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doi   10.1700/1190.13204
Tumori 2012;98(5):622-629



Effects of preoperative radiochemotherapy with capecitabine for resectable locally advanced rectal cancer in elderly patients
Giampiero Ausili Cèfaro1, Domenico Genovesi1, Annamaria Vinciguerra1, Antonietta Augurio1, Monica Di Tommaso1, Rita Marchese1, Valentina Borzillo1, Lucia Tasciotti1, Maria Taraborrelli1, Paolo Innocenti2, Giuseppe Colecchia3, and Marta Di Nicola4
1Radiation Oncology Department, and 2Surgery Department, G. d’Annunzio University, Chieti; 3Surgery Department, Santo Spirito Hospital, Pescara; 4Laboratory of Biostatistics, Department of Biomedical Science, G d’Annunzio University, Chieti, Italy

Key words: rectal cancer, elderly patients, preoperative radiochemotherapy, capecitabine.

Conflict of interest statement: No financial or other relationships that might lead to a conflict of interest are present.

Correspondence to: Domenico Genovesi, MD, Radiation Oncology Department, G d’Annunzio University, SS Annunziata Hospital, Via dei Vestini, 66100, Chieti, Italy.
Tel +39-0871-358244;
fax +39-0871-357473;
email d.genovesi@unich.it

Received August 27, 2011;
accepted April 10, 2012.

abstract

Aims and background. Rectal cancer is a common disease of elderly people. However, patients over 70 years of age are often not included in clinical trials. There is a lack of data concerning the use of radiochemotherapy with capecitabine in elderly patients. The aim of this study was to retrospectively evaluate the impact of preoperative radiochemotherapy with capecitabine on downstaging and sphincter preservation and to assess treatment compliance and toxicity in elderly patients.
Methods. Twenty-six patients with resectable locally advanced rectal cancer (stage II-III/TNM) aged >70 years received preoperative radiotherapy and concurrent oral capecitabine 825 mg/m² twice daily during the whole period of radiotherapy. Two patients who refused surgery after chemoradiation therapy were excluded from the analysis.
Results. Eighty-one percent of patients underwent anterior resection and 18.1% underwent abdominoperineal resection. Overall tumor downstaging, considering both T and N categories, was observed in 18/24 patients (75%). Treatment compliance was good and toxicity rates were similar to those of younger people.
Conclusions. Age is not a contraindication to any therapy and elderly patients who can tolerate radiochemotherapy should be treated like younger patients. Preoperative radiochemotherapy with capecitabine for patients aged >70 years has a good impact on tumor downstaging, increases the feasibility of sphincter-preserving surgery, and is also safe and well tolerated.
Introduction
Rectal cancer is largely a disease of old age and two-thirds of rectal cancers occur in patients over 65 years of age1,2. The increase in cancer incidence, mainly due to the aging of the population and an improving mean life expectancy, has led to a major interest in elderly patients with rectal cancer. Nevertheless, there is little data about rectal cancer in older patients, in particular the very elderly rectal cancer population. This lack of data is primarily due to the fact that older patients are often excluded from clinical trials and treatment strategies for this population are extrapolated from trials conducted in young people 3. In addition, it should be noted that it is difficult to define “elderly patients” and 65-year-old patients are often arbitrarily defined as old4, regardless of a good or poor performance status.
Aging is often associated with a decline in basic activities and an increase in age-dependent diseases5,6 but it is also true that the majority of people aged ≥70 are less likely to be treated with standard care and are often undertreated independently of their performance status or comorbidities7.
The choice of the most appropriate treatment for cancer is difficult because many factors have to be considered in terms of benefits, life expectancy and toxicity. Surgery, chemotherapy and radiotherapy are the standard treatment modalities for locally advanced rectal cancer but there are several unsolved problems concerning the management of elderly people with rectal cancer.
Radical surgery includes procedures such as anterior resection, abdominoperineal resection, Hartmann’s procedure and pelvic exenteration8. Randomized trials demonstrated that preoperative radiotherapy was more efficient than postoperative radiotherapy because it improved local control by reducing local recurrence9-12. The use of preoperative radiotherapy with or without chemotherapy has been shown to have a strong potential in increasing sphincter-saving surgery10,13-15. Some studies showed that preoperative radiotherapy increased the overall survival in the pre-total mesorectal excision (TME) era9 but the survival advantage has not been proved in the TME era12,16.
The clinical benefit together with the feasibility and good tolerability profile of chemoradiation using 5-fluorouracil (5-FU) with or without other chemotherapy agents have been widely demonstrated for rectal cancer in both young and old patients17-22. In recent years, new oral fluoropyrimidines such as capecitabine have been used instead of 5-FU. It has been demonstrated that the pharmacokinetic action of capecitabine mimics that of intravenous 5-FU infusion and that capecitabine has a lower toxicity profile20-27. Some studies demonstrated its safety for elderly patients with rectal cancer, and capecitabine also has the advantage of oral administration28,29.
Most studies of preoperative radiochemotherapy with capecitabine have been performed in young patients and little or nothing is known about elderly people treated with radiochemotherapy with capecitabine followed by curative surgery.
This study was performed to evaluate the use of neoadjuvant radiochemotherapy with capecitabine, investigate the impact of preoperative radiochemotherapy on downstaging and sphincter preservation, and assess the compliance with and toxicity of treatment in elderly patients (>70 years) with locally advanced rectal cancer.
Materials and methods
Between 1 January 2004 and 31 December 2008, 220 patients with histologically proven locally advanced rectal cancer (stage II-III/TNM) were treated at the Radiation Oncology Department of the G. d’Annunzio University in Chieti, Italy. Eighty-eight percent of these patients (194/220) were treated with cisplatin 60 mg/m2 (days 1-29) and i.c. 5-FU 1000 mg/m2 (days 1-4 and 29-32) plus radiotherapy (50.4 Gy/1.8 Gy daily) (PLAFUR schedule). The remaining 12% (26/220), who were aged >70 years, were treated with neoadjuvant radiotherapy and capecitabine. The patients included in this analysis met the following inclusion criteria: clinical T3-T4 and/or N1-N3 M0 stage, no prior radiotherapy to the pelvis, Eastern Cooperative Oncology Group (ECOG) performance status 0-2; granulocyte count >3,000/µL, platelet count >100,000/µL, hemoglobin concentration >10 g/dL, creatinine value ≤1.5 mg/dL, creatinine clearance >65 mL/min, no major intercurrent diseases, adequate heart function and written informed consent. Two patients who refused surgery after chemoradiation therapy were not included in the analysis.
The 24 patients aged >70 years who made up the cohort of this study underwent a pretreatment workup including medical history, physical examination, blood examination, rigid proctoscopy and colonoscopy with tumor biopsy and thoracic/abdominal/pelvic contrast-enhanced multidetector-row CT. Clinical staging was based on CT evaluation and the American Joint Committee on Cancer TNM system was used for cancer staging30.
Information about comorbidity was gathered in an interview with the patient using the Cumulative Illness Rating Scale (CIRS), an index that considers the severity of each health problem31. CIRS consists of 14 questions related to different body systems (Table 1) covering systemic and behavioral-psychiatric disorders. Scoring on the different questions is weighted by the severity of the comorbid condition. Severity scores range from 0 to 4. A score of 0 indicates no medical burden in an organ system; a score of 1 indicates a mild burden; 2 indicates a moderate burden; 3 indicates a severe burden, and 4 indicates a rare degree of extremely severe burden. After completion of the CIRS scores for each patient, the mean overall CIRS score was calculated. We analyzed the results excluding from the calculation of the CIRS scores the rectal cancer that represented part of the same overall pathophysiological profile of the patients.



All patients were treated with radiotherapy and concurrent oral capecitabine (Xeloda, Roche, Seoul, Korea) 825 mg/m² twice daily during the whole period of radiotherapy without weekend breaks.
Tumor site was defined as low for tumors located within 5 cm from the anal verge, medium for tumors located between 6 and 10 cm from the anal verge, and high (or rectosigmoid junction tumor) for tumors between 10 and 16 cm from the anal verge. Rigid proctoscopy and colonoscopy were used to determine the distance from the anal verge.
Patients with rectal cancer located initially 3 cm or less from the anal verge were candidates for abdominoperineal resection while patients with rectal cancer located more than 3 cm from the anal verge were candidates for anterior resection, as judged by the surgeon. The surgical possibility to preserve the sphincter pre- and post-radiotherapy was analyzed by the surgeon in each patient.
After completion of chemoradiation, all patients underwent post-treatment restaging according to the same criteria as used for pretreatment staging. All rectal cancer patients underwent radical surgery with curative intent 6-8 weeks after the chemoradiation treatment.
Patients were followed at 3-month intervals for the first year and then at 6-month intervals the next 4 years. Subsequently, asymptomatic patients were followed once a year.
All patients received preoperative pelvic radiotherapy with a total dose of 50.4 Gy and a dose of 1.8 Gy per fraction. Treatment was given daily, 5 days per week for 5 weeks.
A 3-dimensional radiotherapy technique was used according to the recommendations of the International Commission on Radiation Units and Measurements (ICRU)32. All patients were treated with a 4-field technique (anterior-posterior, posterior-anterior and 2 lateral fields) and a beam energy of 10 MV. Patients were positioned with a full bladder and in the prone position on the up-down table device to displace the small bowel from the fields33.
The clinical target volume included the tumor, mesorectum, internal iliac lymph nodes and obturator lymph nodes with or without the external iliac nodes. The lateral border of the anteroposterior-posteroanterior fields was 1.5-2 cm outside the true bony pelvis; the lower border was 1 cm above the anal verge in patients with tumors of the middle rectum and just below the anal verge in patients with tumors of the lower rectum; the upper border was at least 2 cm above the tumor and not below the sacral promontory. The lateral border encompassed the external iliac lymph nodes in case of low tumor sites, positive external iliac nodes or T4 lesions.
During the course of radiation and chemotherapy treatment, patients were evaluated weekly to assess acute toxicity and compliance with the chemotherapy regimen. After the end of treatment, late effects were recorded at each follow-up examination. Acute toxicity was defined as adverse events occurring during treatment and up to 60 days after the end of radiotherapy. Late toxicity was defined as adverse events occurring after 60 days. Both acute and late toxicity were assessed according to the RTOG toxicity criteria.
Pathological downstaging was defined as any reduction of stage comparing clinical TNM (cTNM) to pathological TNM (ypTNM). Pathological response was evaluated according to the ypTNM and the tumor regression grade (TRG) Mandard score as follows: TRG1 (complete regression), absence of residual tumor cells; TRG2, presence of rare residual cancer cells and prominent fibrosis; TRG3, fibrosis outgrowing residual cancer cells; TRG4, residual cancer cells outgrowing fibrosis; and TRG5, absence of regression34. TRG1 was considered as complete response.
Tumor downstaging was assessed by comparing preoperative clinical stage with postoperative pathological stage and evaluating primary tumor and node reduction. Overall tumor downstaging was defined as a reduction of at least 1 level in both the T and N categories.
Results
The median follow-up was 24 months. Patient and tumor characteristics are shown in Table 2. The median age was 74 years (range 70-88 years). Sixty-nine percent of patients had hypertension and/or cardiovascular disease. All patients had one or more CIRS grade 1 or 2 comorbidities and the mean overall CIRS score was 2.8. The distribution of clinical stage, pathological stage and TRG is shown in Table 3. For 6 patients TRG was unknown because of the lack of histopathological data.
Overall tumor downstaging, considering both T and N categories, was observed in 18/24 patients (75%). Tumor downstaging was observed in 14/24 patients (58.3%) for the T category and in 23/24 patients (92.3%) for the N category. Four patients (16.6%) had no change in either T or N while 2 patients (8.3%) had tumor progression after treatment. Remarkably, a pathological complete response was observed in 16.6% of cases. Moreover, despite 7/24 patients (29.2%) had the presence of stenosis at diagnosis, no patient had a temporary stoma before radiochemotherapy treatment.
The mean tumor distance from the anal verge was 2.6 cm (range 0-10 cm). All patients but 2 had low rectal cancer located initially 3 cm or less from the anal verge. The 2 remaining patients had rectal cancer located 8 and 10 cm from the anal verge, respectively.




All patients underwent surgery by the TME procedure. The 2 patients with tumors located 8 and 10 cm from the anal verge and therefore candidates for sphincter-preserving surgery underwent anterior resection. Of the 22 patients with tumors located ≤3 cm from the anal verge and likely to require sphincter ablation according to previous data reported by surgeons, 81.8% underwent low anterior resection; the remaining 4 patients (18.1%) underwent abdominoperineal resection, including patients who were previously considered candidates for demolitive surgery.
Oral capecitabine was regularly administered and all patients completed the chemotherapy treatment as planned except for 1 patient in whom treatment was interrupted because of hematological toxicity. All patients reached the prescribed radiotherapy dose of 5040 cGy without interruption or prolongation of the overall treatment time except for 1 patient in whom the radiotherapy was stopped at 4680 cGy because of grade 3 (G3) skin toxicity.
Acute hematological toxicity was observed in 2 patients (8.4%), G1 in one case and G2 in the other, both leukopenia. No G3-G4 acute hematological toxicity was observed. Fifteen (62.5%) patients had acute gastrointestinal toxicity: 7/15 patients had G1 toxicity with minor diarrhea (≤2 times daily) without any need for therapy; 8/15 patients had G2 toxicity with moderate diarrhea (3-5 times daily) which resolved completely with mild antidiarrheal therapy. No G3-G4 acute gastrointestinal toxicity was observed. G2 acute genitourinary toxicity was observed in 1 patient while acute skin toxicity was observed in 17/24 patients (70.8%). Acute skin toxicity was mainly observed in patients with very low rectal cancer when the lower border of the radiation field was below the anal verge and the toxicity involved the intergluteal cleft. The distribution of acute toxicity is shown in Table 4.
G1 late hematological toxicity was observed in 1 patient while 10/24 patients (41.7%) had late gastrointestinal toxicity: G1 in 7/10 patients with mild diarrhea and mild cramping without any need for therapy; G2 in 2/10 patients with moderate diarrhea and colicky bowel movements >5 times daily, successfully treated with antidiarrheal therapy, and G3 in 1 patient with rectal bleeding, which was successfully treated with endoscopic ablation therapy. G1 late genitourinary toxicity was observed in 3/24 patients (12.5%) and G3 late genitourinary toxicity in 1 patient. The distribution of late toxicity is shown in Table 5.
Postoperative complications were observed in only 3 patients and all involved anastomotic leakage. Minor complications were observed in an additional 2 patients.
Although this study was performed to evaluate the impact of neoadjuvant capecitabine-based radiochemotherapy on tumor downstaging and sphincter preservation as well as treatment compliance and toxicity in elderly patients (>70 years), of the 24 patients analyzed only 1 patient died of cancer (cancer-specific survival at 24 months: 90 ± 9.5%) while 6 patients (25%) died of other causes (overall survival at 24 months: 73.6 ± 10.8%).






Discussion
It has been widely demonstrated that preoperative radiotherapy, especially in addition to chemotherapy, improves local disease control in patients with locally advanced rectal cancer9,10,12,13,35-37. Neoadjuvant chemoradiation therapy has become the standard of care in such patients38. It is also a valid treatment option to downstage the tumor and make sphincter-preserving procedures possible in more cases.
Several studies have analyzed the use of oral capecitabine and found that the administration of preoperative chemotherapy with radiotherapy was safe and well tolerated and that it had an important impact on downstaging39-46. Most of the recent studies demonstrated a pathological response rate ranging between 4% and 31% with preoperative capecitabine and radiotherapy10,39,41-44,47. In the present study we observed a complete pathological response rate of 16.6% and overall tumor downstaging of 75%.
The impact of radiochemotherapy on sphincter preservation and the downstaging rates shown in our study were similar to those observed in other studies in younger patients. Kim et al.44 in their prospective phase II trial analyzed 95 patients with locally advanced rectal cancer treated with preoperative concurrent radiotherapy and capecitabine. They obtained a complete pathological response rate of 12% and a downstaging rate of 71%. In the multicenter phase II study of De Paoli et al.41, the overall clinical response rate was 58% and the downstaging rate 57%, with a pathological complete response rate of 24% in patients with locally advanced rectal cancer treated with preoperative capecitabine and radiotherapy. Also De Bruin et al.42 analyzed 60 patients treated with preoperative chemoradiation with capecitabine and found that 25% of patients with an initial tumor location less than 5 cm from the anal verge had sphincter preservation. Moreover, a pathological complete response was achieved in 13% of patients while overall tumor and nodal downstaging was seen in 85% of patients.
Another recent analysis47 evaluated the efficacy and tolerability of preoperative chemoradiation with high-dose capecitabine in 15 patients with locally advanced resectable rectal cancer and found that 66% of patients were able to undergo sphincter-preserving surgery. A prospective phase II trial of capecitabine in neoadjuvant treatment of locally advanced resectable rectal cancer demonstrated a pathological complete response in 9.1% of patients and an overall downstaging rate of 49.1%, while the total sphincter-preservation rate was 65.5% 43. Most of these studies analyzed neoadjuvant chemoradiation with capecitabine in a population with a median age ranging from 55 to 67 years41-44. Our analysis has reviewed a population of rectal cancer patients with a median age of 74 years and treated with radiotherapy and capecitabine followed by curative surgery.
Some studies showed that both surgery and radiochemotherapy can be performed safely in the elderly and there is no age-related difference concerning survival for young and elderly patients. It has been also demonstrated that age per se is not a limiting factor for radical radiotherapy48.
A systematic review of 34,194 patients analyzed surgical outcome data from patients divided according to different age groups: younger than 65, 65-74, 75-84 and 85 years or older. The cancer-specific median 5-year survival rates were similar in all age groups for patients who underwent curative surgery49. Also Chiappa et al.50 showed that there was no difference in short-term and long-term outcomes between older and younger colorectal cancer patients after resection.
Several studies examined the clinical experience with chemotherapy, especially 5-FU-based, in elderly people but there is a lack of data regarding the association of preoperative radiotherapy and capecitabine in elderly patients51,52. Moreover, most of the studies that evaluated the association of neoadjuvant radiotherapy with chemotherapy in elderly patients with rectal cancer used different radiotherapy techniques and/or chemotherapy regimens, such as a short course of preoperative radiotherapy11,53,54.
It has been widely demonstrated that capecitabine has less toxicity than bolus treatment and also that most cancer patients preferred oral chemotherapy to intravenous treatment55. In their analysis of 45 patients treated with preoperative chemoradiation with capecitabine in locally advanced rectal cancer, Kim et al.39 saw no G3 or G4 hematological toxicity but observed G3 hand-foot syndrome in 7% of patients, fatigue in 4%, diarrhea in 4%, and radiation dermatitis in 2%.
Other phase II trials of neoadjuvant capecitabine with concurrent radiation have shown that treatment was well tolerated with no G4 toxicity while the most common G3 toxicities were lymphocytopenia (70%), radiation dermatitis (9%), proctitis (4%), neutropenia (2%), anemia (2%), fatigue (2%), and diarrhea (2%)56. Also De Bruin et al.42 in their study of preoperative chemoradiation with capecitabine observed only moderate toxicity with no hematological G3 or G4 toxicities but G2 anemia, leukocytopenia and neutropenia in 7%, 12% and 3% of patients, respectively.
Although with different regimens and doses, the retrospective analysis of Lorchel et al.57 analyzed the use of radiochemotherapy in elderly patients and found that 8/73 patients suffered from WHO grade 3 acute toxicity while no WHO grade 4 or 5 toxicity was observed.
Treatment compliance and tolerance were excellent in our analysis. No G4 toxicity was observed. Acute hematological toxicity was observed in a total of 2 (8.4%) patients. One patient had anemia and the other leukocytopenia. Only 1 patient suffered from G3 skin toxicity.
None of the patients who developed acute or late toxicity required hospitalization and most adverse effects were mild to moderate in intensity. All patients recovered spontaneously with supportive management. Although our study population was over 70 years of age, the overall toxicity profile was quite comparable to those observed in the above-mentioned studies, which included also younger patients.
The low rate of G3 toxicity may be due both to an ECOG performance status of 0-1 in more than 90% of patients and to an overall low comorbidity severity index as measured by CIRS. Usually at our institution we do not treat with preoperative chemoradiation patients of this age group with an ECOG performance status 2 and a comorbidity severity index >2. In the case of a comorbidity severity index of 3, patients are considered fit for the combined treatment only if there is only a single category of comorbidity present and no serious impairment of cardiovascular, hematological and renal function. An alternative therapeutic option for ineligible patients is radiotherapy alone.
The up-down table device to displace the small bowel from the radiation fields proved very useful in this study. In fact, the absolute volume of small bowel receiving ≥15 Gy was <120 cm3, contributing to minimizing severe acute and late toxicity.
Conclusions
An increasing number of rectal cancers have occurred in elderly patients in recent years because of the improving mean life expectancy. Nevertheless, there is a lack of data on the treatment of older patients with rectal cancer, especially concerning the use of preoperative radiochemotherapy with capecitabine. Age is not a contraindication to any therapy and patients aged >70 years who can tolerate radiochemotherapy should be treated like younger patients. This analysis has shown that preoperative radiochemotherapy with capecitabine for patients aged >70 years has a good impact on tumor downstaging; it also increases sphincter-preserving surgery and is safe and well tolerated. Neoadjuvant radiochemotherapy with capecitabine should be considered an effective treatment option to avoid local recurrence and also to improve survival in elderly rectal cancer patients.
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