Rectal Cancer Treatment Without Radiotherapy: Sometimes Less Is More

Locally advanced at diagnosis, rectal cancers (stages 2 and 3) are not operated on immediately and require preoperative treatment to shrink them. Standard care combines chemotherapy and radiotherapy to reduce the tumor as much as possible and prepare the patient for surgery.

Recent research suggests that less treatment can sometimes be more effective. Studies of radiation's role in rectal cancer indicate that it might be omitted to improve quality of life and reduce treatment difficulties and side effects. This makes the findings presented at ASCO 2023 and published concurrently in NEJM from the PROSPECT trial particularly important.

Sometimes Less Is More

The findings showed that preoperative FOLFOX chemotherapy alone was as effective as concurrent chemoradiotherapy for patients with locally advanced rectal cancer who were surgical candidates.

Avoiding pelvic (groin-region) radiation in these patients offers benefits including improved quality of life, fewer side effects and reduced risks of early menopause and infertility.

A Study That Could Change Standard Care

Treatment has advanced considerably since chemotherapy became common in rectal cancer. Improved chemotherapy, more effective surgery and expanded screening have substantially increased early diagnosis. Tumors are increasingly detected at smaller, more accessible stages, potentially making treatment easier and more effective.

The question motivating PROSPECT was: "Can we reserve radiotherapy for patients who truly need it, and should we give it to everyone rather than only those who do not respond to chemotherapy?"

Study Details

The study included 1128 patients with clinical T2 node-positive, T3 node-negative or T3 node-positive rectal cancer who were candidates for sphincter-sparing surgery.

• T2: The tumor has spread into the rectal muscle layer but not beyond the rectum.

• T3: Cancer has extended beyond the muscle layer and outside the rectum but has not yet spread to nearby organs or lymph nodes.

• Node-positive means cancer has spread to lymph nodes around the bowel.

Patients were randomized to modified chemotherapy mFOLFOX6 (585 patients) or standard chemoradiotherapy (543 patients). Mean age was 57; 34.5% were women and 85% were White.

Standard chemoradiotherapy combines pelvic radiation (50.4 Gy over 28 fractions) with radiosensitizing fluorouracil or capecitabine.

The modified regimen, mFOLFOX6, comprises modified oxaliplatin with l-leucovorin and bolus/continuous-infusion 5-fluorouracil.

In the mFOLFOX6 group, patients proceeded directly to surgery if the primary tumor shrank by at least 20% after six cycles. Others received preoperative chemoradiotherapy. Ultimately, 9% received chemoradiotherapy.

Postoperative adjuvant chemotherapy was recommended but not mandatory: six cycles in the mFOLFOX6 group or eight in the chemoradiotherapy group.

According to the results,

• after 58 months of follow-up, mFOLFOX6 was not superior to chemoradiotherapy for disease-free survival (DFS).
• With mFOLFOX6, 5-year disease-free survival was 80.8%, versus 78.6% with chemoradiotherapy. The 5-year overall survival rates were 89.5% with mFOLFOX6 and 90.2% with chemoradiotherapy.
• Local recurrence within 5 years was low: 1.8% with mFOLFOX6 and 1.6% with chemoradiotherapy.

DFS stands for "Disease-Free Survival" and measures how long a patient remains disease-free after completing cancer treatment. It is important for assessing treatment effectiveness and long-term survival.

Grade 3 or higher side effects were twice as common with mFOLFOX6: 41 percent versus 22.8 percent with chemoradiotherapy. Researchers emphasized, however, that chemotherapy treatment also lasted twice as long.

In patient-reported outcomes, mFOLFOX6 produced less diarrhea and better overall bowel function during neoadjuvant treatment. Those assigned chemoradiotherapy reported less anxiety, appetite loss, constipation, depression, difficulty swallowing, breathlessness, edema, fatigue, mucositis, nausea, neuropathy and vomiting during treatment. At 12 months after surgery, these differences disappeared, and mFOLFOX6 patients reported less fatigue and neuropathy and better sexual function than those receiving chemoradiotherapy.

This study and its application are important because they demonstrate an approach that can improve quality of life without compromising outcomes. It may mean less painful, demanding treatment for patients and more efficient use of healthcare resources. This highlights personalized cancer care: different patients may need different approaches depending on tumor characteristics, age, general health and personal priorities. Studies drawing attention to these issues are therefore valuable.