Curative resection for locally advanced sigmoid colon cancer using neoadjuvant chemotherapy with FOLFOX plus panitumumab: A case report.

INTRODUCTION: FOLFOX and panitumumab combined chemotherapy plays an important role for metastatic colorectal cancer. However the usefulness of this regimen for neoadjuvant therapy is unclear. CASE REPORT: A 67-year-old man with abdominal pain and pneumaturia was diagnosed with RAS wild-type sigmoid colon cancer with urinary bladder invasion and colovesical fistulas. Because the cancer was considered to be unresectable, a transverse-loop colostomy was performed. Colonoscopy and computed tomography revealed a marked reduction in the size of the primary tumor after six courses of FOLFOX4 (oxaliplatin, leucovorin, and 5-fluorouracil) plus panitumumab. Laparoscopic sigmoidectomy and partial cystectomy were then performed. The pathological findings based on the resected specimen showed almost complete replacement of the tumor by fibrous tissue, with only a few degenerated tumor glands persisting in the submucosa. The patient's postoperative course was uneventful and he was doing well, without disease recurrence, after 36 months of follow up.
CONCLUSION: To our knowledge, this is the first report of a successful curative resection in a patient with initially unresectable, locally advanced colorectal cancer who was treated with FOLFOX4 combined with panitumumab.

Introduction

Colorectal cancer (CRC) is one of the most commonly diagnosed malignancies in Japan, affecting over 100,000 individuals. It is also the third most common cancer worldwide, with up to 1 million new cases diagnosed each year [1].

Metastatic or postoperative adjuvant chemotherapy for patients with CRC is now internationally accepted as a standard therapy to improve outcome. Moreover, recent studies have demonstrated that preoperative chemotherapy improves the outcome of patients with CRC with liver metastases [2], [3]. Nowadays there are some ongoing clinical trials that evaluate the efficacy of neoadjuvant approach in locally advanced colon cancer. [4], [5], [6] However, little is known about the effect and safety of preoperative chemotherapy for initially unresectable, locally advanced colon cancer without distant metastases.

Panitumumab (Pmab) is an epidermal growth factor receptor (EGFR)-targeted monoclonal antibody that has shown efficacy as monotherapy in phase III studies in patients with chemotherapy-refractory metastatic CRC [7]. It was also shown to improve patient outcome when added to standard chemotherapy, both first-line and subsequently [8].

Here we report the case of a patient with locally advanced sigmoid colon cancer with invasion of the bladder and colovesical fistulas in whom the tumor was radically resected after chemotherapy with FOLFOX4 plus Pmab.

Case report

A 67-year-old man was referred to our institute because of abdominal pain and pneumaturia. Colonoscopy showed a circumferential tumor of the sigmoid colon (Fig. 1a). The resulting constriction blocked passage of the endoscope. Initial computed tomography (CT) and magnetic resonance imaging showed a 4 cm × 4 cm tumor involving the urinary bladder, with a huge pelvic abscess, colovesical fistulas, and many swollen lymph nodes in the mesocolon but no distant metastasis (Fig. 2a–c).

Fig. 1

　(a) Colonoscopy before chemotherapy showed a circumferential tumor in the sigmoid colon, and biopsy specimens revealed moderately differentiated tubular adenocarcinoma. (b)　Colonoscopy after chemotherapy showed an excellent response and the biopsies were negative for cancer cells.

Fig. 2

(a–c)Initial computed tomography showed a circumferential thickening of the sigmoid colon wall and involving urinary bladder with a pelvic abscess and urinary air (colovesical fistula). (d) After six courses of chemotherapy showed improvement of pelvic abscess and marked reduction of the tumor.

Positron emission tomography-CT confirmed the primary tumor in the sigmoid colon and the absence of distant metastasis (Fig. 3). Microscopic examination of the tumor biopsy specimens revealed moderately differentiated tubular adenocarcinoma; the RAS status was wild-type. The patient was considered to have high-risk disease and curative resection was deemed not possible; instead, our multidisciplinary team recommended neoadjuvant chemotherapy. After undergoing a transverse-loop colostomy and improved inflammatory response caused by pelvic abscess, the patient received six courses of FOLFOX4 [oxaliplatin (85 mg/m2 on day 1), leucovorin (100 mg/m2 on days 1 and 2), and 5-fluorouracil (5-FU; 400 mg/m2 as a bolus and 600 mg/m2 as a 22-h continuous infusion on days 1 and 2)] plus Pmab (6 mg/kg) every 2 weeks. Grade 3 neutropenia, according to Common Terminology Criteria for Adverse Events (CTCAE) version 4.0, developed during the last course of chemotherapy, but not febrile neutropenia or related infection. Colonoscopy and abdominal CT after systemic chemotherapy demonstrated marked tumor shrinkage, an improved pelvic abscess, and no mesocolon lymph node metastases (Figs. 1d and 2d). Biopsies of the sigmoid colon were negative for cancer cells. The patient underwent laparoscopic sigmoidectomy and partial cystectomy 3 weeks after the completion of systemic chemotherapy. He recovered uneventfully and was discharged on postoperative day 11.

Fig. 3

PET-CT showed the primary tumor in the sigmoid colon.

On microscopic examination, the specimen resected following therapy was replaced almost completely with fibrous tissue, with only a few degenerated tumor glands remaining in the submucosal layer, and no lymph node metastases (Fig. 4a–b). All margins were free of cancer cells. The patient continues to do well 36 months postoperatively, without any evidence of recurrence.

Fig 4

Microscopic findings with H&E showed the tumor had been almost replaced fibrous tissue, with only two glands cancer cells left in the submucosa.

Discussion

Complete microscopic tumor removal (R0 resection) for CRC has a strong prognostic impact on both recurrence and survival rates [9]. Current guidelines recommend microscopically negative margins as the standard surgical procedure for locally advanced, adherent colon cancer [10]. Incomplete removal of the tumor despite en-bloc multivisceral resections has been reported in 7–35% of patients with locally advanced colon cancer [11], [12], [13], [14]. Cukier et al. reported that neoadjuvant chemoradiotherapy and en-bloc multivisceral resection can result in high rates of R0 resection and excellent local control, with acceptable morbidity, in selected patients with locally advanced, adherent colon cancer [15]. In our patient, considering the difficulty of curative resection due to huge pelvic abscess, with colovesical fistulas, we first performed a transverse colostomy and reduced the risk of infection, followed by systemic neoadjuvant chemotherapy.

Pmab, a fully human monoclonal antibody targeting the EGFR, has been recently combined with 5-FU-based chemotherapy to achieve significant and clinically meaningful improvement in survival in patients with metastatic colon cancer [16]. Leone et al. reported that conversion treatment with Pmab plus XELOX (capecitabine plus oxaliplatin) yielded a strong response and high resectability rates in patients with KRAS wild-type metastatic colon cancer with extensive liver involvement [17]. In the phase II, randomized PEAK [panitumumab plus modified fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) or bevacizumab plus mFOLFOX6 in patients with previously untreated, unresectable, wild-type KRAS exon 2 metastatic colorectal cancer] study [16], the progression-free survival (PFS) of patients with wild-type KRAS exon 2 tumors was similar and their overall survival (OS) was improved with Pmab vs. bevacizumab when combined with mFOLFOX6. Therefore, patients with wild-type RAS tumors in particular seem to clinically benefit from Pmab-containing therapy.

In the PRIME study, 42% of the patients receiving Pmab-FOLFOX4 developed grade 3–4 neutropenia, 39% developed grade 3–4 skin toxicity, and 18% grade 3–4 diarrhea. In the StarPan/STAR-02 study, 21% of the patients with high-risk, locally advanced rectal cancer treated with a neoadjuvant regimen of 5-FU and oxaliplatin-RT plus Pmab achieved pathologic complete remission based on complete tumor regression [18]. In that group, 39% of the patients experienced grade 3–4 diarrhea, with one death due to toxicity, and 19% suffered grade 3–4 skin toxicity. In our patient, pre-emptive supportive treatment, including oral doxycycline and no radiotherapy, might have avoided the development of skin toxicity and diarrhea associated with Pmab administration.

Neoadjuvant chemotherapy is a well-established therapeutic strategy in gastroenterological oncology and more effective than similar postoperative therapy [19], [20], [21]. Although the role of neoadjuvant chemoradiotherapy in the management of locally advanced rectal cancer is well documented [14], [21], there is no clear evidence supporting the use of adjuvant [22], [23] and neoadjuvant FOLFOX4 plus monoclonal antibodies in patients with localized colon cancer without distant metastasis. Foxtrot trial evaluates preoperative 6 weeks of modified de Gramont chemotherapy plus Pmab compared with modified de Gramont chemotherapy alone in patients with radiologically staged, locally advanced, but potentially resectable colon cancer [4]. This trial reported that preoperative chemotherapy is feasible with acceptance toxicity and preoperative morbidity and postoperative results is ongoing. The present case suggests that preoperative FOLFOX4 and Pmab is an effective option for patients with RAS wild-type, locally advanced colon cancer.

Conclusion

In conclusion, we report a first case of curative resection in a patient with initially unresectable, locally advanced colon cancer after a combination regimen of FOLFOX4 plus Pmab. Neoadjuvant chemotherapy using FOLFOX4 plus Pmab might be a promising preoperative strategy for patients with RAS wild-type, locally advanced colon cancer. Clinician should consider that a multi-disciplinary approach is important because locally advanced cases can be brought into conversion surgery by using Pmab containing regimen, and long-term relapse-free survival may be obtained. However, preoperative chemotherapy for colon cancer has yet to be rigorously investigated, such that the associations between systemic preoperative chemotherapy and locally advanced colon cancer remain to be clarified. This case report was accordance with the SCARE guideline [24].

Authors’ contributions

KT wrote the final manuscript and analyzed the results. YF, YH, JM, SM and HK participated in the care of the patients. NY carried out the pathological analysis of the specimen. All authors participated in data collection. YM, YO, and TT participated in revising the manuscript critically. All authors read and approved the final manuscript.

KT, HK, SM performed the surgery. KT, YH, ST, and JM took charge of postoperative care and prepared the manuscript. YM, YF, YO, NI, and TT assisted in drafting the manuscript and reviewed the article. All authors read and approved the final manuscript

Consent

Written informed consent was obtained from the patient for publication of this case report and accompanying images.

Funding

Kenji Tomizawa and the other co-authors have no relevant financial interests to declare in this manuscript.

Ethical approval

All approval has been given.

Competing interests

The authors declare that they have no competing interest.

Guarantor

Kenji Tomizawa, Yuji Miura.