Complete Pathologic Response to Neoadjuvant Chemoimmunotherapy and Oxaliplatin-Induced Fever Associated With IL-6 Release in a Patient With Locally Advanced Colon Cancer

Abstract

Neoadjuvant systemic therapy is a preferred treatment approach for a number of tumor types due to many potential advantages over upfront surgery, including tumor downstaging, early treatment of micrometastatic disease, and providing an in vivo test of tumor biology. For colon cancer, current standard of care is upfront surgery followed by adjuvant systemic therapy in high-risk patients. Concerns about inaccurate radiological staging and tumor progression during preoperative treatment, as well the lack of randomized data demonstrating benefit, are among the reasons for the limited use of neoadjuvant therapy in this disease. Locally advanced colon cancer, defined as primary colon cancer with direct invasion into the adjacent structures or extensive regional lymph node involvement, is not always amenable to pathological complete resection, and when attempted it comes with high incidence of postoperative morbidity and mortality because of the required multivisceral resection. Clinical trials of neoadjuvant chemotherapy for colon cancer to date have been promising with downstaging of disease and higher rates of R0 resection. Here, we report a case of a patient with locally advanced, unresectable, mismatch repair deficient sigmoid colon cancer who was treated with neoadjuvant chemoimmunotherapy followed by surgical resection leading to a complete pathologic response after preoperative systemic chemoimmunotherapy.

Oncology (Williston Park). 2022;36(2):115-119.
DOI: 10.46883/2022.25920944

Introduction

Colon cancer is the third most common cancer in the United States, with 104,270 new cases in 2021. Colorectal cancer (CRC) is now estimated to be the fourth most common cancer in US men and women aged between 30 and 39 years.¹ Advances in our understanding of pathophysiology of these diseases have increased the array of diagnostic and treatment options leading to individualized treatment plans. Screening for deficient DNA mismatch repair (dMMR) has become a standard of care for all individuals with CRC.² dMMR is detected in 15% to 20% of all colon cancer specimens and 10% of rectal cancer specimens. The hallmark of dMMR tumors—microsatellite instability (MSI)—is caused by either a germline mutation in one of the MMR genes (MLH1, MSH2, MSH6, PMS2, and deletion of EPCAM) or by epigenetic silencing of the MLH1 promoter region.³ dMMR tumors of colon differ from MMR-proficient (pMMR) tumors in terms of prognosis, response to treatment, and patterns of metastatic spread.⁴

Over the past decade, treatment modalities for CRC have advanced to include endoscopic and surgical local excision; downstaging with preoperative radiotherapy and systemic therapy; extensive surgery for locoregional and metastatic disease; local ablative therapies for metastases; and chemotherapy, targeted therapy, and immunotherapy. Although these new treatment options have doubled overall survival (OS) for advanced disease for up to 3 years, survival is still best for those with nonmetastatic disease. Locally advanced colon cancer (LACC) with direct invasion to the adjacent structures or with extensive regional lymph node involvement has been difficult to manage because of the difficulties in accomplishing pathological complete resection and high incidence of postoperative morbidity and mortality.⁵ Five-year survival rates for patients with stage IIIB and IIIC colon cancer have been reported to be 46% and 28%, respectively.⁶ While preoperative chemoradiotherapy is now an established standard treatment option for locally advanced rectal cancer,^7,8 the role of neoadjuvant therapy for LACC is still evolving.

Background

Complete removal of the tumor with negative margins (R0 resection) followed by adjuvant chemotherapy has been the only established curative treatment for localized colon cancer. R0 resection can be challenging for LACC, which is defined as a primary tumor that directly invades adjacent structures with or without extensive nodal involvement. Approximately 26% of patients with
colon cancer present with locally advanced disease.⁹ In patients with LACC (high-risk stage II or III disease), the current standard of care may not be optimal, as R0 resection is not always possible in patients with T4b, M0 or N2, M0 disease.¹⁰ Neoadjuvant chemotherapy, an appealing concept in many other tumor types, has not been well established in operable colon cancer. Limitations to its widespread use include concerns about inaccurate radiological staging, tumor progression while undergoing preoperative treatment, and a lack of randomized data demonstrating benefit. However, with recent advances in radiological staging and availability of more effective systemic treatment options—including chemotherapy, immunotherapy, and targeted therapy—neoadjuvant treatment in LACC now is being increasingly explored as a promising new strategy.

For an increasing number of cancers in which the treatment goal is cure, neoadjuvant chemotherapy or chemoradiation prior to surgery has shown superior outcomes. The main driver of prognosis for a patient with localized colon cancer is the risk of later distant metastases; therefore, the opportunity to treat any potential distant micrometastatic disease at the time of diagnosis represents a plausible approach to attain long-term cure.^11-13 While chemoradiation prior to resection is a well-established approach for locally advanced rectal cancer, the role of neoadjuvant therapy in LACC remains unclear. Three studies of preoperative chemoradiation in LACC have reported R0 resection rates of as high as 91% to 100% and occasional pathologic complete response rates of 3% to 31% in this setting.^14-16

A number of single-arm trials have suggested that the use of neoadjuvant fluoropyrimidine oxaliplatin chemotherapy is safe and effective in LACC. In 2 of these studies involving patients with RAS/RAF wild type LACC, a minimum of 2 cycles of neoadjuvant capecitabine and oxaliplatin alone or in combination with panitumumab (Vectibix) showed both radiological and pathological responses, with 2% to 4% of patients achieving complete pathological response at surgery.^17,18 In another study, 4 to 6 cycles of 5-fluorouracil, folinic acid, and oxaliplatin (FOLFOX) or capecitabine and oxaliplatin neoadjuvant chemotherapy were evaluated, and they were found to be safe and effective with a complete pathological response rate of 4.6%.¹⁹ Triplet neoadjuvant chemotherapy with FOLFOX plus irinotecan (FOLFOXIRI) has also been assessed in a phase 2 study; the results showed a trend to greater tumor volume reduction with each subsequent chemotherapy cycle administered compared with patients who received 4 preplanned neoadjuvant cycles.²⁰ FOLFOXIRI was associated with higher rates of adverse effects (AEs), as expected. In all of these nonrandomized phase 2 studies, neoadjuvant chemotherapy did not appear to delay surgery. Rates of perioperative complications, including length of postoperative hospital stay and rates of anastomotic leak, were similar to published data in patients undergoing surgery alone.

The effect on OS in these single-arm studies is encouraging. Five-year survival in small cohorts with T4 disease ranged from the expected 67% to a very promising 95%.19,21 A large cohort study utilizing data from the US National Cancer database showed improved survival in patients with T4b colon cancer who received neoadjuvant chemotherapy, but not in patients with T3 or T4a disease, compared with those who received surgery followed by adjuvant chemotherapy.²²

Case

A White man, aged 45 years, had been experiencing symptoms of intermittent abdominal pain, abdominal distention, and change in bowel habits for the past 2 months. He presented to the emergency department with severe abdominal pain and vomiting. A CT scan of the abdomen and pelvis revealed marked colonic distention and a large (7.2 cm × 7.3 cm × 6.7 cm), heterogeneously enhancing mass in the sigmoid colon involving approximately 13 cm length of the colon; there was moderate infiltration of the surrounding mesenteric fat and mildly enlarged left lower quadrant mesenteric lymph nodes (Figure 1). He was taken to surgery with the intent of exploratory laparotomy and resection of the sigmoid colon mass. Due to size, friability, and bleeding from the mass, it was not possible to resect. Therefore, a takedown of splenic flexure with a loop colostomy was performed instead. Pathology of the mass involving colon and adjacent structures came back as moderately differentiated adenocarcinoma.

FIGURE 1. Large Mass Near the Junction of Descending Colon With Resultant Colonic Obstruction

Immunohistochemical staining for mismatch repair proteins revealed loss of nuclear staining for MLH1 and PMS2, and intact nuclear staining for MSH2 and MSH6 (Figures 2A & 2B). Subsequent BRAF and RAS panel testing was not able to be done due to insufficient tissue for evaluation. A genetic consultation and germline testing was declined by the patient.

FIGURE 2A. Evaluation of Colonic Mass by Hematoxylin Eosin Stain Adenocarcinoma (200× magnification)

FIGURE 2B. Evaluation by Immunoperoxidase Stains for Mismatch Repair Enzymes Shows Loss of Staining for MLH1 and PMS2 (200× magnification)

After discussion in tumor conference, he was started on FOLFOX chemotherapy regimen plus the immunotherapy pembrolizumab (Keytruda). Approximately 2 to 6 hours after each cycle of the FOLFOX regimen, he developed high temperature (range, 102.5° F to 104.0° F), with shivers, rigors, and chills. He was hospitalized with each episode and underwent extensive work-up for fever of unknown origin. Cultures of blood and urine, cultures from his infuseport, and ultimately removal of his infuseport and cultures of the port, as well as imaging studies, revealed no infectious etiology. Due to the timing of fevers, test trials of holding continuous 5-fluorouracil were undertaken but they did not prevent occurrence of febrile episodes.

Based on rarely published data regarding oxaliplatin-induced fever due to release of interleukin-6 (IL-6), and on an elevated IL-6 level during one of his febrile episodes, his chemotherapy was changed to the FOLFIRI regimen. Consequently, he had no more fever or episodes of shivering with FOLFIRI and completed his planned 6 cycles of neoadjuvant chemotherapy (4 cycles of FOLFOX plus 2 cycles of FOLFIRI) along with 6 cycles of pembrolizumab. Restaging CT scans showed almost complete resolution of his sigmoid colon mass (Figure 3). He underwent exploratory laparotomy, sigmoid colon resection with lymph node dissection, reversal of loop colostomy and hernia repair. Pathology showed sigmoid colon resection with no residual tumor, abundant cellular mucin extending from mucosal surface to the serosa consistent with area of treated and destroyed tumor (Figure 3). All 35 mesenteric lymph nodes that were evaluated were negative. There was no lymphovascular or perineural invasion, and pathologic stage was reported as ypT0ypN0.

FIGURE 3. Large Mass Near the Junction of Descending Colon Significantly Smaller With Resultant Resolution of Colonic Obstruction

Discussion

Currently, surgery followed by adjuvant systemic chemotherapy is the standard of care for the curative intent treatment of nonmetastatic colon cancer. R0 surgical resection is among the most important predictors of long-term survival.²³ There is growing interest in exploring the utility of the neoadjuvant approach to convert locally advanced unresectable colon
cancer to a resectable stage with the goal of cure. Because radiologic nodal N staging is less accurate than tumor T staging, definition of LACC has been based mostly on the radiological T stage, focusing on high-risk T3 (>5 mm extramural invasion to pericolic fat) and T4 primary tumors.^24,25

The first phase 3 trial of neoadjuvant chemotherapy for colon cancer from the United Kingdom recruited patients with T3 disease on preoperative staging and randomized them to neoadjuvant chemotherapy ± panitumumab or to immediate surgery followed by adjuvant chemotherapy.²⁶ In the pilot phase of this trial, only higher-risk radiological T3 tumors with ≥5 mm extramural extension or T4 tumors were included, and the results showed downstaging of the primary tumor. Further results of this trial, presented at the 2019 American Society of Clinical Oncology Annual Meeting, showed a significantly reduced rate of incomplete surgical resection (R1 or R2) along with reduced pathological staging and decreased 2-year failure rate (HR, 0.77; 95% CI, 0.56-1.06).²⁷ A subgroup analysis suggested less benefit from neoadjuvant chemotherapy in patients with dMMR tumors.²⁸ Similarly, neoadjuvant chemotherapy in the second phase 3 trial, FOxTROT, resulted in a 74% pathological response rate in the pMMR group, whereas it was only 27% in the dMMR subgroup.²⁹

It is now well established that immune checkpoint inhibitors have increased activity in MSI-high or dMMR solid tumors, and this is true for colon cancer.³⁰ Evidence for the efficacy of immunotherapy in advanced dMMR CRC is growing, with reported objective response rates up to 31% to 40% for single-agent checkpoint inhibitors and 55% for dual-checkpoint inhibition; however, response rates in metastatic pMMR colon cancer are close to 0%.^31-33

The role of immunotherapy in the first-line metastatic dMMR CRC setting has now been confirmed with the results of the KEYNOTE-177 study, which led to the FDA approval of pembrolizumab.³⁴ The role of immunotherapy in the adjuvant setting is currently being studied in the Adjuvant Trial of Deficient Mismatch Repair in Colon Cancer (ATOMIC trial; NCT02912559), which is randomizing patients with stage III dMMR colon cancer to standard chemotherapy alone vs in combination with immunotherapy.³⁵ Immunotherapy with or without chemotherapy may play a significant role in the neoadjuvant treatment of dMMR LACC. However, there are no definitive data regarding chemoimmunotherapy in the neoadjuvant setting. Although 10% to 15% of patients with early-stage CRC present with dMMR disease, only 4% of patients with metastatic colon cancer test positive for dMMR, making more patients with early-stage disease eligible for immunotherapy.

Neoadjuvant immunotherapy is an evolving strategy in oncology. A phase 2 open-label neoadjuvant immunotherapy trial of 32 patients with MSI-high/dMMR nonmetastatic solid tumors (24 colorectal, 1 endometrial, 1 gastric, 1 meningeal, 2 duodenal, 1 ampullary, and 2 pancreatic) showed that neoadjuvant treatment with pembrolizumab was safe, with encouraging clinical activity.³⁶ In the first neoadjuvant immunotherapy trial of colon cancer, the phase 2 NICHE trial, 19 patients with resectable, early-stage colon cancer—both dMMR and pMMR—were treated with ipilimumab at 1 mg/kg on day 1 and nivolumab at 3 mg/kg on days 1 and 15.³⁷ A major pathologic response, defined as <5% residual viable tumor, was observed in 100% (7/7 tumors), and a complete pathologic response was seen in 57% (4/7 tumors) of the dMMR patients. There were no observed major pathologic responses in the pMMR group. More recently, in a final analysis of 35 patients with nonmetastatic resectable CRC (20 with dMMR and 15 with pMMR) treated with neoadjuvant immunotherapy, 12 of 20 patients with dMMR tumors achieved a complete pathologic response; in 19 of 20, a major pathologic response was seen. Interestingly, contrary to other studies, a pathologic response was also noted in 4 of 15 patients with pMMR tumors. In those 4, 3 had a major pathologic response and 1 had a partial response.³⁸

Based on the available data and the extent of the tumor, we treated our patient with FOLFOX every 2 weeks and pembrolizumab every 3 weeks, similar to the regimen in the ATOMIC adjuvant trial. The patient tolerated treatments well except for the very interesting and rare AE of oxaliplatin-induced fever with IL-6 release, which led to the change of the chemotherapy component of his neoadjuvant regimen to FOLFIRI. Oxaliplatin, a third-generation platinum analogue, is a novel compound with proven antitumor activity in CRC. AEs are generally moderate and include peripheral neuropathy along with mild bone marrow suppression and gastrointestinal AEs. A rare reported AE of oxaliplatin is fever up to 102.2° F starting 2 to 6 hours after administration, persisting for up to 3 days, and recurring at the same interval on following administrations of oxaliplatin. This very rarely reported phenomenon has been associated with IL-6 release.³⁹ Blood samples taken from our patient disclosed an increase in IL-6 serum levels parallel to the body temperature, while C-reactive protein values remained unchanged. This interesting finding of elevated IL-6 levels during his FOLFOX treatments made us question the available literature data on the possible role of cytokines in predicting the response and AEs related to immune checkpoint inhibitors. The investigations of TNF-α, IFN-γ, IL-6, IL-8, TGF-β and other cytokines as predictors of the responses and AEs to immune checkpoint inhibitors have produced mixed results. While increased levels of IFN-γ and IFN-γ pathway genes have always acted as positive biomarkers for response and AEs, high baseline and increased levels of IL-8, IL-6, and TGF-β have been negative biomarkers for response and AEs.⁴⁰ Resolution of fever and elevated IL-6 reaction after changing his chemotherapy to FOLFIRI, as well as complete pathologic response in our patient, further supported this being an oxaliplatin-related AE.

Outcome of the Case

After completion of neoadjuvant chemoimmunotherapy, surgical resection revealed a complete pathologic response. Patient is on follow-up with no evidence of disease.

Conclusions

As data continue to unfold, neoadjuvant chemotherapy and/or immunotherapy will likely find their place in the treatment of locally advanced dMMR and pMMR colon cancer. Molecular characterization of tumors, along with the radiologic and pathologic responses to treatment, will determine which populations are most likely to benefit from this approach. Avoiding operative delays in those with a low likelihood of response to cytotoxic treatment will be imperative in appropriate use of this approach. The inclusion of novel approaches, with immunotherapy or other targeted agents outside of traditional chemotherapy, may provide significant survival advantages. Translational studies will be pivotal in our understanding of this new concept, as will immunomodulation studies using antitumor vaccines and chimeric antigen receptor T cells.⁴¹ Clinicians should closely watch this developing area, consider the option of neoadjuvant chemotherapy, and seek out opportunities for participation in ongoing clinical trials.

AUTHOR AFFILIATIONS:

¹Mehmet Sitki Copur, MD, Quan Ly, MD, Jacqueline R. Kelly, MD, MSc; University of Nebraska Medical Center, Omaha, NE.
²Mehmet Sitki Copur, MD, Jacqueline R. Kelly, MD, MSc, Soe Min Tun, MD, MBA, MSc; Morrison Cancer Center, Mary Lanning Healthcare, Hastings, NE.
³Caleb Schroeder, MD; Department of General Surgery, Mary Lanning Healthcare, Hastings, NE.
⁴Whitney Wedel, MD, Nicholas Lintel, MD, Adam Horn, MD; Department of Pathology, Mary Lanning Healthcare, Hastings, NE.
⁵Paul Rodriguez, MD; Department of Radiology, Mary Lanning Healthcare, Hastings, NE.
⁶Bronson Riley, CGC; Genetic Counseling Service, Mary Lanning Healthcare, Hastings, NE.

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