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@ARTICLE{Gani:301283,
      author       = {C. Gani$^*$ and E. Fokas and B. Polat and O. J. Ott and M.
                      Diefenhardt$^*$ and A. Königsrainer and S. Böke$^*$ and A.
                      Kirschniak and R. Bachmann and D. Wichmann and M. Bitzer and
                      S. Clasen and U. Grosse and R. Hoffmann and M. Götz and
                      R.-D. Hofheinz and E. Germer and C.-T. Germer and R. Fietkau
                      and P. Martus and D. Zips$^*$ and C. Rödel$^*$},
      title        = {{O}rgan preservation after total neoadjuvant therapy for
                      locally advanced rectal cancer ({CAO}/{ARO}/{AIO}-16): an
                      open-label, multicentre, single-arm, phase 2 trial.},
      journal      = {The lancet / Gastroenterology $\&$ Hepatology},
      volume       = {10},
      number       = {6},
      issn         = {2468-1253},
      address      = {London},
      publisher    = {Elsevier},
      reportid     = {DKFZ-2025-00968},
      pages        = {562 - 572},
      year         = {2025},
      abstract     = {Total neoadjuvant therapy has been shown to increase
                      pathological complete response and disease-free survival in
                      patients with locally advanced rectal cancer after total
                      mesorectal excision (TME). We hypothesised that total
                      neoadjuvant therapy could maximise the number of patients
                      attaining a clinical complete response who could then be
                      instead referred to organ preservation with watch and
                      wait.This open-label, multicentre, single-arm, phase 2 study
                      (CAO/ARO/AIO-16) was conducted at four centres across
                      Germany. Patients aged 18 years or older with histologically
                      confirmed cT1-2N1-2 or cT3a-dN0/N1-2 rectal adenocarcinoma
                      up to 12 cm from the anal verge and without distant
                      metastases received chemoradiotherapy. Radiotherapy was
                      administered in daily fractions of 1·8 Gy, 5 days per week,
                      starting at day 1 and ending at day 38, for a total of 28
                      fractions and total dose of 50·4 Gy. Concomitant
                      fluorouracil (250 mg/m2 per day as a continuous venous
                      infusion from day 1 to day 14 and day 22 to day 35) and
                      oxaliplatin (50 mg/m2 intravenously on days 1, 8, 22, and
                      29) were administered. Chemoradiotherapy was followed by
                      three cycles of consolidation FOLFOX (fluorouracil [2400
                      mg/m2 over 46 h by continuous venous infusion], oxaliplatin
                      [100 mg/m2 intravenously as a 2-h infusion], and leucovorin
                      [400 mg/m2 intravenously as a 2-h infusion]) starting on
                      days 57, 71, and 85. Response assessment was scheduled on
                      day 106 after the start of total neoadjuvant therapy and
                      included digital rectal examination, rectoscopy, and pelvic
                      MRI. In case of a clinical complete response, patients were
                      scheduled for a watch and wait surveillance protocol.
                      Patients with a near clinical complete response on day 106
                      were offered a second assessment on day 196. In case of
                      conversion to a clinical complete response on this repeated
                      assessment, the same watch and wait surveillance protocol
                      was initiated. Alternatively, local excision was considered
                      on day 196 if technically feasible. In all other cases,
                      immediate TME surgery was recommended. The primary endpoint
                      was the clinical complete response rate on day 106 or 196
                      assessed in patients who started chemoradiotherapy
                      (intention-to-treat population). Toxicity was also assessed
                      in this patient population. The study was registered with
                      ClinicalTrials.gov (NCT03561142) and is complete.Between
                      June 1, 2018, and Oct 7, 2020, we enrolled 93 patients, of
                      whom 91 (mean age 61 years [SD 10]; 61 $[67\%]$ men and 30
                      $[33\%]$ women) started chemoradiotherapy, 88 started
                      consolidation chemotherapy, and 88 had a response assessment
                      on day 106. At this first assessment, 13 $(15\%)$ patients
                      were classified as having a clinical complete response and
                      were assigned to watch and wait, 33 $(38\%)$ met criteria
                      for a near clinical complete response and were scheduled for
                      reassessment, and 42 $(48\%)$ had a poor response and were
                      referred for immediate TME. At the second assessment, on day
                      196, 21 $(64\%)$ of 33 patients converted to a clinical
                      complete response, two underwent local excision with a
                      pathological complete response (and were also assigned to
                      watch and wait), and ten had TME. Therefore, for the primary
                      endpoint, 34 $(37\%)$ of the initial 91 patients attained a
                      clinical complete response after total neoadjuvant therapy.
                      Overall, 33 $(36\%)$ of 91 patients developed grade 3 or 4
                      toxicity during total neoadjuvant therapy. 17 $(19\%)$
                      patients developed grade 3 toxicity during
                      chemoradiotherapy, with no grade 4-5 toxicity occurring at
                      this treatment stage. The most frequently reported grade 3
                      toxicities during chemoradiotherapy were diarrhoea in nine
                      $(10\%)$ patients and infections in six $(7\%).$ During
                      consolidation chemotherapy, 17 $(19\%)$ of 88 patients had
                      grade 3 toxicities, the most common of which were leucopenia
                      (in seven $[8\%]$ patients) and neutropenia (in seven
                      $[8\%]).$ One $(1\%)$ patient had grade 4 neutropenia and
                      one patient died of COVID-19-associated pneumonia. Grade 3
                      and grade 4 adverse events during follow-up were recorded in
                      19 $(21\%)$ of 91 patients.Upfront chemoradiotherapy and
                      three cycles of consolidation FOLFOX result in a high rate
                      of clinical complete response with an acceptable toxicity
                      profile. Total neoadjuvant therapy combined with a watch and
                      wait approach after a clinical complete response can be
                      considered for patients with locally advanced rectal cancer
                      seeking an alternative to TME surgery.Medical Faculty
                      Tübingen.},
      keywords     = {Humans / Rectal Neoplasms: therapy / Rectal Neoplasms:
                      pathology / Neoadjuvant Therapy: methods / Male / Female /
                      Middle Aged / Aged / Adenocarcinoma: therapy /
                      Adenocarcinoma: pathology / Fluorouracil: administration
                      $\&$ dosage / Fluorouracil: therapeutic use / Antineoplastic
                      Combined Chemotherapy Protocols: therapeutic use /
                      Antineoplastic Combined Chemotherapy Protocols:
                      administration $\&$ dosage / Organ Sparing Treatments:
                      methods / Oxaliplatin: administration $\&$ dosage / Adult /
                      Chemoradiotherapy / Chemoradiotherapy, Adjuvant /
                      Leucovorin: administration $\&$ dosage / Watchful Waiting /
                      Fluorouracil (NLM Chemicals) / Oxaliplatin (NLM Chemicals) /
                      Leucovorin (NLM Chemicals)},
      cin          = {TU01 / FM01 / BE01 / HD01},
      ddc          = {610},
      cid          = {I:(DE-He78)TU01-20160331 / I:(DE-He78)FM01-20160331 /
                      I:(DE-He78)BE01-20160331 / I:(DE-He78)HD01-20160331},
      pnm          = {899 - ohne Topic (POF4-899)},
      pid          = {G:(DE-HGF)POF4-899},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:40347958},
      doi          = {10.1016/S2468-1253(25)00049-4},
      url          = {https://inrepo02.dkfz.de/record/301283},
}