Total neoadjuvant therapy is a viable treatment strategy for patients with locally advanced rectal cancer and is associated with improved delivery of planned therapy, increased downstaging, earlier introduction of optimal systemic chemotherapy to address micrometastases, and the potential to sidestep any surgical treatment at all.
Moreover, delivery of all chemotherapy preoperatively obviates the need for postoperative therapy, reducing the duration with a diverting ileostomy and alleviating the need for patients to undergo chemotherapy with a stoma.
Our recent retrospective study, published in June 2018 in JAMA Oncology, included 811 patients — the largest published series on locally advanced rectal cancer (LARC) treated with total neoadjuvant therapy (TNT) to date. We compared TNT with the traditional approach of preoperative chemoradiation (chemoRT) followed by postoperative adjuvant chemotherapy. (1)
Of the 320 patients in the TNT group, 73 did not undergo surgery within 12 months. A total of 67 of those 73 patients (92 percent) had a sustained clinical complete response and elected to continue with nonsurgical treatment. (1) Compared with chemoradiotherapy with planned adjuvant chemotherapy, patients receiving TNT were also more likely to complete the chemotherapy with fewer dose reductions.
These findings provided additional support for the inclusion of TNT in the National Comprehensive Cancer Network’s (NCCN) surgical guidelines for rectal cancer (1) and the call for the strategy to be considered the standard of care for clearly node-positive patients with low-lying rectal tumors.
Total Neoadjuvant Therapy
Patients who require total removal of the rectum and a permanent colostomy experience significant distress and a severely compromised quality of life. The most recent approach for treating patients with LARC (T3, T4, or node positive) has been preoperative chemoRT followed by total mesorectal excision (TME) and postoperative adjuvant chemotherapy with fluorouracil and oxaliplatin. This approach can achieve an overall cure rate of more than 70 percent with excellent local control. As surgical and reconstruction procedures have advanced, chemoRT followed by TME rarely results in the need for a permanent colostomy. However, patients undergoing the approach may still experience significant negative impacts on quality of life, such as an increase in stool frequency, greater urge to defecate, and the need to use pads more often for faecal leakage. (2)
Total neoadjuvant therapy involves chemoradiation and chemotherapy before surgery to optimize the delivery of systemic therapy aimed at micrometastases. Memorial Sloan Kettering Cancer Center and other centers have previously published papers on the benefits of TNT. In our study published in the Journal of the National Comprehensive Cancer Network, 22 of 61 patients (36 percent) treated with induction FOLFOX (folinic acid, fluorouracil, and oxaliplatin) before chemoRT had either a pathological complete response (n=13) or a complete clinical response (n=9), and tolerance rates were high. (3)This study, along with others, (4), (5)led the NCCN to include TNT as a viable treatment strategy for stage II and stage III LARC in its rectal surgery guidelines. (6)
Improved Responses with TNT
In our most recent study, we compared the tolerance of prescribed chemotherapy, tumor response, and short-term oncologic outcomes in two cohorts of patients with LARC (T3, T4, or node positive) at MSK: One group of 308 patients had received TNT, and the other group of 320 patients had been treated with preoperative chemoRT and planned adjuvant chemotherapy. (1)
Our analysis showed that patients in the TNT group received higher percentages of the planned oxaliplatin and fluorouracil prescribed doses compared to the chemoRT with planned adjuvant chemotherapy group. The complete response rate — which included pathological complete response in those who underwent surgery and clinical complete response for at least 12 months post-treatment in patients who did not have surgery — was 36 percent in the TNT group compared to 21 percent in the chemoRT with planned adjuvant chemotherapy group. (1)Patients with stage II tumors had a higher complete response rate of 54 percent (23 of 43 patients) compared to 33 percent (87 of 265 patients) with clinical stage III tumors. Pathological complete response rates were in line with previous results from a multicenter study led by MSK and published in The Lancet, which ranged from 25 to 38 percent. ([vii])
Optimizing Surgical Decisions
In our study, 235 of 308 patients in the TNT cohort had surgery after TNT, and 43 (18 percent) of that subgroup achieved a pathological complete response at 12 months. The remaining 73 patients in the TNT cohort did not have surgery within 12 months post-TNT, and of that subgroup, 67 of them (92 percent) had a sustained complete clinical response and elected nonoperative therapy. (1)
Diverting ileostomy rates after low anterior resection were comparable between the cohorts, but stoma closure was significantly earlier in the TNT group, within 15 weeks for 72 percent of patients compared to only 9 percent in the chemoRT and planned adjuvant chemotherapy group (p < 0.001). (1)
Our findings are indeed encouraging, but larger and longer-term studies are needed to determine if they will translate to improved survival rates. The oncologic goals for treating rectal cancer are to eliminate cancer and prevent recurrence by treating the primary tumor and micrometastases. All aspects of combined treatment for LARC are associated with significant morbidity and long-term functional complications that have an impact on patients’ quality of life. ([viii]) Therefore, it is essential to design an individualized treatment plan for each patient, taking into account the stage and grade of their cancer and through careful consideration of the benefits and risks of all treatment modalities, including chemotherapy, chemoRT, and surgery.
At MSK, our team of multidisciplinary rectal cancer experts includes surgeons, medical oncologists, radiation oncologists, and gastroenterology and preventive oncologists. We consult as a team on each case to develop an individualized treatment plan that includes the most-advanced and comprehensive options for each patient.
Advancing Rectal Cancer Research
We are committed to advancing clinical research to find new ways to improve outcomes for patients. Currently, at MSK, we are conducting 13 clinical trials investigating new chemotherapy, chemoradiation, surgical, and combination therapy approaches for rectal cancer. For example, the Phase II Study of Chemotherapy and Chemoradiation Followed by Surgery or Nonoperative Management in Patients with Stage II or III Rectal Cancer seeks to determine whether additional chemotherapy before surgery is more effective than standard treatment and if some patients can avoid surgical removal of the rectum. The study is currently recruiting participants, and we anticipate completing the study later this year.
We are also participating in the ongoing PROSPECT study, a large multicenter phase II/III randomized, controlled trial examining the effectiveness and longer-term effects of neoadjuvant FOLFOX alone or with radiation therapy for treating patients with LARC who are undergoing surgery.