Intensified Neoadjuvant Chemoradiotherapy for Locally Advanced Rectal Cancer in Elderly Patients: Toxicity, Disease Control, and Survival Outcomes

Accepted Manuscript Intensified neoadjuvant chemoradiotherapy for locally advanced rectal cancer in elderly patients: toxicity, disease control and survival outcomes F. De Felice, Llange K, Rubini F, Bulzonetti N, Caiazzo R, Musio D, Tombolini V PII:

S1533-0028(17)30225-6

DOI:

10.1016/j.clcc.2017.10.005

Reference:

CLCC 399

To appear in:

Clinical Colorectal Cancer

Received Date: 14 June 2017 Revised Date:

23 September 2017

Accepted Date: 10 October 2017

Please cite this article as: De Felice F, K L, F R, N B, R C, D M, V T, Intensified neoadjuvant chemoradiotherapy for locally advanced rectal cancer in elderly patients: toxicity, disease control and survival outcomes, Clinical Colorectal Cancer (2017), doi: 10.1016/j.clcc.2017.10.005. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

ACCEPTED MANUSCRIPT Intensified neoadjuvant chemoradiotherapy for locally advanced rectal cancer in elderly patients: toxicity, disease control and survival outcomes De Felice F1, Llange K1, Rubini F1, Bulzonetti N1, Caiazzo R1, Musio D1, Tombolini V1,2 1

Correspondence to: Francesca De Felice

Department of Radiotherapy, Policlinico Umberto I, “Sapienza” University of Rome,

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Viale del Policlinico 155, 00161 Rome, Italy Phone number: +390649973411 fax number: +390649973411 E-mail: [email protected]

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Department of Radiotherapy, Policlinico Umberto I “Sapienza” University of Rome, Viale del Policlinico 155, Rome, Italy. 2 Spencer-Lorillard Foundation Rome

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Intensified neoadjuvant chemoradiotherapy in elderly rectal cancer

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Conflict of interest statement None

ACCEPTED MANUSCRIPT MicroAbstract Trimodal treatment approach in elderly patients remains an hot topic in locally advanced rectal cancer patients. We investigated the intensified neoadjuvant chemoradiotherapy regimen. Results were encouraging, with good treatment tolerance, low severe toxicity rates and valid 5-year survival outcomes. Intensified neoadjuvant treatment could be proposed in elderly patients with locally advanced rectal cancer.

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Abstract Purpose. To report the treatment compliance, toxicity rates and long-term clinical outcomes of elderly patients treated with intensified neoadjuvant chemoradiotherapy (CRT) for locally advanced rectal cancer (LARC). Methods. We identified a retrospective cohort of patients aged 70 years and older with LARC who received intensified neoadjuvant CRT followed by surgery and adjuvant chemotherapy, between 2007 and 2014. Intensified neoadjuvant CRT consisted of radiotherapy (total dose 50.4/54 Gy) with concomitant oxaliplatin (50 mg/m2/week) and 5-fluorouracil (200 mg/m2/5 daily continuous infusion). Results. A total of 26 patients were included. All patients completed the programmed CRT. Severe acute toxicity was recorded in 19.2% of cases. Conservative surgery was performed in 16 patients and a pathological complete response was achieved in 19.2% of cases. Overall, 26.9% of patients died. The 5-year overall survival and disease free survival rates were 70.6% and 65.5%, respectively. Conclusions. Intensified neoadjuvant CRT is an efficacious and safe treatment option for LARC in elderly patients.

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Key words: Elderly; rectal cancer; oxaliplatin; neoadjuvant treatment; toxicity; compliance; survival.

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Introduction It has been well demonstrated that elderly patients are grossly underrepresented in clinical trials, with less than 10% of patients enrolled [1]. Although, over the past decade, rectal tumor incidence declines in ages ≥ 70 years, definitive clinical data to guide treatment decisions among those patients ages 70 years and older are scarce [2]. Generally, the gold standard therapy for locally advanced rectal cancer (LARC) is a trimodality approach, including neoadjuvant 5fluoropirimidine-based chemoradiotherapy (CRT) followed by surgery and adjuvant chemotherapy [3]. However it bears a distant metastasis of more than 30%. A recent meta-analysis suggests a significant clinical benefit in term of distant failure by adding oxaliplatin to standard fluoropirimidine-based CRT [4]. But, among the trials included, it was not possible to extrapolate patients age details, thus subsequent subset analysis was not performed. Definitive conclusions are still pending and further clinical data are paramount to better clarify the precise role of the intensified neoadjuvant approach, especially in elderly patients. We have realized the importance of analyzing the efficacy and toxicity of multimodal therapy in patients aged 70 years and older. This study was planned to understand treatment effects among elderly LARC patients.

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Methods Patient population. Cases originated from a cohort of LARC patients previously described [5]. We reviewed retrospectively the medical data of all consecutive elderly patients treated for LARC between 2007 and 2014 at our institute. The study was approved by the institutional review board and the scientific review committee (Prot. 464/16). All patients signed an informed consent before treatment. Only patients aged 70 years and older were included in the analysis. All patients had histologically proven rectal adenocarcinoma, clinically staged on endorectal ultrasound and totalbody contrast-enhanced computed tomography (CT) and/or pelvic magnetic resonance imaging (MRI) as T3-4 with or without positive regional lymph nodes and no evidence of distant metastases. To classify patients comorbidities, we used the adult comorbidity evaluation-27 (ACE-27) score, a 27-item validated comorbidity index [6]. Treatment protocol. All patients were treated with an intensified neoadjuvant treatment. Details were described in our previous study [7]. Briefly, RT was delivered with a 3D-conformational multiple field technique at a total dose of 45 Gy (1.8 Gy/fraction) to the whole pelvis, plus 5.4 to 9 Gy (1.8 Gy/fraction) to the tumor volume, with 6 to 15 MV energy photons. Concomitant chemotherapy consisted of weekly oxaliplatin (50 mg/m2, day 1) and 5 daily continuous infusion of 5-fluoruracil (200 mg/m2/day) of each week of RT. Five weeks from the end of CRT, loco-regional clinical response was assessed by abdominal-pelvic CT and/or MRI, using response evaluation criteria in solid tumors (RECIST) guideline [8]. Surgery was planned 7–9 weeks after the end of CRT and its type was left to surgeon’s discretion. Type of adjuvant chemotherapy was chosen by the oncologist. Patient evaluation and follow-up. Toxicity was scored according to the common terminology criteria for adverse events, version 4.0 [9]. After treatment, all patients were monitored by physical examination and trans-rectal ultrasound every 3 months for 2 years, then every 6 months thereafter. Colonoscopy was proposed at 1 year after surgery and then annually. To monitor the presence of potentially local recurrence and distant metastasis, both total body CT and pelvic MRI were recommended annually for up 5 years after CRT. Statistical analysis. Statistical analysis was carried out using R-Studio 0.98.1091 software. Standard descriptive statistics were used to evaluate the distribution of each variable. Continuous variables were presented as medians and ranges, and dichotomous variables were presented as percentages.

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Overall survival (OS) and disease-free survival (DFS) were calculated in months from the date of the end of CRT to the first event, including date of the last follow-up or death (OS) and/or relapse (DFS). pCR was defined as the absence of any residual tumor cells detected in the operative specimen, including the primary tumor area, the whole mesorectal fat and the resected lymph nodes. Patient follow-up was updated to a minimum of at least 2 years. OS and DFS were estimated by the Kaplan-Meier method and survival curves were compared by the log-rank test. Based on their ACE-27 score (0 or ≥1) patients were divided in two groups. Treatment compliance, incidence of toxicity and survival outcomes were compared with Fisher’s test (‫ܨ‬-test) between ACE-27 score = 0 versus ACE-27 score ≥ 1. All reported p values are 2 sided, and p values lower than 0.05 were considered significant.

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Results Patient characteristics. In total 26 patients were included in the study. Patients and tumor characteristics are shown in Table 1. Median age at diagnosis was 74 years (range 70 – 76) and an ACE-27 score ≥ 1 was recorded in 17 patients. The vast majority of patients (n = 24, 92.3%) had regional lymph node involvement at diagnosis. Treatment compliance. All patients completed the programmed CRT. All patients received the RT prescribed total dose. RT was interrupted for acute toxicity in 5 patients (19.2%). Of these, only 1 patient suspended chemotherapy definitely after 3 cycles. Globally, 85% of patients (n = 22) achieved chemotherapy protocol compliance and received 5 (n = 16; 61.5%) or 6 cycles (n = 6; 23%) of OXP. After the end of CRT, a clinical complete response was noted in 6 patients (23%). Clinical tumor re-evaluation was stable in only 2 cases (7.7%). In total, 24 patients (92.3%) underwent surgery. One patient died before surgery and one patient with clinical complete response after CRT was submitted to a wait and see approach due to co-morbidities (ACE-27 score = 1). Conservative surgery was performed in 16 patients (low anterior resection in 10 cases, trans-anal endoscopic microsurgery in 2 cases, different surgical approach in 4 cases). Miles surgery was performed in 7 patients, thus permanent stoma represents only 29.2% of patients. One patient died during surgery. None had positive radial margins. pCR was achieved in 5 cases (19.2%). Toxicity. All patients had acute toxicity associated with CRT. Incidence details are listed in Table 2. Gastrointestinal toxicity was the most common acute complication, and proctitis was the most frequent symptom (n = 18, 69.2%). Overall, severe acute toxicity was recorded in 19.2% of cases (n = 5). No hematologic acute toxicity has been observed. Late CRT treatment-related toxicity was assessed and involved the following conditions: dermatitis (n = 1), proctitis (n = 6), fecal incontinence (n = 2) and venous thrombotic events (n = 3). Late surgical treatment complication was recorded in one patient and clinically it consists in anastomitic fistula. Survival outcomes. Follow-up data were updated in May 2017. At the date of analysis, 7 patients (26.9%) were dead, 16 patients (61.6 %) were alive and 3 patients (11.5%) were lost for follow-up. The 2- and 5- year OS rates were 86.9% (95% CI 0.643 - 0.956) and 70.6% (95% CI 0.454 - 0.858), respectively. Whereas, the 2- and 5-year DFS were estimated at 70.6% (95% CI 0.466 - 0.849) and 65.5% (95% CI 0.423 - 0.813), respectively. Details are presented in Figure 1. Local recurrence was recorded in 2 patients (7.7%). Five patients (19.2%) presented distant metastasis: to liver (n = 2), lung (n = 2) or multiple sites (n = 1). ACE-27 score analysis. At baseline, 9 patients had an ACE-27 score of 0, 14 patients had an ACE27 score of 1 and 3 patients had an ACE-27 score of 2. Globally, the ACE-27 score had no influence on treatment tolerability (p = 0.81), as well as on severe acute toxicity onset (p = 0.46). Patients were assigned to two groups according to ACE-27 score equal to 0 or ≥ 1. The 5-year OS rate was 83.3% (95% CI 0.27 - 0.98) for patients with ACE-27 score = 0 and 64.7% (95% CI 0.34 0.84) with ACE-27 score ≥ 1 (p = 0.74). The 5-year DFS were 83.3% (95% CI 0.27 - 0.98) and 66.8% (95% CI 0.37 - 0.85) for ACE-27 = 0 and ACE-27 ≥ 1 patients, respectively (p = 0.70).

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Discussion This study demonstrates that infensified neoadjuvant CRT is efficacious and associated with low severe toxicity profile. We demonstrated important pCR rate (19.2%), considerable absence of permanent stoma (70.8%) and remarkable 5-year OS and DFS (70.6% and 65.5%, respectively). All patients had received the total prescribed radiotherapy dose and at least five cycles of oxaliplatin were administered to the vast majority of patients (85%). Increased comorbid conditions (ACE-27 score ≥ 1) were not associated with a poor treatment compliance, as well as a negative impact on survival. Currently, clinical data comparing intensified regimen versus standard CRT in geriatric population have not yet been published. Trials specifically designed to assess the impact of oxaliplatin-based CRT in elderly LARC patients would be very welcome. At present, we can only provide indirect comparison of treatments to resolve this issue. In fact, the benefit of neoadjuvant CRT was evaluated in several retrospective studies with disappointing results. Data from French and Italian series showed that neoadjuvant CRT in elderly LARC was a well tolerated treatment, without any significant increase in acute and late toxicities [10-12]. Whereas, Margalit et al. and Cai et al. experiences demonstrated a treatment deviation from the programmed therapy course in the vast majority of patients, suggesting that CRT should be performed with caution in elderly patients [1314]. Guimas et al [15] made similar observations in their study that included 56 elderly patients. Even though globally grade ≥ 3 acute toxicity was recorded in 14.3 % of cases, they noticed an increase in morbidity in the case of the addition of oxaliplatin to standard CRT. Globally, the real impact on clinical outcomes is difficult to quantify, due to studies heterogeneity, especially in term of chemotherapy regimens, radiotherapy dosage and follow-up period. No clear evidenced resulted in prolonging overall and disease-free survival, as well in rate of pCR. However, in our study, the rate of pCR was 19.2%, comparable to the 17% found in the CAO/ARO/AIO-04 German trial – the only one randomized trial that demonstrated a survival benefit following addition of oxaliplatin in LARC [16]. It must be pointed out that the ACCORD12/PRODIGE2 intergroup collected age-related information from their phase III study, in which they compared neoadjuvant fluoropirimidine-based CRT with dose-intensified radiotherapy plus capecitabine and oxaliplatin [17]. In order to explore response and tolerance profile in elderly patients, they performed a subgroup analysis and divided entire patients population into two groups by age: < 70 years (n = 442) and ≥ 70 years (n = 142). Globally, treatment efficacy (pCR 16.9% versus 14.7%), as well as postoperative complications (27.6% versus 27.6%) and 3-year OS (90.7% versus 80.5%) were similar between the two age categories, whereas tolerance was lower in elderly patients. A higher incidence of non-hematologic grade ≥ 3 toxicity was observed in patients ≥ 70 years compared with younger patients (13.6% vs. 21.1%, p = 0.03). In our study, we observed the same acute toxicity trend (19.2%), but a lower surgical complications incidence and a superior treatment efficacy and survival rates. Obviously, the lack of direct comparison underpowered our analysis. Despite the little evidence to support the use of concomitant oxaliplatin in LARC patients, the question is how to consider elderly patients in daily clinical practice, with only limited evidencebased medicine to support decision making. We promote the enrollment of elderly patients into our intensified neoadjuvant setting experience mainly to offer a possible basis for potentially practicechanging conclusions. Recently the international society of geriatric oncology (SIOG) declared the urgently need of guidelines to support radiation oncologists, surgeons and medical oncologists in the treatment of older patients [18]. Although debatable because not adequately powered, our results could provide a rationale for the intensified neoadjuvant CRT use in elderly LARC patient population, even in the absence of a clear survival benefit. Patient pre-existing comorbidities do not costly treatment-related hospitalizations. Additionally, there was no a significant increase in acute and late complications. The choice of chemotherapy regimen intensification was associated with

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high pCR rate and survival. Thus, the addition of oxaliplatin to the standard 5-fluoruracil-based CRT treatment seems to provide clinical benefits, regardless of age and comorbidity. Oxaliplatin seems appropriate and does not limit its applicability in elderly patients. Surely, these patients should be treated in specialized centers where the expertise can guarantee the most favorable treatment care. This study has a number of potential limitations. It is a retrospective analysis with a modest number of patients, limiting its statistical power. However, this is the first long-term follow-up analysis showing oncologic outcomes in elderly LARC patients treated with intensified neoadjuvant CRT. Only few patients were lost at follow up and therefore results were not negatively affected. For sure, it should recognize that these results are primarily hypothesis-generating. A tailored multicenter trial should be designed in order to ensure the adequacy of analysis on the basis of age. Intensified neoadjuvant CRT could be considered a valid treatment option in the geriatric oncologic management. Although the trimodality strategy remains the standard of care, a more conservative approach such as local excision and a wait-and-see policy should be proposed in those elderly patients who have a favorable response (better if complete clinical/radiologic response) to preoperative CRT. However, more accurate investigations are needed.

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Conclusions Intensified neoadjuvant CRT is a safe treatment approach in elderly LARC patients. It provide an appropriate balance between toxicity risk and clinical outcome benefits. Its precise role in the management of LARC elderly patients remains to be defined.

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Acknowledgments None

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Clinical Practice Points • Rectal cancer is a common malignancy, with an increase in cases occurring in elderly patients. • In randomized clinical trials, patients older than 70 years are usually underrepresented. • The optimal treatment approach is currently a matter of debate in elderly patients with locally advanced rectal cancer (LARC). • On the basis of the improved life expectancy, the neoadjuvant cheoradiotherapy (CRT), based on oxaliplatin and 5-fluoruracil, has been tested. • Intensified neoadjuvant CRT seems promising in elderly LARC patients.

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Chemoradiotherapy for Locally Advanced Rectal Cancer: A Single-Institution Experience. Clin Colorectal Cancer. 2016;15(2):e17-22. 6. Piccirillo JF, Tierney RM, Costas I, Grove L, Spitznagel EL Jr. Prognostic importance of comorbidity in a hospital-based cancer registry. JAMA. 2004;291(20):2441-7. 7. Musio D, De Felice F, Bulzonetti N, Guarnaccia R, Caiazzo R, Bangrazi C, Raffetto N, Tombolini V. Neoadjuvant-intensified treatment for rectal cancer: time to change? World J Gastroenterol. 2013;19(20):3052-61. 8. Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 2009; 45:228-47. 9. Cancer Therapy Evaluation Program. Common terminology criteria for adverse events, version 4.0 2009, Available at: http://ctep.cancer.gov. Accessed: May 06, 2017. 10. Tougeron D, Roullet B, Paillot B, Hamidou H, Tourani JM, Bensadoun RJ, Michel P, Silvain C. Safety and outcome of chemoradiotherapy in elderly patients with rectal cancer: results from two French tertiary centres. Dig Liver Dis. 2012;44(4):350-4. 11. Ausili Cèfaro G, Genovesi D, Vinciguerra A, Augurio A, Di Tommaso M, Marchese R, Borzillo V, Tasciotti L, Taraborrelli M, Innocenti P, Colecchia G, Di Nicola M. Effects of preoperative radiochemotherapy with capecitabine for resectable locally advanced rectal cancer in elderly patients. Tumori. 2012;98(5):622-9. 12. De Felice F, Musio D, Izzo L, Pugliese F, Izzo P, Bolognese A, Tombolini V. Preoperative chemoradiotherapy in elderly patients with locally advanced rectal cancer. Biomed Res Int. 2013;2013:610786. 13. Margalit DN, Mamon HJ, Ancukiewicz M, Kobayashi W, Ryan DP, Blaszkowsky LS, Clark J, Willett CG, Hong TS. Tolerability of combined modality therapy for rectal cancer in elderly patients aged 75 years and older. Int J Radiat Oncol Biol Phys. 2011;81(5):e735-41. 14. Cai X, Wu H, Peng J, Zhu J, Cai S, Cai G, Zhang Z. Tolerability and outcomes of radiotherapy or chemoradiotherapy for rectal cancer in elderly patients aged 70 years and older. Radiat Oncol. 2013;8:86. 15. Guimas V, Boustani J, Schipman B, Lescut N, Puyraveau M, Bosset JF, Servagi-Vernat S. Preoperative Chemoradiotherapy for Rectal Cancer in Patients Aged 75 Years and Older: Acute Toxicity, Compliance with Treatment, and Early Results. Drugs Aging. 2016;33(6):419-25. 16. Rödel C, Liersch T, Becker H, Fietkau R, Hohenberger W, Hothorn T, Graeven U, Arnold D, Lang-Welzenbach M, Raab HR, Sülberg H, Wittekind C, Potapov S, Staib L, Hess C, WeigangKöhler K, Grabenbauer GG, Hoffmanns H, Lindemann F, Schlenska-Lange A, Folprecht G, Sauer R; German Rectal Cancer Study Group. Preoperative chemoradiotherapy and postoperative chemotherapy with fluorouracil and oxaliplatin versus fluorouracil alone in locally advanced rectal cancer: initial results of the German CAO/ARO/AIO-04 randomised phase 3 trial. Lancet Oncol. 2012;13(7):679-87. 17. François E, Azria D, Gourgou-Bourgade S, Jarlier M, Martel-Laffay I, Hennequin C, Etienne PL, Vendrely V, Seitz JF, Conroy T, Juzyna B, Gerard JP. Results in the elderly with locally advanced rectal cancer from the ACCOR12/PRODIGE 2 phase III trial: tolerance and efficacy. Radiother Oncol. 2014;110(1):144-9. 18. Papamichael D, Audisio RA, Glimelius B, de Gramont A, Glynne-Jones R, Haller D, Köhne CH, Rostoft S, Lemmens V, Mitry E, Rutten H, Sargent D, Sastre J, Seymour M, Starling N, Van Cutsem E, Aapro M. Treatment of colorectal cancer in older patients: International Society of Geriatric Oncology (SIOG) consensus recommendations 2013. Ann Oncol. 2015;26(3):46376.

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Characteristic Age (years) median (range) Gender male female Smoke yes no ACE-27 score 0 1 2 Clinical tumor stage (T) T1-2 T3 T4 Clinical nodal stage (N) N0 N1 N2 Location from anal verge < 6 cm 6 - 8 cm > 8 cm

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Table 1. Patient characteristics

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Acute toxicity G1-2 (%) G3-4 (%) Allergy immunology Allergic reaction hypersensitivity 1 (3.8) Constitutional symptoms Fatigue 4 (15.4) Fever 2 (7.7) Dermatology skin Rash desquamation 5 (19.2) 1 (3.8) Radiation dermatitis 4 (15.4) Gastrointestinal Constipation 4 (15.4) Diarrhoea 9 (34.6) 2 (7.7) Nausea/vomiting 3 (11.5) Proctitis 16 (61.5) 2 (7.7) Haemorrhage rectum 1 (3.8) Neurology Neuropahy: sensory 6 (23.1) Pain Abdominal pain or cramping 2 (7.7) 1 (3.8) Renal genitourinary Dysuria 6 (23.1) Urinary frequency 1 (3.8) Blood count Haemoglobin -

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Table 2. Acute toxicity

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Figure 1. Kaplan Meier curves of overall survival and disease-free survival

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