Introduction

The incidence of rectal cancer in the European Union is 15-25/100,000 per year (35% of the total colorectal cancer incidence)(1,2). The mortality has decreased with 35% due to prevention, early diagnosis and advances in the multimodal treatment of rectal cancer(1,2). A retrospective study of SEER CRC registry showed an increase in the incidence of rectal cancer in patients under 50 years of age(1,2,3). Approximately 15% of cases have a hereditary component. The most common disorders are Lynch syndrome and familial adenomatous polyposis(1,2).
Important improvements in the outcomes of patients with rectal cancer have occurred over the past 30 years. Advances in surgical pathology, refinements in surgical techniques and instrumentation, new imaging modalities, and the widespread use of neoadjuvant therapy have all contributed to these improvements. Many new systemic treatment options have become available for locally advanced rectal cancers, including: additional chemotherapeutic agents and targeted therapies (vascular-endothelial growth factor and epidermal growth factor receptor inhibitors) which can be added to neoadjuvant and adjuvant regimens or given in combination with radiotherapy as radio-sensitizing agents. An important aim is to treat so that the risk of residual disease in the pelvis, frequently causing a disabling local recurrence, is very low. Neoadjuvant/adjuvant therapy of stage II (T3-4, node-negative disease with tumor penetration through the muscle wall) or stage III (node-positive disease without distant metastasis) rectal cancer often includes locoregional treatment due to the relatively high risk of locoregional recurrence(4,5,6,7,8,9,10). We report a case of a 54-year-old patient diagnosed with locally advanced rectal cancer and treated with a multimodal approach. 

Case report

In November 2013, a 52-year-old female, smoker patient, presented at the primary care physician accusing rectal bleeding, pain and perianal abscess. 
A colonoscopy was performed and she was diagnosed through a biopsy with rectal adenocarcinoma. She was redirected to our department, at the “Prof. Dr. Al. Trestioreanu” Institute of Oncology, in Bucharest. 
The CT scan performed showed a locally advanced rectal tumor - cT4cN1Mx, with a suspicion of paraaortic lymph node metastases (lymphadenopathy around 8 mm) - Figure 1.
Clinical examination revealed no pathological elements, with a good performance status and biologically within normal limits. The tumor board decided that the best treatment sequence was neoadjuvant chemo-radiotherapy and then surgery. A protective ileostomy was performed (Figure 2).

Treatment

The patient started neoadjuvant chemo-radiotherapy in January 2014 (TD=45 Gy, 1.8 Gy per fraction/25 fractions + Capecitabine 1000 mg per day). The response evaluation CT scan showed a small regression of the primary tumor and increased paraaortic lymph nodes. So the patient was restaged: stage IV rectal adenocarcinoma - cT4N1M1a (LYM) - Figure 3.
We evaluated the K-RAS status and the results showed­ that the patient had an exon 4 mutation in the K-RAS gene. Chemotherapy was continued with Cape Ox (Oxaliplatin 130 mg/m2 d1+ Capecitabine 1000 mg/m2, PO, twice daily, for 14 days, repeated every 3 weeks) + Bevacizumab (7.5 mg/kg, d1Q3) for 6 months. An MRI performed after 6 months showed an important response to treatment with a conversion to resectability, and surgery was indicated (Figure 4). 
The patient underwent radical surgery in January 2015 (total hysterectomy with bilateral ovariectomy, rectum amputation and colpectomy). Subsequent chemotherapy was continued with Cape Ox (Oxaliplatin 130 mg/m2 d1+ Capecitabine 1000 mg/m2, PO, twice daily, for 14 days, repeated every 3 weeks) + Bevacizumab (7.5 mg/kg, d1Q3). During chemotherapy, mild gastrointestinal (nausea, vomiting, diarrhea) and hematological toxicity was observed and the patient experienced for a short period of time fatigue, asthenia, muscle weakness, numbness in limbs. The patient had an allergic reaction to Oxaliplatin, so the treatment was switched to FU/leucovorin+Bevacizumab. During this period the patient presented dysuria and her chemistry work-up revealed increased serum creatinine (5.1 mg/dl), hypocalcaemia, hypokalemia, hyponatremia. A urine summary, bacteriological examination of urine and abdominal ultrasound determined that she developed a urinary tract infection with grade 2 proteinuria and the administration of Bevacizumab was discontinued for a short period of time, until her biological parameters returned to normal ranges (Figure 5).

Results/follow-up

The follow-up (clinical and bio-umoral evaluation, CT scan) showed no locoregional tumor relapse, no new metastases and a decrease in size of the paraaortic lymph nodes. The multimodal approach of the treatment (RT/CHT, surgery, CHT, targeted therapy) led to a good outcome in this case, with the conversion to resectability of the rectal tumor and no late important morbidity problems. Regarding prognostic factors in this case - stage IV rectal cancer, with a high risk of recurrence, paraaortic lymph nodes involvement, side effects of the treatment (grade 2 proteinuria) that can lead to discontinuation of Bevacizumab - we can establish a poor prognostic for this patient.

Discussions

The sequence is the most important multimodal therapy in rectal cancer. In this case, the choice of sequence radio-chemotherapy and targeted therapy resulted in partial remission and conversion to resectability of the tumor. In terms of outcome, patient falls in the category of high risk for locoregional recurrence, with a risk of 49% of recurrence in the low pelvic region and presacral regions, as Yu et al. reported in a single center study(1,2). Prevention from local failures with the severe morbidity which may accompany them is very important. The prognosis is also influenced by late effects of treatment toxicity and radio-chemotherapy, with the patient having gastrointestinal toxicity, hematologic and even proteinuria during treatment(1,2,4,7,10).
In a retrospective study published in 2015 by Hsueh-Ju Lu, with a total of 4,527 newly diagnosed CRC patients who were enrolled, the authors aimed to assess the prognostic role of visible paraaortic lymph nodes (PALNs). An inferior overall survival was seen in patients with visible PALNs than in those without visible PALNs (5-year overall survival, 67% vs. 76%, P = 0.015). Lymph vascular invasion, nodal disease (pN+) status, high preoperative serum carcinoembryonic antigen (CEA) levels and visible PALNs ≥10 mm were independent prognostic factors for patients with visible PALNs. They concluded that a prognostic model, which included LVI, pN+ status, preoperative serum CEA level, and the size of visible PALNs, could effectively distinguish the outcome of patients with visible PALNs. Our patient had para-aortic lymph nodes visible on MRI around 1.4 cm and it should be taken in for discussion if radio­therapy of the para-aortic lymph nodes is indicated and what are its benefits for the patient, considering their localization and the toxicities of the radiotherapy treatment(13,14,15).
In 2010, a meta-analysis performed on 16 studies that included 12,268 patients with various malignancies evaluated the risk of developing proteinuria by the addition of Bevacizumab to chemotherapy. The study showed that Bevacizumab added to chemotherapy significantly increased the risk for high-grade proteinuria in patients with different types of cancer. 
The risk is different with dosage of Bevacizumab and tumor type. The incidence of high-grade (grade 3 or 4) proteinuria with Bevacizumab was 2.2%. Compared with chemotherapy alone, Bevacizumab combined with chemotherapy significantly increased the risk for high-grade proteinuria and nephrotic syndrome. Bevacizumab administrated in high doses (10-15 mg/kg) was associated with increased risk for proteinuria. 

The authors concluded that the addition of Bevacizumab to chemotherapy significantly increases the risk for high-grade proteinuria and nephrotic syndrome, with the possibility of developing renal failure and cardiovascular complications. Our patient developed grade 2 proteinuria and the administration of Bevacizumab was discontinued for a short period of time. At the moment, the patient has a normal biological profile, without any proteinuria and she is continuing her treatment in the adjuvant setting(1,2,9,12).

Conclusions

The neo-adjuvant chemotherapy and radiotherapy treatment have a special role in the management of locally advanced rectal cancer, by being able to provide conversion to the stage in which resection can be performed, even if this fact might imply a complex surgical intervention. 
The association of the adjuvant chemotherapy treatment may improve the results and the long-term perspectives of the patients, by decreasing the incidence of local recurrence.  tratament neoadjuvantrectal tumors