Patients with locally advanced rectal cancer with tumors that respond to chemotherapy can safely forego radiation therapy before surgery. Omitting radiation therapy can reduce short- and long-term side effects that impact health related Quality of Life (hrQoL) while providing similar outcomes in disease-free survival and overall survival.

This is the conclusion based on the findings from the phase 3 PROSPECT trial (ClinicalTrials.gov identifier: NCT01515787), a federally funded study, presented at the Annual Meeting of the American Society of Clinical Oncology (ASCO), held June 2 – 6, 2023, in Chicago, Illinois.

The efficacy results of the study were simultaneously published in the New England Journal of Medicine (NEJM), with additional patient reported outcomes published in the Journal of Clinical Oncology.[1][2]

Incidence
In 2023, an estimated 46,050 people will be diagnosed with rectal cancer in the United States. Advances in treatment and early detection for colorectal cancer have led to a steady decrease in mortality rates, with the 5-year relative survival rate for locally advanced rectal cancer at 74%.[3]

However, despite declining mortality rates, incidence is increasing among younger patients. Radiation therapy can have significant short- and long-term toxicities that negatively impact quality of life, including infertility, ovarian failures, the need for a temporary ostomy, diarrhea, cramping, fecal incontinence, and bladder problems. Chemotherapy also has side effects including fatigue, nausea, vomiting, low white blood cell counts, infection, and neuropathy (numbness and tingling in the hands and feet). The results of the PROSPECT trial gives patients alternative treatment options.

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Standard treatment
A standard curative intent treatment for locally advanced rectal cancer includes radiation with sensitizing fluoropyrimidine (5FUCRT; a type of antimetabolite, including Examples are capecitabine, floxuridine, and fluorouracil (5-FU)). This approach improves disease-free survival (DFS) by decreasing pelvic recurrence.  However, this treatment option is known to have short- and long-term toxicity. The PROSPECT trial was designed to compare treatment with mFOLFOX6 chemotherapy with selective use of 5FUCRT (intervention) to 5FUCRT (control) for the neoadjuvant treatment prior to total mesorectal excision for the treatment of locally advanced rectal cancer.

Study design
The phase 3 PROSPECT trial enrolled 1,194 patients from June 2012 to December 2018 with rectal cancer that had spread to nearby tissue or lymph nodes but had not spread to distant organs.

Participating patients were randomly assigned 1:1 (without blinding) to the chemoradiation therapy group (control) or to the mFOLFOX6 chemotherapy (modified FOLFOX6 includes FOLinic acid (also known as leucovorin), Fluorouracil (also known as 5-FU), and OXaliplatin) with selective use of chemoradiation therapy group (intervention), and 1,128 patients went on to receive treatment through the study.

In the control group, 543 patients received chemoradiation with 28 radiation treatments (5040 cGy) over 5.5 weeks before a low anterior resection with total mesorectal excision, which involves removing part of the rectum and surrounding lymph nodes. The chemoradiation was a drug combination called 5FUCRT, a combination of radiation therapy and a sensitizing fluoropyrimidine (either intravenous 5FU or oral capecitabine).

In the intervention group, 585 patients received six cycles of a chemotherapy combination called mFOLFOX6, [4] followed by tumor restaging. If the tumor shrank by 20% or more based on a follow-up MRI of the pelvis, no radiation therapy was given before surgery. If tumors did not shrink by 20% or more, radiation therapy with 5FU or capecitabine was administered before surgery. In the intervention group, 53 people (9%) needed radiation therapy before surgery because the tumors did not shrink by 20% or more. After surgery, physicians and patients could choose to have additional chemotherapy. Most patients in both groups went on to have further postoperative mFOLFOX6 chemotherapy.

Study Findings
Patients were randomly assigned to receive one of two treatments before a sphincter-sparing low anterior resection with a total mesorectal excision, which is surgery to remove tumors in the rectum and surrounding lymph nodes.

The control group received the standard treatment of chemoradiation (a combination of radiation therapy and either 5FU or capecitabine) prior to surgery. This was the standard of care at the time of study design. The experimental group received the chemotherapy combination mFOLFOX6. If the tumor responded well to mFOLFOX6 and shrank by 20% or more, patients immediately had surgery. If the tumor did not shrink by 20% or more or the patient was unable to continue with mFOLFOX6, they received the same chemoradiation as the control group prior to surgery.

After five years, there was no statistically significant difference between the two treatment groups in any of the endpoints studied, meaning that radiation therapy can be safely omitted before surgery if the tumor responds to treatment with mFOLFOX6 chemotherapy. Five years from randomization, the results showed that:

  • Disease-free survival was 78.6% in the chemoradiation group (95% CI, 75.4 to 81.8) and 80.8% in the mFOLFOX6 with selective chemoradiation group (95% CI, 77.9 to 83.7);
  • Overall survival was 90.2% in the chemoradiation group and 89.5% in the mFOLFOX6 with selective chemoradiation group. (hazard ratio for death, 1.04; 95% CI, 0.74 to 1.44);
  • Surgical resection rates (complete removal of the tumor and surrounding tissue) were 97.1% in the chemoradiation group and 98.8% in the mFOLFOX6 with selective chemoradiation group.
  • Local recurrence rates were very low and similar for both groups (2%).
  • Pathologic complete response (no sign of cancer cells in tissue during surgery after treatment) was 24.3% in the chemoradiation group and 21.9% in the mFOLFOX6 with selective chemoradiation group.
  • Only 9% of patients who received mFOLFOX6 in the experimental group needed preoperative chemoradiation.

“This study establishes preoperative therapy with FOLFOX and only selective use of chemoradiation for patients with locally advanced rectal cancer,” said lead author Deb Schrag, MD, FASCO, MPH, chair of the Department of Medicine at Memorial Sloan Kettering Cancer Center.

“Having this option is important for several reasons. First, in many parts of the world, radiation therapy is not readily accessible. An all-chemotherapy approach may make curative intent treatment accessible for patients in these resource-constrained settings. Additionally, given the rising rates of colorectal cancer in young patients, this provides an option for patients who wish to preserve fertility or avoid early menopause,” Schrag concluded.

What’s Next
The trial will continue to follow the participating patients and collect additional data on disease-free survival, overall survival, local recurrence-free survival, and other secondary endpoints for eight years. Further studies will evaluate the biological specimens collected during this study to see if there are any tumor features that are associated with a higher likelihood of responding to chemoradiation or with a higher likelihood of responding to mFOLOFOX6 chemotherapy.

Clinical trials
PROSPECT: Chemotherapy Alone or Chemotherapy Plus Radiation Therapy in Treating Patients With Locally Advanced Rectal Cancer Undergoing Surgery – NCT01515787

Reference
[1] Schrag D, Shi Q, Weiser MR, Gollub MJ, Saltz LB, Musher BL, Goldberg J, Al Baghdadi T, Goodman KA, McWilliams RR, Farma JM, George TJ, Kennecke HF, Shergill A, Montemurro M, Nelson GD, Colgrove B, Gordon V, Venook AP, O’Reilly EM, Meyerhardt JA, Dueck AC, Basch E, Chang GJ, Mamon HJ. Preoperative Treatment of Locally Advanced Rectal Cancer. N Engl J Med. 2023 Jun 4. doi: 10.1056/NEJMoa2303269. Epub ahead of print. PMID: 37272534.
[2] Schrag S, Shi Q, Weiser MR, Gollub MJ, Saltz LB, Musher BL, Goldberg J, Baghdadi TA, et al. PROSPECT: A randomized phase III trial of neoadjuvant chemoradiation versus neoadjuvant FOLFOX chemotherapy with selective use of chemoradiation, followed by total mesorectal excision (TME) for treatment of locally advanced rectal cancer (LARC) (Alliance N1048). J Clin Oncol 41, 2023 (suppl 17; abstr LBA2) DOI 10.1200/JCO.2023.41.17_suppl.LBA2
[3] Colorectal Cancer: Statistics. Cancernet.net. Online. Last accesses on June 2, 2023
[4] Goldberg RM, Sargent DJ, Morton RF, Fuchs CS, Ramanathan RK, Williamson SK, Findlay BP, Pitot HC, Alberts SR. A randomized controlled trial of fluorouracil plus leucovorin, irinotecan, and oxaliplatin combinations in patients with previously untreated metastatic colorectal cancer. J Clin Oncol. 2004 Jan 1;22(1):23-30. doi: 10.1200/JCO.2004.09.046. Epub 2003 Dec 9. PMID: 14665611.

Featured image: Annual meeting, ASCO, McCormick Place, Chicago, IL. Photo courtesy: © 2023 ASCO/Todd Buchanan. Used with permission.

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