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Keywords:

  • Locally advanced colon cancer;
  • neoadjuvant treatment;
  • stage III colon cancer

Abstract

  1. Top of page
  2. Abstract
  3. What is new in this paper?
  4. Introduction
  5. Method
  6. Results
  7. Discussion
  8. Acknowledgements
  9. Author contributions
  10. Conflict of interest
  11. References

Aim

Preoperative chemotherapy followed by radical surgery is an attractive treatment for locally advanced colon cancer (LACC) given the promising results of this approach in other locally advanced tumours. The study evaluates the outcome and treatment-related complications of perioperative oxaliplatin- and capecitabine-based chemotherapy and surgery for clinical Stage III colon cancer.

Method

Twenty-two consecutive patients with a CT-staged LACC were included. All were staged at baseline and before surgery. Surgery-related complications and oncological outcome were determined.

Results

Toxicity was manageable, with 19/22 patients completing the planned chemotherapy protocol. The median time from initial diagnosis to surgery was 65.5 days. The median time from the end of chemotherapy to surgery was 22 days. After neoadjuvant treatment, tumour reduction of 69.5% was observed by CT scan and a 59.9% decrease of SUVmax (standard uptake value) was achieved on positron emission tomography/CT. No progressive disease was reported during preoperative chemotherapy and surgery was performed in all 22 patients. Four patients developed postoperative complications. After a median postoperative follow-up of 14.4 months, the actuarial overall and disease-free survival rates were 100 and 90%.

Conclusion

Neoadjuvant chemotherapy followed by surgery and chemotherapy for LACC is safe without apparent increase of early and medium-term complications.


What is new in this paper?

  1. Top of page
  2. Abstract
  3. What is new in this paper?
  4. Introduction
  5. Method
  6. Results
  7. Discussion
  8. Acknowledgements
  9. Author contributions
  10. Conflict of interest
  11. References

This study reports our preliminary experience of patients with locally advanced colon cancer treated with oxaliplatin- and capecitabine-based perioperative chemotherapy followed by surgery with a focus on the initial diagnostic work-up, the response to the neoadjuvant strategy and the incidence of postoperative complications.

Introduction

  1. Top of page
  2. Abstract
  3. What is new in this paper?
  4. Introduction
  5. Method
  6. Results
  7. Discussion
  8. Acknowledgements
  9. Author contributions
  10. Conflict of interest
  11. References

Colon cancer is the fourth most common cause of cancer death [1]. The presence of lymph node involvement without distant metastases is classified as Stage III disease and it is clinically known as locally advanced colon cancer (LACC) [2]. Locally complete removal of the tumour by surgery (R0 resection) followed by adjuvant chemotherapy is the currently accepted standard of care in LACC, with 5-year survival rates ranging from 73.1% for Stage IIIA to 12.9% for Stage IIIC [2-5]. These data indicate the failure of this treatment to eradicate regional spread and distant micrometastases, with the subsequent risk of disease relapse.

Preoperative (‘neoadjuvant’) chemotherapy is used to treat locally advanced disease in several tumours, including those of the stomach, pancreas, breast and rectum, and this approach may also be applicable to LACC [6, 7]. Tumour response to neodjuvant therapy is a known prognostic parameter that has been correlated with the risk of local and distant failure [8, 9]. Despite several theoretical benefits there is limited experience of the use of neoadjuvant chemotherapy in LACC. Preliminary data from randomized trials have been reported and mature results are eagerly awaited [10-12].

The present study aims to evaluate the efficacy, toxicity profile and compliance of perioperative chemotherapy and surgery in patients with LACC.

Method

  1. Top of page
  2. Abstract
  3. What is new in this paper?
  4. Introduction
  5. Method
  6. Results
  7. Discussion
  8. Acknowledgements
  9. Author contributions
  10. Conflict of interest
  11. References

The study included 22 consecutive patients with clinical Stage III colon cancer scheduled to receive perioperative chemotherapy and surgery within a colorectal multidisciplinary unit in a tertiary centre (Clínica Universidad de Navarra, Spain) between 1 July 2009 and 30 September 2010. The study protocol was approved by the local institutional review board committee and the AEMPS (Agencia Española de Medicamentos y Productos Sanitarios). All patients gave informed signed consent before entry into the trial.

Initial clinical staging was performed in all cases by colonoscopy with biopsy confirmation, tumour marker estimation and whole-body CT scan. In the last nine patients, a whole-body 18fluorodesoxiglucose (18FDG) positron emission tomography/computed tomography (PET-CT) scan (Biograph DUO®, Siemens/CTI, Knoxville, Tennessee, USA) was performed. A dual-time study was implemented, with delayed images after 2 h of 18FDG injection, to evaluate the glucose consumption in an attempt to distinguish between tumour and inflammation.

Eligibility criteria included age over 18 years, a histologically confirmed diagnosis of adenocarcinoma of the colon, Karnofsky performance status >60% or ECOG performance status < 2, haemoglobin >10 g/dl, white blood cells > 3.0 × 109/l, glomerular filtration rate > 50 ml/min, total bilirubin < 25 μmol/l, absence of serious medical comorbidity, and the ability to provide written informed consent. In addition, radiological signs of extramural depth invasion and/or suspicious lymph nodes by CT-scanning, absence of distant metastases and potential resectability were required.

Exclusion criteria included tumours within 15 cm of the anal verge determined by sigmoidoscopy, or below the level of the sacral promontory, as judged by imaging, evidence of distant metastases or peritoneal carcinomatosis by CT or PET/CT scan, colonic obstruction without prior defunction or stent, and the presence of serious medical comorbidity that may prevent neoadjuvant therapy and/or surgery.

Study protocol

All patients received four cycles of oxaliplatin 85 mg/m2 infused over 2 h plus oral capecitabine (1000 mg/m2 orally, twice daily, on days 1–7, on a biweekly basis). A CT or PET-CT scan was performed at baseline and before surgery to assess tumour response, by calculating the differences in tumour volume by CT scan and maximum standard uptake value (SUVmax) by PET-CT.

Three to 4 weeks after finishing chemotherapy patients underwent surgery. The type of surgical procedure was based on the initial clinical staging, regardless of the tumour status after chemotherapy. Histological tumour stages (pTNM) and grades of differentiation (G1–G3) were determined according to guidelines established by the AJCC Cancer Staging Manual [2].

Postoperative complications were defined as any clinical condition that required a prolonged hospital stay or any deviation from the normal postoperative course. Definition of anastomotic leakage included the presence of contrast extravasation in a CT or contrast enema and/or the diagnosis of a pelvic abscess. Postoperative ileus was diagnosed when a nasogastric tube was required or reintroduced after the fifth postoperative day. Operative mortality was defined as death occurring within the first 30 postoperative days or during the same hospital stay after the surgical procedure.

Four weeks after surgery, patients were scheduled to receive four cycles of adjuvant oxaliplatin–capecitabine chemotherapy. Follow-up included physical examination, CEA estimation, CT scan every 4 months and yearly colonoscopy. Additional tests were performed if considered necessary.

Statistical analysis

All the statistical analyses were done using the spss/pc v.15 for Windows statistical package (SPSS, Chicago, Illinois, USA). Results were expressed as median (range) for continuous variables and proportion for qualitative variables. Disease-free survival (DFS), overall survival (OS) and after-relapse survival were studied by Kaplan–Meier method analysis and described as percentage of cumulative survival.

Results

  1. Top of page
  2. Abstract
  3. What is new in this paper?
  4. Introduction
  5. Method
  6. Results
  7. Discussion
  8. Acknowledgements
  9. Author contributions
  10. Conflict of interest
  11. References

Patients

Between 1 July 2009 and 30 September 2010, 22 patients with LACC were treated. The median age was 63 (42–80) years and 17 (77%) were men. Thirteen (59.1%) were American Society of Anesthesiologists (ASA) grade II and nine (40.9%) were ASA III. The median body mass index was 26.3 (20–35.6) kg/m2. Eleven (50%) patients had an associated comorbidity.

All but one patient (95.5%) completed the planned neoadjuvant treatment. The toxicity profile of the chemotherapy regimen is summarized in Table 1. One patient had an asymptomatic pulmonary embolism, another a deep venous thrombosis and a third patient had a urinary tract infection with pyelonephritis. After completion of neoadjuvant chemotherapy the median haemoglobin and platelets were 11.4 g/dl and 190 × 109/l and the median white cell count was 5.5 × 109/l. The median time between the beginning of chemotherapy and surgery was 65.5 (47–73) days and the median time between finishing chemotherapy and surgery was 22 (15–29) days.

Table 1. Neoadjuvant chemotherapy toxicity profile
 Grade 1Grade 2Grade 3Grade 4
n % n % n % n %
  1. HFS, hand–foot syndrome.

Asthenia1463.6627.300
Leucopenia1150.014.500
Neutropenia0313.3418.10
Thrombocytopenia522.714.500
Nausea836.314.500
Vomiting313.3000
Diarrhoea313.3940.914.50
Asthenia731.8836.300
Neurotoxicity1359.1313.300
HFS29.1000
Stomatitis14.5000

A radiological response and a fall of tumour markers were achieved in all patients (Table 2). No progressive disease was observed during the preoperative treatment. The response in two patients is shown in Figure 1.

Table 2. Clinical response to neoadjuvant chemotherapy based on volume modification by CT (22 patients), and SUV modification by positrion emission tomography (nine patients)
 Volume before chemotherapyVolume after chemotherapy% of volume modification
= 22 patients, median (range)53 cm3 (12.8–235)15.3 cm3 (0–39.7)–69.5% (23–100)
 SUVmax before chemotherapySUVmax after chemotherapy% of SUVmax modification
  1. SUV, standard uptake value.

n = 9 patients, median (range)19.5 (11.7–45)6.9 (0–17.3)–59.9% (28.6–100)
Table 3. Histopathological characteristics after chemotherapy in 22 patients determined from examination of the operative specimen
 n (%)
  1. a

    Median (range).

Pathological stage
pT2N03 (13.6)
pT3N011 (50)
pT4N01 (4.5)
pT3N11 (4.5)
pT3N2a5 (22.7)
pT4aN21 (4.5)
Median number of resected nodesa19 (6–49)
Median number of involved nodesa0 (0–11)
Lymphovascular invasion7/22 (31.8)
Perineural invasion4/22 (18.8)
Histological grade
 Low1 (4.5)
 Medium17 (77.3)
 High4 (18.2)
image

Figure 1. The primary tumour before (a) and after (b) chemotherapy in two patients.

Download figure to PowerPoint

Postoperative complications

All patients underwent surgery after preoperative chemotherapy, most (59%) by a laparoscopic approach. Left hemicolectomy was performed in 14 (64%) and an extended right colectomy in eight (36%) patients. Only one patient required an intra-operative blood transfusion. During the postoperative course, four (18%) developed surgical complications including anastomotic leakage (= 2) requiring a second operation, abdominal bleeding (= 1) requiring laparotomy and postoperative ileus (= 1). The median duration of the operation was 180 (98–354) min, the median hospital stay was 6 (4–31) days and the 30-day mortality was zero.

Histopathology

Histopathological examination of the operative specimen showed Stage II in 12 (54.5%) and Stage III in 7 (32%) patients. Lymphovascular invasion or perineural invasion were observed in seven and four patients, respectively. Three patients had Stage I (pT2N0) disease. The median number of harvested nodes was 19 (6–49) and disease-free resection margins were obtained in all cases (Table 3).

Postoperative outcome

Postoperative adjuvant chemotherapy was given to all but three patients. One did not receive the treatment due to an osteoporotic vertebral fracture and two because of surgical complications (anastomotic leakage and abdominal bleeding). At a median interval of 14.4 months from surgery, the actuarial overall and disease-free survival were 100 and 90.9%, respectively. One patient, with a pT3N2b tumour and lymphovascular and perineural invasion, developed liver metastases 9.5 months after surgery. This was resected and the patient is currently free of relapse. Another patient had a pT3N1 tumour with lymphovascular invasion and developed retroperitoneal recurrence 10.8 months after surgery that required chemoradiation.

Discussion

  1. Top of page
  2. Abstract
  3. What is new in this paper?
  4. Introduction
  5. Method
  6. Results
  7. Discussion
  8. Acknowledgements
  9. Author contributions
  10. Conflict of interest
  11. References

The present study suggests that perioperative chemotherapy in a selected group of patients with LACC is safe and well tolerated without added major postoperative-related complications. Neoadjuvant treatment was capable of inducing major tumour regression determined by imaging, and may have an impact on the long-term outcome.

Since the final analysis of mature data from the MOSAIC trial [13] several randomized phase III studies evaluating the efficacy of the most promising agents in the management of metastatic colorectal cancer have yielded consistently disappointing results [14, 15]. Of note, there is no benefit in adding cetuximab [16] or bevacizumab [17] to a FOLFOX regimen for Stage III LACC. In view of these data, and considering the poor pathological response rate achieved with the incorporation of targeted therapies into neoadjuvant schedules for the management of locally advanced rectal cancer, we decided to select a chemotherapy regimen without a monoclonal antibody. Several potential advantages have been advocated for preoperative neoadjuvant chemotherapy including early administration of systemic chemotherapy to decrease the risk of progression of micrometastases, avoidance of the delay to chemotherapy owing to surgical complications that would affect the start of postoperative chemotherapy [18-23], and increase in resectability through tumour regression, making a laparoscopic approach more likely. Neoadjuvant therapy may also provide an in vivo chemosensitivity assay that may be useful in the choice of postoperative treatments. In this study a median interval of 22 days between the end of chemotherapy and surgery was obtained, and > 50% of the patients with a previously bulky tumour could be operated using a laparoscopic approach.

The most important question is how to select patients with LACC suitable for a neoadjuvant strategy. The accuracy of imaging is critical. Twelve patients in the study had a Stage II (pT3/T4 N0) and three had a Stage I (pT2 N0) tumour. Although the promising results reported in this trial may be partly attributed to overtreatment of the disease rather than to a downsizing effect of preoperative chemotherapy, several studies have suggested that CT scanning is able to identify high-risk colon cancer (T3–T4) with minimal overstaging of T1–T2 tumours [24]. Only 7% of T2N0 tumours in the FOXTROT trial were misclassified. In contrast the ability to predict nodal status is poor, with a sensitivity of 68% and a specificity of 42%. Although the size of lymph nodes has been the most frequently used criterion for diagnosing nodal positivity, more reliable features with proper validation for N staging are clearly needed. In a recent trial, Huh et al. evaluated the prognostic value of preoperative CT staging in 536 LACC patients [25]. When radiological and pathological stages were compared, the overall accuracy was 79.1 and 73.3% for T and N stages, respectively. Importantly, the radiological T and N classification was an independent predictor of both overall survival and disease-free survival. Whether the use of PET-CT will provide useful information in the selection process remains to be determined [26].

The present study also shows that administration of neoadjuvant therapy in LACC patients is safe with excellent tolerance to chemotherapy. More than 95% of patients completed neoadjuvant treatment and were completely recovered by the time of surgery. All patients were able to receive the planned number of cycles of adjuvant therapy without any major chemotherapy-related complication in line with the accepted quality of colon cancer surgery [19]. Although the follow-up in this trial is short, preliminary survival times seem promising. Only two relapses have been reported, both in lymph-node-positive cases giving a disease-free survival rate of 90.9%. Clearly, however, a longer follow-up is needed to make any meaningful conclusion.

Limitations

Unlike other recent studies testing the role of preoperative neoadjuvant chemotherapy, a control group is lacking and the sample size is small. Nevertheless, the data add to the growing body of evidence suggesting the feasibility of neoadjuvant chemotherapy for selected patients with LACC. Although the initial oncological outcome seems promising, longer follow-up is necessary to determine the true overall survival rate.

Our data show that neoadjuvant chemotherapy in selected patients with LACC is safe and well tolerated. Moreover, this approach is able to induce major tumour regression in a great proportion of patients while the incidence of postoperative complications does not seem to be increased. On the basis of the current findings, neoadjuvant chemotherapy may be an alternative in the management of patients with LACC.

Acknowledgements

  1. Top of page
  2. Abstract
  3. What is new in this paper?
  4. Introduction
  5. Method
  6. Results
  7. Discussion
  8. Acknowledgements
  9. Author contributions
  10. Conflict of interest
  11. References

The authors would like to thank Sara Calvo Rosenstone and Isabel de Salas for help in editing the manuscript.

Author contributions

  1. Top of page
  2. Abstract
  3. What is new in this paper?
  4. Introduction
  5. Method
  6. Results
  7. Discussion
  8. Acknowledgements
  9. Author contributions
  10. Conflict of interest
  11. References

HJL, PC, BJ and RJ contributed to study conception and design; GI and VC contributed to acquisition of data, CA, AJ and JL contributed to analysis and interpretation of data and AJ, PC and RJ wrote the manuscript. All the authors agreed on the final version. The manuscript is not being considered by another journal.

Conflict of interest

  1. Top of page
  2. Abstract
  3. What is new in this paper?
  4. Introduction
  5. Method
  6. Results
  7. Discussion
  8. Acknowledgements
  9. Author contributions
  10. Conflict of interest
  11. References

The authors declare that they have no financial relationship that might lead to a conflict of interest in relation to the submitted manuscript.

References

  1. Top of page
  2. Abstract
  3. What is new in this paper?
  4. Introduction
  5. Method
  6. Results
  7. Discussion
  8. Acknowledgements
  9. Author contributions
  10. Conflict of interest
  11. References
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