Journal of Chemotherapy
ISSN: 1120-009X (Print) 1973-9478 (Online) Journal homepage: http://www.tandfonline.com/loi/yjoc20
FOLFIRI-bevacizumab and concurrent low-dose radiotherapy in metastatic colorectal cancer: preliminary results of a phase I–II study Alessio G. Morganti, Samantha Mignogna, Luciana Caravatta, Francesco Deodato, Gabriella Macchia, Nunzio M. Plantamura, Mariangela Massaccesi, Vincenzo Picardi, Savino Cilla & Vincenzo Valentini To cite this article: Alessio G. Morganti, Samantha Mignogna, Luciana Caravatta, Francesco Deodato, Gabriella Macchia, Nunzio M. Plantamura, Mariangela Massaccesi, Vincenzo Picardi, Savino Cilla & Vincenzo Valentini (2014) FOLFIRI-bevacizumab and concurrent low-dose radiotherapy in metastatic colorectal cancer: preliminary results of a phase I–II study, Journal of Chemotherapy, 26:6, 353-358 To link to this article: http://dx.doi.org/10.1179/1973947813Y.0000000163
Published online: 27 Jan 2014.
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Anticancer Original Research Paper
FOLFIRI-bevacizumab and concurrent low-dose radiotherapy in metastatic colorectal cancer: preliminary results of a phase I–II study Alessio G. Morganti1,2,3, Samantha Mignogna2, Luciana Caravatta1, Francesco Deodato1, Gabriella Macchia1, Nunzio M. Plantamura1, Mariangela Massaccesi1, Vincenzo Picardi1, Savino Cilla4, Vincenzo Valentini3
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1
Radiation Oncology Unit, Fondazione di Ricerca e Cura ‘Giovanni Paolo II’, Universita` Cattolica del Sacro Cuore, Campobasso, Italy, 2General Oncology Unit, Fondazione di Ricerca e Cura ‘Giovanni Paolo II’, Universita` Cattolica del Sacro Cuore, Campobasso, Italy, 3Radiation Oncology Department, Policlinico Universitario ‘A. Gemelli’, Universita` Cattolica del Sacro Cuore, Rome, Italy, 4Medical Physics Unit, Fondazione di Ricerca e Cura ‘Giovanni Paolo II’, Universita` Cattolica del Sacro Cuore, Campobasso, Italy Background: To evaluate the effectiveness of low-dose radiation therapy (LDRT) and FOLFIRIbevacizumab (FOLFIRI-B) combination in metastatic colorectal cancer. Methods: The primary objective of the study is to raise the clinical complete response (CR) rate from 5% to 25%. Secondary objectives include toxicity and progression-free survival. Patients underwent 12 FOLFIRIB cycles plus two daily LDRT (20 cGy/6-hour interval) on the first and second days of each cycle. Results: CR and toxicity of 10 patients are reported. Considering irradiated sites, 10/10 patients had clinical partial response (PR) (7/10) or CR (3/10). Three clinical PR patients subsequently underwent surgery and reported a pathological CR in the irradiated sites. Grade 3–4 toxicities rate was 30%. With a median followup of 29 months (range: 12–49 months), 2/10 progression of disease in irradiated sites and 3/5 in nonirradiated sites were observed. Conclusions: The very high response rate requires urgent verification in a larger patient series. Keywords: Bevacizumab, Chemo-sensitization, Low-dose radiotherapy, Metastatic colorectal cancer
Introduction Chemotherapy (CHT) is the standard treatment of patients with advanced cancer, being effective in reducing macroscopic lesions and in sterilizing microscopic foci of disease in variable percentage according to the tumour. Unfortunately, at least in non-germinal solid tumours, the complete response (CR) of macroscopic lesions is rare and permanent cure is uncommon. A series of studies have shown that low-dose radiotherapy (LDRT) increases the biological efficacy of CHT. In particular, pre-clinical studies suggest a synergistic effect between LDRT and CHT. The effect enhancement of the latter would be due to increased apoptosis.1,2 This synergistic effect has been demonstrated by in vitro studies for several drugs: carboplatin, cisplatin, docetaxel, etoposide, myocet, gemcitabine, and paclitaxel in a variety of cell lines.1–5
Correspondence to: G. Macchia, Department of Radiation Oncology, Fondazione di Ricerca e Cura ‘Giovanni Paolo II’, Largo A. Gemelli 1, 86100 Campobasso, Italy. Email: [email protected]
ß 2014 Edizioni Scientifiche per l’Informazione su Farmaci e Terapia DOI 10.1179/1973947813Y.0000000163
Furthermore, LDRT has the potential advantage to reduce toxicity when compared to conventional fractionation radiotherapy (RT). Therefore, LDRT could favour the combination of ‘full-dose’ CHT treatments,6,7 with a potential advantage in terms of systemic disease control. Therefore, on the basis of pre-clinical evidence, it is evident that the potential interest in the CHT plus LDRT combination at the price of a low added toxicity gives the possibility of a ‘full-dose’ CHT administration. It was suggested that in this setting, RT should be considered as a new systemic agent labelled with an ‘r’ (e.g. gemcitabinezLDRT: rG).8 However, with rare exceptions,6,7,9,10 clinical experiences in this field are lacking, and the safety and efficacy of these combinations are unknown in the commonly used CHT regimens. Colorectal cancer is one of the tumours with the highest incidence in European countries, although a progressive decrease in the mortality rate has been recorded in the last years.11 CHT schedules incorporating the monoclonal antibody bevacizumab, an
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inhibitor of vascular endothelial growth factor (VEGF), demonstrated efficacy in metastatic colorectal cancer. In particular, the combination of bevacizumab to first-line irinotecan, 5-fluorouracil, and leucovorin produced high response rate, a long interval to progression, and prolonged overall survival in patients with metastatic colorectal cancer, although the CR rate is still disappointing (3.7%).12 The integration of this schedule with LDRT could in theory increase the response rate, but, to date, studies combining LDRTzFOLFIRI-bevacizumab (r-FOLFIRI-B) are still lacking in the literature. A phase I–II study (RAdio-CHEmotherapy with Low fractionation, RACHEL-1 trial), aimed at assessing the rate of clinical response, as well as toxicities and long-term outcomes in metastatic colorectal cancer patients, is currently ongoing in our department and is expected to complete the enrollment within December 2013. In this paper, we present the preliminary analysis of clinical response and toxicities in patients who were treated with r-FOLFIRI-B combination for metastatic colorectal cancer.
Material and Methods Objectives of the study This prospective phase I–II study was approved by the Catholic University Institutional Review Board. All patients gave written informed consent agreeing to be submitted to all the procedures described and for their data to be used prospectively. The primary end point of the study was to evaluate the possibility to raise the rate of clinical CR from above 5% to 25%, whereas secondary end points included the evaluation of toxicity and progression-free survival either in irradiated as well in non-irradiated sites. Progressionfree survival was calculated from the date of enrollment to the date of progression of disease or death, without censoring for treatment discontinuation. Objective tumour response and progression were assessed according to the response evaluation criteria in solid tumours (RECIST criteria).13 After the CT-scan baseline evaluation, the follow-up schedule plans a 12-week-interval evaluation for the first 6 months, every 4 months thereafter or earlier if symptoms occurred. At each follow-up visit, treatment-related morbidity has to be recorded and graded. All CR and partial response (PR) required confirmation at least 4 weeks after they were first noted. Adverse events were assessed prospectively. Grading of toxicity was based on the Common Terminology Criteria for Adverse Events version 3.0, with the highest grade of any observed toxicity reported for each patient14 during treatment or within the first 3 months following treatment.
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Study design The sample size was calculated based on the two-stage design by Simon15 based on previous evidences12 showing a rate of clinical assessed CR to FOLFIRIbevacizumab schedule of 3.75%. The design tested the null hypothesis that the clinical response rate for this population would improve from y5% to the clinically relevant alternative of 25%, using an a error of 0.05 and an b error of 0.2. Thus, the first step was planned to include nine patients. Enrollment interruption and closure of the study were planned in the case of none clinical CR, while in the case of detection of at least one clinical CR, the study would enroll additional eight patients up to a total number of 17 patients. The regimen would be considered inactive if #2/17 CRs were recorded. A comparison of response rate in irradiated sites with non-irradiated sites was also planned.
Eligibility Patients with histological confirmed colorectal cancer were eligible for the study. Inclusion criteria were the following: metastatic colorectal adenocarcinoma with bi-dimensionally measurable disease; Eastern Cooperative Oncology Group performance status #1; adequate bone-marrow function (white blood cell .3000/mm3, platelets .120 000/mm3); adequate renal function (blood urea nitrogen ,25 mg/dl, creatinine ,1.5 mg/dl, and urinary excretion #500 mg of protein per day); normal liver function (bilirubin ,2 mg/dl); and a life expectancy of more than 3 months. Enrollment of patients previously treated with CHT was allowed. Exclusion criteria were the following: irradiation in the same anatomical area within 6 months before the study start, major surgery within 28 days before the study start, clinically significant cardiovascular disease, clinically detectable ascites, pregnancy, or lactation, regular use of aspirin (more than 325 mg per day) or other non-steroidal anti-inflammatory agents, pre-existing bleeding diatheses or coagulopathy, or the need for full-dose anticoagulation, and known central nervous system metastases.
Therapy CHT The FOLFIRI-B regimen consisted of bevacizumab (5 mg/kg), irinotecan (180 mg/m2), bolus fluorouracil (400 mg/m2), and leucovorin (400 mg/m2), with a 46hour infusion of fluorouracil (2400 mg/m2), every 2 weeks. Twelve CHT cycles were planned and administered. Dose reductions were required for all grade 3 or 4 toxicities related to treatment. No dose reductions for the use of bevacizumab were allowed. Treatment was continued until completion of the twelfth cycle of chemoradiation, or disease progression, or unacceptable toxicities, or consent withdrawal.
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The administration of bevacizumab was interrupted at least 4 weeks before planned surgery.
Table 1 Patients characteristics
Radiotherapy Irradiation was performed on the first and second days of each CHT cycle. Two daily fractions (20 cGy each) with at least 6 hours interval were delivered up to a total dose of 960 cGy. In patients with multiple metastatic sites, only one site, chosen on the basis of its potential impact on quality of life, was irradiated. The treatment was performed using appropriate immobilization systems according to the anatomical site (thermoplastic mask, wing-board, custom vaclock bag). All patients underwent CT simulation in the supine. Simulation CT images were taken in 5mm increments over the region of interest. The Clinical Target Volume was defined as the metastatic lesion (Gross Tumour Volume) plus 1 cm circumferential margin. A further isotropic 1 cm margin was added for the Planning Target Volume, except for targets located in the upper abdomen or lungs where 1.5 cm was added in cranio-caudal direction. Threedimensional conformal RT was planned using the Oncentra MasterPlan (Nucletron B.V., Veenendaal, The Netherlands) treatment planning system. Two opposing (antero-posterior and postero-anterior or lateral-lateral) or multiple beams, according to anatomical and tumour site, were used. A daily online correction protocol of isocentre position was applied using portal imaging, with set-up correction in case of deviations .0.5 cm in any direction.16 All stages of the treatment planning process were subjected to a systematic independent check procedure, as previously described.17
Median age, years (range) Male/female ECOG PS 0/1 Site of primary tumour Colon Rectum Previous surgery Previous radiotherapy Previous chemotherapy Site of metastatic disease Liver Lung Peritoneum Lymph nodes Metastatic sites 1 site 2 sites Medical history Diabetes mellitus Hypertension Chronic obstructive bronchopneumopathy Current medication at baseline Antihypertensive Oral hypoglycemic agents
CHT dose adjustment According to haematological toxicity, the following recommendations for dose adjustment were provided. Grade 0–2 toxicity did not require dose reductions. If grade 3 toxicity was registered, a 25% CHT dose reduction dosage was recommended; subsequently, if patient recovered to grade 0–2 before the following cycle start, full-dose (100%) CHT was administered. In the case of grade 4 toxicity, RT and CHT were delayed until the patient toxicity recovery; subsequently, treatment was resumed with a CHT dose reduced by 25%. If patients presented a second episode of grade 4 toxicity, a further 25% dose reduction was performed, while patients with a third episode of grade 4 toxicity were excluded from the study. According to non-haematological toxicity, the following recommendations were provided. Grade 0– 2 toxicity did not require dose reductions, except for grade 2 lung toxicity, in which case RT and CHT were suspended until the resolution of grade 2 toxicity. For grade 3–4 toxicities, both RT and CHT were suspended (except for hyper-transaminasemia grade 3,
No. 65 (48–72) 6/4 6/4 5 5 10 1 1 8 2 1 4 5 5 2 4 1 4 2
Note: ECOG PS: Eastern Cooperative Oncology Group performance status.
nausea, vomiting, and alopecia). Treatment was resumed after recovery of toxicity in the grade #2, with reduction of the CHT doses by 25%. Patients with a second episode of grade 3–4 toxicity received a second reduction of CHT doses of 25%. In patients with a third episode of grade 3–4 non-haematological toxicity, treatment was permanently discontinued.
Results According to the study design, nine patients were enrolled in the first phase and three of them showed a clinical CR at CT-scan evaluation. Therefore, the trial continued and the recruitment was actually ongoing. At the time of analysis, overall 10 patients, four females and six males (median age: 65 years; range: 48–72 years), are currently valuable in terms of clinical response. One patient had received prior CHT for colon cancer. Clinical characteristics are detailed in Table 1. In particular, 60% had 0 Eastern Cooperative Oncology Group (ECOG) performance status score, while 40% had 1. Moreover, the majority of tumours were moderately differentiated (N56, 60%), while four (40%) were poorly differentiated. The rate of grade 3–4 toxicities was 30% as presented in Table 2, with no patients stopping treatment for toxicities. Leukopenia and neutropenia were the most common haematological adverse events (30%), while two patients developed grade 1–2 diarrhoea. The percentage of the planned dose of irinotecan administered was 94.5%; in fact, three patients required CHT dose adjustments for toxicity during treatment. Adverse events related to bevacizumab included one case of
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Figure 1 (A) CT scan showing large liver metastases in a patient with colon carcinoma. (B) CT scan after treatment with lowdose radiotherapy combined with CHT (FOLFIRI plus bevacizumab); residual metastases were resected and pathological examination showed complete pathological response.
to EORTC criteria,18 clinical PR and CR were recorded in 2/4 and 2/4 of these patients, respectively (Table 3). Three patients were subsequently able to undergo resection of metastatic disease in the irradiated sites. Even though these patients had shown a clinical PR (3/3) at CT scan, all of them had a pathological CR. A very clear example is shown in Fig. 1. No wound healing complications were reported in these patients. With a median follow-up of 29 months (range: 12– 49 months), 2/10 progression of disease in irradiated sites (at 22 and 26 months, respectively) (Fig. 2) and 3/5 of disease progression in non-irradiated sites (at 7, 9, and 26 months, respectively) were observed. At the time of analysis, 3 of 10 patients had relapsed in different than irradiated metastatic sites and 3 of 10 patients were died of disease.
hypertension that was safely managed by antihypertensive drugs. No patients showed proteinuria or bleeding. As far as the evaluation of clinical response on the irradiated sites, 10/10 patients had confirmed clinical PR (7/10) or CR (3/10) at CT-scan evaluation. On the other hand, considering not irradiated sites, five patients had confirmed PR (2/5) or stable disease (3/ 5) at CT evaluation. An FDG-PET evaluation of response was carried out in four patients. According
Table 2 Incidence of adverse events (National Cancer Institute — Common Terminology Criteria for Adverse Events) No. of adverse event NCI-CTC toxicity grade Leukopenia Neutropenia Nausea/vomiting Diarrhea Asthenia Hypertension Thromboembolic event
1
1 1 1
2 1 1
3 2 1
4 1
1
Discussion
1
Bevacizumab, a humanized variant of the anti-VEGF monoclonal antibody, has been studied as an antiangiogenic cancer therapeutic either as a single agent
1*
Note: *Venous thrombosis at the site of central venous catheter. Table 3 Tumour response
Response Patient 1 2 3 4 5 6 7 8 9 10
Irradiated site
Non-irradiated site
Pathological evaluation
CR* PR* PR*,{ PR*,{ PR* PR* PR*CR{ PR*CR{ CR* CR*
PR* PR* SD*,{ NE SD* SD* NE NE NE NE
NA CR NA CR NA NA CR NA NA NA
Note: NE: not evaluable (patient without non-irradiated metastatic sites); NA; not assessed (patient not receiving surgery). *CT scan (RECIST criteria). { 18-FDG-PET (EORTC criteria).
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Figure 2 Progression-free actuarial survival in irradiated sites.
FOLFIRI-bevacizumab plus low-dose irradiation
this treatment. Moreover, the excellent results in terms of response may be at least partly explained by the presence of only one metastatic site in 5/10 patients. However, in this preliminary experience of non-standard chemoradiation, an apparent improvement of the response rate compared to patients receiving FOLFIRI-B was observed being 10/10 in irradiated sites with 2/5 in non-irradiated sites. Therefore, these results require urgent verification in a larger sample of patients. If these results are confirmed, given the absence of unexpected toxicity, it will be useful to evaluate the safety and efficacy of LDRT delivered to larger volumes, e.g. whole abdomen irradiation. In colorectal cancer scenario, a similar treatment could be tested both in palliative setting for patients with metastatic abdominal spread, as well in the adjuvant setting for patients with very high risk of abdominal recurrence.
Disclaimer Statements as well in combination with CHT in patients with stage III–IV colon cancer.19 In addition to its direct anti-angiogenic effects, bevacizumab may allow more efficient delivery of CHT by altering tumour vasculature and decreasing the elevated interstitial pressure common in tumours.19 Furthermore, there is a strong rationale for combining RT with anti-angiogenics due to its ability to kill proliferating endothelial cells with an assumption that inhibiting angiogenesis may sensitize endothelial cells to the effects of radiation. Moreover, targeting the vasculature may paradoxically increase oxygenation within tumours, thereby enhancing RT efficacy.20 The use of RT for cancer is also associated with therapeutic challenges that are distinct from those that might be expected with anti-angiogenic agents. Thus, the use of angiogenesis inhibitors in combination with RT should help to overcome the limitations of each with an enhanced efficacy and diminished toxicity.21 Based on these findings, a phase I–II study was designed to evaluate the response rate after rFOLFIRI-B. To the best of our knowledge, this is the first experience of a combination based on LDRT, CHT, and monoclonal anti-VEGF antibody. In the first 10 patients of this two-stage study, the treatment was well tolerated, with no significant toxicity different from those expected in patients receiving FOLFIRI-B regimen. A clinical response rate of 10/10 was recorded. Seven patients had a PR and three patients had a CR at CT-scan evaluation. Three of the partial responders showed a pathologic CR after resection of the irradiated metastatic lesions. The small size of the analysed sample does not allow a definitive assessment of the effectiveness of
Contributors All authors contributed to the conception, drafting, and revision of the text. Funding None. Conflicts of interest No actual or potential conflicts of interest exist regarding this paper. Ethics approval This prospective phase I–II study was approved by the Catholic University Institutional Review Board.
Acknowledgements We sincerely thank Ms M. Buwenge for reviewing and editing the manuscript.
References 1 Dey S, Spring PM, Arnold S, Valentino J, Chendil D, Regine WF, et al. Low-dose fractionated radiation potentiates the effects of Paclitaxel in wild-type and mutant p53 head and neck tumor cell lines. Clin Cancer Res. 2003;9:1557–65. 2 Gupta S, Koru-Sengul T, Arnold SM, Devi GR, Mohiuddin M, Ahmed MM. Low-dose fractionated radiation potentiates the effects of cisplatin independent of the hyper-radiation sensitivity in human lung cancer cells. Mol Cancer Ther. 2011;10(2):292–302. 3 Chendil D, Oakes R, Alcock RA, Patel N, Mayhew C, Mohiuddin M, et al. Low dose fractionated radiation enhances the radiosensitization effect of paclitaxel in colorectal tumor cells with mutant p53. Cancer. 2000;89:1893–900. 4 Spring PM, Arnold SM, Shajahan S, Brown B, Dey S, Lele SM, et al. Low dose fractionated radiation potentiates the effects of taxotere in nude mice xenografts of squamous cell carcinoma of head and neck. Cell Cycle. 2004;3:479–85. 5 Beauchesne PD, Bertrand S, Branche R, Linke SP, Revel R, Dore JF, et al. Human malignant glioma cell lines are sensitive to low radiation doses. Int J Cancer. 2003;105:33–40. 6 Arnold SM, Regine WF, Ahmed MM, Valentino J, Spring P, Kudrimoti M, et al. Low-dose fractionated radiation as a chemopotentiator of neoadjuvant paclitaxel and carboplatin for locally advanced squamous cell carcinoma of the head and neck: results of a new treatment paradigm. Int J Radiat Oncol Biol Phys. 2004;58:1411–7. 7 Arnold SM, Kudrimoti M, Valentino J, Spring P, Ahmed M, Regine W, et al. Potentiating the effect of chemotherapy with low-dose fractionated radiation (LDFRT) in locally advanced
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squamous cell carcinoma of the head and neck. J Clin Oncol. 2005;23(Suppl):3184 (abstract). Regine W, Hanna N, Garofalo MC, Doyle A, Arnold S, Kataria R, et al. Low-dose radiotherapy as a chemopotentiator of gemcitabine in tumors of the pancreas or small bowel: a phase I study exploring a new treatment paradigm. Int J Radiat Oncol Biol Phys. 2007;68:172–7. Kudrimoti M, Warren GW, Valentino JV, Spring PM, Mohiuddin M, St Clair WH, et al. Results of reduction of treatment intensity based on response to a novel induction therapy in stage III and IV head and neck cancer. J Clin Oncol. 2006;24(Suppl):5561 (abstract). Valentini V, Massaccesi M, Balducci M, Mantini G, Micciche´ F, Mattiucci GC, et al. Low-dose hyperradiosensitivity: is there a place for future investigation in clinical settings? Int J Radiat Oncol Biol Phys. 2010;76:535–9. Malvezzi M, Bertuccio P, Levi F, La Vecchia C, Negri E. European cancer mortality predictions for the year 2012. Ann Oncol. 2012;23:1044–52. Hurwitz H, Fehrenbacher L, Novotny W, Cartwright T, Hainsworth J, Heim W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med. 2004;350:2335–42. Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, et al. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute
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ISSN: 1120-009X (Print) 1973-9478 (Online) Journal homepage: http://www.tandfonline.com/loi/yjoc20
FOLFIRI-bevacizumab and concurrent low-dose radiotherapy in metastatic colorectal cancer: preliminary results of a phase I–II study Alessio G. Morganti, Samantha Mignogna, Luciana Caravatta, Francesco Deodato, Gabriella Macchia, Nunzio M. Plantamura, Mariangela Massaccesi, Vincenzo Picardi, Savino Cilla & Vincenzo Valentini To cite this article: Alessio G. Morganti, Samantha Mignogna, Luciana Caravatta, Francesco Deodato, Gabriella Macchia, Nunzio M. Plantamura, Mariangela Massaccesi, Vincenzo Picardi, Savino Cilla & Vincenzo Valentini (2014) FOLFIRI-bevacizumab and concurrent low-dose radiotherapy in metastatic colorectal cancer: preliminary results of a phase I–II study, Journal of Chemotherapy, 26:6, 353-358 To link to this article: http://dx.doi.org/10.1179/1973947813Y.0000000163
Published online: 27 Jan 2014.
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Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=yjoc20 Download by: [University of California Santa Barbara]
Date: 02 April 2016, At: 04:20
Anticancer Original Research Paper
FOLFIRI-bevacizumab and concurrent low-dose radiotherapy in metastatic colorectal cancer: preliminary results of a phase I–II study Alessio G. Morganti1,2,3, Samantha Mignogna2, Luciana Caravatta1, Francesco Deodato1, Gabriella Macchia1, Nunzio M. Plantamura1, Mariangela Massaccesi1, Vincenzo Picardi1, Savino Cilla4, Vincenzo Valentini3
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1
Radiation Oncology Unit, Fondazione di Ricerca e Cura ‘Giovanni Paolo II’, Universita` Cattolica del Sacro Cuore, Campobasso, Italy, 2General Oncology Unit, Fondazione di Ricerca e Cura ‘Giovanni Paolo II’, Universita` Cattolica del Sacro Cuore, Campobasso, Italy, 3Radiation Oncology Department, Policlinico Universitario ‘A. Gemelli’, Universita` Cattolica del Sacro Cuore, Rome, Italy, 4Medical Physics Unit, Fondazione di Ricerca e Cura ‘Giovanni Paolo II’, Universita` Cattolica del Sacro Cuore, Campobasso, Italy Background: To evaluate the effectiveness of low-dose radiation therapy (LDRT) and FOLFIRIbevacizumab (FOLFIRI-B) combination in metastatic colorectal cancer. Methods: The primary objective of the study is to raise the clinical complete response (CR) rate from 5% to 25%. Secondary objectives include toxicity and progression-free survival. Patients underwent 12 FOLFIRIB cycles plus two daily LDRT (20 cGy/6-hour interval) on the first and second days of each cycle. Results: CR and toxicity of 10 patients are reported. Considering irradiated sites, 10/10 patients had clinical partial response (PR) (7/10) or CR (3/10). Three clinical PR patients subsequently underwent surgery and reported a pathological CR in the irradiated sites. Grade 3–4 toxicities rate was 30%. With a median followup of 29 months (range: 12–49 months), 2/10 progression of disease in irradiated sites and 3/5 in nonirradiated sites were observed. Conclusions: The very high response rate requires urgent verification in a larger patient series. Keywords: Bevacizumab, Chemo-sensitization, Low-dose radiotherapy, Metastatic colorectal cancer
Introduction Chemotherapy (CHT) is the standard treatment of patients with advanced cancer, being effective in reducing macroscopic lesions and in sterilizing microscopic foci of disease in variable percentage according to the tumour. Unfortunately, at least in non-germinal solid tumours, the complete response (CR) of macroscopic lesions is rare and permanent cure is uncommon. A series of studies have shown that low-dose radiotherapy (LDRT) increases the biological efficacy of CHT. In particular, pre-clinical studies suggest a synergistic effect between LDRT and CHT. The effect enhancement of the latter would be due to increased apoptosis.1,2 This synergistic effect has been demonstrated by in vitro studies for several drugs: carboplatin, cisplatin, docetaxel, etoposide, myocet, gemcitabine, and paclitaxel in a variety of cell lines.1–5
Correspondence to: G. Macchia, Department of Radiation Oncology, Fondazione di Ricerca e Cura ‘Giovanni Paolo II’, Largo A. Gemelli 1, 86100 Campobasso, Italy. Email: [email protected]
ß 2014 Edizioni Scientifiche per l’Informazione su Farmaci e Terapia DOI 10.1179/1973947813Y.0000000163
Furthermore, LDRT has the potential advantage to reduce toxicity when compared to conventional fractionation radiotherapy (RT). Therefore, LDRT could favour the combination of ‘full-dose’ CHT treatments,6,7 with a potential advantage in terms of systemic disease control. Therefore, on the basis of pre-clinical evidence, it is evident that the potential interest in the CHT plus LDRT combination at the price of a low added toxicity gives the possibility of a ‘full-dose’ CHT administration. It was suggested that in this setting, RT should be considered as a new systemic agent labelled with an ‘r’ (e.g. gemcitabinezLDRT: rG).8 However, with rare exceptions,6,7,9,10 clinical experiences in this field are lacking, and the safety and efficacy of these combinations are unknown in the commonly used CHT regimens. Colorectal cancer is one of the tumours with the highest incidence in European countries, although a progressive decrease in the mortality rate has been recorded in the last years.11 CHT schedules incorporating the monoclonal antibody bevacizumab, an
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inhibitor of vascular endothelial growth factor (VEGF), demonstrated efficacy in metastatic colorectal cancer. In particular, the combination of bevacizumab to first-line irinotecan, 5-fluorouracil, and leucovorin produced high response rate, a long interval to progression, and prolonged overall survival in patients with metastatic colorectal cancer, although the CR rate is still disappointing (3.7%).12 The integration of this schedule with LDRT could in theory increase the response rate, but, to date, studies combining LDRTzFOLFIRI-bevacizumab (r-FOLFIRI-B) are still lacking in the literature. A phase I–II study (RAdio-CHEmotherapy with Low fractionation, RACHEL-1 trial), aimed at assessing the rate of clinical response, as well as toxicities and long-term outcomes in metastatic colorectal cancer patients, is currently ongoing in our department and is expected to complete the enrollment within December 2013. In this paper, we present the preliminary analysis of clinical response and toxicities in patients who were treated with r-FOLFIRI-B combination for metastatic colorectal cancer.
Material and Methods Objectives of the study This prospective phase I–II study was approved by the Catholic University Institutional Review Board. All patients gave written informed consent agreeing to be submitted to all the procedures described and for their data to be used prospectively. The primary end point of the study was to evaluate the possibility to raise the rate of clinical CR from above 5% to 25%, whereas secondary end points included the evaluation of toxicity and progression-free survival either in irradiated as well in non-irradiated sites. Progressionfree survival was calculated from the date of enrollment to the date of progression of disease or death, without censoring for treatment discontinuation. Objective tumour response and progression were assessed according to the response evaluation criteria in solid tumours (RECIST criteria).13 After the CT-scan baseline evaluation, the follow-up schedule plans a 12-week-interval evaluation for the first 6 months, every 4 months thereafter or earlier if symptoms occurred. At each follow-up visit, treatment-related morbidity has to be recorded and graded. All CR and partial response (PR) required confirmation at least 4 weeks after they were first noted. Adverse events were assessed prospectively. Grading of toxicity was based on the Common Terminology Criteria for Adverse Events version 3.0, with the highest grade of any observed toxicity reported for each patient14 during treatment or within the first 3 months following treatment.
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Study design The sample size was calculated based on the two-stage design by Simon15 based on previous evidences12 showing a rate of clinical assessed CR to FOLFIRIbevacizumab schedule of 3.75%. The design tested the null hypothesis that the clinical response rate for this population would improve from y5% to the clinically relevant alternative of 25%, using an a error of 0.05 and an b error of 0.2. Thus, the first step was planned to include nine patients. Enrollment interruption and closure of the study were planned in the case of none clinical CR, while in the case of detection of at least one clinical CR, the study would enroll additional eight patients up to a total number of 17 patients. The regimen would be considered inactive if #2/17 CRs were recorded. A comparison of response rate in irradiated sites with non-irradiated sites was also planned.
Eligibility Patients with histological confirmed colorectal cancer were eligible for the study. Inclusion criteria were the following: metastatic colorectal adenocarcinoma with bi-dimensionally measurable disease; Eastern Cooperative Oncology Group performance status #1; adequate bone-marrow function (white blood cell .3000/mm3, platelets .120 000/mm3); adequate renal function (blood urea nitrogen ,25 mg/dl, creatinine ,1.5 mg/dl, and urinary excretion #500 mg of protein per day); normal liver function (bilirubin ,2 mg/dl); and a life expectancy of more than 3 months. Enrollment of patients previously treated with CHT was allowed. Exclusion criteria were the following: irradiation in the same anatomical area within 6 months before the study start, major surgery within 28 days before the study start, clinically significant cardiovascular disease, clinically detectable ascites, pregnancy, or lactation, regular use of aspirin (more than 325 mg per day) or other non-steroidal anti-inflammatory agents, pre-existing bleeding diatheses or coagulopathy, or the need for full-dose anticoagulation, and known central nervous system metastases.
Therapy CHT The FOLFIRI-B regimen consisted of bevacizumab (5 mg/kg), irinotecan (180 mg/m2), bolus fluorouracil (400 mg/m2), and leucovorin (400 mg/m2), with a 46hour infusion of fluorouracil (2400 mg/m2), every 2 weeks. Twelve CHT cycles were planned and administered. Dose reductions were required for all grade 3 or 4 toxicities related to treatment. No dose reductions for the use of bevacizumab were allowed. Treatment was continued until completion of the twelfth cycle of chemoradiation, or disease progression, or unacceptable toxicities, or consent withdrawal.
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The administration of bevacizumab was interrupted at least 4 weeks before planned surgery.
Table 1 Patients characteristics
Radiotherapy Irradiation was performed on the first and second days of each CHT cycle. Two daily fractions (20 cGy each) with at least 6 hours interval were delivered up to a total dose of 960 cGy. In patients with multiple metastatic sites, only one site, chosen on the basis of its potential impact on quality of life, was irradiated. The treatment was performed using appropriate immobilization systems according to the anatomical site (thermoplastic mask, wing-board, custom vaclock bag). All patients underwent CT simulation in the supine. Simulation CT images were taken in 5mm increments over the region of interest. The Clinical Target Volume was defined as the metastatic lesion (Gross Tumour Volume) plus 1 cm circumferential margin. A further isotropic 1 cm margin was added for the Planning Target Volume, except for targets located in the upper abdomen or lungs where 1.5 cm was added in cranio-caudal direction. Threedimensional conformal RT was planned using the Oncentra MasterPlan (Nucletron B.V., Veenendaal, The Netherlands) treatment planning system. Two opposing (antero-posterior and postero-anterior or lateral-lateral) or multiple beams, according to anatomical and tumour site, were used. A daily online correction protocol of isocentre position was applied using portal imaging, with set-up correction in case of deviations .0.5 cm in any direction.16 All stages of the treatment planning process were subjected to a systematic independent check procedure, as previously described.17
Median age, years (range) Male/female ECOG PS 0/1 Site of primary tumour Colon Rectum Previous surgery Previous radiotherapy Previous chemotherapy Site of metastatic disease Liver Lung Peritoneum Lymph nodes Metastatic sites 1 site 2 sites Medical history Diabetes mellitus Hypertension Chronic obstructive bronchopneumopathy Current medication at baseline Antihypertensive Oral hypoglycemic agents
CHT dose adjustment According to haematological toxicity, the following recommendations for dose adjustment were provided. Grade 0–2 toxicity did not require dose reductions. If grade 3 toxicity was registered, a 25% CHT dose reduction dosage was recommended; subsequently, if patient recovered to grade 0–2 before the following cycle start, full-dose (100%) CHT was administered. In the case of grade 4 toxicity, RT and CHT were delayed until the patient toxicity recovery; subsequently, treatment was resumed with a CHT dose reduced by 25%. If patients presented a second episode of grade 4 toxicity, a further 25% dose reduction was performed, while patients with a third episode of grade 4 toxicity were excluded from the study. According to non-haematological toxicity, the following recommendations were provided. Grade 0– 2 toxicity did not require dose reductions, except for grade 2 lung toxicity, in which case RT and CHT were suspended until the resolution of grade 2 toxicity. For grade 3–4 toxicities, both RT and CHT were suspended (except for hyper-transaminasemia grade 3,
No. 65 (48–72) 6/4 6/4 5 5 10 1 1 8 2 1 4 5 5 2 4 1 4 2
Note: ECOG PS: Eastern Cooperative Oncology Group performance status.
nausea, vomiting, and alopecia). Treatment was resumed after recovery of toxicity in the grade #2, with reduction of the CHT doses by 25%. Patients with a second episode of grade 3–4 toxicity received a second reduction of CHT doses of 25%. In patients with a third episode of grade 3–4 non-haematological toxicity, treatment was permanently discontinued.
Results According to the study design, nine patients were enrolled in the first phase and three of them showed a clinical CR at CT-scan evaluation. Therefore, the trial continued and the recruitment was actually ongoing. At the time of analysis, overall 10 patients, four females and six males (median age: 65 years; range: 48–72 years), are currently valuable in terms of clinical response. One patient had received prior CHT for colon cancer. Clinical characteristics are detailed in Table 1. In particular, 60% had 0 Eastern Cooperative Oncology Group (ECOG) performance status score, while 40% had 1. Moreover, the majority of tumours were moderately differentiated (N56, 60%), while four (40%) were poorly differentiated. The rate of grade 3–4 toxicities was 30% as presented in Table 2, with no patients stopping treatment for toxicities. Leukopenia and neutropenia were the most common haematological adverse events (30%), while two patients developed grade 1–2 diarrhoea. The percentage of the planned dose of irinotecan administered was 94.5%; in fact, three patients required CHT dose adjustments for toxicity during treatment. Adverse events related to bevacizumab included one case of
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Figure 1 (A) CT scan showing large liver metastases in a patient with colon carcinoma. (B) CT scan after treatment with lowdose radiotherapy combined with CHT (FOLFIRI plus bevacizumab); residual metastases were resected and pathological examination showed complete pathological response.
to EORTC criteria,18 clinical PR and CR were recorded in 2/4 and 2/4 of these patients, respectively (Table 3). Three patients were subsequently able to undergo resection of metastatic disease in the irradiated sites. Even though these patients had shown a clinical PR (3/3) at CT scan, all of them had a pathological CR. A very clear example is shown in Fig. 1. No wound healing complications were reported in these patients. With a median follow-up of 29 months (range: 12– 49 months), 2/10 progression of disease in irradiated sites (at 22 and 26 months, respectively) (Fig. 2) and 3/5 of disease progression in non-irradiated sites (at 7, 9, and 26 months, respectively) were observed. At the time of analysis, 3 of 10 patients had relapsed in different than irradiated metastatic sites and 3 of 10 patients were died of disease.
hypertension that was safely managed by antihypertensive drugs. No patients showed proteinuria or bleeding. As far as the evaluation of clinical response on the irradiated sites, 10/10 patients had confirmed clinical PR (7/10) or CR (3/10) at CT-scan evaluation. On the other hand, considering not irradiated sites, five patients had confirmed PR (2/5) or stable disease (3/ 5) at CT evaluation. An FDG-PET evaluation of response was carried out in four patients. According
Table 2 Incidence of adverse events (National Cancer Institute — Common Terminology Criteria for Adverse Events) No. of adverse event NCI-CTC toxicity grade Leukopenia Neutropenia Nausea/vomiting Diarrhea Asthenia Hypertension Thromboembolic event
1
1 1 1
2 1 1
3 2 1
4 1
1
Discussion
1
Bevacizumab, a humanized variant of the anti-VEGF monoclonal antibody, has been studied as an antiangiogenic cancer therapeutic either as a single agent
1*
Note: *Venous thrombosis at the site of central venous catheter. Table 3 Tumour response
Response Patient 1 2 3 4 5 6 7 8 9 10
Irradiated site
Non-irradiated site
Pathological evaluation
CR* PR* PR*,{ PR*,{ PR* PR* PR*CR{ PR*CR{ CR* CR*
PR* PR* SD*,{ NE SD* SD* NE NE NE NE
NA CR NA CR NA NA CR NA NA NA
Note: NE: not evaluable (patient without non-irradiated metastatic sites); NA; not assessed (patient not receiving surgery). *CT scan (RECIST criteria). { 18-FDG-PET (EORTC criteria).
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Figure 2 Progression-free actuarial survival in irradiated sites.
FOLFIRI-bevacizumab plus low-dose irradiation
this treatment. Moreover, the excellent results in terms of response may be at least partly explained by the presence of only one metastatic site in 5/10 patients. However, in this preliminary experience of non-standard chemoradiation, an apparent improvement of the response rate compared to patients receiving FOLFIRI-B was observed being 10/10 in irradiated sites with 2/5 in non-irradiated sites. Therefore, these results require urgent verification in a larger sample of patients. If these results are confirmed, given the absence of unexpected toxicity, it will be useful to evaluate the safety and efficacy of LDRT delivered to larger volumes, e.g. whole abdomen irradiation. In colorectal cancer scenario, a similar treatment could be tested both in palliative setting for patients with metastatic abdominal spread, as well in the adjuvant setting for patients with very high risk of abdominal recurrence.
Disclaimer Statements as well in combination with CHT in patients with stage III–IV colon cancer.19 In addition to its direct anti-angiogenic effects, bevacizumab may allow more efficient delivery of CHT by altering tumour vasculature and decreasing the elevated interstitial pressure common in tumours.19 Furthermore, there is a strong rationale for combining RT with anti-angiogenics due to its ability to kill proliferating endothelial cells with an assumption that inhibiting angiogenesis may sensitize endothelial cells to the effects of radiation. Moreover, targeting the vasculature may paradoxically increase oxygenation within tumours, thereby enhancing RT efficacy.20 The use of RT for cancer is also associated with therapeutic challenges that are distinct from those that might be expected with anti-angiogenic agents. Thus, the use of angiogenesis inhibitors in combination with RT should help to overcome the limitations of each with an enhanced efficacy and diminished toxicity.21 Based on these findings, a phase I–II study was designed to evaluate the response rate after rFOLFIRI-B. To the best of our knowledge, this is the first experience of a combination based on LDRT, CHT, and monoclonal anti-VEGF antibody. In the first 10 patients of this two-stage study, the treatment was well tolerated, with no significant toxicity different from those expected in patients receiving FOLFIRI-B regimen. A clinical response rate of 10/10 was recorded. Seven patients had a PR and three patients had a CR at CT-scan evaluation. Three of the partial responders showed a pathologic CR after resection of the irradiated metastatic lesions. The small size of the analysed sample does not allow a definitive assessment of the effectiveness of
Contributors All authors contributed to the conception, drafting, and revision of the text. Funding None. Conflicts of interest No actual or potential conflicts of interest exist regarding this paper. Ethics approval This prospective phase I–II study was approved by the Catholic University Institutional Review Board.
Acknowledgements We sincerely thank Ms M. Buwenge for reviewing and editing the manuscript.
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