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Reirradiation of locally recurrent rectal cancer: A systematic review

Open AccessPublished:November 26, 2014DOI:https://doi.org/10.1016/j.radonc.2014.11.021

      Abstract

      Background: Many patients with rectal cancer receive radiotherapy as a component of primary multimodality treatment. Although local recurrence is infrequent, reirradiation may be needed to improve resectability and outcomes. This systematic review investigated the effects of reirradiation in terms of feasibility, toxicity, and long-term outcomes. Methods: A Medline, Embase and Cochrane search resulted in 353 titles/abstracts. Ten publications describing seven prospective or retrospective studies were included, presenting results of 375 patients reirradiated for rectal cancer. Results: Median initial radiation dose was 50.4 Gy, median 8–30 months before reirradiation. Reirradiation was mostly administered using hyperfractionated (1.2–1.5 Gy twice-daily) or 1.8 Gy once-daily chemoradiotherapy. Median total dose was 30–40 Gy to the gross tumour volume with 2–4 cm margins. Median survival was 39–60 months in resected patients and 12–16 months in palliative patients. Good symptomatic relief was reported in 82–100%. Acute toxicity with diarrhoea was reported in 9–20%, late toxicity was insufficiently reported. Conclusions: Reirradiation of rectal cancer to limited volumes is feasible. When curative resection is possible, the goal is radical resection and long-term survival, and hyperfractionated chemoradiotherapy should be preferred to limit late toxicity. Reirradiation yielded good symptomatic relief in palliative treatment.

      Keywords

      Rectal cancer is a common disease, with an age-standardised incidence rate of 17.3 per 100,000 person-years for colorectal cancer world-wide [
      • Ferlay J.
      • Shin H.R.
      • Bray F.
      • Forman D.
      • Mathers C.
      • Parkin D.M.
      Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008.
      ]. Improved surgery with total mesorectal excision [
      • Heald R.J.
      • Ryall R.D.
      Recurrence and survival after total mesorectal excision for rectal cancer.
      ] and increased use of preoperative radiotherapy (RT) and chemoradiotherapy (CRT) have led to decreased recurrence rates [

      Improved survival with preoperative radiotherapy in resectable rectal cancer. Swedish Rectal Cancer Trial. N Engl J Med 1997;336(14):980–7.

      ,
      • van Gijn W.
      • Marijnen C.A.
      • Nagtegaal I.D.
      • et al.
      Preoperative radiotherapy combined with total mesorectal excision for resectable rectal cancer: 12-year follow-up of the multicentre, randomised controlled TME trial.
      ,
      • Braendengen M.
      • Tveit K.M.
      • Berglund A.
      • et al.
      Randomized phase III study comparing preoperative radiotherapy with chemoradiotherapy in nonresectable rectal cancer.
      ,
      • Bosset J.F.
      • Collette L.
      • Calais G.
      • et al.
      Chemotherapy with preoperative radiotherapy in rectal cancer.
      ,
      • Gerard J.P.
      • Conroy T.
      • Bonnetain F.
      • et al.
      Preoperative radiotherapy with or without concurrent fluorouracil and leucovorin in T3–4 rectal cancers: results of FFCD 9203.
      ]. Population-based studies have demonstrated increased survival of patients with rectal cancer [
      • De Angelis R.
      • Sant M.
      • Coleman M.P.
      • et al.
      Cancer survival in Europe 1999–2007 by country and age: results of EUROCARE-5-a population-based study.
      ,
      • Bernstein T.E.
      • Endreseth B.H.
      • Romundstad P.
      • Wibe A.
      Improved local control of rectal cancer reduces distant metastases.
      ]. Local recurrence of rectal cancer can be a devastating condition, because of morbidity with intractable pain, pelvic infection, and obstruction, with large impact on health-related quality of life (HRQOL) [
      • Camilleri-Brennan J.
      • Steele R.J.
      The impact of recurrent rectal cancer on quality of life.
      ].
      Although local recurrence rates have decreased, an increasing proportion of patients with local recurrence have previously received high-dose pelvic radiotherapy as part of the primary multimodality treatment, either as preoperative short-course radiotherapy (5 × 5 Gy) or as chemoradiotherapy to 45–50 Gy (1.8–2.0 Gy/fraction). Curative resection of the local recurrence is the most important factor for survival [
      • Bouchard P.
      • Efron J.
      Management of recurrent rectal cancer.
      ]. Reirradiation of previously irradiated patients may increase the rate of radical resection (R0) and may also provide symptom palliation for inoperable tumours [
      • Glimelius B.
      Recurrent rectal cancer. The pre-irradiated primary tumour: can more radiotherapy be given?.
      ]. It is therefore important to determine the safety and benefits of reirradiation in patients with local recurrence.
      In terms of optimising radiotherapy, the tumour should receive a high total dose while sparing the surrounding normal tissue to avoid toxicity. Reirradiation is challenging, because the surrounding normal tissues may have already received doses near the organ- or endpoint-specific tolerance dose during the primary treatment. Robust clinical data on long-term normal tissue recovery and radiation tolerance doses are sparse. Therefore, radiation oncologists have been wary of reirradiation in locally recurrent rectal cancer, due to the fear of serious adverse late effects in normal tissue, particularly of the small intestine and bladder. However, there is increasing evidence in clinical studies that reirradiation is tolerable and yields good results for different tumour locations [
      • Nieder C.
      • Andratschke N.H.
      • Grosu A.L.
      Increasing frequency of reirradiation studies in radiation oncology: systematic review of highly cited articles.
      ]. The potential morbidity caused by retreatment should be weighed against the expected benefits in terms of achieving R0 surgery and long-term survival. If potentially curative treatment is envisaged, the expectation of long survival should drive treatment planning with conformal doses, and hyperfractionation should be considered for radiobiological reasons to reduce the risk of late effects [
      • Joiner M.
      • van der Kogel A.
      Basic clinical radiobiology.
      ].
      The aim of this systematic review was to investigate and evaluate the efficacy and safety in published studies describing the feasibility, outcomes, and toxicity of reirradiation of previously irradiated locally recurrent rectal cancer. The main focus is on external beam reirradiation, all fractionation regimens, with or without concurrent chemotherapy; reirradiation combined with other radiotherapy modalities is only briefly discussed.

      Methods

      This systematic review was based on a research protocol describing the aims and methods. The review is reported according to the guidelines in the PRISMA statement [
      • Moher D.
      • Liberati A.
      • Tetzlaff J.
      • Altman D.G.
      Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement.
      ].

      Search strategy

      A combined search was performed in the Medline, Embase, and Cochrane databases, through December 2012, with updated search August 2013. The search strategy included terms such as (colorectal or rectal or rectum) and (neoplasms or cancer or tumour) and (reirradiation), with no limitations for year of publication. No reviews of this topic were found in the Cochrane database. The titles/abstracts were screened by two of the authors (MGG, CU), and full-text copies of all potentially relevant studies were obtained. Additional studies were identified from the reference lists of full-text articles, and reviewed for potential inclusion.

      Eligibility criteria

      Published full-text studies that evaluated reirradiation of rectal or rectosigmoid cancer were considered for inclusion. Studies of patients with locally recurrent rectal cancer were eligible if they included patients previously irradiated for rectal cancer and if they reported outcomes after additional external beam radiotherapy with or without concomitant chemotherapy. Prospective, retrospective, and randomised controlled trials were eligible. Case reports and reviews were excluded. Studies evaluating external beam reirradiation combined with other radiation techniques such as stereotactic body radiotherapy (SBRT) or intraoperative radiotherapy (IORT) were not included. Eligibility was assessed independently by three of the authors (MGG, CU, BLR), and final inclusion in the review was based on consensus.

      Evaluation of studies

      The three authors assessed quality of the full-text papers independently, before consensus was obtained. Evaluation criteria focused on external validity and included the relevance of the patient population, the homogeneity of the patients and treatments, and the appropriateness of the methods used, based on a revised scoring system from the Norwegian Knowledge Centre for the Health Services.
      Data regarding patient characteristics, previous radiotherapy, reirradiation details, and outcomes were extracted from the studies independently by the three authors and presented in tables. Consensus was obtained on the data extracted, and data presentation and interpretation (all authors). A meta-analysis was not feasible due to heterogeneity of studies and outcomes.

      Endpoints of interest

      For patients treated with curative intent, the effects of reirradiation in terms of R0 resection rate, survival, and acute and late toxicity were evaluated. For patients treated with palliative intent, the effects of reirradiation on symptom palliation, survival, toxicity, and HRQOL were evaluated. The clinical implications of reirradiation in terms of total dose, target volume, and fractionation regimens, and possible recommendations for clinical practice, were discussed.

      Results

      The search resulted in 331 titles/abstracts; the updated yielded an additional 22, and 11 from reference lists, leading to a total of 364 titles/abstracts (Fig. 1). These titles/abstracts were screened, and 48 full-text publications were reviewed. Ten publications describing seven patient cohorts/studies met the inclusion criteria and were included in the final analysis [
      • Mohiuddin M.
      • Lingareddy V.
      • Rakinic J.
      • Marks G.
      Reirradiation for rectal cancer and surgical resection after ultra high doses.
      ,
      • Mohiuddin M.
      • Marks G.M.
      • Lingareddy V.
      • Marks J.
      Curative surgical resection following reirradiation for recurrent rectal cancer.
      ,
      • Lingareddy V.
      • Ahmad N.R.
      • Mohiuddin M.
      Palliative reirradiation for recurrent rectal cancer.
      ,
      • Mohiuddin M.
      • Marks G.
      • Marks J.
      Long-term results of reirradiation for patients with recurrent rectal carcinoma.
      ,
      • Valentini V.
      • Morganti A.G.
      • De Franco A.
      • et al.
      Chemoradiation with or without intraoperative radiation therapy in patients with locally recurrent rectal carcinoma: prognostic factors and long term outcome.
      ,
      • Valentini V.
      • Morganti A.G.
      • Gambacorta M.A.
      • et al.
      Preoperative hyperfractionated chemoradiation for locally recurrent rectal cancer in patients previously irradiated to the pelvis: a multicentric phase II study.
      ,
      • Das P.
      • Delclos M.E.
      • Skibber J.M.
      • et al.
      Hyperfractionated accelerated radiotherapy for rectal cancer in patients with prior pelvic irradiation.
      ,
      • Koom W.S.
      • Choi Y.
      • Shim S.J.
      • et al.
      Reirradiation to the pelvis for recurrent rectal cancer.
      ,
      • Sun D.S.
      • Zhang J.D.
      • Li L.
      • Dai Y.
      • Yu J.M.
      • Shao Z.Y.
      Accelerated hyperfractionation field-involved re-irradiation combined with concurrent capecitabine chemotherapy for locally recurrent and irresectable rectal cancer.
      ,
      • Ng M.K.
      • Leong T.
      • Heriot A.G.
      • Ngan S.Y.
      Once-daily reirradiation for rectal cancer in patients who have received previous pelvic radiotherapy.
      ].
      Figure thumbnail gr1
      Fig. 1Search strategy and inclusion of publications in review.
      There were no randomised controlled studies; all studies were prospective or retrospective (Table 1). A total of 375 patients treated with reirradiation (range 13–103) were included. The studies published up to 2006 included patients with locally recurrent rectal cancer without distant metastases. Later studies also included patients previously irradiated for other pelvic cancers [
      • Das P.
      • Delclos M.E.
      • Skibber J.M.
      • et al.
      Hyperfractionated accelerated radiotherapy for rectal cancer in patients with prior pelvic irradiation.
      ,
      • Ng M.K.
      • Leong T.
      • Heriot A.G.
      • Ngan S.Y.
      Once-daily reirradiation for rectal cancer in patients who have received previous pelvic radiotherapy.
      ]; and in the study by Ng et al., 40% of patients had metastatic disease [
      • Ng M.K.
      • Leong T.
      • Heriot A.G.
      • Ngan S.Y.
      Once-daily reirradiation for rectal cancer in patients who have received previous pelvic radiotherapy.
      ]. The median age ranged from 50 to 69 years, and the proportion of male patients was 52–78%. The median previous RT dose was mostly 50.4 Gy, previous fractionation regimen was rarely described, but assumed to be 1.8–2.0 Gy per fraction. The median time since previous RT varied from 8 to 30 months.
      Table 1Study characteristics, patient characteristics, and details of previous radiotherapy in the included studies.
      Author and Publication yearStudy design and Inclusion periodReirradiated

      N
      Patient populationAge

      median, years

      (range)
      Previous RT dose

      median, Gy

      (range)
      Time since RT

      median, months

      (range)
      Ng 2013
      • Ng M.K.
      • Leong T.
      • Heriot A.G.
      • Ngan S.Y.
      Once-daily reirradiation for rectal cancer in patients who have received previous pelvic radiotherapy.
      Retrospective 1997–200856RC, previous pelvic RT
      Previous RT for other cancer (7%); prostate n=3, endometrial n=1.


      Curative n = 13, Palliative n = 43
      69 (26–88)50.4 Gy (21–64)30 (8–176)
      Sun 2012
      • Sun D.S.
      • Zhang J.D.
      • Li L.
      • Dai Y.
      • Yu J.M.
      • Shao Z.Y.
      Accelerated hyperfractionation field-involved re-irradiation combined with concurrent capecitabine chemotherapy for locally recurrent and irresectable rectal cancer.
      Prospective 2004–200872Recurrent irresectable RC59 (29–78)<50 Gy (NR)25 (13–77)
      Koom 2012
      • Koom W.S.
      • Choi Y.
      • Shim S.J.
      • et al.
      Reirradiation to the pelvis for recurrent rectal cancer.
      Retrospective 2000–200722Recurrent RC50 (33–64)54 Gy (45–59.4)26 (5–72)
      Das 2010
      • Das P.
      • Delclos M.E.
      • Skibber J.M.
      • et al.
      Hyperfractionated accelerated radiotherapy for rectal cancer in patients with prior pelvic irradiation.
      Retrospective 2001–200550RC, previous pelvic RT
      Previous RT for other cancer (14%); cervical n=2, prostate n=2, bladder n=1.


      Primary n = 2, Recurrent n = 48
      60 (32–80)47 Gy (25–70)28 (5–354)
      Valentini 2006
      • Valentini V.
      • Morganti A.G.
      • Gambacorta M.A.
      • et al.
      Preoperative hyperfractionated chemoradiation for locally recurrent rectal cancer in patients previously irradiated to the pelvis: a multicentric phase II study.
      Prospective phase II 1997–200159Recurrent RC

      No extrapelvic disease
      62 (43–77)50.4 Gy (30–55)27 (9–106)
      Mohiuddin 2002
      • Mohiuddin M.
      • Marks G.
      • Marks J.
      Long-term results of reirradiation for patients with recurrent rectal carcinoma.
      NR
      Reirradiation program.
      1987–2000
      103Recurrent RC65 (31–79)50.4 Gy (30–74)19 (2–86)
      Valentini 1999
      • Valentini V.
      • Morganti A.G.
      • De Franco A.
      • et al.
      Chemoradiation with or without intraoperative radiation therapy in patients with locally recurrent rectal carcinoma: prognostic factors and long term outcome.
      Prospective 1989–199713 (subgroup)Recurrent RC

      No metastases
      NRNR (27–59)NR
      Lingareddy 1997
      • Lingareddy V.
      • Ahmad N.R.
      • Mohiuddin M.
      Palliative reirradiation for recurrent rectal cancer.
      NR
      Reirradiation program.
      1987–1993
      52Recurrent RC

      Palliative n = 52
      65 (37–79)50.4 Gy (40–70.2)24 (3–86)
      Mohiuddin 1997
      • Mohiuddin M.
      • Marks G.M.
      • Lingareddy V.
      • Marks J.
      Curative surgical resection following reirradiation for recurrent rectal cancer.
      NR
      Reirradiation program.
      1987–1992
      39Recurrent RC

      Curative n = 39
      61 (31–77)50.4 Gy (40–45) boost up to 6618 (3–456)
      Mohiuddin 1993
      • Mohiuddin M.
      • Lingareddy V.
      • Rakinic J.
      • Marks G.
      Reirradiation for rectal cancer and surgical resection after ultra high doses.
      Phase I/II pilot 1987–199132Recurrent RC

      Curative n = 17, Palliative n = 15
      60 (31–79)45 Gy (30–66)Curative: 8 (3–456)

      Palliative: 27 (3–79)
      NR = not reported in original publication; RC = rectal cancer; RT = radiotherapy.
      a Reirradiation program.
      b Previous RT for other cancer (7%); prostate n = 3, endometrial n = 1.
      c Previous RT for other cancer (14%); cervical n = 2, prostate n = 2, bladder n = 1.
      Reirradiation doses and techniques are summarised in Table 2, and estimates of the EQD2Gy doses in Supplementary Table. An evolution of reirradiation over time was demonstrated. In the early series reported by Mohiuddin et al., reirradiation was administered with either 1.2 Gy twice daily or 1.8 Gy daily to approximately 30 Gy, followed by a boost of 6–20 Gy [
      • Mohiuddin M.
      • Lingareddy V.
      • Rakinic J.
      • Marks G.
      Reirradiation for rectal cancer and surgical resection after ultra high doses.
      ,
      • Mohiuddin M.
      • Marks G.M.
      • Lingareddy V.
      • Marks J.
      Curative surgical resection following reirradiation for recurrent rectal cancer.
      ,
      • Lingareddy V.
      • Ahmad N.R.
      • Mohiuddin M.
      Palliative reirradiation for recurrent rectal cancer.
      ,
      • Mohiuddin M.
      • Marks G.
      • Marks J.
      Long-term results of reirradiation for patients with recurrent rectal carcinoma.
      ]. The median reirradiation dose given was 30.6–36 Gy, delivered by opposed lateral fields or three-field technique, encompassing the presacral region and gross tumour volume (GTV) with 2–4 cm margins, and combined to concomitant 5-fluorouracil (5-FU) continuous infusion. In the prospective study of patients with recurrent rectal cancer reported by Valentini et al., 1.2 Gy twice daily with concomitant 5-FU was given to the GTV plus a 4-cm margin to a total dose of 30 Gy; thereafter, additional CRT to a total of 40.8 Gy was given to GTV plus 2-cm margin [
      • Valentini V.
      • Morganti A.G.
      • Gambacorta M.A.
      • et al.
      Preoperative hyperfractionated chemoradiation for locally recurrent rectal cancer in patients previously irradiated to the pelvis: a multicentric phase II study.
      ]. Das et al. reported on patients who received 1.5 Gy twice daily and concomitant 5-FU. Patients with a long interval since previous treatment (⩾1 year) received a total dose of 39 Gy, and patients with shorter intervals 30 Gy [
      • Das P.
      • Delclos M.E.
      • Skibber J.M.
      • et al.
      Hyperfractionated accelerated radiotherapy for rectal cancer in patients with prior pelvic irradiation.
      ]. The treatment was delivered to GTV with a 2–3 cm margin, mostly by three-field technique.
      Table 2Reirradiaton treatment.
      Author and YearPlanned RT regimen

      fraction dose/total dose
      Reirradiation dose

      median (range)
      Treatment volumeTechniqueCumulative dose

      median (range)
      Concomitant chemotherapy
      Ng 2013
      • Ng M.K.
      • Leong T.
      • Heriot A.G.
      • Ngan S.Y.
      Once-daily reirradiation for rectal cancer in patients who have received previous pelvic radiotherapy.
      1.8 Gy/39.6 Gy39.6 Gy (20–39.6)GTV

      CTV = GTV + 1 cm

      PTV = CTV + 1 cm
      3DCRT 2–4 fields or IMRT87.3 Gy (44.4–108)5-FU
      Sun 2012
      • Sun D.S.
      • Zhang J.D.
      • Li L.
      • Dai Y.
      • Yu J.M.
      • Shao Z.Y.
      Accelerated hyperfractionation field-involved re-irradiation combined with concurrent capecitabine chemotherapy for locally recurrent and irresectable rectal cancer.
      1.2 Gy bid/30–36 Gy (n = 18)

      Non-resectable:

      redraw GTV, total 51.6–56.4 Gy (n = 54)
      GTV

      CTV = GTV + 1 cm

      PTV = CTV + 1 cm
      3DCRT 5–8 fieldsNRCapecitabine
      Koom 2012
      • Koom W.S.
      • Choi Y.
      • Shim S.J.
      • et al.
      Reirradiation to the pelvis for recurrent rectal cancer.
      1.8–3 Gy/NR50.2 Gy (30–66)GTV + 2–3 cm3DCRT or IMRT or tomotherapy103.3 Gy (81–119.4)Yes
      Das 2010
      • Das P.
      • Delclos M.E.
      • Skibber J.M.
      • et al.
      Hyperfractionated accelerated radiotherapy for rectal cancer in patients with prior pelvic irradiation.
      1.5 Gy bid/30–39 Gy
      Total dose 39Gy if time since previous RT⩾1year, 30Gy if time since previous RT<1year.
      39 Gy (94%)

      30 Gy (6%)
      GTV + 2–3 cm3-fieldNRCapecitabine
      Valentini 2006
      • Valentini V.
      • Morganti A.G.
      • Gambacorta M.A.
      • et al.
      Preoperative hyperfractionated chemoradiation for locally recurrent rectal cancer in patients previously irradiated to the pelvis: a multicentric phase II study.
      1.2 Gy bid/30 Gy (PTV2)

      +1.2 Gy bid/10.8 Gy (PTV1)
      40.8 GyGTV + 4 cm (PTV2)

      GTV + 2 cm (PTV1)
      3DCRTNR5-FU
      Mohiuddin 2002
      • Mohiuddin M.
      • Marks G.
      • Marks J.
      Long-term results of reirradiation for patients with recurrent rectal carcinoma.
      1.2 Gy bid/30 Gy + boost 6–20 Gy
      Higher boost dose if >1year interval from initial RT.
      (n = 43)

      or

      1.8 Gy/30.6 Gy + boost 6–20 Gy (n = 60)
      34.8 Gy (15–49.2)Presacral region and

      GTV + 2–4 cm

      Boost: GTV + 2 cm
      2 lateral fields or 3-field85.8 Gy (70.6–108)5-FU
      Valentini 1999
      • Valentini V.
      • Morganti A.G.
      • De Franco A.
      • et al.
      Chemoradiation with or without intraoperative radiation therapy in patients with locally recurrent rectal carcinoma: prognostic factors and long term outcome.
      1.8 Gy/23.4 Gy23.4 GyGTV + 1.5 cm

      + posterior pelvis
      Box or 3-fieldNR5-FU/MMC
      Lingareddy 1997
      • Lingareddy V.
      • Ahmad N.R.
      • Mohiuddin M.
      Palliative reirradiation for recurrent rectal cancer.
      1.2 Gy bid/30 Gy + boost 6–20 Gy (n = 22)

      or

      1.8 Gy/30.6 Gy + boost 6–20 Gy (n = 30)
      30.6 Gy (19.8–40.8)Presacral region and

      GTV + 2–3 cm

      Boost: GTV + ⩽2 cm
      2 lateral fields84.4 Gy (66.6–104.9)5-FU
      Mohiuddin 1997
      • Mohiuddin M.
      • Marks G.M.
      • Lingareddy V.
      • Marks J.
      Curative surgical resection following reirradiation for recurrent rectal cancer.
      1.2 Gy bid/30 Gy + boost 6–20 Gy
      Boost if >1year from initial RT.
      (n = 21)

      or

      1.8 Gy/30.6 Gy + boost 6–20 Gy
      Boost if >1year from initial RT.
      (n = 18)
      36 Gy (19.8–49.2)Presacral region and

      GTV + min 2 cm

      Boost: limited tumour volumes
      2 lateral fields85.7 Gy (70.6–99.8)5-FU
      Mohiuddin 1993
      • Mohiuddin M.
      • Lingareddy V.
      • Rakinic J.
      • Marks G.
      Reirradiation for rectal cancer and surgical resection after ultra high doses.
      Curative:

      1.2 Gy bid/30 Gy ± boost 10 Gy (n = 17)

      Palliative:

      1.8 Gy/30 Gy ± boost 10 Gy (n = 15)
      34.2 Gy (19.8–47.7)Posterior half pelvis

      Boost GTV + <2 cm
      2 lateral fieldsNR (70.6–111.6)5-FU
      Bid: two fractions daily; GTV: gross tumour volume; CTV: clinical target volume; PTV: planning target volume; 3-field: 1 posterior and 2 lateral fields.
      3DCRT: 3-dimensional conformal radiotherapy; IMRT: intensity-modulated radiotherapy; 5-FU: 5-fluorouracil; MMC: Mitomycin C; NR: not reported.
      a Total dose 39 Gy if time since previous RT ⩾ 1 year, 30 Gy if time since previous RT < 1 year.
      b Higher boost dose if >1 year interval from initial RT.
      c Boost if >1 year from initial RT.
      Koom et al. reported on a smaller series of patients treated more heterogeneously with 1.8–3.0 Gy once daily, to a median reirradiation dose of 50.2 Gy, with techniques including conformal RT, intensity-modulated radiation therapy (IMRT), and tomotherapy [
      • Koom W.S.
      • Choi Y.
      • Shim S.J.
      • et al.
      Reirradiation to the pelvis for recurrent rectal cancer.
      ]. Sun et al. reported on patients treated with 1.2 Gy twice daily to a reirradiation dose of 30–36 Gy delivered by 5–8 fields delivered to GTV plus 2 cm, with concomitant capecitabine [
      • Sun D.S.
      • Zhang J.D.
      • Li L.
      • Dai Y.
      • Yu J.M.
      • Shao Z.Y.
      Accelerated hyperfractionation field-involved re-irradiation combined with concurrent capecitabine chemotherapy for locally recurrent and irresectable rectal cancer.
      ]. In non-resectable patients, the GTV was redrawn and RT continued to a total dose of 51.6–56.4 Gy, thus delivering a high reirradiation dose to patients with irresectable local recurrence.
      Finally, Ng et al. reported on patients with rectal cancer who had had previous pelvic radiotherapy, of whom 40% had metastatic disease. They were treated with 1.8 Gy once daily to a reirradiation dose of 39.6 Gy, with concomitant 5-FU. The treatment volume included GTV plus a 2-cm margin; most patients were treated by three-field technique and some with IMRT [
      • Ng M.K.
      • Leong T.
      • Heriot A.G.
      • Ngan S.Y.
      Once-daily reirradiation for rectal cancer in patients who have received previous pelvic radiotherapy.
      ].
      To summarise the treatment given, reirradiation for rectal cancer was mostly given with hyperfractionated chemoradiotherapy to total doses of 30–40 Gy, although higher doses have been explored. Once-daily reirradiation was mostly used for palliative intent. The treatment volumes encompassed the tumour with margins, in newer studies delivered by multiple fields.
      The median follow-up time ranged from 15 to 36 months (Table 3). R0 resection was obtained in 39–89% of patients who underwent tumour resection; the wide range probably reflecting differences in patient selection. Further local recurrence occurred in approximately 50% of resected patients. The median survival ranged from 39 to 60 months in resected patients and from 12 to 16 months in palliative patients.
      Table 3Treatment results after reirradiation. Radical surgery and survival after reirradiation. Symptom palliation in non-resected patients.
      Data from selected studies where palliation was reported, and median reirradiation dose was ⩾30Gy. The publications by Mohiuddin et al. [16] and Lingareddy et al. [18] also reported on symptom palliation, but these patients are included in the publication by Mohiuddin et al. [19].
      Author

      year
      Follow-up

      median, months

      (range)
      Surgery

      tumour resection,

      n (%)
      Survival
      Survival: either median survival or overall survival was reported.


      median, months
      Symptom palliation,

      n (%)
      AllResectedPalliative
      Ng 2013
      • Ng M.K.
      • Leong T.
      • Heriot A.G.
      • Ngan S.Y.
      Once-daily reirradiation for rectal cancer in patients who have received previous pelvic radiotherapy.
      15 (1–108)Surgery 12/56 (21%)193915Overall RR 88%, CR 24/49 (49%) PR 19/49 (39%)
      Resection 11/56 (20%)Rectal bleeding/discharge 100%
      R0: 8GI CR 50% PR 50%
      Pain CR 47% PR 44%
      Urinary CR 1/1 (100%)
      Vaginal bleeding CR 2/3 (67 %)
      Sun 2012
      • Sun D.S.
      • Zhang J.D.
      • Li L.
      • Dai Y.
      • Yu J.M.
      • Shao Z.Y.
      Accelerated hyperfractionation field-involved re-irradiation combined with concurrent capecitabine chemotherapy for locally recurrent and irresectable rectal cancer.
      24 (10–57)Resection 18/72 (25%)32Pain relief 29/31 (94%)
      R0: 16Tenesmus relief 23/28 (82%)
      Koom 2012
      • Koom W.S.
      • Choi Y.
      • Shim S.J.
      • et al.
      Reirradiation to the pelvis for recurrent rectal cancer.
      20 (7–91)Resection 5/22 (23%)21
      Das 2010
      • Das P.
      • Delclos M.E.
      • Skibber J.M.
      • et al.
      Hyperfractionated accelerated radiotherapy for rectal cancer in patients with prior pelvic irradiation.
      25 (0–71)Resection 18/50 (36%)266016
      R0: 7
      Valentini 2006
      • Valentini V.
      • Morganti A.G.
      • Gambacorta M.A.
      • et al.
      Preoperative hyperfractionated chemoradiation for locally recurrent rectal cancer in patients previously irradiated to the pelvis: a multicentric phase II study.
      36 (9–69)Resection 30/59 (51%)42Pain relief 20/24 (83%)
      R0: 21
      Mohiuddin 2002
      • Mohiuddin M.
      • Marks G.
      • Marks J.
      Long-term results of reirradiation for patients with recurrent rectal carcinoma.
      24 (3–84)Surgery 41/103 (40%)264414Bleeding CR 21/21 (100%)
      Resection 34/103 (33%)Pain CR 25/46 (54%) PR 13/46 (28%)
      Mass effect CR 9/36 (25%) PR 23/36 (64%)
      Valentini 1999
      • Valentini V.
      • Morganti A.G.
      • De Franco A.
      • et al.
      Chemoradiation with or without intraoperative radiation therapy in patients with locally recurrent rectal carcinoma: prognostic factors and long term outcome.
      NRResection 4/13 (31%)
      Lingareddy 1997
      • Lingareddy V.
      • Ahmad N.R.
      • Mohiuddin M.
      Palliative reirradiation for recurrent rectal cancer.
      16NA12
      Mohiuddin 1997
      • Mohiuddin M.
      • Marks G.M.
      • Lingareddy V.
      • Marks J.
      Curative surgical resection following reirradiation for recurrent rectal cancer.
      36 (24–77)Resection 31/39 (79%)45
      R0: 27
      Mohiuddin 1993
      • Mohiuddin M.
      • Lingareddy V.
      • Rakinic J.
      • Marks G.
      Reirradiation for rectal cancer and surgical resection after ultra high doses.
      NR (12–72)Surgery 17/32 (53%)14
      Resection 15/32 (49%)
      Operated: number of patients operated; Reirradiated: number of patients reirradiated.
      R0: number of patients with microscopic radical resection; NR: not reported; RR: response rate; CR: complete response; PR: partial response.
      a Data from selected studies where palliation was reported, and median reirradiation dose was ⩾30 Gy. The publications by Mohiuddin et al.
      • Mohiuddin M.
      • Lingareddy V.
      • Rakinic J.
      • Marks G.
      Reirradiation for rectal cancer and surgical resection after ultra high doses.
      and Lingareddy et al.
      • Lingareddy V.
      • Ahmad N.R.
      • Mohiuddin M.
      Palliative reirradiation for recurrent rectal cancer.
      also reported on symptom palliation, but these patients are included in the publication by Mohiuddin et al.
      • Mohiuddin M.
      • Marks G.
      • Marks J.
      Long-term results of reirradiation for patients with recurrent rectal carcinoma.
      .
      b Survival: either median survival or overall survival was reported.
      A high proportion of patients reirradiated with palliative intent to median doses of ⩾30 Gy obtained symptomatic relief (Table 3). The proportion with complete or partial pain relief ranged from 83% to 94%. Rectal bleeding resolved completely in 100% of patients. The majority (>80%) of patients experienced partial or complete symptom relief from gastrointestinal symptoms or rectal mass. The median duration of symptom relief was 8 months for mass effect, 9 months for pain, and 10 months for bleeding [
      • Lingareddy V.
      • Ahmad N.R.
      • Mohiuddin M.
      Palliative reirradiation for recurrent rectal cancer.
      ,
      • Mohiuddin M.
      • Marks G.
      • Marks J.
      Long-term results of reirradiation for patients with recurrent rectal carcinoma.
      ].
      The rate of treatment interruption or termination due to toxicity was >30% in the earlier studies by Mohiuddin et al. (Table 4) [
      • Mohiuddin M.
      • Lingareddy V.
      • Rakinic J.
      • Marks G.
      Reirradiation for rectal cancer and surgical resection after ultra high doses.
      ,
      • Mohiuddin M.
      • Marks G.M.
      • Lingareddy V.
      • Marks J.
      Curative surgical resection following reirradiation for recurrent rectal cancer.
      ,
      • Lingareddy V.
      • Ahmad N.R.
      • Mohiuddin M.
      Palliative reirradiation for recurrent rectal cancer.
      ,
      • Mohiuddin M.
      • Marks G.
      • Marks J.
      Long-term results of reirradiation for patients with recurrent rectal carcinoma.
      ] and was later reduced to 13% [
      • Valentini V.
      • Morganti A.G.
      • De Franco A.
      • et al.
      Chemoradiation with or without intraoperative radiation therapy in patients with locally recurrent rectal carcinoma: prognostic factors and long term outcome.
      ] and 4% [
      • Sun D.S.
      • Zhang J.D.
      • Li L.
      • Dai Y.
      • Yu J.M.
      • Shao Z.Y.
      Accelerated hyperfractionation field-involved re-irradiation combined with concurrent capecitabine chemotherapy for locally recurrent and irresectable rectal cancer.
      ,
      • Ng M.K.
      • Leong T.
      • Heriot A.G.
      • Ngan S.Y.
      Once-daily reirradiation for rectal cancer in patients who have received previous pelvic radiotherapy.
      ]. This reduction in acute toxicity seems to be correlated with increasingly conformal radiotherapy and smaller margins to the GTV, and possibly better selection. The most commonly observed grade 3–4 toxicities were diarrhoea and skin reactions (Table 4), the frequency were reduced in the later studies.
      Table 4Acute and late toxicity after reirradiation.
      Author

      year
      Acute toxicity
      Toxicity scored by Common Toxicity Criteria (CTC) or RTOG score.
      grade 3 or 4
      Treatment break or termination (toxicity)Late toxicity, n
      Ng 2013
      • Ng M.K.
      • Leong T.
      • Heriot A.G.
      • Ngan S.Y.
      Once-daily reirradiation for rectal cancer in patients who have received previous pelvic radiotherapy.
      Skin 5%

      Gastrointestinal 9%

      Mucositis 2%
      Termination 4%Infection/abscess/drainage/discharge 4/12, fistula 1/12, urinary infection/retention 2/12, small bowel obstruction 1/12, delayed wound healing 1/12, skin ulceration 1/43
      Sun 2012
      • Sun D.S.
      • Zhang J.D.
      • Li L.
      • Dai Y.
      • Yu J.M.
      • Shao Z.Y.
      Accelerated hyperfractionation field-involved re-irradiation combined with concurrent capecitabine chemotherapy for locally recurrent and irresectable rectal cancer.
      Diarrhoea 10%

      Granulocytopenia 8%
      Termination 4%Skin fibrosis 4/72, urinary incontinence/dysuria 4/72, small bowel obstruction 1/72
      Koom 2012
      • Koom W.S.
      • Choi Y.
      • Shim S.J.
      • et al.
      Reirradiation to the pelvis for recurrent rectal cancer.
      Diarrhoea 9%Grade 3–4 toxicity 8/22 – small bowel obstruction, fistula, urinary stricture, haematologic
      Das 2010
      • Das P.
      • Delclos M.E.
      • Skibber J.M.
      • et al.
      Hyperfractionated accelerated radiotherapy for rectal cancer in patients with prior pelvic irradiation.
      Nausea/vomiting 4%Grade 3 toxicity 12/50 – small bowel obstruction, wound complication, abscess, fistula, ureteral stricture/leakage, haemorrhage, joint disease, nausea

      Grade 4 toxicity 1/50 – cystitis
      Valentini 2006
      • Valentini V.
      • Morganti A.G.
      • Gambacorta M.A.
      • et al.
      Preoperative hyperfractionated chemoradiation for locally recurrent rectal cancer in patients previously irradiated to the pelvis: a multicentric phase II study.
      Gastrointestinal 5%Break 10%

      Termination 3%
      Skin fibrosis 2/59, impotence 2/59, urinary incontinence/dysuria 2/59, small bowel obstruction 1/59
      Mohiuddin 2002
      • Mohiuddin M.
      • Marks G.
      • Marks J.
      Long-term results of reirradiation for patients with recurrent rectal carcinoma.
      Diarrhoea 20%

      Moist desquamation 8%

      Mucositis 4%
      Break 22%

      Termination 15%
      Diarrhoea 8/103, small bowel obstruction 15/103, fistula (recurrence) 4/103, skin ulceration 2/103
      Valentini 1999
      • Valentini V.
      • Morganti A.G.
      • De Franco A.
      • et al.
      Chemoradiation with or without intraoperative radiation therapy in patients with locally recurrent rectal carcinoma: prognostic factors and long term outcome.
      Haematologic/diarrhoea 8% (same patient)
      Lingareddy 1997
      • Lingareddy V.
      • Ahmad N.R.
      • Mohiuddin M.
      Palliative reirradiation for recurrent rectal cancer.
      Diarrhoea 19%

      Perineal skin breakdown 8%

      Mucositis 4%
      Break/termination 31%Small bowel obstruction 9/52, cystitis 3/52, fistula 4/52, skin ulceration 1/52
      Mohiuddin 1997
      • Mohiuddin M.
      • Marks G.M.
      • Lingareddy V.
      • Marks J.
      Curative surgical resection following reirradiation for recurrent rectal cancer.
      Diarrhoea 13%

      Moist desquamation 10%

      Mucositis 5%

      Delayed wound healing 6%
      Break 18%

      Termination 13%
      Chronic diarrhoea 3/39, small bowel obstruction 6/39, fistula (recurrence) 3/39, coloanal stricture 2/6
      Mohiuddin 1993
      • Mohiuddin M.
      • Lingareddy V.
      • Rakinic J.
      • Marks G.
      Reirradiation for rectal cancer and surgical resection after ultra high doses.
      Diarrhoea 13%

      Skin reaction 13%

      Pelvic abscess 6%
      Delayed wound healing 2/17, small bowel obstruction 1/17, coloanal stricture 1/5
      a Toxicity scored by Common Toxicity Criteria (CTC) or RTOG score.
      Late toxicity was not prospectively evaluated probably because most studies were retrospective, follow-up was relatively short, and patients treated with palliative intent had limited life expectancy. The most commonly reported late toxicities were gastrointestinal and urinary complications such as small bowel obstruction, fistula, stricture, chronic diarrhoea, and cystitis (Table 4). Factors that influenced the development of late toxicity included surgery [
      • Das P.
      • Delclos M.E.
      • Skibber J.M.
      • et al.
      Hyperfractionated accelerated radiotherapy for rectal cancer in patients with prior pelvic irradiation.
      ,
      • Koom W.S.
      • Choi Y.
      • Shim S.J.
      • et al.
      Reirradiation to the pelvis for recurrent rectal cancer.
      ], prior radiotherapy dose [
      • Das P.
      • Delclos M.E.
      • Skibber J.M.
      • et al.
      Hyperfractionated accelerated radiotherapy for rectal cancer in patients with prior pelvic irradiation.
      ], interval between initial radiotherapy and reirradiation [
      • Mohiuddin M.
      • Marks G.
      • Marks J.
      Long-term results of reirradiation for patients with recurrent rectal carcinoma.
      ], tumour location within the pelvis [
      • Koom W.S.
      • Choi Y.
      • Shim S.J.
      • et al.
      Reirradiation to the pelvis for recurrent rectal cancer.
      ], and fractionation regimen [
      • Mohiuddin M.
      • Marks G.
      • Marks J.
      Long-term results of reirradiation for patients with recurrent rectal carcinoma.
      ]. None of the studies evaluated health-related HRQOL.

      Discussion

      This systematic review of reirradiation for patients with locally recurrent rectal cancer revealed that reirradiation is feasible and has acceptable acute toxicity, although there is limited evidence on late toxicity. Reirradiation was delivered as hyperfractionated or once-daily regimens to total doses of 30–40 Gy to the GTV with 2–4 cm margins, and concurrent chemotherapy. The aims of the treatment were to achieve a curative resection with radical surgery, or to obtain tumour control and symptom palliation.
      Radical surgery is the main predictor for increased survival [
      • Bouchard P.
      • Efron J.
      Management of recurrent rectal cancer.
      ,
      • Dresen R.C.
      • Gosens M.J.
      • Martijn H.
      • et al.
      Radical resection after IORT-containing multimodality treatment is the most important determinant for outcome in patients treated for locally recurrent rectal cancer.
      ]. Thus, an aggressive multimodal and surgical approach is justified if R0 resection may be possible. Surgery of local recurrence is challenging, since the normal anatomical boundaries and surgical planes have been distorted and previous radiotherapy may have induced fibrosis, and because recurrence often involves other pelvic organs or structures [
      • Bouchard P.
      • Efron J.
      Management of recurrent rectal cancer.
      ]. Reirradiation may downsize the tumour and increase the chance of an R0 resection [
      • Dresen R.C.
      • Gosens M.J.
      • Martijn H.
      • et al.
      Radical resection after IORT-containing multimodality treatment is the most important determinant for outcome in patients treated for locally recurrent rectal cancer.
      ], although it is not clear whether all patients benefit from reirradiation. Patients who underwent tumour resection experienced a longer median survival than patients with inoperable disease [
      • Mohiuddin M.
      • Marks G.
      • Marks J.
      Long-term results of reirradiation for patients with recurrent rectal carcinoma.
      ,
      • Valentini V.
      • Morganti A.G.
      • Gambacorta M.A.
      • et al.
      Preoperative hyperfractionated chemoradiation for locally recurrent rectal cancer in patients previously irradiated to the pelvis: a multicentric phase II study.
      ,
      • Das P.
      • Delclos M.E.
      • Skibber J.M.
      • et al.
      Hyperfractionated accelerated radiotherapy for rectal cancer in patients with prior pelvic irradiation.
      ,
      • Ng M.K.
      • Leong T.
      • Heriot A.G.
      • Ngan S.Y.
      Once-daily reirradiation for rectal cancer in patients who have received previous pelvic radiotherapy.
      ], however more toxicity was reported in patients who underwent surgery [
      • Koom W.S.
      • Choi Y.
      • Shim S.J.
      • et al.
      Reirradiation to the pelvis for recurrent rectal cancer.
      ,
      • Ng M.K.
      • Leong T.
      • Heriot A.G.
      • Ngan S.Y.
      Once-daily reirradiation for rectal cancer in patients who have received previous pelvic radiotherapy.
      ]. It was difficult to know whether late toxicity was due to radiotherapy, surgery, or symptoms from further recurrence. Future studies are needed to define the optimal curative treatment for previously irradiated patients with recurrent rectal cancer.
      The distinction between curative and palliative intent is often not clear, and in several studies reviewed this depended on whether patients were eligible for curative resection after reirradiation. Patients reirradiated with palliative intent had a shorter median survival, but reported good symptom palliation of bleeding, pain, and gastrointestinal symptoms [
      • Mohiuddin M.
      • Lingareddy V.
      • Rakinic J.
      • Marks G.
      Reirradiation for rectal cancer and surgical resection after ultra high doses.
      ,
      • Lingareddy V.
      • Ahmad N.R.
      • Mohiuddin M.
      Palliative reirradiation for recurrent rectal cancer.
      ,
      • Mohiuddin M.
      • Marks G.
      • Marks J.
      Long-term results of reirradiation for patients with recurrent rectal carcinoma.
      ,
      • Valentini V.
      • Morganti A.G.
      • Gambacorta M.A.
      • et al.
      Preoperative hyperfractionated chemoradiation for locally recurrent rectal cancer in patients previously irradiated to the pelvis: a multicentric phase II study.
      ,
      • Sun D.S.
      • Zhang J.D.
      • Li L.
      • Dai Y.
      • Yu J.M.
      • Shao Z.Y.
      Accelerated hyperfractionation field-involved re-irradiation combined with concurrent capecitabine chemotherapy for locally recurrent and irresectable rectal cancer.
      ,
      • Ng M.K.
      • Leong T.
      • Heriot A.G.
      • Ngan S.Y.
      Once-daily reirradiation for rectal cancer in patients who have received previous pelvic radiotherapy.
      ]. This is in line with a recent review of palliative radiotherapy for rectal cancer, reporting good symptomatic relief [
      • Cameron M.G.
      • Kersten C.
      • Vistad I.
      • Fossa S.
      • Guren M.G.
      Palliative pelvic radiotherapy of symptomatic incurable rectal cancer – a systematic review.
      ], and a review reporting efficacy of reirradiation for bone metastases [
      • Wong E.
      • Hoskin P.
      • Bedard G.
      • et al.
      Re-irradiation for painful bone metastases – a systematic review.
      ]. The need for symptom palliation and the expected benefits of reirradiation must be weighed against the expected survival.
      The main organs at risk are the small bowel and the bladder. Clinical evidence concerning reirradiation tolerance is lacking [
      • Nieder C.
      • Milas L.
      • Ang K.K.
      Tissue tolerance to reirradiation.
      ], and dose constraints are not given. For small bowel, there are suggestions for constraints in the literature to minimise acute toxicity [
      • Kavanagh B.D.
      • Pan C.C.
      • Dawson L.A.
      • et al.
      Radiation dose–volume effects in the stomach and small bowel.
      ], and experimental evidence suggests consequential chronic damage; however, a correlation with late toxicity has not been established. For bladder, experimental studies suggest no late toxicity recovery, and a strong consequential component [
      • Joiner M.
      • van der Kogel A.
      Basic clinical radiobiology.
      ], but reliable tolerance data are not known. Surgery following reirradiation is often extensive and may result in colostomy and urostomy. Furthermore, complications such as perforation, obstruction, bleeding, incontinence, and fistula are also associated with persistent or recurrent disease [
      • Mohiuddin M.
      • Marks G.
      • Marks J.
      Long-term results of reirradiation for patients with recurrent rectal carcinoma.
      ,
      • Das P.
      • Delclos M.E.
      • Skibber J.M.
      • et al.
      Hyperfractionated accelerated radiotherapy for rectal cancer in patients with prior pelvic irradiation.
      ]. Reirradiation should be given to limited volumes using small margins and highly conformal therapy, thereby reducing small bowel and bladder doses [
      • Joiner M.
      • van der Kogel A.
      Basic clinical radiobiology.
      ,
      • Kavanagh B.D.
      • Pan C.C.
      • Dawson L.A.
      • et al.
      Radiation dose–volume effects in the stomach and small bowel.
      ].
      HRQOL was not reported in any of the reirradiation studies, but in disease-free patients after radiotherapy and surgery for recurrent rectal cancer, acceptable HRQOL has been described even after pelvic exenteration [
      • Guren M.G.
      • Wiig J.N.
      • Dueland S.
      • et al.
      Quality of life in patients with urinary diversion after operation for locally advanced rectal cancer.
      ,
      • Thaysen H.V.
      • Jess P.
      • Laurberg S.
      Health-related quality of life after surgery for primary advanced rectal cancer and recurrent rectal cancer: a review.
      ]. On the other hand, significant deterioration occurs in patients with progressive disease [
      • Camilleri-Brennan J.
      • Steele R.J.
      The impact of recurrent rectal cancer on quality of life.
      ]. Future trials should address patient-reported outcomes and HRQOL after reirradiation for recurrent rectal cancer.
      Most studies included in this review used hyperfractionated radiotherapy, administered in 1.2–1.5 Gy fractions twice daily, at least for curative treatment [
      • Mohiuddin M.
      • Lingareddy V.
      • Rakinic J.
      • Marks G.
      Reirradiation for rectal cancer and surgical resection after ultra high doses.
      ,
      • Mohiuddin M.
      • Marks G.M.
      • Lingareddy V.
      • Marks J.
      Curative surgical resection following reirradiation for recurrent rectal cancer.
      ,
      • Lingareddy V.
      • Ahmad N.R.
      • Mohiuddin M.
      Palliative reirradiation for recurrent rectal cancer.
      ,
      • Mohiuddin M.
      • Marks G.
      • Marks J.
      Long-term results of reirradiation for patients with recurrent rectal carcinoma.
      ,
      • Valentini V.
      • Morganti A.G.
      • De Franco A.
      • et al.
      Chemoradiation with or without intraoperative radiation therapy in patients with locally recurrent rectal carcinoma: prognostic factors and long term outcome.
      ,
      • Valentini V.
      • Morganti A.G.
      • Gambacorta M.A.
      • et al.
      Preoperative hyperfractionated chemoradiation for locally recurrent rectal cancer in patients previously irradiated to the pelvis: a multicentric phase II study.
      ,
      • Das P.
      • Delclos M.E.
      • Skibber J.M.
      • et al.
      Hyperfractionated accelerated radiotherapy for rectal cancer in patients with prior pelvic irradiation.
      ,
      • Sun D.S.
      • Zhang J.D.
      • Li L.
      • Dai Y.
      • Yu J.M.
      • Shao Z.Y.
      Accelerated hyperfractionation field-involved re-irradiation combined with concurrent capecitabine chemotherapy for locally recurrent and irresectable rectal cancer.
      ]. Once-daily fractions of 1.8 Gy were mostly an option for palliative treatment or patient preference [
      • Mohiuddin M.
      • Lingareddy V.
      • Rakinic J.
      • Marks G.
      Reirradiation for rectal cancer and surgical resection after ultra high doses.
      ,
      • Mohiuddin M.
      • Marks G.M.
      • Lingareddy V.
      • Marks J.
      Curative surgical resection following reirradiation for recurrent rectal cancer.
      ,
      • Lingareddy V.
      • Ahmad N.R.
      • Mohiuddin M.
      Palliative reirradiation for recurrent rectal cancer.
      ,
      • Mohiuddin M.
      • Marks G.
      • Marks J.
      Long-term results of reirradiation for patients with recurrent rectal carcinoma.
      ,
      • Koom W.S.
      • Choi Y.
      • Shim S.J.
      • et al.
      Reirradiation to the pelvis for recurrent rectal cancer.
      ,
      • Ng M.K.
      • Leong T.
      • Heriot A.G.
      • Ngan S.Y.
      Once-daily reirradiation for rectal cancer in patients who have received previous pelvic radiotherapy.
      ]. The fractionation regimens were probably chosen due to radiobiological rationale, extrapolation from other tumour sites, and feasibility. Although several studies used different regimens, patients were not randomised, making comparison between schedules difficult.
      The rationale for hyperfractionated, accelerated therapy is that small fraction doses increases the therapeutic ratio by exploiting the difference in fractionation sensitivity between tumour (high α/β) and late-reacting normal tissue (low α/β) [
      • Fowler J.F.
      The linear-quadratic formula and progress in fractionated radiotherapy.
      ]. Reirradiation doses can be recalculated to equivalent doses delivered with 2 Gy fractions (EQD2Gy) for comparison of fractionation schemes (EQD2Gy = n * d * ((d + α/β)/(2 + α/β))). A total dose of 39.6 Gy delivered with 1.2 Gy/fraction gives EQD2Gy = 33.3 Gy for late-reacting tissue (α/β = 3 Gy), and a higher EQD2Gy = 37.0 Gy for tumour (α/β = 10 Gy), assuming adequate time between the fractions to allow normal tissue recovery. Repair half-times for human small bowel are not certain, but assuming an incomplete repair factor of 0.063 based on animal models [
      • Joiner M.
      • van der Kogel A.
      Basic clinical radiobiology.
      ], normal tissue has full recovery by 6 h.
      Hyperfractionated reirradiation should theoretically be the preferred treatment for patients with curative intent. It may also be considered in patients with inoperable tumour with a relatively long life expectancy, with the aim of durable local control. Although some patients with metastatic disease have long survival with combination chemotherapy, many patients with disseminated disease or poor performance status have a short life expectancy, and the risk of late effects is less relevant. For these patients, once-daily reirradiation has been shown to be feasible and effective [
      • Glimelius B.
      Recurrent rectal cancer. The pre-irradiated primary tumour: can more radiotherapy be given?.
      ,
      • Ng M.K.
      • Leong T.
      • Heriot A.G.
      • Ngan S.Y.
      Once-daily reirradiation for rectal cancer in patients who have received previous pelvic radiotherapy.
      ] and should in our opinion be considered the preferred treatment regimen, considering convenience and patient preference.
      Although treatment techniques have become more sophisticated with time, the treatment principles remained the same. In earlier studies, computed tomography (CT) was probably not used for treatment planning; the target volume was the gross tumour with margins of 2–4 cm and the presacral space, given by opposed lateral fields to spare the anteriorly situated small bowel [
      • Mohiuddin M.
      • Lingareddy V.
      • Rakinic J.
      • Marks G.
      Reirradiation for rectal cancer and surgical resection after ultra high doses.
      ,
      • Mohiuddin M.
      • Marks G.M.
      • Lingareddy V.
      • Marks J.
      Curative surgical resection following reirradiation for recurrent rectal cancer.
      ,
      • Lingareddy V.
      • Ahmad N.R.
      • Mohiuddin M.
      Palliative reirradiation for recurrent rectal cancer.
      ,
      • Mohiuddin M.
      • Marks G.
      • Marks J.
      Long-term results of reirradiation for patients with recurrent rectal carcinoma.
      ,
      • Valentini V.
      • Morganti A.G.
      • De Franco A.
      • et al.
      Chemoradiation with or without intraoperative radiation therapy in patients with locally recurrent rectal carcinoma: prognostic factors and long term outcome.
      ]. In recent studies, the GTV was delineated and margins of 1 cm to the clinical target volume (CTV) and 1 cm to the planning target volume (PTV) were added [
      • Valentini V.
      • Morganti A.G.
      • Gambacorta M.A.
      • et al.
      Preoperative hyperfractionated chemoradiation for locally recurrent rectal cancer in patients previously irradiated to the pelvis: a multicentric phase II study.
      ,
      • Das P.
      • Delclos M.E.
      • Skibber J.M.
      • et al.
      Hyperfractionated accelerated radiotherapy for rectal cancer in patients with prior pelvic irradiation.
      ,
      • Koom W.S.
      • Choi Y.
      • Shim S.J.
      • et al.
      Reirradiation to the pelvis for recurrent rectal cancer.
      ,
      • Sun D.S.
      • Zhang J.D.
      • Li L.
      • Dai Y.
      • Yu J.M.
      • Shao Z.Y.
      Accelerated hyperfractionation field-involved re-irradiation combined with concurrent capecitabine chemotherapy for locally recurrent and irresectable rectal cancer.
      ,
      • Ng M.K.
      • Leong T.
      • Heriot A.G.
      • Ngan S.Y.
      Once-daily reirradiation for rectal cancer in patients who have received previous pelvic radiotherapy.
      ]. Treatment was delivered by conformal radiotherapy or IMRT [
      • Koom W.S.
      • Choi Y.
      • Shim S.J.
      • et al.
      Reirradiation to the pelvis for recurrent rectal cancer.
      ,
      • Ng M.K.
      • Leong T.
      • Heriot A.G.
      • Ngan S.Y.
      Once-daily reirradiation for rectal cancer in patients who have received previous pelvic radiotherapy.
      ], in order to deliver high tumour doses with acceptable small intestine and bladder doses. There was a trend towards less acute and late toxicity in the recent studies, probably due to better conformal treatment.
      The total dose administered was mostly at the level of 30–40 Gy; however, some studies administered a higher dose to a smaller volume, depending on time elapsed since previous radiotherapy [
      • Mohiuddin M.
      • Marks G.
      • Marks J.
      Long-term results of reirradiation for patients with recurrent rectal carcinoma.
      ] or in inoperable patients [
      • Sun D.S.
      • Zhang J.D.
      • Li L.
      • Dai Y.
      • Yu J.M.
      • Shao Z.Y.
      Accelerated hyperfractionation field-involved re-irradiation combined with concurrent capecitabine chemotherapy for locally recurrent and irresectable rectal cancer.
      ]. One study showed that reirradiation doses >50 Gy increased the infield progression-free survival [
      • Koom W.S.
      • Choi Y.
      • Shim S.J.
      • et al.
      Reirradiation to the pelvis for recurrent rectal cancer.
      ]. For patients with inoperable disease, it seems that higher doses can be administered safely, especially with conformal CRT or IMRT, provided sufficiently low normal tissue doses. Escalated doses to 51.6–56.4 Gy (hyperfractionated, shrinking-field after 36 Gy) with 5–8 fields were administered in one study, with dose limitation to the bladder of 30 Gy and to the small intestine 10 Gy for <50% of volume [
      • Sun D.S.
      • Zhang J.D.
      • Li L.
      • Dai Y.
      • Yu J.M.
      • Shao Z.Y.
      Accelerated hyperfractionation field-involved re-irradiation combined with concurrent capecitabine chemotherapy for locally recurrent and irresectable rectal cancer.
      ]. A short time interval since previous radiotherapy may result in worse radiation tolerance [
      • Mohiuddin M.
      • Marks G.
      • Marks J.
      Long-term results of reirradiation for patients with recurrent rectal carcinoma.
      ,
      • Das P.
      • Delclos M.E.
      • Skibber J.M.
      • et al.
      Hyperfractionated accelerated radiotherapy for rectal cancer in patients with prior pelvic irradiation.
      ]. Modern imaging (i.e., magnetic resonance imaging and positron emission tomography) and radiotherapy techniques (e.g., conformal RT and IMRT) permit more precise target delineation, accurate dose distribution, and narrow margins (e.g., cone beam CT and image-guided radiotherapy), increasing accuracy and allowing for individualised treatment.
      Reirradiation has been combined with IORT, where high radiation doses are delivered to the tumour bed while organs at risk are displaced or shielded from the radiation field. Large retrospective institutional series from experienced centres have been published in which subgroups received reirradiation to 30–30.6 Gy followed by resection and IORT [
      • Dresen R.C.
      • Gosens M.J.
      • Martijn H.
      • et al.
      Radical resection after IORT-containing multimodality treatment is the most important determinant for outcome in patients treated for locally recurrent rectal cancer.
      ,
      • Haddock M.G.
      • Miller R.C.
      • Nelson H.
      • et al.
      Combined modality therapy including intraoperative electron irradiation for locally recurrent colorectal cancer.
      ,
      • Mannaerts G.H.
      • Martijn H.
      • Crommelin M.A.
      • et al.
      Intraoperative electron beam radiation therapy for locally recurrent rectal carcinoma.
      ,
      • Bosman S.J.
      • Holman F.A.
      • Nieuwenhuijzen G.A.
      • Martijn H.
      • Creemers G.J.
      • Rutten H.J.
      Feasibility of reirradiation in the treatment of locally recurrent rectal cancer.
      ]. Good local control and survival was shown, and results after reirradiation were as good as after conventional preoperative irradiation [
      • Bosman S.J.
      • Holman F.A.
      • Nieuwenhuijzen G.A.
      • Martijn H.
      • Creemers G.J.
      • Rutten H.J.
      Feasibility of reirradiation in the treatment of locally recurrent rectal cancer.
      ]. Reirradiation has been combined with hyperthermia [
      • Juffermans J.H.
      • Hanssens P.E.
      • van Putten W.L.
      • van Rhoon G.C.
      • van Der Z.J.
      Reirradiation and hyperthermia in rectal carcinoma: a retrospective study on palliative effect.
      ,
      • Milani V.
      • Pazos M.
      • Issels R.D.
      • et al.
      Radiochemotherapy in combination with regional hyperthermia in preirradiated patients with recurrent rectal cancer.
      ] and has also been delivered with brachytherapy [
      • Wang J.J.
      • Yuan H.S.
      • Li J.N.
      • Jiang Y.L.
      • Tian S.Q.
      • Yang R.J.
      CT-guided radioactive seed implantation for recurrent rectal carcinoma after multiple therapy.
      ] in patient series. SBRT for reirradiation poses an interesting possibility for delivering high doses to restricted volumes with very tight margins [
      • Mantel F.
      • Flentje M.
      • Guckenberger M.
      Stereotactic body radiation therapy in the re-irradiation situation – a review.
      ], although there are limited data for recurrent rectal cancer, SBRT has been used for presacral or pelvic wall recurrences [
      • Kim M.S.
      • Choi C.
      • Yoo S.
      • et al.
      Stereotactic body radiation therapy in patients with pelvic recurrence from rectal carcinoma.
      ,
      • Defoe S.G.
      • Bernard M.E.
      • Rwigema J.C.
      • Heron D.E.
      • Ozhasoglu C.
      • Burton S.
      Stereotactic body radiotherapy for the treatment of presacral recurrences from rectal cancers.
      ].
      Tumour classification according to the site of recurrence within the pelvis or according to degree of fixation, determined by preoperative imaging [
      • Bouchard P.
      • Efron J.
      Management of recurrent rectal cancer.
      ,
      • Suzuki K.
      • Gunderson L.L.
      • Devine R.M.
      • et al.
      Intraoperative irradiation after palliative surgery for locally recurrent rectal cancer.
      ,
      • Moore H.G.
      • Shoup M.
      • Riedel E.
      • et al.
      Colorectal cancer pelvic recurrences: determinants of resectability.
      ], may be helpful for decisions in the multidisciplinary team (MDT) conference. Axial tumours were most often resectable, in contrast with lateral or posterior tumours; however, more toxicity was observed, probably due to higher small bowel and bladder doses [
      • Koom W.S.
      • Choi Y.
      • Shim S.J.
      • et al.
      Reirradiation to the pelvis for recurrent rectal cancer.
      ]. Presacral recurrence had the worst prognosis and anastomotic recurrence the most favourable prognosis [
      • Kusters M.
      • Dresen R.C.
      • Martijn H.
      • et al.
      Radicality of resection and survival after multimodality treatment is influenced by subsite of locally recurrent rectal cancer.
      ]. Patients with higher fixation grades had worse outcomes [
      • Hahnloser D.
      • Nelson H.
      • Gunderson L.L.
      • et al.
      Curative potential of multimodality therapy for locally recurrent rectal cancer.
      ]. A recent review of curative treatment of locally recurrent rectal cancer emphasised the importance of careful patient selection and optimised multimodality treatment [
      • Tanis P.J.
      • Doeksen A.
      • van Lanschot J.J.
      Intentionally curative treatment of locally recurrent rectal cancer: a systematic review.
      ]. Patients should ideally be treated by experienced clinicians in specialist centres [

      Consensus statement on the multidisciplinary management of patients with recurrent and primary rectal cancer beyond total mesorectal excision planes. Br J Surg 2013;100(8):1009–14.

      ].
      Future trials should aim at prospective assessment of tumour and normal tissue doses, investigate the optimal fractionation regimen, and the acute and late toxicity including patient-reported outcomes and HRQOL. Central review of CTV delineation in rectal cancer may increase the CTV uniformity, and can be used for quality assurance for radiation treatment [
      • Joye I.
      • Lambrecht M.
      • Jegou D.
      • Hortobagyi E.
      • Scalliet P.
      • Haustermans K.
      Does a central review platform improve the quality of radiotherapy for rectal cancer? Results of a national quality assurance project.
      ,
      • Melidis C.
      • Bosch W.R.
      • Izewska J.
      • et al.
      Radiation therapy quality assurance in clinical trials – global harmonisation group.
      ]. Methods for standardised data collection in rectal cancer has been described as a tool to aid personalised medicine [
      • Meldolesi E.
      • van Soest J.
      • Dinapoli N.
      • et al.
      An umbrella protocol for standardized data collection (SDC) in rectal cancer: a prospective uniform naming and procedure convention to support personalized medicine.
      ].
      In summary, although treatment of previously irradiated patients with recurrent rectal cancer is a challenge, several studies have shown that reirradiation is feasible, safe, and effective in terms of achieving radical resection or palliation. Retreatment is likely to be even safer with modern staging and radiotherapy techniques, allowing for increased accuracy and individualised radiotherapy. Patients should undergo adequate diagnosis and MDT discussion in experienced centres, and ideally be included in prospective trials. When the intent is curative treatment, patients should undergo hyperfractionated chemoradiotherapy followed by radical surgery. If the intent is clearly palliative and life expectancy is short, patients are probably best treated by once-daily chemoradiotherapy.

      Conflict of interest statement

      The authors declare that no conflicts of interest exist.

      Acknowledgement

      Librarian Marie Isachsen provided valuable help with the literature search.

      Appendix A. Supplementary data

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