. Since this is not a prospectively randomized trial, nevertheless, slight imbalances between the two treatment groups should be mentioned as they cannot be fully excluded to have exerted some bias onto the results: (1) patients had UICC 1997 stage IV tumors in 69% without additional chemotherapy versus 55% with sequential chemotherapy. (2) ECOG performance status 3 was 19% versus 10% in the respective groups. Whilst patients can be reliably grouped into the ECOG performance score, there is much more difficulty considering the usefulness of UICC stages for patients with PaCa whose tumors cannot be resected. Especially, pretherapeutic CT and MRI cannot detect nodal spread with sufficient accuracy, but nodal spread has a major impact on UICC grouping. The same is true for the low accuracy of imaging to discriminate between T3 and T4 tumors. The consequences of these uncertainties onto UICC stage grouping may be described in an example: a patient with a T3 N0 tumor would be grouped into UICC 1997 stage II, whereas a patient with a T4 N0 tumor would be regarded as UICC 1997 stage IV. While there is no clear evidence for a specific chemotherapeutic schedule after CRT to be given at this time, we recommend to integrate a 6-week break from any treatment after completion of CRT to allow for mucosal recovery [29]. We can safely propose to use a regimen of gemcitabine (e.g., 1,000 mg/m2 days 1, 8, 15 q28d) until progression of the disease similar to the schedule reported by Kachnic et al. [16] with gastric acid control medication. The best sequencing of CRT and chemotherapy for patients with locally advanced disease is not known yet. But the results of the fully accrued RTOG 97-04 study for patients with resected tumors [30] and the results of a currently active prospectively randomized multicenter trial from Germany for patients with locally advanced tumors [36] are expected to shed more light onto this treatment aspect.
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Address for Correspondence Thomas B. Brunner, MD Department of Radiation Oncology University of Erlangen-Nuremberg Universitätsstraße 27 91054 Erlangen Germany Phone (+49/9131) 853-3405, Fax -4185 e-mail:
[email protected]
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