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Neoadjuvant therapy improves outcomes for locally advanced rectal cancer
Total neoadjuvant therapy prior to chemoradiotherapy facilitated delivery of systemic therapy and improved treatment response among patients with locally advanced rectal cancer, according to results of a retrospective cohort analysis.
“To our knowledge, this single-institution study represents the largest published series of patients with locally advanced rectal cancer treated with neoadjuvant chemotherapy followed by chemoradiotherapy,” Andrea Cercek, MD, medical oncologist in the department of medicine at Memorial Sloan Kettering Cancer Center, and colleagues wrote. “Our findings are consistent with previous studies demonstrating higher compliance and lower toxic event rates for total neoadjuvant therapy-based regimens, although response rates in those studies varied, with partial complete response rates ranging from 14% to 36%.”
Preoperative chemoradiotherapy followed by total mesorectal excision and postoperative chemotherapy with fluorouracil and oxaliplatin is standard treatment for stage II to stage III locally advanced rectal cancer. However, previous research showed induction or consolidation chemotherapy with chemoradiotherapy prior to surgery for locally advanced rectal cancer has substantial benefits, including improved delivery of planned therapy and increased downstaging.
Cercek and colleagues assessed tolerance of prescribed chemotherapy, tumor response and short-term oncologic outcomes of 308 patients (58.8% men) treated with total neoadjuvant therapy compared with 320 patients (60% men) treated with chemoradiotherapy with planned adjuvant chemotherapy.
The mean age of all patients was 56.7 years (standard deviation, 12.9). Patients in the chemoradiotherapy group tended to be older and less likely to have stage III disease than those in the total neoadjuvant therapy group.
Total neoadjuvant therapy comprised induction chemotherapy in the form of folinic acid, fluorouracil and oxaliplatin (FOLFOX) for eight cycles (n = 288), capecitabine and oxaliplatin for five cycles (n = 17), or weekly fluorouracil/leucovorin and biweekly oxaliplatin (n = 3).
Chemoradiotherapy began 2 to 3 weeks after induction therapy and consisted of 25 to 28 radiotherapy fractions with 225 mg/m2 concurrent infusional fluorouracil or 825 mg/m2 oral capecitabine twice daily.
Patients underwent 3-D conformal radiotherapy or intensity-modulated radiotherapy with 45 Gy in 1.8 Gy fractions to the pelvis and 5.4 Gy to the tumor.
Following neoadjuvant therapy, patients underwent proctoscopy, CT and MRI restaging.
The neoadjuvant therapy group received higher portions of oxaliplatin and fluorouracil dose compared with the chemoradiotherapy and planned adjuvant therapy group.
Results showed 17% of patients in the chemoradiotherapy group who underwent surgery within 1 year after completion of neoadjuvant therapy experienced pathologic complete response.
Eight-percent of the chemoradiotherapy group (n = 24) did not undergo surgery within 1 year. Of these, 79% experienced sustained clinical complete response.
Most patients (76%) in the total neoadjuvant therapy group underwent surgery within 1 year after completion of therapy, of whom 18% experienced pathologic complete response. The remaining patients (n = 73) did not undergo surgery within 1 year, of whom 92% achieved clinical complete response.
Combined complete response rate at 1 year was 36% in the total neoadjuvant therapy group and 21% in the chemoradiotherapy group.
Among patients who underwent surgery within 1 year, median time to surgery following completion of therapy was longer in the total neoadjuvant therapy group (63 days vs. 56 days; P < .002).
Nonoperative treatment appeared more common in the total neoadjuvant therapy group than the chemoradiotherapy group (24% vs. 8%), for an absolute difference of 16 percentage points (P < .001).
Analysis of folinic acid, fluorouracil and oxaliplatin prescription and dosing indicated patients in the total neoadjuvant therapy group had higher average doses of fluorouracil (96% vs. 88%; P = .003), fewer dose reductions (50% vs. 64%; P < .001) and underwent a higher number of cycles (95% vs. 83%; P < .001). Results appeared similar for oxaliplatin tolerability.
Limitations of the study included its retrospective, single-center design and limited follow-up data.
“Total neoadjuvant therapy was associated with improved delivery of systemic therapy and increased response to treatment, and it provides a promising platform for nonoperative watch-and-wait protocols,” the researchers wrote.
The study demonstrated that total neoadjuvant therapy can enhance recurrence-free organ preservation rates at 1 year. However, there are still risks, according to Theodore S. Hong, MD, director of gastrointestinal radiation oncology at Massachusetts General Hospital, and David P. Ryan, MD, clinical director of the Massachusetts General Hospital Cancer Center.
“Chemotherapy is associated with a mortality risk, and it is possible that oxaliplatin may incur durable neuropathy without any impact on cancer control,” Hong and Ryan wrote in a related editorial. “If [total neoadjuvant therapy] is used to enhance organ preservation, it will be important to make the risks and benefits very clear to patients.”
Total neoadjuvant therapy may be considered standard of care for select patients who are node-positive with low-lying rectal tumors, as well as those with high-risk, locally advanced disease, they wrote.
“A note of caution should be sounded around the value of moving this strategy to patients with lower-risk, locally advanced cancers because these patients may not need any chemotherapy,” they wrote. – by Melinda Stevens
Disclosures: The authors, Hong and Ryan report no relevant financial disclosures.
Perspective
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Wafik S. El-Deiry
The current standard of care for locally advanced rectal cancer (T3/T4 or node positive) involves neoadjuvant chemoradiotherapy followed by surgery and then adjuvant chemotherapy, typically with 6 months of FOLFOX. This study looked at “total neoadjuvant therapy” that delivered both chemoradiotherapy and 4 months (8 cycles) of systemic FOLFOX chemotherapy prior to surgery. The study reported outcomes on the 308 patients who received eight cycles of FOLFOX followed by chemoradiation within the total neoadjuvant therapy cohort; an additional 79 patients received the chemoradiation followed by FOLFOX but their outcomes were not provided. Part of the rationale for earlier systemic chemotherapy is to suppress micrometastases.
The results of the nonrandomized retrospective study show, in a large cohort of patients in each group — 320 received chemoradiation with the planned eight cycles of FOLFOX adjuvant chemotherapy and 308 received total neoadjuvant therapy with eight cycles of FOLFOX followed by chemoradiation —that total neoadjuvant therapy is feasible. This study also shows that the pathologic complete response rate among those who underwent surgery plus the clinical complete response rate among those who didn’t was 36% in the total neoadjuvant therapy group and 21% in the conventional chemoradiation with planned adjuvant chemotherapy group at 1 year after completion of treatment.
Total neoadjuvant therapy is an acceptable treatment strategy for locally advanced rectal cancer and this study supports the National Comprehensive Cancer Network recommendation with an apparent advantage in terms of organ preservation, including some patients who were able to avoid surgery (22% of patients who received total neoadjuvant therapy).
It is mentioned that patients who received total neoadjuvant therapy tolerated FOLFOX better than those who received it in the adjuvant setting. A significant number of patients (22%) who received total neoadjuvant therapy did not undergo surgery within 12 months, and this group appears to have done quite well, with 92% having a sustained clinical complete response at 12 months, with no evidence of either local or distant recurrence. More insight into the decision to forego surgery in this 22% is clearly of great interest, as well as predictors — eg, genomics — of favorable outcomes in both groups.
The PROSPECT trial (NCT01515787) is addressing whether some patients may be able to avoid local radiotherapy if they receive early systemic chemotherapy. More needs to be done to figure out who can safely avoid surgery in terms of specific criteria, with some focus on stage II vs. stage III. Prospective trial design with randomization to total neoadjuvant therapy vs. conventional preoperative chemoradiotherapy and adjuvant therapy is needed along with, as the authors state, longer outcomes beyond 12 months after treatment (ie, DFS, OS). The total neoadjuvant therapy approach — including the early use of systemic chemotherapy — is a reasonable treatment strategy for locally advanced rectal cancer.