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Oxaliplatin-based chemotherapy in the treatment of elderly patients with metastatic colorectal cancer (CRC)
Archives of Gerontology and Geriatrics 55 (2012) 271–275
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Oxaliplatin-based chemotherapy in the treatment of elderly patients with metastatic colorectal cancer (CRC) Massimiliano Berretta a,*, Ernesto Zanet a,b, Guglielmo Nasti c, Arben Lleshi a, Sergio Frustaci a, Francesco Fiorica d, Alessandra Bearz a, Renato Talamini e, Chiara Lestuzzi f, Renzo Lazzarini g, Rossella Fisichella b, Renato Cannizzaro h, Rosario Vincenzo Iaffaioli c, Salvatore Berretta b, Umberto Tirelli a a
Department of Medical Oncology, National Cancer Institute, IRCCS, Via Franco Gallini 2, I-33081 Aviano (PN), Italy Department of Surgery, University of Catania, Policlinico Universitario ‘‘G. Rodolico’’, Via S.Sofia 78, I-95123, Catania, Italy c Division of Medical Oncology B, Istituto Nazionale per lo Studio e la Cura dei Tumori ‘‘Fondazione Pascale’’, Via Mariano Semola, I-80131, Napoli, Italy d Division of Oncology Radiotherapy, Arcispedale S’Anna Universitary Hospital, C.so Giovecca 203, I-44100 Ferrara, Italy e Unit of Epidemiology and Biostatistics,, National Cancer Institute, IRCCS, Via Franco Gallini 2, I-33081 Aviano (PN), Italy f Division of Cardiology, National Cancer Institute, IRCCS, Via Franco Gallini 2, I-33081 Aviano (PN), Italy g Pharmacy Unit, Drug Information Centre, National Cancer Institute, IRCCS, Via Franco Gallini, 2, I-33081 Aviano (PN), Italy h Gastroenterology Unit, National Cancer Institute, IRCCS, Via Franco Gallini, 2, Aviano (PN), I-33081, Italy b
A R T I C L E I N F O
A B S T R A C T
Article history: Received 6 July 2011 Received in revised form 22 August 2011 Accepted 23 August 2011 Available online 19 September 2011
Elderly patients constitute a subpopulation with special clinical features that differ from those of the general population and are under-represented in clinical trials. We retrospectively analyzed the toxicity and efficacy of oxaliplatin-based chemotherapy in the treatment of elderly patients affected by metastatic (m) CRC. Seventy-five consecutive patients aged 65–75 years (median age 71 years), 51 males and 24 females, with mCRC and measurable disease, were analyzed. The primary site of metastases was the liver (38.6% of patients). The majority of patients had a performance status (PS) according to the Eastern Cooperative Oncology Group (ECOG) PS before treatment of 0–1 (96%). The overall response rate was 57.3%, median progression-free survival was 7 months and median overall survival was 27 months. The main hematological and extra-hematological toxicities (grade 3 or 4) were neutropenia (20.0%), and neurological toxicity or diarrhea (6.7%), respectively. No toxic death occurred. Oxaliplatin-based chemotherapy maintains its efficacy, and safety in elderly patients with mCRC and good PS. This regimen should be considered in the treatment of this particular setting of patients. ß 2011 Elsevier Ireland Ltd. All rights reserved.
Keywords: Colorectal cancer Cancer therapy in elderly Metastatic cancer Oxaliplatin
1. Introduction CRC is one of the most common malignancies and the second cause of cancer death in the US and most European countries. Its incidence has been increasing in the last decades, primarily as a consequence of the aging of the population (Hill and Doyon, 2007). In Europe more than 40% of new CRCs are diagnosed in patients older than 75 years (Gatta et al., 1998). Given the great number of elderly patients affected by CRC, it is important to assess systemically their management with modern chemotherapeutic regimens. Most of these patients will need a cytotoxic therapy, either as adjuvant treatment to primary surgery or for palliative reasons.
* Corresponding author. Tel.: +39 0434 659 724; fax: +39 0434 659 531. E-mail address: [email protected] (M. Berretta). 0167-4943/$ – see front matter ß 2011 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.archger.2011.08.016
However, there is still uncertainty regarding to what extent systemic chemotherapy should be offered to elderly patients with CRC. This fact is related to the unfortunate under-representation or even exclusion of elderly patients from clinical trials and also to the total lack of studies in unfit elderly patients (Folprecht et al., 2004). Noteworthy, elderly patients are characterized by frequent incidence of age-related co-morbidities such as impaired renal, cardiac, and liver function, general decline in health, loss of autonomy, and cognitive impairment that may impact the therapeutic decision (Mahoney et al., 2000; Extermann et al., 2003). Fluoropyrimidines have long been the backbone of therapy for advanced CRC. At this time, there is little debate that 5-fluorouracil (5-FU) based regimens improve outcomes, including response rates (RRs), progression free-survival (PFS), and overall survival (OS) in mCRC compared to best supportive care, even among the elderly population (Au et al., 2003; Honecker et al., 2003). Moreover, some investigators observed that elderly patients with
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good PS could tolerate adjuvant and palliative chemotherapy as well as younger patients (Berretta et al., 2008; Chiara et al., 1998; Popescu et al., 1999) with no increased toxicity, particularly when a continuous infusion 5-FU regimen was used (Feliu et al., 2005). New more active drugs, like irinotecan and oxaliplatin, have been recently introduced into the treatment of colon cancer and only lately some authors have reported their use in elderly patients (Comella et al., 2005; Kim et al., 2005; Sastre et al., 2005; Goldberg et al., 2006; Rosati and Cordio, 2006; Berretta et al., 2008, 2011). In particular, oxaliplatin and 5-FU have a synergistic activity both in vitro and in vivo studies against colon cancer cells (De Gramont et al., 1997; Raymond et al., 1998). In recent years, several regimens with oxaliplatin in combination with leucovorin and 5FU in continuous infusion have been developed (De Gramont et al., 1997, 2000; Andre´ et al., 1998, 1999; Maindrault-Goebel et al., 1999), such as FOLFOX-2 and FOLFOX-4. The overall results suggest at least a similar activity in older patients, in comparison to the general population, though there are conflicting results regarding the toxicities in elderly patients. In particular, hematologic and oxaliplatin-induced neurotoxicity (particularly among diabetics) are of main concern (Mattioli et al., 2005; Goldberg et al., 2006; Figer et al., 2007). We report our experience on the use of chemotherapy in elderly patients with mCRC. In particular, in this study we explore feasibility and safety of oxaliplatin-based chemotherapy in our cohort of mCRC elderly patients, and we report data on treatment response, toxicity and survival.
ECG, chest radiograph and abdominal CT were performed before treatment start. During the treatment, blood counts were performed on day 7 of the first two cycles, and then at the beginning of each following cycle, together with blood chemistry. Tumor response studies were performed every 6 cycles or earlier in case of clinical deterioration.
2. Patients and methods
3. Results
2.1. Patients selection
Between March 1993 and March 2009, 75 patients were enrolled in the study. All patients were assessable for toxicity and antitumoral activity. Baseline patient characteristics are listed in Table 1. The majority of patients were male (68%). Median patient age was 71 years (range 65–85). The majority of patients had an ECOG PS before treatment of 0–1 (96%), and more than half had only one metastatic location. At diagnosis 34.7% of patients had stage D disease, 45.3% had stage C disease and 20% A–B Dukes stage. Liver was interested by metastases in 38.6% of the patients, lung in 26.7% of the patients, liver and lung, together, in 26.7% of
From September 1998 to March 2009, 75 consecutive patients affected by metastatic adenocarcinoma of the colon or rectum (histologically confirmed), with adequate organ functions (defined as less than two times upper normal values of internal ranges), absence of major chronic diseases, bi-dimensionally measurable metastases evaluated by Computed Tomography (CT) scans) and ECOG PS < 2, were considered eligible for this study. The median age was of 71 years (range 65–85). 2.2. Treatment schedule Chemotherapy treatment was administered according to FOLFOX-4 regimen (leucovorin 200 mg/m2/day in a 2-h infusion, followed by bolus 5-FU 400 mg/m2/day and 5-FU 600 mg/m2/day, in a 22-h infusion, days 1 and 2, every 2 weeks, plus oxaliplatin 85 mg/m2 in a 2-h infusion without prior mixing on day 1. Cycles were repeated at 2-week intervals) or FOLFOX-2 regimen (oxaliplatin 100 mg/m2 as a 2-h infusion on day 1, leucovorin 500 mg/m2 as a 2-h infusion on days 1 and 2 followed by 5-FU 1.5 g/m2 as 22-h infusion for 2 consecutive days. Cycles were repeated at 2-week intervals). Treatment was maintained until either disease progressed or unacceptable toxicity appeared. Patients received antiemetic prophylaxis as routine practice of each participating center. The prophylactic use of colony-stimulating factors was not allowed. The treatment was reduced to 75% of the calculated dose when hematological toxicity greater than G3 occurred. 2.3. Evaluation during the study At baseline, patients underwent a clinical history and physical examination, blood counts, liver and kidney function tests and evaluation of electrolyte concentrations, and prothrombine time.
2.4. Evaluation of efficacy and toxicity Tumor response was evaluated by investigators according to the response evaluation criteria in solid tumors (RECIST) (Therasse et al., 2000) at 3-month intervals until the disease progression or patient death. Toxicity was evaluated at the beginning of each cycle using the National Cancer Institute Common Toxicity criteria scale, version 2.0. 2.5. Statistical analysis The PFS and OS times were calculated from the start of treatment until documentation of disease progression or death, respectively. Data on RRs are expressed as the proportion of responders (complete response and partial response) in relation to all the other categories (stable disease, progressive disease and not classified). Survival analyses were calculated according to Kaplan– Meier method (Kaplan and Meier, 1958) and differences between subgroups were assessed by means of the log-rank test (Mantel, 1966). In all cases, statistical significance was claimed as p < 0.05 (two-sided) (Armitage and Berry, 1987).
Table 1 Clinical features of the 75 patients with mCRC. Characteristics Sex Male Female Age (years) Median (range) Dukes’ stage A+B C D Primary tumor Colon Rectum PS 0 1 2 Reduction dose (%) Never 75% Sites of metastasis Liver Lung Liver and lung Others
n (%) 51 (68.0) 24 (32.0) 71 (65–85) 15 (20.0) 34 (45.3) 26 (34.7) 74 (98.7) 1 (1.3) 43 (57.3) 29 (38.7) 3 (4.0) 58 (77.3) 17 (22.7) 29 20 20 6
(38.6) (26.7) (26.7) (8.0)
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the patients. Forty percent of the patients had received adjuvant chemotherapy with fluorouracil plus leucovorin or oral fluoropyrimidines. 3.1. Treatment compliance A total of 712 chemotherapy courses were administered. Seventeen patients (22.7%) received 75% of the planned treatment because of G3 persistent neutropenia. 3.2. Safety The hematological and non-hematological toxicities of the patients are listed in Table 2. The main hematological toxicity was grade 3–4 neutropenia in 20.0% of patients. Among nonhematological toxicities neurological toxicity and diarrhea were the more frequent with grade 3–4 occurring in 6.7% of patients. No deaths due to toxicity occurred.
Fig. 1. Overall survival probability of 75 elderly patients with colon cancer.
3.3. Response to treatment The 75 patients included in the study were considered assessable for response. Complete response was achieved in 18 patients (24%), and partial response was achieved in 25 patients (33.3%) for a total overall response rate of 57.3%. Disease response was assessed by CT scan after six cycles. Eighteen patients achieved disease stabilization. Consequently, 81.3% of all patients included in the study obtained disease control. 3.4. Survival analysis Figs. 1 and 2 show overall survival and time to progression curves. After a median follow-up of 27 months (1–124 months) at the time of analysis, only one patient is alive. The median PFS was 7.0 months (range 1–37), and the median overall survival time was 27 months (range 1–124) (Figs 1 and 2, respectively). 3.5. Prognostic factors An analysis of prognostic factors affecting survival (including sex, initial ECOG PS, location of metastases, Dukes stage, and dose chemotherapy reduction) was performed. Only Dukes stage at CRC diagnosis significantly influenced survival (x2 = 33.82; p < 0.0001).
Table 2 Hematological and non-hematological toxicity based on WHO criteria of 75 patients with mCRC. WHO grade Thrombocytopenia G0 G1–G2 G3–G4 Neutropenia G0 G1–G2 G3–G4 Nausea and vomiting G0 G1–G2 G3–G4 Diarrhea G0 G1–G2 G3–G4 Neurological G0 G1–G2 G3–G4
n (%) 57 (76.0) 14 (18.7) 4 (5.3) 39 (52.0) 21 (28.0) 15 (20.0) 55 (73.3) 19 (25.3) 1 (1.4) 46 (61.3) 24 (32.0) 5 (6.7) 51 (68.0) 19 (25.3) 5 (6.7)
Fig. 2. PS probability of 68 elderly patients with CCR.
4. Discussion Chronologic age has been a major barrier for clinicians to offer the best treatment modalities to elderly population. However, chronologic age does not always correspond to real physiologic age. Aging is characterized by presence of co-morbidities such as diabetes, cardiovascular disease and by the development of physiologic changes in all organs which will affect how a chemotherapeutic agent is absorbed, metabolized and eliminated. However, increasing chronologic age does not equate to a uniform decline in physiologic reserve of all systems in all individuals. Elderly population is not homogenous in health status: some are healthy, while others are extremely frail, affected by one or more co-morbid diseases that may influence treatment tolerance. It’s important to notice that elderly patients are under-represented in clinical trials, but also that the few included share a good performance status, are highly functional and independent. Data obtained from this selected studies cannot be extended to general population, without rough approximations. CRC is one of the most common cancers in Europe, just following to lung cancer (Ferlay et al., 2007). The median age of presentation is in the seventh decade of life, and approximately the 30–40% of the patients is 75 years or older. With the aging of the population, it is expected that CRC becomes more common in older individuals. In spite of the magnitude of the problem, the treatment of CRC in elderly patients remains a challenge. Notably, elderly patients are less treated with chemotherapy, both in adjuvant and palliative setting, than general population (Schrag et al., 2001). This trend may be attributed to (1) few data on safety and feasibility of chemotherapy in CRC elderly patients that are often excluded from studies; (2) concerns about toxic effects of drugs influencing
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Table 3 Published data about oxaliplatin-based chemotherapy in elderly patients. Reference
Setting
Regimen
Median age (yrs)
ORR (%)
Comella et al. (2005) Kim et al. (2005) Goldberg et al. (2006) Figer et al. (2007) Berretta et al. (2008) Rosati et al. (2009) Sastre et al. (2009) Berretta et al. (2011)
m m Adj + m m m m m m
XELOX FOLFOX4 FOLFOX4 FOLFOX FOLFOX2 XELOX vs. XELIRI FUOX vs. XELOX FOLFOX4
75 75 73 77 73 75 73 72
41 43.8 59.4 55 38 34.9; 38 44.4
ORR: overall response rate; Adj: adjuvant; m: metastatic.
quality of life; (3) presence of multiple co-morbidities that may influence the treatment tolerance. Palliative chemotherapy remains the mainstay of treatment for patients with non-resectable or mCRC. Systemic chemotherapy may prolong survival, decreases tumor-related symptoms, improves general wellbeing or maintains it for a longer period of time when compared with the best supportive care. Several studies have shown that elderly patients obtain a similar benefit than younger patients (Berardi et al., 2005; Goldberg et al., 2006; Folprecht et al., 2008; Power and Lichtman, 2010). Moreover, overall available data suggests that toxicity does not seem to show different patterns in patients over and under 70 years (Comella et al., 2005; Feliu et al., 2005; Sastre et al., 2005; Figer et al., 2007). Some authors demonstrated a 5-FU mediated greater grade 3–4 toxicity in patients aged above 70 years (58% vs. 36%, p = 0.001) (Stein et al., 1995), whereas others have not been able to confirm this finding (Ko¨hne et al., 2002). This difference could be explained by the dosing schedule, with bolus administration associated to increased hematological toxicity versus less toxic infusion 5-FU schedule. Moreover, several regimens based on high-dose continuous and bolus 5-FU and oxaliplatin were developed by De Gramont et al. (1997), and were characterized by interesting response rates and acceptable toxicities (De Gramont et al., 1997, 2000). More recently, many authors have reported the safety and the efficacy of oxaliplatin-based chemotherapy in the treatment of CRC (both adjuvant and palliative setting) elderly patients (Table 3) (Comella et al., 2005; Kim et al., 2005; Goldberg et al., 2006; Figer et al., 2007; Berretta et al., 2008, 2011; Rosati et al., 2009; Sastre et al., 2009). Initial studies (De Gramont et al., 2000) reported an increase of gastrointestinal toxicity in patients older than 65 years of age with FOLFOX regimen and a small but significant increase in G3–G4 neutropenia and thrombocytopenia; but this has not been confirmed by later trials (Goldberg et al., 2006; Figer et al., 2007; Sastre et al., 2009). Furthermore, a reduction in the rate of these toxicities has been achieved remaining similar efficacy (Mattioli et al., 2005; Tournigand et al., 2006) through several modifications in the FOLFOX regimen (fractionated oxaliplatin or dose reduction) or the association with neuroprotective agents. In this study, we investigated activity and safety of oxaliplatinbased chemotherapy in the treatment of mCRC elderly patients. We can summarize our results as follows. First, we obtained a complete response in 18 patients (24.0%) and a partial response in 25 patients (33.3%) for a total overall response rate of 57.3%. This outcome translated in a median PFS of 7 months and a median overall survival time of 27 months. These results are similar to those reported in the literature (Table 3) and suggest that combination chemotherapy should not be denied to elderly patients who have been selected carefully on the basis of PS and comorbidities, and who are willing to receive curative treatment for their cancer.
Second, among analyzed prognostic factors (including sex, initial ECOG PS, location of metastases, Dukes stage, dose chemotherapy reduction) only Dukes stage at CRC diagnosis significantly influenced survival (x2 = 33.82; p < 0.0001), similarly to general population. Third, the main G3–G4 hematological toxicity was neutropenia (15 patients, 20%), while G3–G4 neurological toxicity and diarrhea (non-hematological) occurred both in 5 patients only (6.7%). Moreover, no patient was admitted to the hospital because of toxicity and no toxic deaths occurred. Fourth, it is to point out that the patients included into this study are a subpopulation of elderly patients characterized by their good PS and free from the typical geriatric syndromes. As a consequence, our data corroborating the safety and feasibility of oxaliplatin-based chemotherapy in advanced CRC elderly patients should be extended with caution to the entire elderly population. Moreover, we hardly encourage studies including less fit and frail patients that represent a large part of elderly population affected by cancer. In conclusion, chronologic age should not be a limiting factor for the decision-making process for patients with advanced CRC who are considering treatment with oxaliplatin-based chemotherapy. However, elderly patients should be individually examined for PS, the presence or absence of comorbid medical conditions, independence in activities of daily living and carefully assessed as concerns relative risks and benefits for treatment. Our data add to those in the literature that support the use of adequate chemotherapy for elderly patients in good clinical conditions. Careful monitoring for toxicity and rapid intervention with supportive care measures when toxicity occurs is also mandatory, particularly in elderly patients. Conflict of interest statement None. Acknowledgement The authors thank Mrs. Paola Favetta, for her expert assistance in the preparation and correction of the manuscript. References Andre´, T., Bensmaine, M.A., Louvet, C., Francois, E., Lucas, V., Desseigne, F., Beerblock, K., Bouche´, O., Carola, E., Merrouche, Y., Morvan, F., Dupont-Andre´, G., De Gramont, A., 1999. Multicenter phase II study of bimonthly high-dose leucovorin, fluorouracil infusion and oxaliplatin for metastatic colorectal cancer resistant to the same leucovorin and fluorouracil regimen. J. Clin. Oncol. 17, 3560–3568. Andre´, T., Louvet, C., Raymond, E., Tournigand, C., De Gramont, A., 1998. Bimonthly high-dose leucovorin, 5-fluorouracil infusion and oxaliplatin (FOLFOX3) for metastatic colorectal cancer resistant to the same leucovorin and 5-fluorouracil regimen. Ann. Oncol. 9, 1251–1253. Armitage, P., Berry, G., 1987. Statistical Methods in Medical Research. Blackwell Sci. Publication, London.
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Oxaliplatin-based chemotherapy in the treatment of elderly patients with metastatic colorectal cancer (CRC) Massimiliano Berretta a,*, Ernesto Zanet a,b, Guglielmo Nasti c, Arben Lleshi a, Sergio Frustaci a, Francesco Fiorica d, Alessandra Bearz a, Renato Talamini e, Chiara Lestuzzi f, Renzo Lazzarini g, Rossella Fisichella b, Renato Cannizzaro h, Rosario Vincenzo Iaffaioli c, Salvatore Berretta b, Umberto Tirelli a a
Department of Medical Oncology, National Cancer Institute, IRCCS, Via Franco Gallini 2, I-33081 Aviano (PN), Italy Department of Surgery, University of Catania, Policlinico Universitario ‘‘G. Rodolico’’, Via S.Sofia 78, I-95123, Catania, Italy c Division of Medical Oncology B, Istituto Nazionale per lo Studio e la Cura dei Tumori ‘‘Fondazione Pascale’’, Via Mariano Semola, I-80131, Napoli, Italy d Division of Oncology Radiotherapy, Arcispedale S’Anna Universitary Hospital, C.so Giovecca 203, I-44100 Ferrara, Italy e Unit of Epidemiology and Biostatistics,, National Cancer Institute, IRCCS, Via Franco Gallini 2, I-33081 Aviano (PN), Italy f Division of Cardiology, National Cancer Institute, IRCCS, Via Franco Gallini 2, I-33081 Aviano (PN), Italy g Pharmacy Unit, Drug Information Centre, National Cancer Institute, IRCCS, Via Franco Gallini, 2, I-33081 Aviano (PN), Italy h Gastroenterology Unit, National Cancer Institute, IRCCS, Via Franco Gallini, 2, Aviano (PN), I-33081, Italy b
A R T I C L E I N F O
A B S T R A C T
Article history: Received 6 July 2011 Received in revised form 22 August 2011 Accepted 23 August 2011 Available online 19 September 2011
Elderly patients constitute a subpopulation with special clinical features that differ from those of the general population and are under-represented in clinical trials. We retrospectively analyzed the toxicity and efficacy of oxaliplatin-based chemotherapy in the treatment of elderly patients affected by metastatic (m) CRC. Seventy-five consecutive patients aged 65–75 years (median age 71 years), 51 males and 24 females, with mCRC and measurable disease, were analyzed. The primary site of metastases was the liver (38.6% of patients). The majority of patients had a performance status (PS) according to the Eastern Cooperative Oncology Group (ECOG) PS before treatment of 0–1 (96%). The overall response rate was 57.3%, median progression-free survival was 7 months and median overall survival was 27 months. The main hematological and extra-hematological toxicities (grade 3 or 4) were neutropenia (20.0%), and neurological toxicity or diarrhea (6.7%), respectively. No toxic death occurred. Oxaliplatin-based chemotherapy maintains its efficacy, and safety in elderly patients with mCRC and good PS. This regimen should be considered in the treatment of this particular setting of patients. ß 2011 Elsevier Ireland Ltd. All rights reserved.
Keywords: Colorectal cancer Cancer therapy in elderly Metastatic cancer Oxaliplatin
1. Introduction CRC is one of the most common malignancies and the second cause of cancer death in the US and most European countries. Its incidence has been increasing in the last decades, primarily as a consequence of the aging of the population (Hill and Doyon, 2007). In Europe more than 40% of new CRCs are diagnosed in patients older than 75 years (Gatta et al., 1998). Given the great number of elderly patients affected by CRC, it is important to assess systemically their management with modern chemotherapeutic regimens. Most of these patients will need a cytotoxic therapy, either as adjuvant treatment to primary surgery or for palliative reasons.
* Corresponding author. Tel.: +39 0434 659 724; fax: +39 0434 659 531. E-mail address: [email protected] (M. Berretta). 0167-4943/$ – see front matter ß 2011 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.archger.2011.08.016
However, there is still uncertainty regarding to what extent systemic chemotherapy should be offered to elderly patients with CRC. This fact is related to the unfortunate under-representation or even exclusion of elderly patients from clinical trials and also to the total lack of studies in unfit elderly patients (Folprecht et al., 2004). Noteworthy, elderly patients are characterized by frequent incidence of age-related co-morbidities such as impaired renal, cardiac, and liver function, general decline in health, loss of autonomy, and cognitive impairment that may impact the therapeutic decision (Mahoney et al., 2000; Extermann et al., 2003). Fluoropyrimidines have long been the backbone of therapy for advanced CRC. At this time, there is little debate that 5-fluorouracil (5-FU) based regimens improve outcomes, including response rates (RRs), progression free-survival (PFS), and overall survival (OS) in mCRC compared to best supportive care, even among the elderly population (Au et al., 2003; Honecker et al., 2003). Moreover, some investigators observed that elderly patients with
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good PS could tolerate adjuvant and palliative chemotherapy as well as younger patients (Berretta et al., 2008; Chiara et al., 1998; Popescu et al., 1999) with no increased toxicity, particularly when a continuous infusion 5-FU regimen was used (Feliu et al., 2005). New more active drugs, like irinotecan and oxaliplatin, have been recently introduced into the treatment of colon cancer and only lately some authors have reported their use in elderly patients (Comella et al., 2005; Kim et al., 2005; Sastre et al., 2005; Goldberg et al., 2006; Rosati and Cordio, 2006; Berretta et al., 2008, 2011). In particular, oxaliplatin and 5-FU have a synergistic activity both in vitro and in vivo studies against colon cancer cells (De Gramont et al., 1997; Raymond et al., 1998). In recent years, several regimens with oxaliplatin in combination with leucovorin and 5FU in continuous infusion have been developed (De Gramont et al., 1997, 2000; Andre´ et al., 1998, 1999; Maindrault-Goebel et al., 1999), such as FOLFOX-2 and FOLFOX-4. The overall results suggest at least a similar activity in older patients, in comparison to the general population, though there are conflicting results regarding the toxicities in elderly patients. In particular, hematologic and oxaliplatin-induced neurotoxicity (particularly among diabetics) are of main concern (Mattioli et al., 2005; Goldberg et al., 2006; Figer et al., 2007). We report our experience on the use of chemotherapy in elderly patients with mCRC. In particular, in this study we explore feasibility and safety of oxaliplatin-based chemotherapy in our cohort of mCRC elderly patients, and we report data on treatment response, toxicity and survival.
ECG, chest radiograph and abdominal CT were performed before treatment start. During the treatment, blood counts were performed on day 7 of the first two cycles, and then at the beginning of each following cycle, together with blood chemistry. Tumor response studies were performed every 6 cycles or earlier in case of clinical deterioration.
2. Patients and methods
3. Results
2.1. Patients selection
Between March 1993 and March 2009, 75 patients were enrolled in the study. All patients were assessable for toxicity and antitumoral activity. Baseline patient characteristics are listed in Table 1. The majority of patients were male (68%). Median patient age was 71 years (range 65–85). The majority of patients had an ECOG PS before treatment of 0–1 (96%), and more than half had only one metastatic location. At diagnosis 34.7% of patients had stage D disease, 45.3% had stage C disease and 20% A–B Dukes stage. Liver was interested by metastases in 38.6% of the patients, lung in 26.7% of the patients, liver and lung, together, in 26.7% of
From September 1998 to March 2009, 75 consecutive patients affected by metastatic adenocarcinoma of the colon or rectum (histologically confirmed), with adequate organ functions (defined as less than two times upper normal values of internal ranges), absence of major chronic diseases, bi-dimensionally measurable metastases evaluated by Computed Tomography (CT) scans) and ECOG PS < 2, were considered eligible for this study. The median age was of 71 years (range 65–85). 2.2. Treatment schedule Chemotherapy treatment was administered according to FOLFOX-4 regimen (leucovorin 200 mg/m2/day in a 2-h infusion, followed by bolus 5-FU 400 mg/m2/day and 5-FU 600 mg/m2/day, in a 22-h infusion, days 1 and 2, every 2 weeks, plus oxaliplatin 85 mg/m2 in a 2-h infusion without prior mixing on day 1. Cycles were repeated at 2-week intervals) or FOLFOX-2 regimen (oxaliplatin 100 mg/m2 as a 2-h infusion on day 1, leucovorin 500 mg/m2 as a 2-h infusion on days 1 and 2 followed by 5-FU 1.5 g/m2 as 22-h infusion for 2 consecutive days. Cycles were repeated at 2-week intervals). Treatment was maintained until either disease progressed or unacceptable toxicity appeared. Patients received antiemetic prophylaxis as routine practice of each participating center. The prophylactic use of colony-stimulating factors was not allowed. The treatment was reduced to 75% of the calculated dose when hematological toxicity greater than G3 occurred. 2.3. Evaluation during the study At baseline, patients underwent a clinical history and physical examination, blood counts, liver and kidney function tests and evaluation of electrolyte concentrations, and prothrombine time.
2.4. Evaluation of efficacy and toxicity Tumor response was evaluated by investigators according to the response evaluation criteria in solid tumors (RECIST) (Therasse et al., 2000) at 3-month intervals until the disease progression or patient death. Toxicity was evaluated at the beginning of each cycle using the National Cancer Institute Common Toxicity criteria scale, version 2.0. 2.5. Statistical analysis The PFS and OS times were calculated from the start of treatment until documentation of disease progression or death, respectively. Data on RRs are expressed as the proportion of responders (complete response and partial response) in relation to all the other categories (stable disease, progressive disease and not classified). Survival analyses were calculated according to Kaplan– Meier method (Kaplan and Meier, 1958) and differences between subgroups were assessed by means of the log-rank test (Mantel, 1966). In all cases, statistical significance was claimed as p < 0.05 (two-sided) (Armitage and Berry, 1987).
Table 1 Clinical features of the 75 patients with mCRC. Characteristics Sex Male Female Age (years) Median (range) Dukes’ stage A+B C D Primary tumor Colon Rectum PS 0 1 2 Reduction dose (%) Never 75% Sites of metastasis Liver Lung Liver and lung Others
n (%) 51 (68.0) 24 (32.0) 71 (65–85) 15 (20.0) 34 (45.3) 26 (34.7) 74 (98.7) 1 (1.3) 43 (57.3) 29 (38.7) 3 (4.0) 58 (77.3) 17 (22.7) 29 20 20 6
(38.6) (26.7) (26.7) (8.0)
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the patients. Forty percent of the patients had received adjuvant chemotherapy with fluorouracil plus leucovorin or oral fluoropyrimidines. 3.1. Treatment compliance A total of 712 chemotherapy courses were administered. Seventeen patients (22.7%) received 75% of the planned treatment because of G3 persistent neutropenia. 3.2. Safety The hematological and non-hematological toxicities of the patients are listed in Table 2. The main hematological toxicity was grade 3–4 neutropenia in 20.0% of patients. Among nonhematological toxicities neurological toxicity and diarrhea were the more frequent with grade 3–4 occurring in 6.7% of patients. No deaths due to toxicity occurred.
Fig. 1. Overall survival probability of 75 elderly patients with colon cancer.
3.3. Response to treatment The 75 patients included in the study were considered assessable for response. Complete response was achieved in 18 patients (24%), and partial response was achieved in 25 patients (33.3%) for a total overall response rate of 57.3%. Disease response was assessed by CT scan after six cycles. Eighteen patients achieved disease stabilization. Consequently, 81.3% of all patients included in the study obtained disease control. 3.4. Survival analysis Figs. 1 and 2 show overall survival and time to progression curves. After a median follow-up of 27 months (1–124 months) at the time of analysis, only one patient is alive. The median PFS was 7.0 months (range 1–37), and the median overall survival time was 27 months (range 1–124) (Figs 1 and 2, respectively). 3.5. Prognostic factors An analysis of prognostic factors affecting survival (including sex, initial ECOG PS, location of metastases, Dukes stage, and dose chemotherapy reduction) was performed. Only Dukes stage at CRC diagnosis significantly influenced survival (x2 = 33.82; p < 0.0001).
Table 2 Hematological and non-hematological toxicity based on WHO criteria of 75 patients with mCRC. WHO grade Thrombocytopenia G0 G1–G2 G3–G4 Neutropenia G0 G1–G2 G3–G4 Nausea and vomiting G0 G1–G2 G3–G4 Diarrhea G0 G1–G2 G3–G4 Neurological G0 G1–G2 G3–G4
n (%) 57 (76.0) 14 (18.7) 4 (5.3) 39 (52.0) 21 (28.0) 15 (20.0) 55 (73.3) 19 (25.3) 1 (1.4) 46 (61.3) 24 (32.0) 5 (6.7) 51 (68.0) 19 (25.3) 5 (6.7)
Fig. 2. PS probability of 68 elderly patients with CCR.
4. Discussion Chronologic age has been a major barrier for clinicians to offer the best treatment modalities to elderly population. However, chronologic age does not always correspond to real physiologic age. Aging is characterized by presence of co-morbidities such as diabetes, cardiovascular disease and by the development of physiologic changes in all organs which will affect how a chemotherapeutic agent is absorbed, metabolized and eliminated. However, increasing chronologic age does not equate to a uniform decline in physiologic reserve of all systems in all individuals. Elderly population is not homogenous in health status: some are healthy, while others are extremely frail, affected by one or more co-morbid diseases that may influence treatment tolerance. It’s important to notice that elderly patients are under-represented in clinical trials, but also that the few included share a good performance status, are highly functional and independent. Data obtained from this selected studies cannot be extended to general population, without rough approximations. CRC is one of the most common cancers in Europe, just following to lung cancer (Ferlay et al., 2007). The median age of presentation is in the seventh decade of life, and approximately the 30–40% of the patients is 75 years or older. With the aging of the population, it is expected that CRC becomes more common in older individuals. In spite of the magnitude of the problem, the treatment of CRC in elderly patients remains a challenge. Notably, elderly patients are less treated with chemotherapy, both in adjuvant and palliative setting, than general population (Schrag et al., 2001). This trend may be attributed to (1) few data on safety and feasibility of chemotherapy in CRC elderly patients that are often excluded from studies; (2) concerns about toxic effects of drugs influencing
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Table 3 Published data about oxaliplatin-based chemotherapy in elderly patients. Reference
Setting
Regimen
Median age (yrs)
ORR (%)
Comella et al. (2005) Kim et al. (2005) Goldberg et al. (2006) Figer et al. (2007) Berretta et al. (2008) Rosati et al. (2009) Sastre et al. (2009) Berretta et al. (2011)
m m Adj + m m m m m m
XELOX FOLFOX4 FOLFOX4 FOLFOX FOLFOX2 XELOX vs. XELIRI FUOX vs. XELOX FOLFOX4
75 75 73 77 73 75 73 72
41 43.8 59.4 55 38 34.9; 38 44.4
ORR: overall response rate; Adj: adjuvant; m: metastatic.
quality of life; (3) presence of multiple co-morbidities that may influence the treatment tolerance. Palliative chemotherapy remains the mainstay of treatment for patients with non-resectable or mCRC. Systemic chemotherapy may prolong survival, decreases tumor-related symptoms, improves general wellbeing or maintains it for a longer period of time when compared with the best supportive care. Several studies have shown that elderly patients obtain a similar benefit than younger patients (Berardi et al., 2005; Goldberg et al., 2006; Folprecht et al., 2008; Power and Lichtman, 2010). Moreover, overall available data suggests that toxicity does not seem to show different patterns in patients over and under 70 years (Comella et al., 2005; Feliu et al., 2005; Sastre et al., 2005; Figer et al., 2007). Some authors demonstrated a 5-FU mediated greater grade 3–4 toxicity in patients aged above 70 years (58% vs. 36%, p = 0.001) (Stein et al., 1995), whereas others have not been able to confirm this finding (Ko¨hne et al., 2002). This difference could be explained by the dosing schedule, with bolus administration associated to increased hematological toxicity versus less toxic infusion 5-FU schedule. Moreover, several regimens based on high-dose continuous and bolus 5-FU and oxaliplatin were developed by De Gramont et al. (1997), and were characterized by interesting response rates and acceptable toxicities (De Gramont et al., 1997, 2000). More recently, many authors have reported the safety and the efficacy of oxaliplatin-based chemotherapy in the treatment of CRC (both adjuvant and palliative setting) elderly patients (Table 3) (Comella et al., 2005; Kim et al., 2005; Goldberg et al., 2006; Figer et al., 2007; Berretta et al., 2008, 2011; Rosati et al., 2009; Sastre et al., 2009). Initial studies (De Gramont et al., 2000) reported an increase of gastrointestinal toxicity in patients older than 65 years of age with FOLFOX regimen and a small but significant increase in G3–G4 neutropenia and thrombocytopenia; but this has not been confirmed by later trials (Goldberg et al., 2006; Figer et al., 2007; Sastre et al., 2009). Furthermore, a reduction in the rate of these toxicities has been achieved remaining similar efficacy (Mattioli et al., 2005; Tournigand et al., 2006) through several modifications in the FOLFOX regimen (fractionated oxaliplatin or dose reduction) or the association with neuroprotective agents. In this study, we investigated activity and safety of oxaliplatinbased chemotherapy in the treatment of mCRC elderly patients. We can summarize our results as follows. First, we obtained a complete response in 18 patients (24.0%) and a partial response in 25 patients (33.3%) for a total overall response rate of 57.3%. This outcome translated in a median PFS of 7 months and a median overall survival time of 27 months. These results are similar to those reported in the literature (Table 3) and suggest that combination chemotherapy should not be denied to elderly patients who have been selected carefully on the basis of PS and comorbidities, and who are willing to receive curative treatment for their cancer.
Second, among analyzed prognostic factors (including sex, initial ECOG PS, location of metastases, Dukes stage, dose chemotherapy reduction) only Dukes stage at CRC diagnosis significantly influenced survival (x2 = 33.82; p < 0.0001), similarly to general population. Third, the main G3–G4 hematological toxicity was neutropenia (15 patients, 20%), while G3–G4 neurological toxicity and diarrhea (non-hematological) occurred both in 5 patients only (6.7%). Moreover, no patient was admitted to the hospital because of toxicity and no toxic deaths occurred. Fourth, it is to point out that the patients included into this study are a subpopulation of elderly patients characterized by their good PS and free from the typical geriatric syndromes. As a consequence, our data corroborating the safety and feasibility of oxaliplatin-based chemotherapy in advanced CRC elderly patients should be extended with caution to the entire elderly population. Moreover, we hardly encourage studies including less fit and frail patients that represent a large part of elderly population affected by cancer. In conclusion, chronologic age should not be a limiting factor for the decision-making process for patients with advanced CRC who are considering treatment with oxaliplatin-based chemotherapy. However, elderly patients should be individually examined for PS, the presence or absence of comorbid medical conditions, independence in activities of daily living and carefully assessed as concerns relative risks and benefits for treatment. Our data add to those in the literature that support the use of adequate chemotherapy for elderly patients in good clinical conditions. Careful monitoring for toxicity and rapid intervention with supportive care measures when toxicity occurs is also mandatory, particularly in elderly patients. Conflict of interest statement None. Acknowledgement The authors thank Mrs. Paola Favetta, for her expert assistance in the preparation and correction of the manuscript. References Andre´, T., Bensmaine, M.A., Louvet, C., Francois, E., Lucas, V., Desseigne, F., Beerblock, K., Bouche´, O., Carola, E., Merrouche, Y., Morvan, F., Dupont-Andre´, G., De Gramont, A., 1999. Multicenter phase II study of bimonthly high-dose leucovorin, fluorouracil infusion and oxaliplatin for metastatic colorectal cancer resistant to the same leucovorin and fluorouracil regimen. J. Clin. Oncol. 17, 3560–3568. Andre´, T., Louvet, C., Raymond, E., Tournigand, C., De Gramont, A., 1998. Bimonthly high-dose leucovorin, 5-fluorouracil infusion and oxaliplatin (FOLFOX3) for metastatic colorectal cancer resistant to the same leucovorin and 5-fluorouracil regimen. Ann. Oncol. 9, 1251–1253. Armitage, P., Berry, G., 1987. Statistical Methods in Medical Research. Blackwell Sci. Publication, London.
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