Chemoradiotherapy with FOLFOX plus cetuximab in locally advanced oesophageal cancer: The GERCOR phase II trial ERaFOX

European Journal of Cancer 56 (2016) 115e121

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Clinical Trial

Chemoradiotherapy with FOLFOX plus cetuximab in locally advanced oesophageal cancer: The GERCOR phase II trial ERaFOX* Ge´rard Lledo a,b,*, Florence Huguet b,c, Benoist Chibaudel b,d, Fre´de´ric Di Fiore e, Laurent Mineur f, Marie-Pierre Galais g, Pascal Artru a, Vale´rie Blondin e, Olivier Dupuis h, Menouar Samir Abdiche i, Nicolas Jovenin j, Astrid Pozet k, Franck Bonnetain k, Mohamed Attia b, Laetitia Dahan l, Aimery de Gramont b,d a

Gastroenterology Department, Private Hospital Jean Mermoz, Lyon, France Groupe Coope´rateur Multidisciplinaire en Oncologie (GERCOR), Paris, France c Radiation Oncology Department, Tenon Universitary Hospital, Assistance Publique e Hoˆpitaux Universitaires Paris Est, University Pierre and Marie Curie Paris 6, Institut Universitaire de Cance´rologie, Paris, France d Medical Oncology Department, Saint-Antoine Universitary Hospital, Paris, France e Digestive Oncology Unit, Hepatogastroenterology Department, University Hospital, Rouen, France f Radiation Oncology Department, Institut Sainte-Catherine, Avignon, France g Digestive Oncology Unit, Centre Re´gional Franc¸ois Baclesse, Caen, France h Clinique Victor Hugo, Le Mans, France i Radiation Oncology Department, Robert Boulin Hospital, Libourne, France j Medical Oncology Department, Institut Jean Godinot, Reims, France k Methodology and Quality of Life Unit in Cancer, EA 3181, Universitary Hospital of Besanc¸on, Besanc¸on, France l Digestive Oncology Unit, University Hospital la Timone, Marseille, France b

Received 29 June 2015; received in revised form 13 December 2015; accepted 18 December 2015

Available online 2 February 2016

KEYWORDS Oesophageal cancer; Oxaliplatin; Radiotherapy;

Abstract Background: To determine efficacy and toxicity of radiation therapy combined with oxaliplatin, 5-fluorouracil, and folinic acid (FOLFOX) and cetuximab in patients with locally advanced oesophageal cancer.

* Presented in part at the Gastrointestinal Symposium of the American Society of Clinical Oncology (ASCO), 2010, 22e24 January, Orlando, FL (abstract #68), and the Gastrointestinal Symposium of the ASCO, 2011, 20e22 January, San Francisco, CA (abstract #8). * Corresponding author: Hoˆpital Prive´ Jean Mermoz, 55, avenue Jean Mermoz, 69008 Lyon, France. Tel.: þ33 4 78 78 10 51; fax: þ33 4 78 74 07 92. E-mail address: [email protected] (G. Lledo).

http://dx.doi.org/10.1016/j.ejca.2015.12.020 0959-8049/ª 2015 Elsevier Ltd. All rights reserved.

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Chemoradiotherapy; FOLFOX; Cetuximab

G. Lledo et al. / European Journal of Cancer 56 (2016) 115e121

Patients and methods: Patients with stage III oesophageal or gastro-oesophageal junction cancer were enrolled in a Simon’s two-stage phase II study. Patients received FOLFOX and weekly cetuximab on week 1e10 with concurrent radiotherapy (50.4 Gy in 30 fractions) on week 5e10. Primary end-point was clinical overall response rate (ORR). An ORR rate of more than 50% was expected. Results: Among the 79 included patients, clinical ORR was 77% with 40% complete responses. Median overall survival and progression-free survival were 21.6 and 11.3 months, respectively. The most common grade IIIeIV toxicities observed during experimental chemoimmunotherapy followed by chemoradiation included neutropenia (28%), oesophagitis (12%), rash (11%), and allergy (9%). There was one treatment-related death due to oesophagitis with gastrointestinal bleeding. Conclusions: Cetuximab-FOLFOX regimen combined with radiotherapy demonstrated its efficacy and was well tolerated. Unfortunately, these results were not confirmed in two recent phase III studies. ª 2015 Elsevier Ltd. All rights reserved.

1. Introduction Oesophageal cancer is the eighth-most common cancer worldwide, with 481,000 new cases estimated in 2008, and the sixth-most common cause of death from cancer [1]. There are two main histological types of oesophageal cancer, squamous cell carcinoma (SCC) and adenocarcinoma (AC). Recently, the incidence of AC of the lower oesophagus and gastro-oesophageal junction (GEJ) has increased whilst the incidence of SCC has fallen slightly in populations of the Western countries. Surgery is the cornerstone in the treatment of oesophageal cancer and is considered for all patients with potentially resectable tumours. Patients with localised tumours not considered for surgery can be treated with chemoradiation (CRT) with curative intent. The role of neoadjuvant CRT remains highly debated despite numerous clinical trials [2]. In the past few years, optimisation of CRT was addressed by combining different chemotherapy regimens with radiation therapy (RT). The most commonly used regimen in combination with RT is cisplatin and 5fluorouracil (5FU) [3]. The FOLFOX regimen, a combination of oxaliplatin, 5FU and folinic acid, used with concurrent RT provided a similar outcome when compared to cisplatin-5FU in a phase III trial, with similar tolerance but is more convenient to administer [4]. Epidermal growth factor receptor (EGFR) expression occurs in 30e50% of oesophageal cancer patients and is a bad prognosis factor [5]. Radiation induces an increase in the expression of EGFR in cancer cells and blockade of EGFR by cetuximab sensitises cells to the effects of radiation in vitro and in vivo [6]. It has been suggested that addition of cetuximab to standard chemotherapy for metastatic oesophageal SCC might increase treatment efficacy [7]. In locally advanced oesophageal cancer, cetuximab in combination with CRT showed promising results in a phase IB/II trial [8].

The ERaFOX phase II study was designed to evaluate the efficacy and tolerance of cetuximab in combination with FOLFOX-based chemotherapy and CRT in locally advanced oesophageal or GEJ carcinomas. 2. Patients and methods 2.1. Patient eligibility criteria Previously untreated patients with histologically confirmed SCC or AC of the thoracic oesophagus or the GEJ were included in this prospective multicentre trial. Patients with stage III were eligible. Other eligibility criteria included age 18e70 years, Eastern Cooperative Oncology Group performance status of 0e1, and adequate haematological, renal and hepatic function. All patients provided their written informed consent before registration. The protocol was approved by the Centre Le´on Be´rard (Lyon Sud-Est IV, France) ethics committee (ClinicalTrials.gov study identifier: NCT00578201). 2.2. Treatment All included patients were scheduled to receive a twostage treatment consisting of two cycles of induction chemotherapy followed by CRT with three concurrent cycles of chemotherapy (Fig. 1). The induction chemotherapy consisted of two cycles of FOLFOX (oxaliplatin 85 mg/m2 on day 1, folinic acid 400 mg/m2 on day 1, followed by 5FU 2400 mg/m2 as 44 h infusion), given every 2 weeks, and cetuximab (first infusion 400 mg/m2 then 250 mg/m2), given weekly. Induction chemotherapy was followed by RT combined with three concurrent cycles of chemotherapy (same regimen but 5FU infusion dose reduced to 1800 mg/m2). Anti-histaminic prophylaxis was given to every patient before administration of cetuximab.

G. Lledo et al. / European Journal of Cancer 56 (2016) 115e121 I N C L U S I O N

Cycle 1

Cycle 2

Cycle 3

Cycle 4

Cycle 5

RT 50.4 Gy

FOLFOX

cetuximab

E V A L U A T I O N

117

Surgery No PD

Observation FOLFOX-cetuximab Salvage surgery

PD

2nd line of chemotherapy Best supportive care

radiation therapy

Fig. 1. Trial design.

Three-dimensional conformal RT of 50.4 Gy (28 fractions of 1.8 Gy) was given over 6 weeks. The target volume included all known areas of disease with a 4-cm cranial and caudal margin and a 1.5-cm lateral margin. Custom blocking was used to reduce unnecessary radiation dose to normal structures including: spinal cord, liver, heart and lungs. The study stopped after CRT completion. 2.3. Pre-treatment evaluation Pre-treatment evaluation consisted of a physical examination, thoraco-abdomino-pelvic computed tomography (CT) scan, oesophagogastroduodenoscopy with biopsies, bronchoscopy, head and neck examination, and laboratory tests. Endoscopic ultrasonography (EUS) was compulsory considering the degree of oesophageal stenosis. Positron emission tomography scan was optional. Dysphagia was graded according to Atkinson’s scale (grade 0: ability to eat normal diet, grade I: ability to eat some solid food, grade II: ability to eat some semi-solid food, grade III: ability to swallow liquid only, and grade IV: complete obstruction) [9]. 2.4. Efficacy evaluation criteria Primary end-point The primary efficacy end-point was the clinical overall response rate (ORR) defined as the sum of clinical complete response (CR) and clinical partial response (PR) rates. CR was defined as an absence of detectable tumour on CT scan and oesophagoscopy and complete disappearance of ulceration or stenosis and negative biopsy findings. PR was defined as at least a 30% decrease in the sum of diameters of target lesions or the disappearance of radiographic evidence of disease on CT scan with residual tumour cells in the endoscopic biopsy. All patients were evaluated for response by tumour measurement 4e6 weeks after CRT completion. Patients were followed every 2 months during the first year

then every 4 months during the second year and every 6 months thereafter. CT scan and oesophagoscopy were performed every 4 months during the first year and every 6 months thereafter. Secondary end-points Secondary end-points were OS, progression-free survival (PFS) and toxicity. OS was defined as the time interval from patient inclusion to death (from all causes). PFS was defined as the time interval from inclusion to first disease progression or death from any cause if disease progression did not occur. All patients who had received at least one dose of CT and/or one fraction of radiotherapy were considered evaluable for safety and tolerance. Toxicity was graded according to the National Cancer Institute Common Toxicity Criteria version 3.0. 2.5. Statistical analysis This is a one-arm phase II trial. Using two-stage minimax Simon design, with unilateral alpha type one error of 5% and a statistical power of 90% with the following hypotheses H0: an ORR of 30% would be considered as uninteresting and H1: an ORR rate of more than 50% was expected, a sample size of 79 patients was needed [10]. This design required at least 12 responses amongst the first 41 patients to continue to enrol the next 38 patients. Otherwise, the trial would have stopped for futility. A total of at least 31 responses in 79 patients were required at the end of the trial for the treatment to be considered sufficiently promising to warrant further study [10]. A subgroup analysis according to histological subtype was planned. Data were prospectively collected at inclusion, after completion of the treatment and at regular follow-up intervals. The intent-to-treat (ITT) population included all patients. ORR was described using frequency and percent with 95% confidence interval (CI) in ITT population. Univariate and multivariate logistic regression analyses were used to study independent prognostic factors of ORR. Median follow-up was calculated by

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the reverse KaplaneMeier method [11]. Time to event end-points including OS and PFS estimates were computed using the KaplaneMeier method and compared using the log-rank test [12]. In order to assess the precision of the obtained estimates, hazard ratio (HR) and 95% CI were assessed from Cox proportional hazard models. Multiple logistic regression analysis was used to study prognostic factors. Analyses were performed using SAS software version 9.3 and R version 2.15.3. 3. Results 3.1. Patient characteristics Between November 2007 and February 2010, 79 patients with previously untreated locally advanced oesophageal cancer were enrolled. The pre-treatment characteristics are listed in Table 1 and demonstrate a predominantly male population (76%) with SCC histology (67%). Of the 79 patients, tumour stenosis precluded EUS in 25. 3.2. Treatment characteristics Of the 79 eligible patients treated with induction chemotherapy, 77 (97%) received at least 75% of the oxaliplatin planned dose and 70 (89%) received at least 75% of the cetuximab planned dose during the induction phase. Cetuximab was discontinued due to drug-related severe allergy (seven patients) and grade IIIeIV rash (two patients). Seventy-four patients (94%) were treated with concurrent CRT after induction chemotherapy. Of those, 73 patients (97%) received the RT according to the protocol at the planned dose of 50.4 Gy, and one patient discontinued RT after 46.4 Gy because of asthenia. Five patients (6%) received CRT off-protocol due to discontinuation of cetuximab during the induction phase (RT with concurrent FOLFOX without cetuximab). In eight patients (10%), a temporary discontinuation of RT was needed, mainly for toxicity. 3.3. Tolerance All Common Terminology Criteria for Adverse Events (CTCAE) adverse events reported during treatment are shown in Table 2. The most common grade IIIeIV toxicities included neutropenia (28%), oesophagitis (12%), rash (11%), and allergy (9%). There was one treatment-related death (1%) due to oesophagitis with gastrointestinal bleeding. 3.4. Response to CRT Of the 79 patients, 32 had a clinical CR (40.5%) and 29 had a clinical PR (37%), resulting in a clinical ORR of 77% (95% CI: 68e86.5). A total of six patients were classified as stable. Of the nine patients (11%) who had

Table 1 Pre-treatment characteristics of patients. Characteristics

Number of patients (n Z 79)

Age (years) Median  standard deviation 63  10.4 Range 23e79 Gender Male 60 Female 19 ECOG performance status 0 47 1 31 Not available 1 Histological type SCC 53 Adenocarcinoma 25 Undifferentiated 1 Tumour location Upper third oesophagus 12 Middle third oesophagus 29 Lower third oesophagus 33 Gastroesophageal junction 5 EUS staging II 11 III 39 EUS not done because of 29 oesophageal stenosis BMI Median  standard deviation 24  4.8 Range 14e34 Weight loss (>5% within 6 months prior to inclusion) Yes 56 No 23 Degree of dysphagia (Atkinson’s score) 0: absent 24 I: solid 28 II: semi-solid 19 III: liquid 5 IV: aphagia 3

Total (%)

76 24 60 39 1 67 32 1 15 37 42 6 14 49 37

71 29 30 36 24 6 4

Abbreviations: BMI, body mass index; ECOG, Eastern Cooperative Oncology Group; EUS, endoscopic ultrasonography; SCC, squamous cell carcinoma.

tumour progression (PD), five patients experienced locoregional failure and four had distant metastasis. Three patients were not assessable for response. The ORR was of 75.5% in SCC patients and 80% in AC patients (p Z 0.7). In univariate analysis, only two factors predicted for a worse ORR: denutrition (odds ratio [OR], 0.13; p Z 0.01) and a high Atkinson’s score (OR, 0.22; p Z 0.008). Multivariable logistic regression analysis showed the Atkinson’s score at baseline (score 0e2 versus 3e4; OR, 3.7; 95% CI: 0.99e14.3; p Z 0.05) as the only significant independent predictive factor for ORR. Of the 70 patients without disease progression after CRT, 17 underwent tumour resection. 3.5. Survival All 79 patients were included in ITT analysis. At the time of analysis, 35 patients died. Median follow-up

G. Lledo et al. / European Journal of Cancer 56 (2016) 115e121

Table 2 Treatment-related CTCAE toxicities during induction chemotherapy and chemoradiotherapy. Adverse events Induction chemotherapy (n [ 79) Haematological Anaemia Neutropenia Febrile neutropenia Thrombocytopaenia Non-haematological Nausea/vomiting Diarrhoea Stomatitis Neurotoxicity Rash Oesophagitis Alopecia Allergy/infusion reaction* Chemoradiotherapy (n [ 74) Haematological Anaemia Neutropenia Febrile neutropenia Thrombocytopaenia Non-haematological Nausea/vomiting Diarrhoea Stomatitis Neurotoxicity Rash Oesophagitis Alopecia Allergy/infusion reaction*

Grade (%) 0

I

II

III

IV

57 0 100 86

40.5 81 0 14

2.5 11.5 0 0

0 2.5 0 0

0 5 0 0

61 83.5 82 52 39 86 100 91

26 11.5 13 45.5 30 11 0 0

10 1 4 2.5 23 1.5 0 0

1.5 4 1 0 6.5 1.5 0 0

1.5 0 0 0 1.5 0 0 9

57 0 97 0

40.5 51.5 1.5 44

2.5 18.5 1.5 46

0 17 0 7

0 13 0 3

21 8 11 57 33 33 0 0

8 4 12 3 26 22 0 0

4 3 6 0 11 11 0 0

0 0 0 0 0 3# 0 0

119

41.2e65) and 31% (95% CI: 17.8e44.7), respectively (Fig. 2B). Univariate Cox analysis highlighted two predictive factors decreasing the probability of PFS: BMI < 18.5 (HR, 2.1; p Z 0.04) and a high Atkinson’s score (HR, 1.6; p Z 0.001). In multivariate Cox analysis, the only independent prognostic factor found to significantly decrease the probability of PFS was Atkinson’s score (score 0e2 versus 3e4; HR, 10.6; 95% CI: 2.5e44.3; p Z 0.001). 4. Discussion

67 85 71 40 30 31 100 100

*Five patients experienced cetuximab-related anaphylaxis. #One patient experienced grade IV oesophagitis and one patient experienced grade V oesophagitis.

time was 19.4 months (16.5e22 months). Median OS was 21.6 months (95% CI: 15.9 to not reached). OS at 1 and 2 years was 70% (95% CI: 57.8e78.7) and 40% (95% CI: 25.7e54.6), respectively (Fig. 2A). Univariate Cox analysis associated four predictive factors with a decreased probability of OS: histological SCC type (HR, 2.83; p Z 0.02), stage III (HR, 2.53; p Z 0.04), body mass index (BMI) <18.5 (HR, 2.34; p Z 0.01), and high Atkinson’s score (HR, 2.13; p Z 0.004). In multivariate Cox analysis, two independent prognostic factors were significantly associated with a decreased probability of OS: histological type (SCC versus AC; HR, 2.53; 95% CI: 0.98e6.49; p Z 0.05) and Atkinson’s score (score 0e2 versus 3e4; HR, 4.5; 95% CI: 1.07e18.5; p Z 0.03). At the time of analysis, 41 patients had disease progression or died. Among the 36 patients who presented with a recurrence, 17 (47%) had a locoregional recurrence and 19 (53%) had a metastatic recurrence. The rate of distant metastasis was of 25% in SCC patients and 24% in AC patients. Median PFS was 13.8 months (95% CI: 9.7e19.7). PFS at 1 and 2 years was 54% (95% CI:

The EGFR pathway seems to play an important role in the carcinogenesis of oesophageal tumours [5]. In this prospective phase II trial, we evaluated the efficacy of a sequential approach with the combination of FOLFOX and cetuximab as induction therapy followed by RT with concurrent FOLFOX and cetuximab in patients with advanced oesphageal cancers. The results demonstrated an ORR of 77%. Interestingly, ORR was not correlated to the histological type but to the patients’ nutrition status reflected by the BMI and Atkinson’s score of dysphagia. In univariate and multivariate analyses, Atkinson’s score of dysphagia was established as a factor correlating with ORR, OS and PFS. The ERaFOX regimen achieved a median OS of 21.6 months. Our results compare well with data from previous clinical trials using cetuximab in this setting [8, 13e18] (Table 3). In our study, the combination of RT, FOLFOX, and cetuximab was well tolerated, with rates of grade IIIeIV haematological and non-haematological toxicities comparable to those of De Vita et al. who used the same regimen [13]. Moreover, our rate of non-haematological toxicities was lower than those reported in phase III trials by Crosby and Suntharalingam et al. suggesting a good tolerance profile of this regimen [17, 18]. The efficacy of anti-EGFR monoclonal antibodies in combination with chemotherapy has been reported in two recent phase III clinical trials. In phase II/III trial SCOPE1, 285 patients with oesophageal carcinoma were randomised between CRT and CRT with concurrent cetuximab [17]. The addition of cetuximab to CRT resulted in increased toxicity and worse OS. Recent phase III RTOG 0436 study evaluated the addition of cetuximab to CRT with concurrent paclitaxel and cisplatin [18]. The 2-year OS rate was identical for both treatment arms (42%). In the REAL3 phase III trial including patients with advanced oesophagogastric cancers, the addition of panitumumab to chemotherapy combining epirubicin, oxaliplatin and capecitabine resulted in worse OS [19]. The EXPAND phase III study also showed no benefit from adding cetuximab to firstline chemotherapy with capecitabine and cisplatin in advanced gastric cancer [20]. These results are disappointing considering the solid scientific rational underlying the use of cetuximab in this

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Fig. 2. Overall survival (A) and progression-free survival (B) evaluated in the intent-to-treat population. Table 3 Studies about chemoradiotherapy with concurrent cetuximab in advanced oesophageal cancers. Study

Year

Phase

Ruhstaller et al [8].

2011

I/II

De Vita et al [13].

2011

Tomblyn et al [14]. Chen et al [15].

Treatment schema

CR rate (%)

Grade IIIeIV toxicities (%)

OS (%)

28

CDDP-TXT-cetux  2 then RT 45 Gy þ CDDP-cetux  TXT

68 (pCR)

e

e

II

41

FOLFOX-cetux  4 then RT 50.4 Gy þ cetux

27 (pCR)

H 30% NH 30%

85% at 3 years

2012

II

21

CDDP-CPT11-cetux  4 with RT 50.4 Gy during cycle 3 and 4

6

H þ NH 86%

33% at 2 years

2012

II

31

CDDP-TXL-cetux with RT 59.4 Gy

69

H 29% NH 25%

e

Oxaliplatin-tegafur-cetux with RT 59.4 Gy

44

e

e

CDDP-cape  4 with RT 50 Gy during cycle 3 and 4 Idem þ cetux

e

H 28% NH 63% H 21% NH 79%

56% at 2 years, p Z 0.03 41% at 2 years

59 p Z 0.7 56

H þ NH 67%

42% at 2 years

H þ NH 71%

43% at 2 years

40.5 (pCR: 63)

H 31% NH 38%

40% at 2 years

Ho¨llander et al [16].

2012

I

Crosby et al [17].

2013

II/III

Suntharalingam et al [18].

2014

III

N pts

11 258

344

CDDP-TXL with RT 50.4 Gy Idem þ cetux

Present study

2015

II

79

FOLFOX-cetux  5 with RT 50.4 Gy during cycle 3, 4, and 5

e

Abbreviations: N pts, number of patients; OS, overall survival; pCR, pathological complete response; CR, complete response; RT, radiation therapy; CT, chemotherapy; CDDP, cisplatin; FOLFOX, oxaliplatin, 5-fluorouracil, and folinic acid; TXT, docetaxel; TXL, paclitaxel; CPT11, irinotecan; cetux, cetuximab; cape, capecitabine; H, haematological; NH, non-haematological.

setting. We could hypothesise that the benefit of cetuximab in combination with CRT has been underestimated given that these studies enrolled patients with a mixture of SCC and AC. Indeed, 32% of the patients had an AC. As oesophageal SCC shares many similarities with head and neck SCC, SCC could have had higher chances of treatment than AC. However, in our study as reported in SCOPE1 and RTOG 0436 trials, patients with SCC had no more benefit from cetuximab compared to patients with AC [17, 18]. There is still a need to improve the outcome of oesophageal cancer patients. As their prognosis depends

upon local control and the absence of metastasis, local and systemic treatments should be intensified. The question of the optimal radiation dose has been debated for many years [21, 22]. New techniques of RT, such as intensity-modulated RT, allow us to increase the dose received by the tumour while simultaneously reducing the dose to organs at risk [23]. The randomised phase II CONCORDE trial is currently evaluating CRT at a dose of 50 Gy versus CRT at 66 Gy using modern RT with concurrent FOLFOX. Even if our study reached its primary end-point, the use of cetuximab in combination with FOLFOX-based

G. Lledo et al. / European Journal of Cancer 56 (2016) 115e121

CRT in patients with oesophageal cancer cannot be recommended. Other therapeutic targeted to oesophageal cancer and strategies with intensified RT should be tested in this setting. Conflict of interest statement FH: honoraries from Merck KgaA. The other authors declare no conflict of interest. Support Assistance Publique e Hoˆpitaux de Paris, Direction de la Recherche Clinique et du De´veloppement Ile de France, Hoˆpital Saint-Louis, 1 avenue Vellefaux, 75475 Paris Cedex 10, France, and Groupe Coope´rateur Multidisciplinaire en Oncologie, 51 rue du Faubourg Saint-Antoine, 75011 Paris, France. Merck KGaA has supported this trial (e.g. medical grant/product donation) and reviewed this manuscript, but the views and opinions described do not necessarily reflect those of Merck KGaA.

Acknowledgements The authors would like to thank Dr Fre´de´rique Maindrault-Goebel (GERCOR) for her contribution to this study. Editorial assistance in the preparation of the manuscript was provided by Dr. Magdalena Benetkiewicz, which was founded by GERCOR.

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