Total Neoadjuvant Therapy Versus Standard Neoadjuvant Chemoradiation for Locally Advanced Rectal Cancer
Condition: Rectal Cancer
MeSH terms: Rectal Neoplasms
Study type: Interventional
Phase: Phase 2

Summary: 
      The National Comprehensive Cancer Network (NCCN) guidelines recommend trimodality treatment
      for patients with middle and low LARC with neoadjuvant chemoradiotherapy (NA-CRT), surgical
      resection with TME, plus additional chemotherapy (CT), in the adjuvant setting. This has
      markedly reduced pelvic local recurrence from historically about 25% to about 5-10%. However,
      the 5-year distant relapse is approximately 30% and continues to be the major cause of rectal
      cancer death.

      One strategy to address this issue is to deliver induction chemotherapy before surgery.
      Induction chemotherapy may be associated with better treatment compliance and may enable full
      systemic doses of chemotherapy to be delivered.

      The above cited considerations, plus favorable data from preliminary reports exploring this
      strategy, provides a solid rationale for shifting systemic treatment earlier into the
      treatment paradigm. The current study will evaluate the efficacy and the safety of total
      neoadjuvant therapy with standard neoadjuvant chemoradiotherapy for locally advanced rectal
      cancer patients as regards effects on tumor downstaging, pathological complete response,
      surgical difficulty and early functional outcome.
    

Detailed description: 
      Colorectal cancer is the third most commonly diagnosed cancer and the third leading cause of
      cancer death in men and women in the USA.

      Surgery using the total mesorectal excision (TME) remains the cornerstone of curative therapy
      for patients with nonmetastatic, locally advanced middle and low rectal cancer (LARC).

      The National Comprehensive Cancer Network (NCCN) guidelines recommend trimodality treatment
      for patients with middle and low LARC with neoadjuvant chemoradiotherapy (NA-CRT), surgical
      resection with TME, plus additional chemotherapy (CT), in the adjuvant setting.

      This has markedly reduced pelvic local recurrence from historically about 25% to about 5-10%.
      However, the 5-year distant relapse is approximately 30% and continues to be the major cause
      of rectal cancer death.

      Several other trials have attempted to demonstrate the benefits of postoperative chemotherapy
      as an adjunct to preoperative radiation and surgery. These trials either failed to
      demonstrate an advantage, or were closed early due to poor accrual. One common theme among
      these trials is poor compliance with adjuvant chemotherapy. Completion rates for planned
      chemotherapy ranged from 43 to 74% in these trials.

      The current rectal cancer treatment might lead to delay in the initiation of adjuvant
      chemotherapy especially in patients with postoperative complications, and this delay is
      theoretically disadvantageous in that it allows a window for growth of distant
      micrometastases which may already exist.

      One strategy to address this issue is to deliver induction chemotherapy before surgery.
      Induction chemotherapy may be associated with better treatment compliance and may enable full
      systemic doses of chemotherapy to be delivered.

      Other theoretical advantage of induction chemotherapy includes the possibility of shrinking
      or downstaging a locally advanced tumor, thereby facilitating more effective local treatment.

      Initial chemotherapy also permits delivery of chemotherapy agents directly to the primary
      tumor while it has a fully intact vasculature, undisrupted by radiation or surgery.

      It was supposed that increased chemoradiation-to-surgery interval would result in increased
      fibrosis and surgical difficulty.However, previous studies showed no increase in the
      technical difficulty of the operation with total neoadjuvant therapy.

      The above cited considerations, plus favorable data from preliminary reports exploring this
      strategy, provides a solid rationale for shifting systemic treatment earlier into the
      treatment paradigm. The current study will evaluate the efficacy and the safety of total
      neoadjuvant therapy with standard neoadjuvant chemoradiotherapy for locally advanced rectal
      cancer patients as regards effects on tumor downstaging, pathological complete response,
      surgical difficulty and early functional outcome.
    

Intervention name(s): Radiotherapy; consolidation chemotherapy; TME or APR
Intervention type(s): Radiation; Drug; Procedure
Intervention description(s): radiotherapy 45 Gy/ 25 fractions then boost 5.4 Gy/3 fractions with concurrent bolus 5-fluorouracil; 6 cycles of FOLFOX or CAPOX; total mesorectal excision or abdominoperineal resection
Other intervention name(s): Radiation therapy; CTX; proctectomy
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Single (Participant)
Primary purpose: Treatment