- Email: [email protected]
STAR-02 Study)
original article
Annals of Oncology 22: 2424–2430, 2011 doi:10.1093/annonc/mdq782 Published online 8 March 2011
Phase II study of panitumumab, oxaliplatin, 5-fluorouracil, and concurrent radiotherapy as preoperative treatment in high-risk locally advanced rectal cancer patients (StarPan/STAR-02 Study) C. Pinto1*, F. Di Fabio1, E. Maiello2, S. Pini1, T. Latiano2, C. Aschele3, C. Garufi4, A. Bochicchio5, G. Rosati6, G. Aprile7, S. Giaquinta1, V. Torri8, A. Bardelli9, M. Gion10 & A. Martoni1
Received 20 October 2010; revised 19 December 2010; accepted 21 December 2010
original article
Background: The aim of this phase II study was to assess the activity of panitumumab in combination with oxaliplatin, 5-fluorouracil, and external radiotherapy (RT) as preoperative treatment in locally advanced rectal cancer patients. Patients and methods: Patients had rectal adenocarcinoma, cT3N+ or cT4N2/+ stage, located <12 cm from the anal margin. Panitumumab was administered before the start of chemo-RT, and every 2 weeks in combination with 5fluorouracil–oxaliplatin with concurrent RT. Rectal surgery was carried out 7–8 weeks after the end of neoadjuvant treatment. The primary end point was a pathological complete response rate of 25%. Results: Sixty patients were enrolled from February 2007 to October 2009. Fifty-five (91.7%) patients underwent surgery. Rate of pathological complete response was 21.1% (95% confidence interval 10.4% to 31.6%). Pathological downstaging occurred in 33 of 57 (57.9%) patients. Grade 3–4 toxicity during neoadjuvant treatment was diarrhea (38.9%), cutaneous reactions (18.6%), nausea (5.1%), asthenia (3.4%), anorexia (3.4%), and neutropenia (1.7%). One toxic death was observed for diarrhea. Conclusions: In our study, the primary end point is not reached and panitumumab combination treatment was associated with high incidence of grade 3–4 diarrhea. The higher pathological complete response rate in comparison with the results of previous neoadjuvant rectal cancer trials with anti-epidermal growth factor receptor monoclonal antibodies supports further studies necessary to understand the possibility of optimal regimens and sequences with chemo-RT. Key words: 5-fluorouracil, chemoradiotherapy, oxaliplatin, panitumumab, radiotherapy, rectal cancer
introduction In locally advanced rectal cancer (LARC) patients, neoadjuvant preoperative chemoradiation has been shown to increase the pathological complete response (pCR) and locoregional control but has not demonstrated an improvement in overall survival (OS) [1–3]. Currently, preoperative 5-fluorouracil and radiotherapy (RT) followed by total mesorectal excision (TME) is standard treatment in this patient setting. Two phase III trials, ACCORD 12/0405 Prodige 2 and Studio Terapia Adiuvante Retto (STAR)-01, added oxaliplatin in preoperative
*Correspondence to: Dr C. Pinto, Medical Oncology Unit, S. Orsola-Malpighi Hospital, via Albertoni 15, 40138 Bologna, Italy. Tel: +39-0516362349; Fax: +39-0516362508; E-mail: [email protected]
chemotherapy without obtaining a statistically significant increase in pCR [4, 5]. Epidermal growth factor receptor (EGFR) is a transmembrane glycoprotein that is a member of the tyrosine kinase growth factor receptor superfamily. EGFR represents an important therapeutic target in cancer, and regulates cellular growth, survival, proliferation, and differentiation. In rectal cancer, EGFR is overexpressed in 50%–70% of primary tumors [6]. In patients with rectal cancer after preoperative chemo-RT, EGFR overexpression is related to a decrease in the pathologically documented response (pathological response), disease-free survival (DFS), and OS [7, 8]. The pCR rate has been considered a prognostic factor for LARC patients undergoing neoadiuvant chemo-RT, and pCR has been associated with favorable DFS and OS [9, 10].
ª The Author 2011. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected]
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1 Medical Oncology Unit, S. Orsola-Malpighi Hospital, Bologna; 2Medical Oncology Unit, IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo; 3Department of Medical Oncology, National Cancer Institute, Genoa; 4Department of Medical Oncology, Regina Elena Cancer Institute, Rome; 5Medical Oncology Unit, CROB, Rionero in Vulture; 6Medical Oncology Unit, S. Carlo Hospital, Potenza; 7Medical Oncology Unit, SM Misericordia Hospital, Udine; 8Oncology Department, Mario Negri Institute, Milan; 9Laboratory of Molecular Genetics, Institute for Cancer Research and Treatment, University of Turin Medical School, Candiolo, Turin; 10Centre for the Study of Biological Markers of Malignancy, General Regional Hospital, Venice, Italy
original article
Annals of Oncology
patients and methods study design We conducted a multicenter phase II study approved by the local ethical committee, registered with the health authorities (EUDRACT 2007-00153334). The primary end point was pCR rate. Secondary end points were median survival time (OS), time to DFS, surgery sphincter preservation, and toxicity. The biological and metabolic markers are investigated in a collateral study (Figure 1).
patient eligibility criteria The eligibility criteria included the following: histologically proven rectal adenocarcinoma of the mid-low rectum (within 12 cm from the anal verge), Karnofsky performance status ‡70%, stage cT3N+M0 and cT4N2/+ M0 [N+ stage, three or more lymph nodes of diameter ‡0.5 cm measured by endorectal ultrasound or one or more lymph nodes of diameter ‡1 cm measured by magnetic resonance (MR)], no previous treatment with chemotherapy or radiation therapy, neutrophil count ‡1500/ll, platelet count ‡100 000/ll, hemoglobin level ‡9.0 g/dl, serum creatinine level £1.5 · upper limit of normal (ULN), alanine aminotransferase and aspartate aminotransferase levels £2.5 · ULN, total bilirubin level £1.5 · ULN, and signed written informed consent.
pretreatment evaluation The baseline evaluation included history, physical examination (including digital rectal examination), recording of concomitant medication,
laboratory tests (hematology and clinical chemistry, carcinoembryonic antigen), full colonoscopy, rigid rectoscopy, biopsy, endorectal ultrasound and/or pelvic MR, and computed tomography (CT) of the thorax, abdomen, and pelvis.
panitumumab and chemo-RT treatment Panitumumab at the dose of 6 mg/kg i.v. over 1 h was administered 2 weeks before the start of chemo-RT (day 214), and after in combination with chemo-RT every 2 weeks, for a total of three times. 5-Fluorouracil was delivered at the dose of 225 mg/m2/day in continuous infusion via a central venous catheter concurrent with RT (days 1–38). Oxaliplatin was given at the dose of 60 mg/m2 i.v. weekly over 2 h, for a total of six courses. Patients were irradiated in prone position by a linear accelerator with a minimal energy of 6 MeV through a three- or four-field box technique. The target volume included all the macroscopic tumors, the mesorectum, and the internal iliac and presacral nodes up to the L5/S1 interspace. External iliac and inguinal nodes were irradiated in stage cT4 tumors and in those extending in the anal canal, respectively. A total RT dose of 5040 cGy was delivered in 28 daily fractions of 1.8 Gy, on 5 consecutive days per week.
surgery and histopathology Surgical treatment was planned after 7–8 weeks from the end of preoperative chemo-RT. TME was carried out according to a standardized technique. The pathological response criteria were assessed on the basis of pathological findings of the surgical specimen. The resected specimens were staged using the American Joint Committee on Cancer TNM (tumor– node–metastasis) system [22]. A radical resection (R0) was defined as the removal of all macroscopic tumor tissue, no evidence of distant metastases, the absence of microscopic residual tumor, free resection margins, and lymphadenectomy extended beyond involved nodes at postoperative pathological examination. A resection was judged as nonradical when microscopic (R1 £1 mm) or macroscopic (R2) residual tumor was found. Furthermore, each specimen was classified using a tumor regression grade proposed by Dworak et al. [23]. Tumor downstaging was determined by comparing the pathological stage with the baseline clinical TNM stage; pCR was defined as the absence of viable tumor cells in the primary tumor and lymph nodes (ypT0N0).
postoperative chemotherapy Postoperative chemotherapy with FOLFOX4 regimen in combination with panitumumab for eight cycles was planned after surgical treatment after a minimum of four weeks and a maximum of six weeks.
statistical analysis The primary end point was the pCR rate after neoadjuvant treatment. A pCR rate of 25% was considered to qualify the experimental treatment as promising for additional study. Using Fleming’s [24] single-stage design, adapted for binomial distribution according to A’Hearn [25], a total recruitment of 53 subjects and a critical value of 19 responses have defined a study with 85% power to reject the null hypothesis that the pCR is £24% using a one-sided 10% significance level when the true pCR is ‡40%.
biological and positron emission tomography studies
Figure 1. Study design. CI, continuous infusion; FDG–PET, 2-[fluorine18]fluoro-2-deoxy-D-glucose–positron emission tomography.
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Mutational status analyses of KRAS, BRAF, and PIK3CA were carried out in biopsy before treatment. Genomic DNA was extracted from highly enriched paraffin-embedded tumor specimens. The status of KRAS (exon 2), BRAF (exon 15), and PIK3CA (exons 9, 20) was ascertained by PCR amplification followed by direct sequencing. Serum vascular endothelial growth factor (sVEGF), plasma VEGF (pVEGF), serum E-selectin, transforming growth factor-a (TGF-a), and epidermal growth factor (EGF) levels were determined on day 214 (baseline) and on days 1 (after panitumumab), 8 and 22 (during
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Monoclonal antibodies against EGFR (cetuximab, panitumumab) have shown activity in patients with chemorefractory metastatic colorectal cancer and as first-line therapy in metastatic colorectal cancer [11–15]. In two phase III trials, panitumumab (Vectibix; Amgen Inc, Thousand Oaks, CA), a fully human monoclonal immunoglobulin G2 antibody, added to first- (FOLFOX) and second-line (FOLFIRI) chemotherapy significantly increased the response rate in metastatic colorectal cancer patients. Radiation increases EGFR expression in cancer cells, and the EGFR signaling blockade sensitizes the cells to the effects of radiation [16, 17]. In a phase III study with cetuximab and concurrent RT in patients with locally advanced head and neck cancer, locoregional control and OS significantly improved [18, 19]. Various mechanisms for this cetuximab synergistic activity have been proposed, including the inhibition of repopulation during RT fractions [20, 21]. In the present phase II study, the efficacy of the addition of panitumumab to 5-fluorouracil and oxaliplatin chemotherapy with concurrent external RT was investigated as neoadjuvant treatment in LARC high-risk patients.
original article
Annals of Oncology
treatment), and 36 (before surgery). Biomarker levels were assessed using commercial quantitative sandwich enzyme immunoassays [Quantikine Human VEGF Immunoassay (R&D Systems, Minneapolis, MN); Human sE-selectin ELISA (Bender MedSystems, San Diego, CA); Quantikine Human EGF Immunoassay (R&D Systems); RayBio Human TGFa (RayBiotech, Norcross, GA)]. 2-[Fluorine-18]fluoro-2-deoxy-D-glucose (FDG)–PET scan evaluation was carried out at initial diagnosis (baseline), before the first panitumumab administration (on day 214), and after the end of chemoRT (before surgery). Standard uptake value (SUV1 basal, SUV2 after the first panitumumab administration, and SUV3 before surgery) was determined from the most active tumor site. FDG–PET scan was carried out following a standard procedure, as reported elsewhere, using a dedicated PET–CT tomograph (GE Discovery) [26]. The acquisition time was in a two-dimensional mode for 4 min per bed position, and the attenuation correction was carried out using a CTbased method (120 kV, 80 mA).
results
treatment exposure Fifty percent of patients had at least one dose reduction, and 5.6% required a 0%–25% dose reduction of the preoperative treatment. The dose intensities of panitumumab,
surgical procedures and pathological responses Data on the surgical procedures and the pathological responses are listed in Table 3. Five patients did not undergo surgery: two patients due to disease progression (one liver metastasis, one lung metastasis) during the neoadjuvant treatment, one patient died due to gastrointestinal toxicity (diarrhea) correlated to treatment, and two patients due to refusal. Fifty-five (91.7%) patients underwent surgery and were assessable for pathological response. TME surgery was carried out in all patients. Forty-six (83.6%) patients were treated with a low anterior resection, 4 (7.3%) with a Hartmann’s procedure, and 5 (9.1%) with an abdominoperineal resection. No postoperative deaths occurred. Resection (R0) at the primary tumor site was achieved in 43 of 55 (78.2%) patients. Sphincter-sparing surgery was carried out in 50 of 55 (90.9%) patients and in 7 of 16 (43.8%) patients assessed to require an abdominoperineal resection before neoadjuvant treatment. pCR (ypT0N0) rate of 21.1% (95% confidence interval 10.4% to 31.6%) was observed in 12 of 57 patients (55 resected and 2 clinical disease progression). Table 2. Dose intensity of neoadjuvant treatment Dose intensity (n = 55)
>90% (%)
90%–60% (%)
<60% (%)
Panitumumab 5-Fluorouracil Oxaliplatin Radiotherapy
76.4 65.4 54.5 90.9
14.5 21.9 27.3 5.4
9.1 12.7 18.2 3.6
Table 1. Patient characteristics (N = 60) Characteristics Sex Male Female Age (years) Median Range Karnofsky performance status Median Range Distance from the anal margin (cm) Median Range Clinical stage at diagnosis cT3N+ cT4N2 cT4N+ cT3Nx cT4Nx
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n
%
40 20
66.7 33.3
60 37–75 90 80–100 6 0–12 41 4 11 1 3
68.3 6.7 18.3 1.7 5
Table 3. Surgical parameters and pathological response (operated patients, n = 55)
Type of surgical treatment Anterior resection Hartman resection Abdominoperineal resection Sphincter preserving Yes No Residual tumor R0 R1 R2 Assessable patients (n = 57)a ypT0N0 Pathological downstaging
n
%
46 4 5
83.6 7.3 9.1
50 5
90.9 9.1
43 11 1
78.2 20.0 1.8
12 33
21.1 57.9
a
Two resected patients for disease progression.
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patient population From February 2007 to October 2009, 60 patients in 11 Italian centers were enrolled. All 60 patients were assessed for safety, and 57 were assessable for response. Three patients were not assessable for response as one patient died of gastrointestinal toxicity in week 5 of treatment, and two patients refused surgery. The patient characteristics are listed in Table 1. The majority of patients were men (66.7%); their median age was 60 years (range 37–75 years) and the median Karnofsky performance status 90 (range 80–100). Median distance from the anal margin was 6 cm (range 0–12 cm). The clinical stage was cT3 in 42 of the 60 (70.0%) patients and cT4 in 18 (30.0%). The majority of patients (52/60; 86.6%) had lymph node involvement (cN+).
5-fluorouracil, oxaliplatin, and RT are reported in Table 2. Panitumumab dose intensity >90% was delivered in 42 of 55 (76.4%) patients. The dose of 5-fluorouracil and oxaliplatin was reduced >40% due to toxicity in 12.7% and 18.2% of patients, respectively. The full dose of planned RT was administered in 47 of 55 (85.5%) patients and >90% in 50 of 55 (90.9%) patients. Eighteen patients with T4 tumors had received the extended nodal irradiation of the external iliac.
original article
Annals of Oncology
Table 4. Neoadjuvant treatment toxicity Toxicity
Grade 3/4 n %
Total n %
8 6 5 2
13.5 10.1 8.4 3.4
1 0 1 0
1.7 0 1.7 0
9 6 6 2
15.2 10.1 10.1 3.4
13 17 11 21 11 13 7
22.0 28.8 18.6 35.6 18.6 22.0 11.8
2 3 1 23 0 0 0
3.4 5.1 1.7 38.9 0 0 0
15 20 12 44 11 13 7
25.4 33.9 20.2 74.5 18.6 22.0 11.8
35 4 6 8 2 6 5 18 1
59.3 6.7 10.1 13.5 3.4 10.1 8.4 30.5 1.7
11 0 1 0 0 0 0 2 1
18.6 0 1.7 0 0 0 0 3.4 1.7
46 4 7 8 2 6 5 20 2
77.9 6.7 11.8 13.5 3.4 10.1 8.4 33.9 3.4
Compared with the clinical stage before neoadjuvant treatment, a pathological downstaging (T and/or N) occurred in 33 of 57 (57.9%) patients.
safety All 60 patients were evaluated for toxicity. Adverse events observed during the neoadjuvant treatment are listed in Table 4. Diarrhea was the most observed toxicity, occurring in 23 (38.9%) patients, with grades 3–4. Grade 3 nausea and vomiting occurred in three (5.1%) and one (1.7%) patients, respectively. Grade 3 neutropenia was recorded in only one (1.7%) patient; no cases of grade 3–4 thrombocytopenia and anemia were observed. All grades of acne-like rash occurred in 46 patients (77.9%), and grades 3–4 were observed in 11 (18.6%). One toxic death was observed for diarrhea. biomarker and PET studies Mutational status of KRAS, BRAF, and PIK3CA was evaluated in 27 of 55 (49.1%) patients. KRAS mutations were detected in 4 (14.8%) of the tumors analyzed (G12A and G12D, one case each; G13D, two cases) and BRAF in 1 of 27 (3.7%) cases (V600E). No PIK3CA mutations were found. In this patient cohort, oncogenic activation of KRAS was not significantly associated with the pathological responses. Twenty-three patients enrolled in two centers were available for the biomarker evaluation (Table 5) and 28 patients for the FDG–PET study. The median basal values of circulating biomarkers (at day 214) were as follows: sVEGF 465.7 pg/ml, pVEGF 114.2 pg/ml, E-selectin 35.0 ng/ml, TGF-a 33.5 pg/ml, and EGF
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All patients (n = 23)
Day 214, Median
Day 1 Median
P
Day 36 Median
TGF-a (pg/ml) 33.50 68.10 0.006 68.10 EGF (pg/ml) 534.40 418.30 0.821 339.00 sVEGF (pg/ml) 465.70 555.00 0.027 548.20 pVEGF (pg/ml) 114.20 107.90 0.322 214.90 E-selectin (ng/ml) 35.00 50.50 0.000 44.80 Downstaging patients (n = 14)/non-downstaging patients (n = 9) Day 214 Median P TGF-a (pg/ml) Downstaging Non-downstaging EGF (pg/ml) Downstaging Non-downstaging sVEGF (pg/ml) Downstaging Non-downstaging pVEGF (pg/ml) Downstaging Non-downstaging E-selectin (ng/ml) Downstaging Non-downstaging
Day 1 Median
P
Day 36 Median
P 0.001 0.001 0.227 0.124 0.011
P
37.99 29.70
0.305
68.14 67.14
0.860
71.09 66.36
0.953
543.49 381.58
0.201
395.08 439.51
0.804
368.15 309.16
0.440
460.3 473.6
0.781
496.4 690.1
0.414
497.4 717.7
0.350
105.8 248.6
0.250
96.9 373.8
0.010
164.7 283.5
0.078
34.23 37.76
0.557
50.53 50.13
0.860
42.32 48.96
0.827
TGF, transforming growth factor; EGF, epidermal growth factor; sVEGF, serum vascular endothelial growth factor; pVEGF, plasma vascular endothelial growth factor.
534.4 pg/ml. Panitumumab treatment increased the levels of TGF-a, sVEGF, and E-selectin. On day 1 after only one panitumumab administration, the sVEGF, E-selectin, and TGFa median values presented the following higher levels as compared with baseline: sVEGF 555.0 pg/ml (P = 0.027), Eselectin 50.5 ng/ml (P < 0.001), and TGF-a 68.1 pg/ml (P = 0.006) in all patients. Up-regulation of pVEGF after panitumumab administration was observed in patients with pathological downstaging (373.8 pg/ml; P = 0.01). The decrease in EGF level was observed soon after panitumumab administration (418.3 pg/ml; P = 0.82) and it reached a significant level at day 36 (339.0 pg/ml; P = 0.001). No correlations were found between EGF level modifications and the pathological response. The median SUV1 of PET scan was 16.1 (range 6.1–26.9) and after only panitumumab administration (SUV2) it decreased to 10.2 (range 1.9–25.2; P = 0.019). SUV3 further decreased to 4.9 (range 0–17; P < 0.001). The decrease of SUV2 and SUV3 was not related to pathological downstaging.
postoperative chemotherapy Postoperative chemotherapy with FOLFOX4 in combination with panitumumab was administered in 40 of 55 (72.7%) patients.
discussion In LARC patients, the randomized phase III trials STAR-01 and ACCORD 12/0405 Prodige 2 showed a pCR rate of 16%
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Hematologic Leukopenia Anemia Neutropenia Thrombocytopenia Gastrointestinal Anorexia Nausea Vomiting Diarrhea Weight loss Abdominal pain Stomatitis Cutaneous Acneiform rash Nails Itch Peripheral neuropathy Hand–foot syndrome Hepatic Cystitis Asthenia Allergy
Grade 1/2 n %
Table 5. Circulating biomarker levels
original article
Annals of Oncology
chemo-RT in these phase II studies [27–31, 33] might arise from changes in tumor cell proliferation and cell cycle distribution after cetuximab administration, with cell arrest in G1 or G2/M and a failure to pass through the S phase. This hypothesis is supported by evidence in the pathological and molecular evaluation from the Belgian study that cetuximab down-regulated genes involved in proliferation (PIK3R1, CGREF1, PLAGL1), confirmed by immunohistochemistry for Ki67 [34]. Capecitabine–5-fluorouracil and oxaliplatin both produced their optimal cytotoxic and radiosensitizing effects when cells proliferate into the S/G2/M phase. Therefore, these cellular modifications could produce an antagonistic effect on fluoropyrimidine–oxaliplatin chemo-RT but would be less likely to be impacted by irinotecan. One possible explanation for the higher pCR in StarPan Study could arise from the different chemotherapy schedules employed that could overcome the antagonistic effect of anti-EGFR monoclonal antibodies. In our study, 5fluorouracil is administered continuously (without intervals) and oxaliplatin weekly for six times, at the full optimal dose, maintaining the synergistic and radiosensitizing effect of the two drugs [35]. These activities were lacking when 5fluorouracil and capecitabine are administered in monotherapy (27–30) or in combination with oxaliplatin with intermittent schedules [31]. In combination with irinotecan, the activity seems to be preserved only with full capecitabine dose [32, 33]. In our StarPan Study, although the number of assessed patients was small, the presence of KRAS and BRAF mutations in the pretherapeutic biopsy was not correlated with the pathological tumor response. The significance of KRAS and BRAF mutations in patients with rectal cancer submitted to preoperative chemo-RT is not well known. In one study in 37 patients, the presence of specific KRAS mutations (codons 12, 13, and 61) was an indicator of tumor response in patients with LARC treated by preoperative 5-fluorouracil-based chemo-RT [36]. The mutation status of KRAS and BRAF in 95 LARC patients treated with 5-fluorouracil-based neoadjuvant chemo-RT was not correlated with pathological response [37]. The results of three phase II studies in patients with LARC treated with cetuximab in combination with chemo-RT did not show a significantly better response in tumor without KRAS mutations [34, 38, 39]. In our study, the circulating levels of the EGFR ligands (TGFa, EGF) and vascular factors (sVEGF, E-selectin) were modified
Table 6. Phase II studies of preoperative chemoradiation using anti-EGFR monoclonal antibodies Authors (reference)
Phase
n
mAB
5FU
Bertolini et al. [27] Machiels et al. [28] Eisterer et al. [29] Velenik et al. [30] Ro¨del et al. [31] Hong et al. [32] Horisberger et al. [33] StarPan (current study)
II I/II II II I/II II II II
40 40 28 37 48 10 50 60
Cet Cet Cet Cet Cet Cet Cet Pan
+
Cape + + + + + +
+
Oxa
Iri
+ + + +
RT dose (Gy)
pCR (%)
50.4 45 45 45–50.4 50.4 50.4 50.4 50.4
7.5 5 0 8.1 8 20 8 21.1
mAB, monoclonal antibody; 5FU, 5-fluorouracil; Cape, capecitabine; Oxa, oxaliplatin; Iri, irinotecan; RT, radiotherapy; pCR, pathological complete response; Cet, cetuximab; Pan, panitumumab.
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and 19%, respectively, using a neoadjuvant combination of fluoropyrimidine, oxaliplatin, and RT [4, 5]. The addition of anti-EGFR monoclonal antibodies to preoperative concurrent RT and chemotherapy regimens was postulated to improve pCR. The phase II trials of preoperative chemoradiation using anti-EGFR monoclonal antibodies are summarized in Table 6. In the Italian phase II study, cetuximab and a continuous infusion of 5-fluorouracil 225 mg/m2/day concomitantly with RT (50.4 Gy in 25–28 fractions) were administered in 40 patients, with pCR in 3 patients (8%) [27]. In the Belgian phase I/II study, 40 patients were treated with cetuximab in combination with capecitabine 650 and 825 mg/m2 twice daily (dose recommended) continuously for the duration of RT (45 Gy in 25 fractions), with pCR in 2 patients (5%) [28]. No pCR was obtained in 28 patients treated with cetuximab in combination with capecitabine 825 mg/m2 twice daily on RT days (45 Gy in 25 fractions) [29]. Velenik et al. [30] treated 37 patients with cetuximab added to capecitabine 825 mg/m2 twice daily continuously for the duration of RT (45 Gy in 25 fractions), obtaining pCR in 3 (8%) patients. The association of cetuximab with capecitabine 825 mg/m2 twice daily (days 1–14 and 22–35), oxaliplatin 50 mg/m2 (days 1, 8, 22, and 29), and RT (50.4 Gy in 28 fractions) was evaluated in 48 patients and a pCR was reached in 4 (9%) patients [31]. Two phase II trials evaluated the addition of cetuximab to capecitabine–irinotecan and RT. Cetuximab was added to capecitabine 825 mg/m2 twice daily (5 days a week), irinotecan 40 mg/m2 (days 1, 8, 15, 22, and 29), and RT (50.4 Gy in 28 fractions) in 10 patients, with pCR in 2 (20%) patients [32]. In the MARGIT Study, 50 patients received cetuximab in combination with capecitabine 500 mg/m2 twice daily continuously, irinotecan 40 mg/m2 (days 1, 8, 15, 22, and 29), and RT (50.4 Gy in 28 fractions), obtaining pCR in 4 (8%) patients [33]. In the StarPan (STAR-02) Study, the primary end point is not reached, with a pCR rate of 21.1%. However, in this trial, the addition of panitumumab to 5-fluorouracil–oxaliplatin chemo-RT showed a high pCR rate as compared with the results of the phase II studies based on cetuximab– fluoropyrimidine combination with or without oxaliplatin. These data should be interpreted as hypothesis-generating in regard to the chemo-RT schedules. The biological mechanisms for the disappointing results of cetuximab in combination with fluoropyrimidine-based
original article
Annals of Oncology
Volume 22 | No. 11 | November 2011
funding Amgen–Dompe`, Italy [drug (panitumumab, Vectibix) and educational grant (20062089)].
disclosure The authors declare no conflict of interest.
references 1. Sauer R, Becker H, Hohenberger W et al. Preoperative versus postoperative chemoradiotherapy for rectal cancer. N Engl J Med 2004; 351: 1731–1740. 2. Gerard JP, Conroy T, Bonnetain F et al. Preoperative radiotherapy with or without concurrent fluorouracil and leucovorin in T3-4 rectal cancers: results of FFCD 9203. J Clin Oncol 2006; 24: 4620–4625. 3. Bosset JF, Collette L, Calais G et al. Chemotherapy with preoperative radiotherapy in rectal cancer. N Engl J Med 2006; 355: 1114–1123. 4. Ge´rard JP, Azria D, Gourgou-Bourgade S et al. Comparison of two neoadjuvant chemoradiotherapy regimens for locally advanced rectal cancer: results of the phase III trial ACCORD 12/0405-Prodige 2. J Clin Oncol 2010; 28: 1638–1644. 5. Aschele C, Pinto C, Cordio S et al. Preoperative fluorouracil (FU)-based chemoradiation with and without weekly oxaliplatin in locally advanced rectal cancer: pathologic response analysis of the Studio Terapia Adiuvante Retto (STAR)-01 randomized phase III trial. J Clin Oncol 2009; 27: 170S; Proc ASCO, 233A. 6. Giralt J, de las HM, Cerezo L et al. The expression of epidermal growth factor receptor results in a worse prognosis for patients with rectal cancer treated with preoperative radiotherapy: a multicenter, retrospective analysis. Radiother Oncol 2005; 74: 101–108. 7. Kim J-S, Kim J-M, Li S et al. Epidermal growth factor receptor as a predictor of tumor downstaging in locally advanced rectal cancer patients treated with preoperative chemoradiotherapy. Int J Radiat Oncol Biol Phys 2006; 66: 195–200. 8. Koop R, Rothbauer E, Mueller E et al. Reduced survival of rectal cancer patients with increased tumor epidermal growth factor receptor levels. Dis Colon Rectum 2003; 46: 1391–1399. 9. Rodel C, Martus P, Papadoupolos T et al. Prognostic significance of tumor regression after preoperative chemoradiotherapy for rectal cancer. J Clin Oncol 2005; 23: 8688–8696. 10. Capirci C, Valentini V, Cionini L et al. Prognostic value of pathological complete response after neoadjuvant therapy in locally advanced rectal cancer: long term analysis on 566 ypCR patients. Int J Radiat Oncol Biol Phys 2008; 72: 99–107. 11. Cunningham D, Humblet Y, Siena S et al. Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med 2004; 351: 337–345. 12. Van Cutsem E, Peeters M, Siena S et al. Open-label phase III trial of panitumumab plus best supportive care compared with best supportive care alone in patients with chemotherapy-refractory metastatic colorectal cancer. J Clin Oncol 2007; 25: 1658–1664. 13. Van Cutsem E, Lang I, Folprecht G et al. Cetuximab plus FOLFIRI in the treatment of metastatic colorectal cancer (mCRC): the influence of KRAS and BRAF biomarkers on outcome: updated data from the CRYSTAL trial. J Clin Oncol 2010; 28: 15S; Proc ASCO, 3570A. 14. Siena S, Tabernero J, Cunningham D et al. Randomized phase III study of panitumumab (pmab) with FOLFOX4 compared to FOLFOX4 alone as first-line treatment (tx) for metastatic colorectal cancer (mCRC): PRIME trial. J Clin Oncol 2010; 28: 15S; Proc ASCO, 3566A. 15. Peeters M, Price TJ, Hotko YS et al. Randomized phase III study of panitumumab (pmab) with FOLFIRI versus FOLFIRI alone as second-line treatment (tx) in patients (pts) with metastatic colorectal cancer (mCRC): analysis by tumor epidermal growth factor receptor (EGFR) staining. J Clin Oncol 2010; 28: 15S; Proc ASCO, 3565A.
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after only panitumumab administration. TGF-a, sVEGF, and E-selectin were up-regulated in almost all patients independently of response. In the preoperative treatment of rectal cancer, a similar up-regulation of circulating levels of TGF-a was observed after cetuximab administration alone [34]. The increase in angiogenetic factors is similar to that seen in a phase II study with bevacizumab in neoadjuvant chemoradiation of rectal cancer [40]. Moreover, results from our study suggest that in the responder patients, the higher EGF basal levels may up-regulate the EGFR, while the earlier circulating EGF level decrease could serve as a predictor of tumor downstaging. In our study, the FDG uptake (a measure of tumor metabolic rate) was decreased compared with the basal value by panitumumab administration alone and markedly by combination therapy. The earlier changes in the PET evaluation appear to be correlated to reduction in the tumor cell proliferation after panitumumab administration alone, and afterward, the addition of chemo-RT to panitumumab increases the cytotoxic activity. Earlier PET evaluation in this patient setting is not predictive of pathological response but may be only a marker of cellular proliferation down-regulation. The gastrointestinal toxicity was the main toxicity of the StarPan Study. This panitumumab combination treatment was associated with very high incidence of grade 3–4 diarrhea that reached 38.9%. The rate of grade 3–4 of diarrhea in two fluoropyrimidine–oxaliplatin phase III trials was 12.6% and 15% [4, 5], and varied from 5% to 30% in the cetuximab combination phase II studies [27–31]. In our study, therefore, the addition of panitumumab is likely to have been the main factor for the increase in grade 3–4 diarrhea. The specific side-effect associated with panitumumab was skin rash (77.9% all grades, and 18.6% of grades 3–4). In conclusion, in the StarPan/STAR-02 Study the primary end point is not reached and the panitumumab combination treatment was associated with high incidence of grade 3–4 diarrhea (with one toxic death). Therefore, this regimen is unsuitable for further testing. The integration of anti-EGFR monoclonal antibodies into rectal cancer preoperative chemoradiation schedules is an interesting and attractive hypothesis, but the interactions between biological therapy and radiochemotherapy could be modified with the different agents applied, treatment schedules, and sequences. The higher pCR obtained in this study in comparison with the previous published phase II studies with an anti-EGFR agent in combination with fluoropyrimidine–oxaliplatin and RT may guide to developing some hypotheses. This result could be correlated to the different modalities of chemotherapy regimen administered. Further translational and clinical studies will be necessary to understand the potential molecular pathways involved in anti-EGFR response, and optimal regimens and sequences with chemo-RT. The radiosensitizing properties of anti-EGFR in preclinical systems, the results of our study in pathological response and toxicity and the activity of cetuximab in combination with RT alone in head and neck cancers [18–20], represent the background of the next STAR Study (Rap Study/STAR-03) that will evaluate panitumumab in combination with only RT in low-risk LARC.
original article
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31. Ro¨del C, Arnold D, Hipp M et al. Phase I-II trial of cetuximab, capecitabine, oxaliplatin, and radiotherapy as preoperative treatment in rectal cancer. Int J Radiat Oncol Biol Phys 2008; 70: 1081–1086. 32. Hong YS, Kim DY, Lee KS et al. Phase II study of preoperative chemoradiation (CRT) with cetuximab, irinotecan and capecitabine in patients with locally advanced resectable rectal cancer. J Clin Oncol 2007; 25: 18S; Proc ASCO, 4045A. 33. Horisberger K, Treschl A, Mai S et al. Cetuximab in combination with capecitabine, irinotecan, and radiotherapy for patients with locally advanced rectal cancer: results of a phase II MARGIT trial. Int J Radiat Oncol Biol Phys 2009; 74: 1487–1493. 34. Debucquoy A, Haustermans K, Daemen A et al. Molecular response to cetuximab and efficacy of preoperative cetuximab-based chemoradiation in rectal cancer. J Clin Oncol 2009; 27: 2751–2757. 35. Aschele C, Friso ML, Pucciarelli S et al. A phase I-II study of weekly oxaliplatin, 5-fluorouracil continuous infusion and preoperative radiotherapy in locally advanced rectal cancer. Ann Oncol 2005; 16: 1140–1146. 36. Luna-Pe´rez P, Segura J, Alvarado I et al. Specific c-K-ras gene mutations as a tumor-response marker in locally advanced rectal cancer treated with preoperative chemoradiotherapy. Ann Surg Oncol 2000; 7: 727–731. 37. Gaedcke J, Grade M, Jung K et al. KRAS and BRAF mutations in patients with rectal cancer treated with preoperative chemoradiotherapy. Radiother Oncol 2010; 94: 76–81. 38. Bengala C, Bettelli S, Bertolini F et al. Epidermal growth factor receptor gene copy number, K-ras mutation and pathological response to preoperative cetuximab, 5-FU and radiation therapy in locally advanced rectal cancer. Ann Oncol 2009; 20: 469–474. 39. Kim S, Shim E, Yeo H et al. KRAS mutation status and clinical outcome of preoperative chemoradiation (CRT) with or without cetuximab in locally advanced rectal cancer (LARC): a pooled analysis of two phase II trials. J Clin Oncol 2010; 28: 15S; Proc ASCO, 3650A. 40. Willett CG, Duda DG, Di Tomaso E et al. Efficacy, safety, and biomarkers of neoadjuvant bevacizumab, radiation therapy, and fluorouracil in rectal cancer: a multidisciplinary phase II study. J Clin Oncol 2009; 27: 3020–3026.
appendix The following investigators enrolled patients in the StarPan/ STAR-02 study: Davide Tassinari, Department of Medical Oncology, Degli Infermi Hospital, Rimini, Italy; Graziella Pinotti, Medical Oncology Unit, Macchi Hospital, Varese, Italy; Monica Lencioni, Division of Medical Oncology, S. Chiara Hospital, Pisa, Italy; Francesca Pucci, Medical Oncology, Maggiore Hospital, Parma, Italy.
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16. Bonner JA, Maihle NJ, Folven BR et al. The interaction of epidermal growth factor and radiation in human head and neck squamous cell carcinoma cell lines with vastly different radiosensitivities. Int J Radiat Oncol Biol Phys 1994; 29: 243–247. 17. Liang K, Ang KK, Milas L et al. The epidermal growth factor receptor mediates radioresistance. Int J Radiat Oncol Biol Phys 2003; 57: 246–254. 18. Bonner JA, Harari PM, Giralt J et al. Radiotherapy plus cetuximab for squamouscell carcinoma of the head and neck. N Engl J Med 2006; 354: 567–578. 19. Bonner JA, Harari PM, Giralt J et al. Radiotherapy plus cetuximab for locoregionally advanced head and neck cancer: 5-year survival data from a phase 3 randomised trial, and relation between cetuximab-induced rash and survival. Lancet Oncol 2010; 11: 21–28. 20. Baumann M, Krause M, Dikomey E et al. EGFR-targeted anti-cancer drugs in radiotherapy: preclinical evaluation of mechanisms. Radiother Oncol 2007; 83: 238–248. 21. Glynne-Jones R, Mawdsley S, Harrison M. Cetuximab and chemoradiation for rectal cancer—is the water getting muddy? Acta Oncol 2010; 49: 278–286. 22. Greene LP, Balch CM, Fleming ID et al. AJCC Cancer Staging Manual, 6th edition. New York: Springer 2002. 23. Dworak O, Keilholz L, Hoffmann A. Pathological features of rectal cancer after preoperative radiochemotherapy. Int J Colorectal Dis 1997; 12: 19–23. 24. Fleming TR. One-sample multiple testing procedure for phase II clinical trials. Biometrics 1982; 38: 143–151. 25. A’Hearn RP. Sample size tables for exact phase II clinical trials. Stat Med 2001; 20: 859–866. 26. Martoni A, Di Fabio F, Pinto C et al. Prospective study on the 18F-FDG-PET/CT predictive and prognostic value in patients treated with neoadjuvant chemoradiation therapy and radical surgery for locally advanced rectal cancer. Ann Oncol 2011; 22: 650–656. 27. Bertolini F, Chiara S, Bengala C et al. Neoadjuvant treatment with single-agent cetuximab followed by 5-FU, cetuximab, and pelvic radiotherapy: a phase II study in locally advanced rectal cancer. Int J Radiat Oncol Biol Phys 2009; 73: 466–472. 28. Machiels JP, Sempoux C, Scalliet P et al. Phase I/II study of preoperative cetuximab, capecitabine, and external beam radiotherapy in patients with rectal cancer. Ann Oncol 2007; 18: 738–744. 29. Eisterer WM, De Vries A, Oefner D et al. Neoadjuvant chemoradiation therapy with capecitabine (X) plus cetuximab (C), and external beam radiotherapy (RT) in locally advanced rectal cancer (LARC): ABCSG trial R03. J Clin Oncol 2009; 27: 15S; Proc ASCO, A4109. 30. Velenik V, Ocvirk J, Oblak I et al. A phase II study of cetuximab, capecitabine and radiotherapy in neoadjuvant treatment of patients with locally advanced resectable rectal cancer. Eur J Surg Oncol 2010; 36: 244–250.
Annals of Oncology
Annals of Oncology 22: 2424–2430, 2011 doi:10.1093/annonc/mdq782 Published online 8 March 2011
Phase II study of panitumumab, oxaliplatin, 5-fluorouracil, and concurrent radiotherapy as preoperative treatment in high-risk locally advanced rectal cancer patients (StarPan/STAR-02 Study) C. Pinto1*, F. Di Fabio1, E. Maiello2, S. Pini1, T. Latiano2, C. Aschele3, C. Garufi4, A. Bochicchio5, G. Rosati6, G. Aprile7, S. Giaquinta1, V. Torri8, A. Bardelli9, M. Gion10 & A. Martoni1
Received 20 October 2010; revised 19 December 2010; accepted 21 December 2010
original article
Background: The aim of this phase II study was to assess the activity of panitumumab in combination with oxaliplatin, 5-fluorouracil, and external radiotherapy (RT) as preoperative treatment in locally advanced rectal cancer patients. Patients and methods: Patients had rectal adenocarcinoma, cT3N+ or cT4N2/+ stage, located <12 cm from the anal margin. Panitumumab was administered before the start of chemo-RT, and every 2 weeks in combination with 5fluorouracil–oxaliplatin with concurrent RT. Rectal surgery was carried out 7–8 weeks after the end of neoadjuvant treatment. The primary end point was a pathological complete response rate of 25%. Results: Sixty patients were enrolled from February 2007 to October 2009. Fifty-five (91.7%) patients underwent surgery. Rate of pathological complete response was 21.1% (95% confidence interval 10.4% to 31.6%). Pathological downstaging occurred in 33 of 57 (57.9%) patients. Grade 3–4 toxicity during neoadjuvant treatment was diarrhea (38.9%), cutaneous reactions (18.6%), nausea (5.1%), asthenia (3.4%), anorexia (3.4%), and neutropenia (1.7%). One toxic death was observed for diarrhea. Conclusions: In our study, the primary end point is not reached and panitumumab combination treatment was associated with high incidence of grade 3–4 diarrhea. The higher pathological complete response rate in comparison with the results of previous neoadjuvant rectal cancer trials with anti-epidermal growth factor receptor monoclonal antibodies supports further studies necessary to understand the possibility of optimal regimens and sequences with chemo-RT. Key words: 5-fluorouracil, chemoradiotherapy, oxaliplatin, panitumumab, radiotherapy, rectal cancer
introduction In locally advanced rectal cancer (LARC) patients, neoadjuvant preoperative chemoradiation has been shown to increase the pathological complete response (pCR) and locoregional control but has not demonstrated an improvement in overall survival (OS) [1–3]. Currently, preoperative 5-fluorouracil and radiotherapy (RT) followed by total mesorectal excision (TME) is standard treatment in this patient setting. Two phase III trials, ACCORD 12/0405 Prodige 2 and Studio Terapia Adiuvante Retto (STAR)-01, added oxaliplatin in preoperative
*Correspondence to: Dr C. Pinto, Medical Oncology Unit, S. Orsola-Malpighi Hospital, via Albertoni 15, 40138 Bologna, Italy. Tel: +39-0516362349; Fax: +39-0516362508; E-mail: [email protected]
chemotherapy without obtaining a statistically significant increase in pCR [4, 5]. Epidermal growth factor receptor (EGFR) is a transmembrane glycoprotein that is a member of the tyrosine kinase growth factor receptor superfamily. EGFR represents an important therapeutic target in cancer, and regulates cellular growth, survival, proliferation, and differentiation. In rectal cancer, EGFR is overexpressed in 50%–70% of primary tumors [6]. In patients with rectal cancer after preoperative chemo-RT, EGFR overexpression is related to a decrease in the pathologically documented response (pathological response), disease-free survival (DFS), and OS [7, 8]. The pCR rate has been considered a prognostic factor for LARC patients undergoing neoadiuvant chemo-RT, and pCR has been associated with favorable DFS and OS [9, 10].
ª The Author 2011. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected]
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1 Medical Oncology Unit, S. Orsola-Malpighi Hospital, Bologna; 2Medical Oncology Unit, IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo; 3Department of Medical Oncology, National Cancer Institute, Genoa; 4Department of Medical Oncology, Regina Elena Cancer Institute, Rome; 5Medical Oncology Unit, CROB, Rionero in Vulture; 6Medical Oncology Unit, S. Carlo Hospital, Potenza; 7Medical Oncology Unit, SM Misericordia Hospital, Udine; 8Oncology Department, Mario Negri Institute, Milan; 9Laboratory of Molecular Genetics, Institute for Cancer Research and Treatment, University of Turin Medical School, Candiolo, Turin; 10Centre for the Study of Biological Markers of Malignancy, General Regional Hospital, Venice, Italy
original article
Annals of Oncology
patients and methods study design We conducted a multicenter phase II study approved by the local ethical committee, registered with the health authorities (EUDRACT 2007-00153334). The primary end point was pCR rate. Secondary end points were median survival time (OS), time to DFS, surgery sphincter preservation, and toxicity. The biological and metabolic markers are investigated in a collateral study (Figure 1).
patient eligibility criteria The eligibility criteria included the following: histologically proven rectal adenocarcinoma of the mid-low rectum (within 12 cm from the anal verge), Karnofsky performance status ‡70%, stage cT3N+M0 and cT4N2/+ M0 [N+ stage, three or more lymph nodes of diameter ‡0.5 cm measured by endorectal ultrasound or one or more lymph nodes of diameter ‡1 cm measured by magnetic resonance (MR)], no previous treatment with chemotherapy or radiation therapy, neutrophil count ‡1500/ll, platelet count ‡100 000/ll, hemoglobin level ‡9.0 g/dl, serum creatinine level £1.5 · upper limit of normal (ULN), alanine aminotransferase and aspartate aminotransferase levels £2.5 · ULN, total bilirubin level £1.5 · ULN, and signed written informed consent.
pretreatment evaluation The baseline evaluation included history, physical examination (including digital rectal examination), recording of concomitant medication,
laboratory tests (hematology and clinical chemistry, carcinoembryonic antigen), full colonoscopy, rigid rectoscopy, biopsy, endorectal ultrasound and/or pelvic MR, and computed tomography (CT) of the thorax, abdomen, and pelvis.
panitumumab and chemo-RT treatment Panitumumab at the dose of 6 mg/kg i.v. over 1 h was administered 2 weeks before the start of chemo-RT (day 214), and after in combination with chemo-RT every 2 weeks, for a total of three times. 5-Fluorouracil was delivered at the dose of 225 mg/m2/day in continuous infusion via a central venous catheter concurrent with RT (days 1–38). Oxaliplatin was given at the dose of 60 mg/m2 i.v. weekly over 2 h, for a total of six courses. Patients were irradiated in prone position by a linear accelerator with a minimal energy of 6 MeV through a three- or four-field box technique. The target volume included all the macroscopic tumors, the mesorectum, and the internal iliac and presacral nodes up to the L5/S1 interspace. External iliac and inguinal nodes were irradiated in stage cT4 tumors and in those extending in the anal canal, respectively. A total RT dose of 5040 cGy was delivered in 28 daily fractions of 1.8 Gy, on 5 consecutive days per week.
surgery and histopathology Surgical treatment was planned after 7–8 weeks from the end of preoperative chemo-RT. TME was carried out according to a standardized technique. The pathological response criteria were assessed on the basis of pathological findings of the surgical specimen. The resected specimens were staged using the American Joint Committee on Cancer TNM (tumor– node–metastasis) system [22]. A radical resection (R0) was defined as the removal of all macroscopic tumor tissue, no evidence of distant metastases, the absence of microscopic residual tumor, free resection margins, and lymphadenectomy extended beyond involved nodes at postoperative pathological examination. A resection was judged as nonradical when microscopic (R1 £1 mm) or macroscopic (R2) residual tumor was found. Furthermore, each specimen was classified using a tumor regression grade proposed by Dworak et al. [23]. Tumor downstaging was determined by comparing the pathological stage with the baseline clinical TNM stage; pCR was defined as the absence of viable tumor cells in the primary tumor and lymph nodes (ypT0N0).
postoperative chemotherapy Postoperative chemotherapy with FOLFOX4 regimen in combination with panitumumab for eight cycles was planned after surgical treatment after a minimum of four weeks and a maximum of six weeks.
statistical analysis The primary end point was the pCR rate after neoadjuvant treatment. A pCR rate of 25% was considered to qualify the experimental treatment as promising for additional study. Using Fleming’s [24] single-stage design, adapted for binomial distribution according to A’Hearn [25], a total recruitment of 53 subjects and a critical value of 19 responses have defined a study with 85% power to reject the null hypothesis that the pCR is £24% using a one-sided 10% significance level when the true pCR is ‡40%.
biological and positron emission tomography studies
Figure 1. Study design. CI, continuous infusion; FDG–PET, 2-[fluorine18]fluoro-2-deoxy-D-glucose–positron emission tomography.
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Mutational status analyses of KRAS, BRAF, and PIK3CA were carried out in biopsy before treatment. Genomic DNA was extracted from highly enriched paraffin-embedded tumor specimens. The status of KRAS (exon 2), BRAF (exon 15), and PIK3CA (exons 9, 20) was ascertained by PCR amplification followed by direct sequencing. Serum vascular endothelial growth factor (sVEGF), plasma VEGF (pVEGF), serum E-selectin, transforming growth factor-a (TGF-a), and epidermal growth factor (EGF) levels were determined on day 214 (baseline) and on days 1 (after panitumumab), 8 and 22 (during
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Monoclonal antibodies against EGFR (cetuximab, panitumumab) have shown activity in patients with chemorefractory metastatic colorectal cancer and as first-line therapy in metastatic colorectal cancer [11–15]. In two phase III trials, panitumumab (Vectibix; Amgen Inc, Thousand Oaks, CA), a fully human monoclonal immunoglobulin G2 antibody, added to first- (FOLFOX) and second-line (FOLFIRI) chemotherapy significantly increased the response rate in metastatic colorectal cancer patients. Radiation increases EGFR expression in cancer cells, and the EGFR signaling blockade sensitizes the cells to the effects of radiation [16, 17]. In a phase III study with cetuximab and concurrent RT in patients with locally advanced head and neck cancer, locoregional control and OS significantly improved [18, 19]. Various mechanisms for this cetuximab synergistic activity have been proposed, including the inhibition of repopulation during RT fractions [20, 21]. In the present phase II study, the efficacy of the addition of panitumumab to 5-fluorouracil and oxaliplatin chemotherapy with concurrent external RT was investigated as neoadjuvant treatment in LARC high-risk patients.
original article
Annals of Oncology
treatment), and 36 (before surgery). Biomarker levels were assessed using commercial quantitative sandwich enzyme immunoassays [Quantikine Human VEGF Immunoassay (R&D Systems, Minneapolis, MN); Human sE-selectin ELISA (Bender MedSystems, San Diego, CA); Quantikine Human EGF Immunoassay (R&D Systems); RayBio Human TGFa (RayBiotech, Norcross, GA)]. 2-[Fluorine-18]fluoro-2-deoxy-D-glucose (FDG)–PET scan evaluation was carried out at initial diagnosis (baseline), before the first panitumumab administration (on day 214), and after the end of chemoRT (before surgery). Standard uptake value (SUV1 basal, SUV2 after the first panitumumab administration, and SUV3 before surgery) was determined from the most active tumor site. FDG–PET scan was carried out following a standard procedure, as reported elsewhere, using a dedicated PET–CT tomograph (GE Discovery) [26]. The acquisition time was in a two-dimensional mode for 4 min per bed position, and the attenuation correction was carried out using a CTbased method (120 kV, 80 mA).
results
treatment exposure Fifty percent of patients had at least one dose reduction, and 5.6% required a 0%–25% dose reduction of the preoperative treatment. The dose intensities of panitumumab,
surgical procedures and pathological responses Data on the surgical procedures and the pathological responses are listed in Table 3. Five patients did not undergo surgery: two patients due to disease progression (one liver metastasis, one lung metastasis) during the neoadjuvant treatment, one patient died due to gastrointestinal toxicity (diarrhea) correlated to treatment, and two patients due to refusal. Fifty-five (91.7%) patients underwent surgery and were assessable for pathological response. TME surgery was carried out in all patients. Forty-six (83.6%) patients were treated with a low anterior resection, 4 (7.3%) with a Hartmann’s procedure, and 5 (9.1%) with an abdominoperineal resection. No postoperative deaths occurred. Resection (R0) at the primary tumor site was achieved in 43 of 55 (78.2%) patients. Sphincter-sparing surgery was carried out in 50 of 55 (90.9%) patients and in 7 of 16 (43.8%) patients assessed to require an abdominoperineal resection before neoadjuvant treatment. pCR (ypT0N0) rate of 21.1% (95% confidence interval 10.4% to 31.6%) was observed in 12 of 57 patients (55 resected and 2 clinical disease progression). Table 2. Dose intensity of neoadjuvant treatment Dose intensity (n = 55)
>90% (%)
90%–60% (%)
<60% (%)
Panitumumab 5-Fluorouracil Oxaliplatin Radiotherapy
76.4 65.4 54.5 90.9
14.5 21.9 27.3 5.4
9.1 12.7 18.2 3.6
Table 1. Patient characteristics (N = 60) Characteristics Sex Male Female Age (years) Median Range Karnofsky performance status Median Range Distance from the anal margin (cm) Median Range Clinical stage at diagnosis cT3N+ cT4N2 cT4N+ cT3Nx cT4Nx
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n
%
40 20
66.7 33.3
60 37–75 90 80–100 6 0–12 41 4 11 1 3
68.3 6.7 18.3 1.7 5
Table 3. Surgical parameters and pathological response (operated patients, n = 55)
Type of surgical treatment Anterior resection Hartman resection Abdominoperineal resection Sphincter preserving Yes No Residual tumor R0 R1 R2 Assessable patients (n = 57)a ypT0N0 Pathological downstaging
n
%
46 4 5
83.6 7.3 9.1
50 5
90.9 9.1
43 11 1
78.2 20.0 1.8
12 33
21.1 57.9
a
Two resected patients for disease progression.
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patient population From February 2007 to October 2009, 60 patients in 11 Italian centers were enrolled. All 60 patients were assessed for safety, and 57 were assessable for response. Three patients were not assessable for response as one patient died of gastrointestinal toxicity in week 5 of treatment, and two patients refused surgery. The patient characteristics are listed in Table 1. The majority of patients were men (66.7%); their median age was 60 years (range 37–75 years) and the median Karnofsky performance status 90 (range 80–100). Median distance from the anal margin was 6 cm (range 0–12 cm). The clinical stage was cT3 in 42 of the 60 (70.0%) patients and cT4 in 18 (30.0%). The majority of patients (52/60; 86.6%) had lymph node involvement (cN+).
5-fluorouracil, oxaliplatin, and RT are reported in Table 2. Panitumumab dose intensity >90% was delivered in 42 of 55 (76.4%) patients. The dose of 5-fluorouracil and oxaliplatin was reduced >40% due to toxicity in 12.7% and 18.2% of patients, respectively. The full dose of planned RT was administered in 47 of 55 (85.5%) patients and >90% in 50 of 55 (90.9%) patients. Eighteen patients with T4 tumors had received the extended nodal irradiation of the external iliac.
original article
Annals of Oncology
Table 4. Neoadjuvant treatment toxicity Toxicity
Grade 3/4 n %
Total n %
8 6 5 2
13.5 10.1 8.4 3.4
1 0 1 0
1.7 0 1.7 0
9 6 6 2
15.2 10.1 10.1 3.4
13 17 11 21 11 13 7
22.0 28.8 18.6 35.6 18.6 22.0 11.8
2 3 1 23 0 0 0
3.4 5.1 1.7 38.9 0 0 0
15 20 12 44 11 13 7
25.4 33.9 20.2 74.5 18.6 22.0 11.8
35 4 6 8 2 6 5 18 1
59.3 6.7 10.1 13.5 3.4 10.1 8.4 30.5 1.7
11 0 1 0 0 0 0 2 1
18.6 0 1.7 0 0 0 0 3.4 1.7
46 4 7 8 2 6 5 20 2
77.9 6.7 11.8 13.5 3.4 10.1 8.4 33.9 3.4
Compared with the clinical stage before neoadjuvant treatment, a pathological downstaging (T and/or N) occurred in 33 of 57 (57.9%) patients.
safety All 60 patients were evaluated for toxicity. Adverse events observed during the neoadjuvant treatment are listed in Table 4. Diarrhea was the most observed toxicity, occurring in 23 (38.9%) patients, with grades 3–4. Grade 3 nausea and vomiting occurred in three (5.1%) and one (1.7%) patients, respectively. Grade 3 neutropenia was recorded in only one (1.7%) patient; no cases of grade 3–4 thrombocytopenia and anemia were observed. All grades of acne-like rash occurred in 46 patients (77.9%), and grades 3–4 were observed in 11 (18.6%). One toxic death was observed for diarrhea. biomarker and PET studies Mutational status of KRAS, BRAF, and PIK3CA was evaluated in 27 of 55 (49.1%) patients. KRAS mutations were detected in 4 (14.8%) of the tumors analyzed (G12A and G12D, one case each; G13D, two cases) and BRAF in 1 of 27 (3.7%) cases (V600E). No PIK3CA mutations were found. In this patient cohort, oncogenic activation of KRAS was not significantly associated with the pathological responses. Twenty-three patients enrolled in two centers were available for the biomarker evaluation (Table 5) and 28 patients for the FDG–PET study. The median basal values of circulating biomarkers (at day 214) were as follows: sVEGF 465.7 pg/ml, pVEGF 114.2 pg/ml, E-selectin 35.0 ng/ml, TGF-a 33.5 pg/ml, and EGF
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All patients (n = 23)
Day 214, Median
Day 1 Median
P
Day 36 Median
TGF-a (pg/ml) 33.50 68.10 0.006 68.10 EGF (pg/ml) 534.40 418.30 0.821 339.00 sVEGF (pg/ml) 465.70 555.00 0.027 548.20 pVEGF (pg/ml) 114.20 107.90 0.322 214.90 E-selectin (ng/ml) 35.00 50.50 0.000 44.80 Downstaging patients (n = 14)/non-downstaging patients (n = 9) Day 214 Median P TGF-a (pg/ml) Downstaging Non-downstaging EGF (pg/ml) Downstaging Non-downstaging sVEGF (pg/ml) Downstaging Non-downstaging pVEGF (pg/ml) Downstaging Non-downstaging E-selectin (ng/ml) Downstaging Non-downstaging
Day 1 Median
P
Day 36 Median
P 0.001 0.001 0.227 0.124 0.011
P
37.99 29.70
0.305
68.14 67.14
0.860
71.09 66.36
0.953
543.49 381.58
0.201
395.08 439.51
0.804
368.15 309.16
0.440
460.3 473.6
0.781
496.4 690.1
0.414
497.4 717.7
0.350
105.8 248.6
0.250
96.9 373.8
0.010
164.7 283.5
0.078
34.23 37.76
0.557
50.53 50.13
0.860
42.32 48.96
0.827
TGF, transforming growth factor; EGF, epidermal growth factor; sVEGF, serum vascular endothelial growth factor; pVEGF, plasma vascular endothelial growth factor.
534.4 pg/ml. Panitumumab treatment increased the levels of TGF-a, sVEGF, and E-selectin. On day 1 after only one panitumumab administration, the sVEGF, E-selectin, and TGFa median values presented the following higher levels as compared with baseline: sVEGF 555.0 pg/ml (P = 0.027), Eselectin 50.5 ng/ml (P < 0.001), and TGF-a 68.1 pg/ml (P = 0.006) in all patients. Up-regulation of pVEGF after panitumumab administration was observed in patients with pathological downstaging (373.8 pg/ml; P = 0.01). The decrease in EGF level was observed soon after panitumumab administration (418.3 pg/ml; P = 0.82) and it reached a significant level at day 36 (339.0 pg/ml; P = 0.001). No correlations were found between EGF level modifications and the pathological response. The median SUV1 of PET scan was 16.1 (range 6.1–26.9) and after only panitumumab administration (SUV2) it decreased to 10.2 (range 1.9–25.2; P = 0.019). SUV3 further decreased to 4.9 (range 0–17; P < 0.001). The decrease of SUV2 and SUV3 was not related to pathological downstaging.
postoperative chemotherapy Postoperative chemotherapy with FOLFOX4 in combination with panitumumab was administered in 40 of 55 (72.7%) patients.
discussion In LARC patients, the randomized phase III trials STAR-01 and ACCORD 12/0405 Prodige 2 showed a pCR rate of 16%
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Hematologic Leukopenia Anemia Neutropenia Thrombocytopenia Gastrointestinal Anorexia Nausea Vomiting Diarrhea Weight loss Abdominal pain Stomatitis Cutaneous Acneiform rash Nails Itch Peripheral neuropathy Hand–foot syndrome Hepatic Cystitis Asthenia Allergy
Grade 1/2 n %
Table 5. Circulating biomarker levels
original article
Annals of Oncology
chemo-RT in these phase II studies [27–31, 33] might arise from changes in tumor cell proliferation and cell cycle distribution after cetuximab administration, with cell arrest in G1 or G2/M and a failure to pass through the S phase. This hypothesis is supported by evidence in the pathological and molecular evaluation from the Belgian study that cetuximab down-regulated genes involved in proliferation (PIK3R1, CGREF1, PLAGL1), confirmed by immunohistochemistry for Ki67 [34]. Capecitabine–5-fluorouracil and oxaliplatin both produced their optimal cytotoxic and radiosensitizing effects when cells proliferate into the S/G2/M phase. Therefore, these cellular modifications could produce an antagonistic effect on fluoropyrimidine–oxaliplatin chemo-RT but would be less likely to be impacted by irinotecan. One possible explanation for the higher pCR in StarPan Study could arise from the different chemotherapy schedules employed that could overcome the antagonistic effect of anti-EGFR monoclonal antibodies. In our study, 5fluorouracil is administered continuously (without intervals) and oxaliplatin weekly for six times, at the full optimal dose, maintaining the synergistic and radiosensitizing effect of the two drugs [35]. These activities were lacking when 5fluorouracil and capecitabine are administered in monotherapy (27–30) or in combination with oxaliplatin with intermittent schedules [31]. In combination with irinotecan, the activity seems to be preserved only with full capecitabine dose [32, 33]. In our StarPan Study, although the number of assessed patients was small, the presence of KRAS and BRAF mutations in the pretherapeutic biopsy was not correlated with the pathological tumor response. The significance of KRAS and BRAF mutations in patients with rectal cancer submitted to preoperative chemo-RT is not well known. In one study in 37 patients, the presence of specific KRAS mutations (codons 12, 13, and 61) was an indicator of tumor response in patients with LARC treated by preoperative 5-fluorouracil-based chemo-RT [36]. The mutation status of KRAS and BRAF in 95 LARC patients treated with 5-fluorouracil-based neoadjuvant chemo-RT was not correlated with pathological response [37]. The results of three phase II studies in patients with LARC treated with cetuximab in combination with chemo-RT did not show a significantly better response in tumor without KRAS mutations [34, 38, 39]. In our study, the circulating levels of the EGFR ligands (TGFa, EGF) and vascular factors (sVEGF, E-selectin) were modified
Table 6. Phase II studies of preoperative chemoradiation using anti-EGFR monoclonal antibodies Authors (reference)
Phase
n
mAB
5FU
Bertolini et al. [27] Machiels et al. [28] Eisterer et al. [29] Velenik et al. [30] Ro¨del et al. [31] Hong et al. [32] Horisberger et al. [33] StarPan (current study)
II I/II II II I/II II II II
40 40 28 37 48 10 50 60
Cet Cet Cet Cet Cet Cet Cet Pan
+
Cape + + + + + +
+
Oxa
Iri
+ + + +
RT dose (Gy)
pCR (%)
50.4 45 45 45–50.4 50.4 50.4 50.4 50.4
7.5 5 0 8.1 8 20 8 21.1
mAB, monoclonal antibody; 5FU, 5-fluorouracil; Cape, capecitabine; Oxa, oxaliplatin; Iri, irinotecan; RT, radiotherapy; pCR, pathological complete response; Cet, cetuximab; Pan, panitumumab.
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and 19%, respectively, using a neoadjuvant combination of fluoropyrimidine, oxaliplatin, and RT [4, 5]. The addition of anti-EGFR monoclonal antibodies to preoperative concurrent RT and chemotherapy regimens was postulated to improve pCR. The phase II trials of preoperative chemoradiation using anti-EGFR monoclonal antibodies are summarized in Table 6. In the Italian phase II study, cetuximab and a continuous infusion of 5-fluorouracil 225 mg/m2/day concomitantly with RT (50.4 Gy in 25–28 fractions) were administered in 40 patients, with pCR in 3 patients (8%) [27]. In the Belgian phase I/II study, 40 patients were treated with cetuximab in combination with capecitabine 650 and 825 mg/m2 twice daily (dose recommended) continuously for the duration of RT (45 Gy in 25 fractions), with pCR in 2 patients (5%) [28]. No pCR was obtained in 28 patients treated with cetuximab in combination with capecitabine 825 mg/m2 twice daily on RT days (45 Gy in 25 fractions) [29]. Velenik et al. [30] treated 37 patients with cetuximab added to capecitabine 825 mg/m2 twice daily continuously for the duration of RT (45 Gy in 25 fractions), obtaining pCR in 3 (8%) patients. The association of cetuximab with capecitabine 825 mg/m2 twice daily (days 1–14 and 22–35), oxaliplatin 50 mg/m2 (days 1, 8, 22, and 29), and RT (50.4 Gy in 28 fractions) was evaluated in 48 patients and a pCR was reached in 4 (9%) patients [31]. Two phase II trials evaluated the addition of cetuximab to capecitabine–irinotecan and RT. Cetuximab was added to capecitabine 825 mg/m2 twice daily (5 days a week), irinotecan 40 mg/m2 (days 1, 8, 15, 22, and 29), and RT (50.4 Gy in 28 fractions) in 10 patients, with pCR in 2 (20%) patients [32]. In the MARGIT Study, 50 patients received cetuximab in combination with capecitabine 500 mg/m2 twice daily continuously, irinotecan 40 mg/m2 (days 1, 8, 15, 22, and 29), and RT (50.4 Gy in 28 fractions), obtaining pCR in 4 (8%) patients [33]. In the StarPan (STAR-02) Study, the primary end point is not reached, with a pCR rate of 21.1%. However, in this trial, the addition of panitumumab to 5-fluorouracil–oxaliplatin chemo-RT showed a high pCR rate as compared with the results of the phase II studies based on cetuximab– fluoropyrimidine combination with or without oxaliplatin. These data should be interpreted as hypothesis-generating in regard to the chemo-RT schedules. The biological mechanisms for the disappointing results of cetuximab in combination with fluoropyrimidine-based
original article
Annals of Oncology
Volume 22 | No. 11 | November 2011
funding Amgen–Dompe`, Italy [drug (panitumumab, Vectibix) and educational grant (20062089)].
disclosure The authors declare no conflict of interest.
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after only panitumumab administration. TGF-a, sVEGF, and E-selectin were up-regulated in almost all patients independently of response. In the preoperative treatment of rectal cancer, a similar up-regulation of circulating levels of TGF-a was observed after cetuximab administration alone [34]. The increase in angiogenetic factors is similar to that seen in a phase II study with bevacizumab in neoadjuvant chemoradiation of rectal cancer [40]. Moreover, results from our study suggest that in the responder patients, the higher EGF basal levels may up-regulate the EGFR, while the earlier circulating EGF level decrease could serve as a predictor of tumor downstaging. In our study, the FDG uptake (a measure of tumor metabolic rate) was decreased compared with the basal value by panitumumab administration alone and markedly by combination therapy. The earlier changes in the PET evaluation appear to be correlated to reduction in the tumor cell proliferation after panitumumab administration alone, and afterward, the addition of chemo-RT to panitumumab increases the cytotoxic activity. Earlier PET evaluation in this patient setting is not predictive of pathological response but may be only a marker of cellular proliferation down-regulation. The gastrointestinal toxicity was the main toxicity of the StarPan Study. This panitumumab combination treatment was associated with very high incidence of grade 3–4 diarrhea that reached 38.9%. The rate of grade 3–4 of diarrhea in two fluoropyrimidine–oxaliplatin phase III trials was 12.6% and 15% [4, 5], and varied from 5% to 30% in the cetuximab combination phase II studies [27–31]. In our study, therefore, the addition of panitumumab is likely to have been the main factor for the increase in grade 3–4 diarrhea. The specific side-effect associated with panitumumab was skin rash (77.9% all grades, and 18.6% of grades 3–4). In conclusion, in the StarPan/STAR-02 Study the primary end point is not reached and the panitumumab combination treatment was associated with high incidence of grade 3–4 diarrhea (with one toxic death). Therefore, this regimen is unsuitable for further testing. The integration of anti-EGFR monoclonal antibodies into rectal cancer preoperative chemoradiation schedules is an interesting and attractive hypothesis, but the interactions between biological therapy and radiochemotherapy could be modified with the different agents applied, treatment schedules, and sequences. The higher pCR obtained in this study in comparison with the previous published phase II studies with an anti-EGFR agent in combination with fluoropyrimidine–oxaliplatin and RT may guide to developing some hypotheses. This result could be correlated to the different modalities of chemotherapy regimen administered. Further translational and clinical studies will be necessary to understand the potential molecular pathways involved in anti-EGFR response, and optimal regimens and sequences with chemo-RT. The radiosensitizing properties of anti-EGFR in preclinical systems, the results of our study in pathological response and toxicity and the activity of cetuximab in combination with RT alone in head and neck cancers [18–20], represent the background of the next STAR Study (Rap Study/STAR-03) that will evaluate panitumumab in combination with only RT in low-risk LARC.
original article
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appendix The following investigators enrolled patients in the StarPan/ STAR-02 study: Davide Tassinari, Department of Medical Oncology, Degli Infermi Hospital, Rimini, Italy; Graziella Pinotti, Medical Oncology Unit, Macchi Hospital, Varese, Italy; Monica Lencioni, Division of Medical Oncology, S. Chiara Hospital, Pisa, Italy; Francesca Pucci, Medical Oncology, Maggiore Hospital, Parma, Italy.
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