Chemotherapy Alone for Patients With Stage II/III Rectal Cancer Undergoing Radical Surgery

This prospective pilot study attempted to determine the efficacy of preoperative chemotherapy with six cycles of FOLFOX 6 followed by radical surgery followed by six additional cycles of FOLFOX 6 for patients with stage II/III rectal cancer. The overall response rate was 68.8%. Neoadjuvant chemotherapy (FOLFOX) without radiotherapy is active and safe but cannot be considered a standard of care until the results of prospective randomized phase III trials are available.

Abstract

Purpose.

The purpose of this prospective pilot study was to determine the efficacy of preoperative chemotherapy with six cycles of FOLFOX 6 (without radiation therapy) followed by radical surgery followed by six additional cycles of FOLFOX 6 for patients with stage II/III rectal cancer.

Patients and Methods.

From January 2010 to January 2014, patients with locally advanced rectal cancer who met the eligibility criteria were enrolled in this study. Patients received FOLFOX 6 chemotherapy comprising oxaliplatin and leucovorin calcium i.v. over 2 hours on day 1, then bolus, and then continuous fluorouracil i.v. over 46 hours on days 1 and 2. Treatment was repeated every 14 days for 6 courses followed by radical surgery followed by additional 6 cycles of FOLFOX 6.

Results.

In total, 45 patients were enrolled in this study. In the preoperative re-evaluation, the overall response rate was 68.8% (clinical complete response was 4.4%, and the partial response was 64.4%). There were 14 cases (31.2%) of stable disease. No patients had progressive disease. Postoperatively, the pathologic complete response rate was 8 of 45 (17.8%; 95% confidence interval [CI]: 8.9%–28.9%). The median follow-up was 29 months (range 9–54 months). The actuarial 3-year overall survival and disease-free survival rates for all patients were 80.8% (standard error, 1.877; 95% CI: 69.3%–92.3%) and 67.9% (standard error, 2.319; 95% CI: 54.3%–81.5%), respectively.

Conclusion.

Neoadjuvant chemotherapy (FOLFOX) without radiotherapy is active and safe but cannot be considered a standard of care until the results of prospective randomized phase III trials are available.

Implications for Practice:

Neoadjuvant radiotherapy of rectal cancer represents the current standard of care. However, its use is also associated with short-term toxicity and long-term morbidity. With the increasing use of total mesorectal resection resulting in better local control and advances in systemic therapy for colorectal cancer, this study highlights the question of whether radiation is a necessary component of neoadjuvant therapy for all patients with rectal cancer or whether select patients could be spared the additional toxicities and inconvenience of radiotherapy. This study suggests that neoadjuvant FOLFOX without radiotherapy is active and safe, but it could not be considered a standard of care till now.

Introduction

The inclusion of radiation in the neoadjuvant therapy of rectal cancer represents the current standard of care, based primarily on the reduction of local recurrence and improvement in rates of sphincter preservation, both of which are significant quality-of-life benefits for patients [1]. However, the use of radiation is also associated with the potential for significant short-term toxicity and long-term morbidity, including infertility and sexual dysfunction, abdominal fibrosis, autonomic nerve injuries resulting in abnormal bowel and bladder function, increased risk for pelvic fractures, and decreased bone marrow reserve, which would be potentially detrimental to therapy in the setting of recurrent or metastatic disease [2–6]. Therefore, it is logical to question whether radiation is a necessary component of neoadjuvant therapy for all patients with rectal cancer or whether select patients could be spared the additional toxicities and inconvenience of radiotherapy [7]. Another important consideration favoring this chemotherapy is substantially less travel time/treatment time for patients given the elimination of daily neoadjuvant radiation.

Although the increasing use of total mesorectal resection (TME), have resulted in higher complete resection rates, fewer positive margins [7], and significantly less local recurrence rates [8–11], long-term (12 years) follow-up of one of the short-course radiation trials (the Dutch TME trial [12]) showed that 10-year survival was significantly improved in patients with stage III disease with a negative circumferential margin in the radiotherapy plus surgery group compared with the group that received surgery alone (50% vs. 40%; p = .032) [13]. However, this long follow-up showed that secondary malignancies and other nonrectal cancer causes of death were more frequent in the radiotherapy group than in the control group (14% vs. 9% for secondary malignancies), negating any survival advantage in the node-negative subpopulation [13].

In addition, advances in systemic therapy for colorectal cancer, including the addition of oxaliplatin to fluoropyrimidines, have resulted in improved response rates as high as 70% [14, 15], which could be potentially beneficial in the neoadjuvant setting. With better local control, an increasing percentage of patients with rectal cancer will experience relapse at a systemic level, providing a rationale for the investigation of oxaliplatin-based systemic therapy without radiotherapy for these patients. Lower rates of intra-abdominal metastases discovered at surgery in patients treated with oxaliplatin in the ACCORD12, STAR-01, and AIO trials [16–18] suggest that adding this agent to neoadjuvant therapy may improve control of micrometastatic disease. The toxicity profile of oxaliplatin is well documented. Primarily, toxicities include severe peripheral neuropathy linked to acute and cumulative doses of oxaliplatin [19]. The Food and Drug Administration reported that more than 70% of patients receiving oxaliplatin had some degree of peripheral neuropathy [20], which is often the cause for treatment discontinuation. Despite these adverse life-altering side effects, oxaliplatin therapy is a treatment choice in a large group of cancer patients, including those with colorectal cancer [21]. In this study, this approach (preoperative fluorouracil, leucovorin, and oxaliplatin with no radiotherapy [RT]) in patients with locally advanced rectal cancer was tested in a prospective pilot study. The aim of this study is to determine the efficacy of preoperative chemotherapy with 6 cycles of FOLFOX 6 (without radiation therapy) followed by radical surgery followed by 6 additional cycles of FOLFOX 6. The primary endpoint of this trial was pathologic complete response. Secondary endpoints included observation of toxic side effects, patterns of disease relapse, disease-free survival, and overall survival outcomes.

Patients and Methods

In total, 45 rectal cancer patients who were diagnosed at the Department of Surgical Oncology, South Egypt Cancer Institute and Department of Surgery, Faculty of Medicine, Assiut University and who satisfied the following criteria were entered in this trial. To be eligible, patients must have had histologically proven adenocarcinoma of the rectum (based on proctoscopy and biopsy) with no distant metastases. Tumor stage must have been II or III assessed by clinical examination, transrectal ultrasonography (TRUS), magnetic resonance imaging (MRI), and computerized tomography (CT) scan. Patients must have had no prior chemotherapy or pelvic irradiation. Other eligibility criteria included Eastern Cooperative Oncology Group performance status 0–2, age 18 years or older, pretreatment absolute neutrophil count of ≥1,000/mm³, platelet count of ≥100,000/mm³, and serum creatinine ≤ 1.5 × upper limit of normal (ULN); bilirubin was ≤1.5 × ULN; alanine aminotransferase was ≤2.5 × ULN. Patients with T4b, locally unresectable, or known metastases and those with serious comorbid disease that prevented delivery of full treatment were excluded from eligibility, as were pregnant women because of the potential teratogenic or abortifacient effects of oxaliplatin and fluorouracil (5-FU)/leucovorin. All patients provided a written informed consent. All patients were assessed by history, clinical examination, complete blood count, blood chemistry, TRUS, proctoscopy and biopsy, CT scan of the chest and abdomen, and MRI of the pelvis.

Treatment Regimen

Patients received FOLFOX 6 chemotherapy comprising oxaliplatin and leucovorin calcium i.v. over 2 hours on day 1, then bolus, and then continuous fluorouracil i.v. over 46 hours on days 1 and 2 (Table 1). Treatment was repeated every 14 days for 6 courses in the absence of disease progression or unacceptable toxicity. Then patients were re-evaluated clinically and radiologically by MRI of the pelvis. Then they proceeded to surgery.

Table 1.

Drugs and doses used and guidelines followed

Within 4 weeks after completion of neoadjuvant therapy, patients underwent open surgery by midline incision and exploration of the abdomen to exclude metastatic disease and evaluate resectability of the tumor. The rectum was always mobilized off the sacrum using sharp dissection along the parietal fascia, ensuring en bloc resection of the mesorectum with proximal safety at 6–10 cm and distal safety at 2 cm. Frozen-section examination was used to confirm the lack of tumor cells in the distal margin. Total mesorectal excision was completed by anterior resection of Dixon or an abdominoperineal resection according to the distance of the tumor from the anal verge and sphincteric function. Anastomosis was done by the hand-sewn method or by the stapler method. In all cases, lateral lymph node dissection and pelvic autonomic nerve preservation were carried out in persisting T3 patients whose MRI pelvic examination revealed a nodal diameter of >5 mm with a heterogeneous pattern.

Operative mortality was defined as deaths that occurred during the same hospital stay or within 30 days following the primary operation. Operative morbidity was defined as complications that contributed to prolonged hospital stay or led to additional interventions or procedures. Duration of hospital stay was defined as duration from time of operation until discharge.

Within 4 weeks after surgery, patients received the same chemotherapy regimen of FOLFOX 6 every 14 days for 6 courses in the absence of disease recurrence or unacceptable toxicity. Any patient with positive resection margins was offered postoperative radiation. However, all patients included in this study were found to have negative resection margins, so no postoperative radiation was given.

Follow-up

Patients were evaluated every cycle for acute toxicity. Clinical examination and complete blood count were performed. Toxic side effects were assessed according to National Cancer Institute Common Toxicity Criteria (version 2.0). After completion of study treatment, patients were followed every 3 months for the first 2 years, every 6 months for the next 3 years, and annually thereafter. During such visits, history and physical examination were taken, and blood samples were obtained to check carcinoembryonic antigen (CEA). Further imaging (chest, abdominal, and pelvic imaging) and endoscopy were done if the CEA level was ≥10 IU/L or clinical suspicion of recurrence. Colonoscopy was done 1, 3, and 5 years postoperatively unless there was suspicion of recurrence.

Statistical Analysis

Kaplan-Meier product-limit estimates were used to estimate the probabilities of overall survival (OS) and disease-free survival (DFS). DFS was defined as the probability of remaining free of invasive local recurrence, distant metastasis, or death. Patients whose cause of death was unknown were assumed to have died of rectal cancer. Actuarial survival rates were calculated from the time of diagnosis to the time of the last follow-up visit or death. Statistical analysis was performed using IBM SPSS Statistics for Windows, version 22.0 (IBM Corp., Armonk, NY).

Results

From January 2010 to January 2014, 45 patients with locally advanced rectal cancer were enrolled in this study. Patient characteristics are shown in Table 2.

Table 2.

Baseline characteristics of the patients

Clinical and Radiological Evaluation After Neoadjuvant Chemotherapy

In the preoperative re-evaluation, clinical complete response was observed in 2 patients (4.4%), and 29 (64.4%) patients were judged as having a partial response. Thus the overall response rate (complete response [CR] plus partial response [PR]) was 68.8%. There were 14 cases (31.2%) of stable disease. No patients had progressive disease.

Surgery

All patients underwent total mesorectal excision completed by anterior resection of Dixon (24 patients: 17 male and 7 female) or abdominoperineal resection (21 patients: 13 male and 8 female). Anastomosis was done by hand sewing in 20 patients and by stapling in 4 patients. Covering colostomy was done in three cases of anterior resection patients because they were diabetic and were not well prepared and closed later on. The radical resection rate was 100%.

There was no perioperative mortality and no intraoperative morbidity, whereas postoperative morbidity were presented in 5 patients, with 3 patients complaining of pelvic collections, which were treated conservatively by medical treatment, sonar guided aspiration and follow-up in 2 patients, whereas the other one was in need of sonar-guided tubal drainage. Two patients suffered from delayed wound healing caused by diabetes and wound infection; one of them was treated by repeated dressing and medical treatment while the other was in need of reclosure. The mean hospital stay was 8.3 days.

Pathological Evaluation

Postoperatively, the pathological stage was compared with clinical stage before chemotherapy. The pathologic complete response rate was 8 of 45 (17.8%; 95% CI, 8.9%–28.9%). Of those 45 patients, 27 (60%) had reduced tumor-regional lymph node staging (TN staging). Table 3 shows the relationship between baseline and pathological staging of the study patients. T category downstaging was observed in 35 patients (77.8%). Of 29 patients who had clinical N1 or N2 before treatment, N category downstaging (cN+ to pN0) was detected in 24 (82.8%).

Table 3.

The relationship between baseline and pathological staging of the study patients

Postoperative Chemotherapy

Of 45 patients, 41 (91.1%) completed all 18 weeks of postoperative FOLFOX 6 chemotherapy. The other four patients did not complete postoperative chemotherapy because of its toxicity (three during the first three cycles and one during the final three cycles).

Survival

The median follow-up was 29 months (range, 9–54 months). The actuarial 3-year overall survival and disease-free survival for all patients was 80.8% (standard error, 1.877; 95% CI, 69.3%–92.3%) and 67.9% (standard error, 2.319; 95% CI, 54.3%–81.5%), respectively (Figs. 1, 2). In total, 3 patients had local recurrences, 7 developed distant metastases (lung n = 2, liver n = 3, and multiple sites n = 2), and 1 had both local and distant disease as their first sites of treatment failure. None of the former metastatic cases developed local recurrence during further follow-up. Of 45 patients, 8 (17.8%) have died. Cause of death was progressive cancer in all cases.

Figure 1.

Overall survival of study patients.

Figure 2.

Disease-free survival of study patients.

Toxicity

As shown in Table 4, most toxicity was grade I or II level. It shows the incidences of grade 3/4 toxicities during neoadjuvant chemotherapy. There were no deaths related to chemotherapy. No grade 3/4 thrombocytopenia or febrile neutropenia toxicity was seen. The most common nonhematological toxicity was nausea and/or vomiting (71.1%).

Table 4.

Neoadjuvant chemotherapy-induced toxicity during neoadjuvant chemotherapy

Discussion

This study aimed to assess the role of neoadjuvant chemotherapy without RT for clinical stage II/III rectal cancer. The evaluation of neoadjuvant chemotherapy for rectal cancer could not be separated from the accurate judgment of rectal cancer staging before and after treatment. Assessments commonly entailed the use of the following modalities: proctoscopy, TRUS, CT, MRI, and pathology. In our study, the objective response rate was 68.8%, and pathological downstaging was 77.8% (35 of 45) with an R0 resection rate of 100%.

Unexpectedly, the clinical complete response (cCR) (4.4%) observed in the study patients was much less than the pathologic complete response rate (pCR) was 8 of 45 (17.8%; 95% CI, 8.9%–28.9%). However, a similar discrepancy between cCR and pCR was reported by Uehara et al. [22] (3.3% and 13.3%, respectively). In contrast, many studies [23–26] reported higher cCR than pCR. This difference can be attributed to the methods of reassessment. Our patients were re-evaluated clinically and radiologically only by MRI of the pelvis with a known proportion of false positive results [27], whereas the other four studies used a combination of proctoscopy, endorectal ultrasound, computed tomography or MRI, and biopsy information to determine response.

Our results compared favorably with pCR rates of 8%–15% among historical controls treated with fluoropyrimidine-based CRT in patients with locally advanced rectal cancer [6, 18–28]. Based on its role in resected stage III colon cancer and its radiosensitizing properties, the addition of oxaliplatin to the standard fluoropyrimidine-based CRT was tested in many studies [1]. However, the reported pCR of our patients is comparable with those reported by the studies using neoadjuvant oxaliplatin- and fluoropyrimidine-based CRT in patients with locally advanced rectal cancer. Most of these studies primarily evaluated pCR and surgical outcomes, including sphincter preservation and postoperative complication rates. Reported pCR rates varied between 7% and 28% [29–34].

Two preliminary studies from Memorial Sloan Kettering Cancer Center investigators have evaluated outcomes with neoadjuvant chemotherapy alone in patients with intermediate-risk rectal cancer. In both reports, the R0 resection rate was 100%. The first one was a small, retrospective study that evaluated patients with colon and rectal cancers who received preoperative FOLFOX alone, either because of suspected metastatic disease or contraindications to or refusal of RT. Of the 20 patients (6 with rectal cancer) treated with FOLFOX or FOLFOX plus bevacizumab without RT, 7 (35%) achieved a pCR. Of the 6 patients with rectal cancer who received preoperative FOLFOX, 2 achieved a pCR, and an additional 3 had 90% positive treatment effect [35]. The other report was a prospective pilot study of neoadjuvant chemotherapy alone in patients with clinical stage II/III rectal cancer (non-T4 tumors, candidates for sparing surgery, and a nonthreatened circumferential resection margin [CRM] by MRI) were treated with six cycles of FOLFOX plus bevacizumab alone. The primary outcome was R0 resection rate. On preliminary report, 31 patients were enrolled. Twenty-nine patients completed neoadjuvant chemotherapy and had clinical regression, proceeding to surgery without preoperative RT. All patients had R0 resections with 27% pCR rate. With 4 years of follow-up, there have been no local recurrences [36, 37]. These better outcomes compared with our findings can be explained by using this protocol in patients with intermediate-risk rectal cancer only and the addition of bevacizumab. Based on these promising short-term results, a large, randomized phase II/III study comparing preoperative 5-FU/RT with neoadjuvant FOLFOX alone for intermediate-risk rectal cancer is ongoing in the U.S. [38].

On the contrary, our results are superior to those reported by Uehara et al. [22], who conducted a phase II trial to confirm the safety and efficacy of neoadjuvant chemotherapy (oxaliplatin and capecitabine and bevacizumab) without RT for MRI-defined poor-risk disease only [22]. Among the 29 patients who completed the scheduled chemotherapy, a pathological complete response was observed in 13%, and good tumor regression was exhibited in 37%. The completion rate of this experimental treatment was 84%, the R0 resection rate was 90%, and a postoperative complication occurred in 43% [22]. Also, a large, randomized trial comparing preoperative 5-FU/RT with neoadjuvant chemotherapy alone for selected poor-risk disease or with neoadjuvant chemotherapy followed by selective use of RT is awaited [39].

In comparison with the reported results of other studies using standard preoperative radiochemotherapy in patients with locally advanced resectable rectal cancer, the findings of this study showed noninferior overall survival. Comparing the outcome in patients with locally advanced low rectal cancer treated by neoadjuvant chemoradiation followed by sphincter-saving resection against those who underwent abdominoperineal resection, Gawad et al. [40] reported 3-year OS of 85.4% and 84.9%, respectively. In a similar study by Elwanis et al. [41], the 2-year survival for all patients was 79%. Eitta et al. [42] tested two different approaches of preoperative radiotherapy, either short-course or long-course radiotherapy in patients with resectable rectal cancer. The 2-year OS rate was 64% ± 3% and 66% ± 2%, respectively. In the NSABP R-03 trial, the 5-year OS rate was 74.5% for patients who received preoperative radiochemotherapy that contained 5-FU [28]. In the EORTC 22921 trial, patients with locally advanced resectable rectal cancer were randomly assigned to receive preoperative radiotherapy, preoperative chemoradiotherapy, preoperative radiotherapy and postoperative chemotherapy, or preoperative chemoradiotherapy and postoperative chemotherapy. The combined 5-year OS rate for all 4 groups was 65.2% [43]. The main limitation of this study is that it was too small to meaningfully compare the local failure rate with those in the literature or stratify the patients’ outcome by the risk factors.

With regard to the acute toxicities during neoadjuvant therapy, both grade 3/4 hematologic toxicity and neuropathy were slightly higher in our study (8.9% and 2.2%, respectively) compared with the others (3.6%–6% and 0%–1%, respectively) using the conventional 5-FU/RT [6, 17, 44, 45]. The other grade 3/4 toxicities seemed to be equivalent. In comparison with those using preoperative chemotherapy alone, the other studies incorporating bevacizumab in their protocol reported a high rate of anastomotic leakage, which might result from bevacizumab-related delayed wound healing [22, 35–37].

Conclusion

We found that neoadjuvant FOLFOX without radiotherapy is active and safe but cannot be considered a standard of care until the results of prospective randomized phase III trials are available. In view of the noninferior 5-year overall survival, this approach seems reasonable for some patients, for example, young females because of concerns about ovarian dysfunction with radiotherapy, patients with contraindications to radiotherapy, and patients with rectal cancers in which the surgical CRM is found to be clear by MRI.

Author Contributions

Conception/Design: Samy M. AlGizawy

Provision of study material or patients: Samy M. AlGizawy, Hoda H. Essa, Badawy M. Ahmed

Collection and/or assembly of data: Samy M. AlGizawy, Hoda H. Essa, Badawy M. Ahmed

Data analysis and interpretation: Samy M. AlGizawy, Hoda H. Essa

Manuscript writing: Samy M. AlGizawy

Final approval of manuscript: Samy M. AlGizawy, Hoda H. Essa, Badawy M. Ahmed

Disclosures

The authors indicated no financial relationships.