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Japanese Journal of Clinical Oncology Advance Access originally published online on June 2, 2009
Japanese Journal of Clinical Oncology 2009 39(8):528-533; doi:10.1093/jjco/hyp045
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© The Author (2009). Published by Oxford University Press. All rights reserved

A Case Report of Pathologically Complete Response of a Huge Rectal Cancer after Systemic Chemotherapy with mFOLFOX6

Kae Okoshi1,{dagger}, Satoshi Nagayama1{dagger}, Moritoshi Furu2, Yukiko Mori1, Akihiko Yoshizawa3, Junya Toguchida2,4 and Yoshiharu Sakai1

1 Department of Surgery, Graduate School of Medicine, Kyoto University
2 Department of Tissue Regeneration, Institute for Frontier Medical Sciences, Kyoto University
3 Department of Diagnostic Pathology, Kyoto University Hospital
4 Center for iPS Research and Application, iCeMS, Kyoto University, Kyoto, Japan

For reprints and all correspondence: Satoshi Nagayama, Department of Surgery, Graduate School of Medicine, Kyoto University, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan. E-mail: nagayama{at}kuhp.kyoto-u.ac.jp

Received November 18, 2008; accepted April 19, 2009


   Abstract
TOP
 Abstract
INTRODUCTION
 CASE REPORT
 DISCUSSION
 Funding
 Conflict of interest statement
 References
 
A 54-year-old man was referred to our hospital because of a huge, unresectable rectal cancer occupying his entire pelvic space with a solitary liver metastasis. He had undergone a laparotomy for surgical resection, but ended up with a sigmoid colostomy due to possible invasion into the urinary bladder and pelvic wall. At the completion of seven cycles of FOLFOX regimen, radiographic examination revealed remarkable reduction of the primary rectal tumor and regional lymph nodes, and also a complete response (CR) of the liver metastasis. The tumor was extirpated without any macroscopic residues by a low anterior resection of the rectum, along with a partial resection of the urinary bladder and seminal vesicles. Since pathological and immunohistochemical examinations showed no viable cancer cells in any parts of the resected specimens, the lesion was regarded as a pathologically CR. Analysis for single-nucleotide polymorphisms in the genes involved in nucleotide excision repair, excision repair cross-complementing group 1 and xeroderma pigmentosum group D, showed a genotypic pattern sensitive to oxaliplatin. To our knowledge, this is a rare case of an initially unresectable primary rectal cancer, which was down-staged to a pathologically CR by FOLFOX chemotherapy instead of chemoradiotherapy.

Key Words: complete response • rectal cancer • mFOLFOX6 • ERCC1 • XPD


   INTRODUCTION
TOP
 Abstract
 INTRODUCTION
CASE REPORT
 DISCUSSION
 Funding
 Conflict of interest statement
 References
 
The FOLFOX regimen, which includes bolus/infusional 5-fluorouracil with folinic acid modulation and oxaliplatin, has become one of the most common first-line treatments for patients with metastatic colorectal cancer (mCRC) (1,2). In spite of the high response rates to the FOLFOX regimen, a pathologically complete response (CR) of mCRC to systemic chemotherapy has rarely been achieved. Benoist et al. (3) demonstrated that in 83% of liver metastases down-sized to a CR on imaging by systemic chemotherapy, persistent macroscopic or microscopic residual disease or early recurrence in situ was observed at surgery, on pathological examination or during the follow-up period. With respect to the treatment for advanced rectal cancers, pre-operative chemoradiotherapy (CRT) followed by surgical resection was superior in terms of local control of these cancers (4,5). However, a definite treatment guideline for huge rectal cancers with possible invasion into the surrounding tissues has not been established.

Here, we present a case of a primarily unresectable huge rectal cancer with liver metastasis. This patient responded remarkably to the FOLFOX regimen and achieved a pathologically CR following radical resection. In addition, we analyzed the single-nucleotide polymorphisms (SNPs) of excision repair cross-complementing group 1 (ERCC1) and xeroderma pigmentosum group D (XPD) to investigate the association between genotype and the response to oxaliplatin (6).


   CASE REPORT
TOP
 Abstract
 INTRODUCTION
 CASE REPORT
DISCUSSION
 Funding
 Conflict of interest statement
 References
 
A 54-year-old man underwent a colonoscopic examination at another hospital because of persistent diarrhea and bloody stool. A bulky tumor was detected at 15 cm from the anal verge, and he was diagnosed with a moderately differentiated tubular adenocarcinoma on pathological examination of the biopsy samples (Fig. 1D). Since his symptoms deteriorated due to progression of this severely stenotic lesion, a laparotomy was performed for surgical resection, although pre-operative computed tomographic (CT) scans showed evidence of possible invasion to the urinary tract and sacrum. At surgery, the tumor could barely be mobilized due to direct invasion into the surrounding tissues, and the operation ended in a simple sigmoid colostomy to relieve his condition due to impaired defecation and to initiate oral intake. He was then referred to our hospital for further treatment of the huge rectal cancer.


Figure 1
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  		Figure 1. Pre-treatment radiographic and pathological findings. CT scans showed a huge tumor occupying the entire pelvic space, with possible invasion into the bladder and sacrum (A and B) along with a solitary liver metastasis (arrow) adjacent to the inferior vena cava (C). Biopsy samples from the rectal tumor showed evidence of a moderately differentiated, tubular adenocarcinoma without any deposits of mucin (D) (HE, x100). An asterisk indicates the bladder. CT, computed tomography; HE, hematoxylin and eosin.

 
Subsequent CT scans showed a huge tumor occupying the pelvic space with possible invasion to the abdominal wall, bladder and/or sacrum, along with swollen regional lymph nodes and a solitary liver tumor of 1 cm in diameter adjacent to the inferior vena cava (Fig. 1A–C). Magnetic resonance (MR) T2-weighted imaging of the pelvis demonstrated that the tumor consisted of two different components of low and high intensity, which seemed to reflect the epithelial and mucinous pathohistological features, respectively (Fig. 2C and E). Positron emission tomography with 18-fluorodeoxyglucose (FDG-PET)/CT fusion imaging confirmed the solitary liver metastasis without any other distant metastatic lesions (Fig. 2A). In addition, FDG-PET/MR fusion imaging revealed the presence of lymph node metastases in the regional mesentery. The FDG uptake signals were more prominent in the epithelial component of the tumor when compared with the mucinous component (Fig. 2G).


Figure 2
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  		Figure 2. Marked radiographic changes before (A, C, E and G) and after (B, D, F and H) mFOLFOX6 therapy. Before the initiation of chemotherapy, a solitary liver metastasis was detected adjacent to the inferior vena cava using FDG-PET/CT fusion imaging (A), which was down-staged to a CR by seven cycles of mFOLFOX6 therapy (B). Pre-treatment T2-weighted MR images showed a huge advanced rectal cancer of low (solid arrow) and high (open arrow) intensity, with possible invasion to the bladder (asterisk) (C and E). This huge tumor, especially the low-intensity component, shrank markedly following the chemotherapy, and invasion to the bladder was not well documented on T2-weighted MR images (D and F). In addition, the uptake signals of FDG decreased remarkably in the low-intensity component of the tumor after the chemotherapy, whereas the mucinous component remained almost signal-void on FDG-PET/MR fusion imaging (G and H). (A and B) FDG-PET/CT fusion images and (G and H) FDG-PET/MR fusion images. The solid and open arrows indicate the low- and high-intensity components of the tumor, respectively. The bladder is marked by an asterisk. mFOLFOX6, modified FOLFOX6; FDG-PET, positron emission tomography with 18-fluorodeoxyglucose; CR, complete response; MR, magnetic resonance.

 
Since his general condition had improved with sufficient oral intake, systemic chemotherapy with a modified FOLFOX6 regimen (mFOLFOX6) was started at an outpatient clinic, as described previously (7). Briefly, the regimen was repeated every 2 weeks: 85 mg/m2 oxaliplatin, 200 mg/m2 leucovorin (LV) and 600 mg/m2 5-fluorouracil (5-FU) bolus on day 1, and 2400 mg/m2 5-FU as a 46 h continuous infusion starting on day 1. After seven cycles of mFOLFOX6 were completed without any serious complications, the low-intensity component of the pelvic tumor disappeared almost completely, and the high-intensity component also decreased in size on T2-weighted MR imaging (Fig. 2D and F). The metastatic regional lymph nodes also showed a partial response in size to the chemotherapy. In terms of tumor cell viability evaluated by FDG-PET/MR fusion imaging, both components of the pelvic tumor were almost signal-void, suggesting the disappearance of most of the viable cancer cells (Fig. 2H). The liver metastasis was rendered undetectable without any uptake signals on FDG-PET/CT fusion imaging, indicative of a CR on imaging (Fig. 2B). In addition, there was no evidence of any de novo detectable metastatic lesions. The high level of carcinoembryonic antigen before chemotherapy (656 ng/ml) rapidly decreased and became normalized (3.1 ng/ml) at the completion of the seven cycles of mFOLFOX6 (Fig. 3).


Figure 3
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  		Figure 3. Changes in serum CEA levels during the chemotherapy, showing a rapid decrease below the cut-off value (<5 ng/ml). For 10 months after the radical surgery, the CEA levels were within the cut-off value. CEA, carcinoembryonic antigen.

 
On achievement of a fairly good response to chemotherapy, he opted to undergo surgical treatment. The primary cancer was located at the upper rectum without any evidence of peritoneal dissemination. No metastatic tumors were detected in the liver on visual inspection or palpation and liver resection was not performed. The large rectal tumor was successfully mobilized and extirpated without any macroscopic residues by an anterior resection of the rectum, along with a partial resection of the urinary bladder and seminal vesicles. Since the pelvic side wall, sacrum, ureters and prostate gland remained intact without any direct invasion of the tumor, reconstruction of the urinary tract was not indicated. The resected tumor was large at 60 x 67 x 53 mm in size. The whole specimen was divided into 17 sections at 5 mm intervals and stained with hematoxylin and eosin for thorough histopathological analyses. Surprisingly, histopathological examination of the surgical specimen including the primary rectal tumor and regional lymph nodes demonstrated only large deposits of mucin without any malignant cells, surrounded by fibrotic and granulomatous tissues with moderate infiltration of inflammatory cells (Fig. 4A). Although there was a possibility that this was the remnants of a mucinous adenocarcinoma, no residual cancer cells were detected in any part of the primary tumor and lymph nodes by immunohistochemical examination using a pan-cytokeratin monoclonal antibody (AE1/AE3 clone, Dako, Japan) (Fig. 4B). Therefore, the rectal lesion was considered to be a pathologically CR.


Figure 4
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  		Figure 4. Pathological findings of specimens extirpated following systemic chemotherapy. (A) Scattered large deposits of mucin were surrounded by fibrotic and granulomatous tissues in the rectal tumor and lymph nodes (HE, x100). (B) No malignant epithelial cells were detected in any regions of the specimen by immunohistochemical examination using a monoclonal antibody for pan-cytokeratins (AE1/AE3), indicating the complete disappearance of the cancer cells (x100). As positive controls, normal epithelial cells adjacent to the lesion were clearly immunostained (arrow). An inset in Fig. 4B shows a higher magnification view of the cytokeratin-immunopositive normal epithelial cells (x400).

 
Systemic chemotherapy using the sLV5FU2 regimen (1) was continued after the operation. The reasons for the choice of sLV5FU2 regimen were as follows: (i) the patient complained of persistent sensory neuropathy caused by pre-operative mFOLFOX6 treatment and (ii) pathologically curative resection of the primary rectal cancer was achieved and there were no definite metastatic lesions detected in the liver or lung on post-operative CT scans. Twelve cycles of sLV5FU2 were administered, and there were no signs of recurrence or metastasis at 10 months post-operatively.

In order to examine the association between pharmacogenetic profiling and the response to oxaliplatin, the SNPs of the genes involved in the nucleotide excision repair (NER) pathways, ERCC1 and XPD, were analyzed using genomic DNA extracted from leukocytes in the peripheral blood, as described previously (6). Genotyping of the polymorphisms showed a C/C at codon 118 in the ERCC1 gene and an A/A at codon 751 in the XPD gene (Fig. 5). It has been reported that this combination of SNPs is sensitive to oxaliplatin and thus produced the favorable prognosis in this case (6).


Figure 5
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  		Figure 5. Analysis of the SNPs of the ERCC1 (A) and XPD (B) genes, showing a genotype of a C/C at codon 118 (exon 4) in the ERCC1 gene and an A/A at codon 751 (exon 23) in the XPD gene. SNPs, single-nucleotide polymorphisms; ERCC1, excision repair cross-complementing group 1; XPD, xeroderma pigmentosum group D.

 

   DISCUSSION
TOP
 Abstract
 INTRODUCTION
 CASE REPORT
 DISCUSSION
Funding
 Conflict of interest statement
 References
 
CRT is considered to be the first-line treatment for advanced rectal cancer because of excellent rates of local control when compared with chemotherapy alone (4,5). However, there are no definite protocols established with respect to the treatment of huge rectal cancers with possible invasion into the surrounding tissues. In this case, we chose chemotherapy alone for the two following reasons: (i) radiotherapy would induce adverse effects including radiation-related enteritis and adhesion ileus because of the comparatively wider irradiation field and (ii) a single liver metastasis was already evident, and any potential micrometastases should be eradicated as soon as possible. We considered that intensive systemic chemotherapy instead of CRT should be the first-line therapy for unresectable rectal cancers with distant metastases.

As shown by MR imaging, the primary rectal cancer consisted of two different components: a solid component of low intensity filled with epithelial malignant cells and a mucinous component of high intensity. It was not well documented whether the mucinous component contained any malignant cells before the initiation of chemotherapy. The biopsy sample likely reflected the solid component only, since the mucinous component was located far from the rectal wall. In addition, FDG-PET is markedly less sensitive for the detection of mucinous adenocarcinomas in which the mucin deposits occupy more than half of the lesion (8–10). However, the mucinous component was reduced in volume in response to chemotherapy on MR imaging, which was not prominent when compared with the solid portion. Furthermore, detailed pathological examination showed that the rectal tumor and regional lymph nodes contained mucin deposits without any cytokeratin-immunopositive cancer cells. These findings imply that systemic chemotherapy possibly eradicated the mucin-producing malignant cells present in the primary lesion and metastatic lymph nodes. We considered that both components responded dramatically to the chemotherapy, and a pathologically CR was achieved. In the literature, mucinous colorectal cancers were more resistant to chemotherapy when compared with non-mucinous cancers (11) and were associated with a poorer prognosis in a retrospective study involving 1160 patients (12). In contrast, even the mucinous tumor cells were sensitive to systemic chemotherapy with mFOLFOX6 in this case, which prompted us to examine the genetic background with respect to sensitivity to oxaliplatin.

There is a substantial chance that in living cells, assorted DNA damage may occur due to genetic mutations, oxidative stress, radiation, chemicals and other factors. In correcting this DNA damage, there are at least four repair mechanisms documented according to types of damage: base excision repair, mismatch repair, double-strand break repair and NER. Among these mechanisms, the NER pathway is essential to repair severe damage to the DNA such as pyrimidine dimers, cross-links and bulky adducts induced especially by platinum-containing chemotherapeutic agents. The degree of chemoresistance to platinum-containing agents was associated with the expression levels of genes in the NER pathway, which determined the capacity to repair DNA damage (13,14). It is postulated that SNPs in the ERCC1 and XPD genes involved in the NER pathway may modulate the DNA repair capacity and thus affect individual responses to oxaliplatin-containing chemotherapy. Ruzzo et al. (6) demonstrated that genotypes of a T/T at codon 118 in the ERCC1 gene combined with either an A/C or a C/C at codon 751 in the XPD gene were significantly associated with an unfavorable progression-free survival in patients with advanced colorectal cancers treated with the FOLFOX4 regimen. In contrast, patients of the genotypes shown in this case (ERCC1-118 C/C and XPD-751 A/A) produced the most favorable prognosis. Therefore, the achievement of a pathologically CR in this case was partially attributable to the inherent genotype.

Although it is another intriguing issue whether these genetic markers correlate with tumor phenotypes, we could not analyze the correlations because of the absence of cancer cells in the extirpated tissues. Several immunohistochemical studies on ERCC1 expression in non-small cell lung cancer tissues demonstrated that cisplatin-based chemotherapy was beneficial in patients with ERCC1-negative tumors, although there was no genetic information available in these studies (15–17).

According to the revised Bethesda guidelines for Lynch syndrome, microsatellite instability (MSI) testing is recommended in patients between ages 50 and 59 years with particular pathological features (18). Because of the patient's age and radiographic features of mucinous component, the patient may have an MSI phenotype. However, we could not examine an MSI status in the rectal cancer, because there were no cancer cells detected in the extirpated tissues and the pre-operative biopsy sample was insufficient for further genomic analysis. According to the study by Lan et al. (19), there is a possibility of compensatory relationship or cross-talk between mismatch repair system and NER system involving ERCC1. Therefore, the determination of MSI status would provide a clue to elucidate the responsiveness to platinum-containing agents.

For patients with advanced rectal cancers, pre-operative CRT followed by radical resection is a standard therapy, since CRT is effective in controlling local recurrences (4,5). However, pre-operative CRT does not contribute to improvement in overall survival rates (4), increases post-operative short-term complications (20) and causes bowel and sexual dysfunction in a long-term observation (21,22). In contrast, pre-operative chemotherapy is unlikely to cause these short- and long-term complications and also can be effective in regulating micrometastases in distant organs. In addition, ERCC1/XPD genotyping can be performed using blood samples. Therefore, we hypothesize that systemic chemotherapy could be one of the pre-operative treatment options for some patients with advanced rectal cancers when the SNPs in the ERCC1 and XPD genes are determined not to be of the risk genotypes (ERCC1-118 T/T and XPD-751 A/C or C/C) before the initiation of pre-operative treatment. Nevertheless, further study is still needed to predict the responsiveness to systemic chemotherapy and to select subgroups of good vs. poor responders.


   Funding
TOP
 Abstract
 INTRODUCTION
 CASE REPORT
 DISCUSSION
 Funding
Conflict of interest statement
 References
 
This work was supported in part by Grants-in-Aid for Scientific Research (No.20591589) from the Japan Society for the Promotion of Science.


   Conflict of interest statement
TOP
 Abstract
 INTRODUCTION
 CASE REPORT
 DISCUSSION
 Funding
 Conflict of interest statement
References
 
None declared.


   Footnotes
 
{dagger} These authors contributed equally to this work. Back


   References
TOP
 Abstract
 INTRODUCTION
 CASE REPORT
 DISCUSSION
 Funding
 Conflict of interest statement
 References
 
1 de Gramont A, Figer A, Seymour M, Homerin M, Hmissi A, Cassidy J, et al. Leucovorin and fluorouracil with or without oxaliplatin as first-line treatment in advanced colorectal cancer. J Clin Oncol (2000) 18:2938–47.[Abstract/Free Full Text]

2 André T, Boni C, Mounedji-Boudiaf L, Navarro M, Tabernero J, Hickish T, et al, Multicenter International Study of Oxaliplatin/5-Fluorouracil/Leucovorin in the Adjuvant Treatment of Colon Cancer (MOSAIC) Investigators. Oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment for colon cancer. N Engl J Med (2004) 350:2343–51.[Abstract/Free Full Text]

3 Benoist S, Brouquet A, Penna C, Julié C, El Hajjam M, Chagnon S, et al. Complete response of colorectal liver metastases after chemotherapy: does it mean cure? J Clin Oncol (2006) 24:3939–45.[Abstract/Free Full Text]

4 Kapiteijn E, Marijnen CA, Nagtegaal ID, Putter H, Steup WH, Wiggers T, et al. Preoperative radiotherapy combined with total mesorectal excision for resectable rectal cancer. N Engl J Med (2001) 345:638–46.[Abstract/Free Full Text]

5 Sauer R, Becker H, Hohenberger W, Rödel C, Wittekind C, Fietkau R, et al. Preoperative versus postoperative chemoradiotherapy for rectal cancer. N Engl J Med (2004) 351:1731–40.[Abstract/Free Full Text]

6 Ruzzo A, Graziano F, Loupakis F, Rulli E, Canestrari E, Santini D, et al. Pharmacogenetic profiling in patients with advanced colorectal cancer treated with first-line FOLFOX-4 chemotherapy. J Clin Oncol (2007) 25:1247–54.[Abstract/Free Full Text]

7 Matsumoto S, Nishimura T, Kanai M, Mori Y, Nagayama S, Kawamura J, et al. Safety and efficacy of modified FOLFOX6 for treatment of metastatic or locally advanced colorectal cancer. A single-institution outcome study. Chemotherapy (2008) 54:395–403.[CrossRef][Web of Science][Medline]

8 Whiteford MH, Whiteford HM, Yee LF, Ogunbiyi OA, Dehdashti F, Siegel BA, et al. Usefulness of FDG-PET scan in the assessment of suspected metastatic or recurrent adenocarcinoma of the colon and rectum. Dis Colon Rectum (2000) 43:759–67.[CrossRef][Web of Science][Medline]

9 Kim BT, Kim Y, Lee KS, Yoon SB, Cheon EM, Kwon OJ, et al. Localized form of bronchioloalveolar carcinoma: FDG PET findings. Am J Roentgenol (1998) 170:935–9.[Abstract/Free Full Text]

10 Higashi K, Ueda Y, Seki H, Yuasa K, Oguchi M, Noguchi T, et al. Fluorine-18-FDG PET imaging is negative in bronchioloalveolar lung carcinoma. J Nucl Med (1998) 39:1016–20.[Abstract/Free Full Text]

11 Negri FV, Wotherspoon A, Cunningham D, Norman AR, Chong G, Ross PJ. Mucinous histology predicts for reduced fluorouracil responsiveness and survival in advanced colorectal cancer. Ann Oncol (2005) 16:1305–10.[Abstract/Free Full Text]

12 Papadopoulos VN, Michalopoulos A, Netta S, Basdanis G, Paramythiotis D, Zatagias A, et al. Prognostic significance of mucinous component in colorectal carcinoma. Tech Coloproctol (2004) 8:s123–5.[CrossRef][Medline]

13 Altaha R, Liang X, Yu JJ, Reed E. Excision repair cross complementing-group 1: gene expression and platinum resistance. Int J Mol Med (2004) 14:959–70.[Web of Science][Medline]

14 Weaver DA, Crawford EL, Warner KA, Elkhairi F, Khuder SA, Willey JC. ABCC5, ERCC2, XPA, and XRCC1 transcript abundance levels correlate with cisplatin chemoresistance in non-small cell lung cancer cell lines. Mol Cancer (2005) 4:18.[CrossRef][Medline]

15 Azuma K, Komohara Y, Sasada T, Terazaki Y, Ikeda J, Hoshino T, et al. Excision repair cross-complementation group 1 predicts progression-free and overall survival in non-small cell lung cancer patients treated with platinum-based chemotherapy. Cancer Sci (2007) 98:1336–43.[CrossRef][Medline]

16 Hwang IG, Ahn MJ, Park BB, Ahn YC, Han J, Lee S, et al. ERCC1 expression as a prognostic marker in N2(+) nonsmall-cell lung cancer patients treated with platinum-based neoadjuvant concurrent chemoradiotherapy. Cancer (2008) 113:1379–86.[CrossRef][Web of Science][Medline]

17 Olaussen KA, Dunant A, Fouret P, Brambilla E, André F, Haddad V, et al. DNA repair by ERCC1 in non-small-cell lung cancer and cisplatin-based adjuvant chemotherapy. N Engl J Med (2006) 355:983–91.[Abstract/Free Full Text]

18 Jenkins MA, Hayashi S, O'shea AM, Burgart LJ, Smyrk TC, Shimizu D, et al. Pathology features in Bethesda guidelines predict colorectal cancer microsatellite instability: a population-based study. Gastroenterology (2007) 133:48–56.[CrossRef][Web of Science][Medline]

19 Lan L, Hayashi T, Rabeya RM, Nakajima S, Kanno S, Takao M, et al. Functional and physical interactions between ERCC1 and MSH2 complexes for resistance to cis-diamminedichloroplatinum(II) in mammalian cells. DNA Repair (Amst) (2004) 3:135–43.[CrossRef][Medline]

20 Marijnen CA, Kapiteijn E, van de Velde CJ, Martijn H, Steup WH, Wiggers T, et al. Acute side effects and complications after short-term preoperative radiotherapy combined with total mesorectal excision in primary rectal cancer: report of a multicenter randomized trial. J Clin Oncol (2002) 20:817–25.[Abstract/Free Full Text]

21 Peeters KC, van de Velde CJ, Leer JW, Martijn H, Junggeburt JM, Kranenbarg EK, et al. Late side effects of short-course preoperative radiotherapy combined with total mesorectal excision for rectal cancer: increased bowel dysfunction in irradiated patients—a Dutch colorectal cancer group study. J Clin Oncol (2005) 23:6199–206.[Abstract/Free Full Text]

22 Marijnen CA, van de Velde CJ, Putter H, van den Brink M, Maas CP, Martijn H, et al. Impact of short-term preoperative radiotherapy on health-related quality of life and sexual functioning in primary rectal cancer: report of a multicenter randomized trial. J Clin Oncol (2005) 23:1847–58.[Abstract/Free Full Text]


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