Intensity modulated radiotherapy delivers competitive local control rate with limited acute toxicity in the adjuvant treatment of rectal cancer

Intensity modulated radiotherapy delivers competitive local control rate with limited acute... Abstract Background Intensity-modulated radiotherapy (IMRT) has yet to show its capability in the adjuvant treatment of locally advanced rectal cancer. The purpose of this study is to evaluate the clinical efficacy and safety profile of IMRT in the adjuvant treatment of rectal cancer. Method Consecutive patients with resected locally advanced rectal cancer who had IMRT as part of adjuvant treatment between 2008 and 2014 were identified. The medical records and dosimetric parameters of 72 patients were retrospectively examined. Results The median follow-up time was 4.36 years (range 0.16–8.49 years). Overall survival rate and disease-free survival rate at 3 year was 79% (95% CI: 66.4–7.3%) and 70% (95% CI: 56.6–79.6%), respectively. Local control rate was 95%. The median bowel bag V45 was 282 ml (249–458 ml) and bone marrow V40 was 29%. Most acute toxicities were self-limited. Concurrent use of chemotherapy was associated with greater odds of ≥Grade 2 acute neutropenia (OR 25.44, P = 0.022). Conclusion Integration of IMRT in the adjuvant treatment of rectal cancer is promising with competitive local control rate. Acute toxicities are mostly self-limited. rectal cancer, adjuvant treatment, intensity modulated radiotherapy, neutropenia Introduction Radiotherapy has been an integral part of rectal cancer treatment. In the past few decades, radiotherapy has been consistently improving the outcome of rectal cancer treatment (1,2). Intensity modulated radiotherapy (IMRT), with the combination of inverse planning and multileaf collimator, has made possible not only the intended delivering target coverage, but also reduction of undesired dose to neighboring organs. To date, most existing literatures on IMRT focused on the preoperative management of rectal cancer (3–6), yet this approach is not without caveats. First, in the absence of reliable preoperative imaging, a 10th of patients who were initially diagnosed with locally advanced rectal cancer might have had unnecessary chemoradiotherapy, as shown in the German study (7). Moreover, advances in imaging technology has yet to completely solve this dilemma (8). Secondly, although preoperative chemoradiotherapy has shown to increase sphinter saving surgeries (7), this may only apply to a specific subgroup of patients, as sphinter saving surgery may be unnecessary and sometimes unavoidable even with chemoradiotherapy. In addition to that, the toxicity profile superiority of preoperative chemoradiotherapy may be controversial, as one large American study has shown (9). Lastly, the superiority in survival outcome of preoperative chemoradiotherapy has not been shown in two major randomized controlled trials (7,9). The need for toxicity reducing technology is never an understatement, especially when early introduction of systemic therapy is of paramount importance (10,11). As Kang et al. pointed out, early initiation of adjuvant chemotherapy may have a positive impact on the relapse free survival and overall survival of colorectal cancer (12). Kang’s finding on survival outcome was supported by a large meta-analysis, in which 14 studies were included (13). Meticulous works on combination systemic therapy have lead to improvement in the survival outcomes (14–17), yet with increased toxicity profile. As Braun et al. has pointed out, up to 40% of patient on combination chemotherapy such as FOLFOX are at risk of serious hematotoxicity (18). The added toxicity of combination chemotherapy have made chemoradiotherapy challenging. To meet these demands, clinical experiences on the adjuvant IMRT on locally advanced rectal cancer is urgently needed. This study aimed to examine the toxicities, oncologic outcomes and interaction of radiotherapy with fluorouracil (5-Fu)-based regimen in the adjuvant treatment of locally advanced rectal cancer with IMRT. Material and method Patient selection Seventy-two patients with rectal cancer treated with adjuvant IMRT were identified at our department. Patients with limited number of metastatic lesions at time of diagnosis were included. Electronic medical records and dose–volume–histogram (DVH) were meticulous reviewed. All pathologic findings were re-staged on the eighth AJCC staging manual. This study was approved by the Institution Review board at Chia-Yi Christian hospital. Treatment Surgery All patients had total mesorectal excision (TME) prior to chemotherapy and/or chemoradiotherapy. Surgeons had the ultimate decision in the preservation of anus. Extended Lymph node dissection was indicated for clinically suspected nodes. Radiotherapy Indications for adjuvant RT were in line with the guideline propose by the National Comprehensive Cancer Network (NCCN). The indications included T3-4N0 and any T + N1-2 diseases. T1-2N0 with unfavorable features, such as lymphovascular extension and close margin were also offered adjuvant RT. All patients had computed tomography (CT) based procedure in the supine position with full bladder. Immobilization with body foam is the practice at our institution. Body markers were used to position the patient on treatment couch. Gross tumor volumes (GTV) were reconstructed by registrating the preoperative CT/magnetic resonance imaging (MRI) images to their simulation counterparts. The intermediate risk clinical target volume (CTV-M) included the remaining rectum, if present, the mesorectum, and the internal iliac lymph nodes. CTV-M would also included and the external iliac lymph nodes if tumoral invasion of anterior pelvic organs was identified on pathologic record. PTV4500 is a 5 mm expansion of CTV-M. The longitudinal extends of high risk clinical target volumes (CTV-H) included the parts of the remaining rectum that was within 2-cm longitude to the surgical anastomosis, whereas the circumferential extent of CTV-H included the mesorectal bed and terminates at uninvolved muscle, bone or air. For ≤T3 lesions, an 5 mm expansion of the CTV-H yielded PTV5040, whereas T4 lesions got expanded 5 mm to yield PTV5400. All PTVs were treated at 1.8 Gy fractions. The available IMRT system at our institution consisted of Eclipse treatment planning system (Eclipse, Varian Medical Systems, Palo Alto, CA) and Clinac iX (Eclipse, Varian Medical Systems, Palo Alto, CA). Coverage of the PTV by at least 95% of the prescribed dose was mandatory. All treatment plans has coplanar beams. 6-MV and 15-MV photon were available for radiation delivery. For the inverse planning, the organs at risk included the urinary bladder, femoral heads, cauda equina, and bowel bag. All organs at risk were re-assessed with reference to the publication by Gay et al. (19). The bone marrow was not intentionally constructed at the time of planning, but was reconstructed for analysis. Chemotherapy Fluorouracil, in either intravenous or oral form, was the backbone of chemotherapy. For those considered at high risk of developing distant metastasis, adjuvant chemotherapy could precede chemoradiotherapy. Combination regimens, such as FOLFOX and FOLFIRI were allowed during chemoradiotherapy. Of note, oxaliplatin and irinotecan were not universally reimbursed by the National Health Insurance program until early 2009. Chemotherapy preceded radiotherapy when the time between surgery and RT exceeded 30 days, unless contraindicated. Toxicity assessment The treating clinician evaluated patients weekly at the time of adjuvant radiotherapy and made records on acute toxicities. Chart review was performed and toxicity data collected. Acute toxicities were revised according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) v4.0. Follow-up Patients were followed at our institution at 3-month interval after completing the scheduled treatment. Radiological studies such as CT/MRI were arranged at 3-month intervals and as clinically indicated. Tumor markers were examined if they correlated with the patient’s clinical course. Local failures were identified as recurrence in the PTV5040/5400, regional failures as that within PTV4500. Recurrence beyond the pelvic region was considered distant failure. Statistical analysis All statistical analyses were performed by using the SPSS software for Windows (version 21.0; IBM Corporation, Somers, NY, USA). To investigate risk factors of limiting toxicities, we calculated odds ratios (ORs) and 95% confidence intervals (CIs) by using logistic regression model. A two-tailed P value less than 0.05 was considered statistically significant. We also used R (version 3.2.1, R foundation for Statistical Computing, Vienna, Austria), with the KMsurv, survfit and survival packages to measure the death and/or treatment failures rates in this study with Kaplan–Meier analysis. The occurrence of death was considered an event in the overall survival curve. Death and/or treatment failures were considered events in disease-free survival. Results Patient, tumor and treatment characteristics Relevant clinicopathologic factors are summarized in Table 1. Median body mass index was 23 kg/m2 (Q1–Q3: 20–25) whereas the median distance of the tumor from the anal verge was 10 cm (Q1–Q3: 5–15). Locally advanced rectal cancers, defined as T3/4N0 and Tany + N1-2 constituted the majority of study population. There were three T1N0s and one T2N0 lesions. Indications for adjuvant radiotherapy included very close proximity (<2 cm) to anal verge in addition to LVI in one T2N0, close margin (close longitudinal margin or severe dysplasia on longitudinal margin) in two T1N0s, limited surgery from previous pelvic procedure in one T1N0 Table 1. Patient and tumor characteristics   Number  %  Gender   Female  29  40   Male  43  60  Age, years   <65  37  51   ≥65  35  49  Performance status   0  11  15   1  49  68   2  12  17  Bleeding   Yes  52  72   No  20  28  Abdominal pain   Yes  16  22   No  56  78  Obstruction   Yes  31  43   No  41  57  Body weight loss   Yes  6  8   No  66  92  Anemia   Yes  10  14    No  62  86  Distance from anal verge, cm   0–≤5  18  25   5–≤5  22  31   >10  32  44  Anal preservation surgery   Yes  69  96   No  3  4  pT   1  3  4   2  9  13   3  53  74   4a  6  8   4b  1  1  pN   0  24  33   1  16  22   2  32  44  pM   0  69  96   1  3  4  Histology   Adenocarcinoma  69  96   Mucinous adenocarcinoma  3  4  Grading   Well differentiated  1  1   Moderately differentiated  67  93   Poorly differentiated  2  2   Not available  2  2  Lymphovascular invasion   Yes  58  81   No  14  19  Perineural invasion   Yes  27  38   No  45  62  Extend of resection   R0  69  96   R1  3  4   R0  0  0    Number  %  Gender   Female  29  40   Male  43  60  Age, years   <65  37  51   ≥65  35  49  Performance status   0  11  15   1  49  68   2  12  17  Bleeding   Yes  52  72   No  20  28  Abdominal pain   Yes  16  22   No  56  78  Obstruction   Yes  31  43   No  41  57  Body weight loss   Yes  6  8   No  66  92  Anemia   Yes  10  14    No  62  86  Distance from anal verge, cm   0–≤5  18  25   5–≤5  22  31   >10  32  44  Anal preservation surgery   Yes  69  96   No  3  4  pT   1  3  4   2  9  13   3  53  74   4a  6  8   4b  1  1  pN   0  24  33   1  16  22   2  32  44  pM   0  69  96   1  3  4  Histology   Adenocarcinoma  69  96   Mucinous adenocarcinoma  3  4  Grading   Well differentiated  1  1   Moderately differentiated  67  93   Poorly differentiated  2  2   Not available  2  2  Lymphovascular invasion   Yes  58  81   No  14  19  Perineural invasion   Yes  27  38   No  45  62  Extend of resection   R0  69  96   R1  3  4   R0  0  0  Table 1. Patient and tumor characteristics   Number  %  Gender   Female  29  40   Male  43  60  Age, years   <65  37  51   ≥65  35  49  Performance status   0  11  15   1  49  68   2  12  17  Bleeding   Yes  52  72   No  20  28  Abdominal pain   Yes  16  22   No  56  78  Obstruction   Yes  31  43   No  41  57  Body weight loss   Yes  6  8   No  66  92  Anemia   Yes  10  14    No  62  86  Distance from anal verge, cm   0–≤5  18  25   5–≤5  22  31   >10  32  44  Anal preservation surgery   Yes  69  96   No  3  4  pT   1  3  4   2  9  13   3  53  74   4a  6  8   4b  1  1  pN   0  24  33   1  16  22   2  32  44  pM   0  69  96   1  3  4  Histology   Adenocarcinoma  69  96   Mucinous adenocarcinoma  3  4  Grading   Well differentiated  1  1   Moderately differentiated  67  93   Poorly differentiated  2  2   Not available  2  2  Lymphovascular invasion   Yes  58  81   No  14  19  Perineural invasion   Yes  27  38   No  45  62  Extend of resection   R0  69  96   R1  3  4   R0  0  0    Number  %  Gender   Female  29  40   Male  43  60  Age, years   <65  37  51   ≥65  35  49  Performance status   0  11  15   1  49  68   2  12  17  Bleeding   Yes  52  72   No  20  28  Abdominal pain   Yes  16  22   No  56  78  Obstruction   Yes  31  43   No  41  57  Body weight loss   Yes  6  8   No  66  92  Anemia   Yes  10  14    No  62  86  Distance from anal verge, cm   0–≤5  18  25   5–≤5  22  31   >10  32  44  Anal preservation surgery   Yes  69  96   No  3  4  pT   1  3  4   2  9  13   3  53  74   4a  6  8   4b  1  1  pN   0  24  33   1  16  22   2  32  44  pM   0  69  96   1  3  4  Histology   Adenocarcinoma  69  96   Mucinous adenocarcinoma  3  4  Grading   Well differentiated  1  1   Moderately differentiated  67  93   Poorly differentiated  2  2   Not available  2  2  Lymphovascular invasion   Yes  58  81   No  14  19  Perineural invasion   Yes  27  38   No  45  62  Extend of resection   R0  69  96   R1  3  4   R0  0  0  Three patients had resectable metastasis at time of surgery. Those metastatic lesions were located in the lung, liver and in para-aortic lymph nodes. All but three patients had sphinter saving surgeries. Table 2 illustrates the relevant treatment parameters, dosimetric data were also included. Thirty-eight (53%) of all patients had adjuvant chemotherapy before radiotherapy. The median interval between surgery and radiotherapy was 75 days (Q1–Q3:63–83 days). PTVH alone was treated because of previously existing gastrointestinal conditions in two patients. All but five were reluctant to concurrent chemotherapy at the time of radiotherapy. Two patients withdrew themselves from treatment within first week into treatment with personal considerations. Both were above the age of 70. Table 2. Treatment related factors   Number  %  Completion of assigned treatment   Yes  65  90   Withdrew within first week for personal considerations  2  3   Premature termination due to treatment related toxicity  5  7  Period between surgery and RT   ≤30 days  29  40   31–60 days  39  54   ≥61 days  4  6  Adjuvant chemotherapy before chemoradiotherapy   Yes  38  53   No  34  47  Concurrent chemoradiotherapy   Yes  67  93   No  5  7  Chemoradiotherapy with oxaliplatin   Yes  17  24   No  55  76  Chemoradiotherapy with Irinotecan   Yes  8  11   No  64  99    Median  Q1–Q3  Interval between surgery and radiotherapy (days)  75  63–83  Duration of radiotherapy (days)  38  37–42  Dose to PTVM (cGy)  4500  4500  Dose to PTVH (cGy)  5040  5040  Bowel bag V45 (cc)  282  196–361  Bone marrow volume (cc)  933  808–1087  Mean marrow dose (cGy)  2990  2934–3249  Bone marrow V40 (%)  29  25–35    Number  %  Completion of assigned treatment   Yes  65  90   Withdrew within first week for personal considerations  2  3   Premature termination due to treatment related toxicity  5  7  Period between surgery and RT   ≤30 days  29  40   31–60 days  39  54   ≥61 days  4  6  Adjuvant chemotherapy before chemoradiotherapy   Yes  38  53   No  34  47  Concurrent chemoradiotherapy   Yes  67  93   No  5  7  Chemoradiotherapy with oxaliplatin   Yes  17  24   No  55  76  Chemoradiotherapy with Irinotecan   Yes  8  11   No  64  99    Median  Q1–Q3  Interval between surgery and radiotherapy (days)  75  63–83  Duration of radiotherapy (days)  38  37–42  Dose to PTVM (cGy)  4500  4500  Dose to PTVH (cGy)  5040  5040  Bowel bag V45 (cc)  282  196–361  Bone marrow volume (cc)  933  808–1087  Mean marrow dose (cGy)  2990  2934–3249  Bone marrow V40 (%)  29  25–35  Table 2. Treatment related factors   Number  %  Completion of assigned treatment   Yes  65  90   Withdrew within first week for personal considerations  2  3   Premature termination due to treatment related toxicity  5  7  Period between surgery and RT   ≤30 days  29  40   31–60 days  39  54   ≥61 days  4  6  Adjuvant chemotherapy before chemoradiotherapy   Yes  38  53   No  34  47  Concurrent chemoradiotherapy   Yes  67  93   No  5  7  Chemoradiotherapy with oxaliplatin   Yes  17  24   No  55  76  Chemoradiotherapy with Irinotecan   Yes  8  11   No  64  99    Median  Q1–Q3  Interval between surgery and radiotherapy (days)  75  63–83  Duration of radiotherapy (days)  38  37–42  Dose to PTVM (cGy)  4500  4500  Dose to PTVH (cGy)  5040  5040  Bowel bag V45 (cc)  282  196–361  Bone marrow volume (cc)  933  808–1087  Mean marrow dose (cGy)  2990  2934–3249  Bone marrow V40 (%)  29  25–35    Number  %  Completion of assigned treatment   Yes  65  90   Withdrew within first week for personal considerations  2  3   Premature termination due to treatment related toxicity  5  7  Period between surgery and RT   ≤30 days  29  40   31–60 days  39  54   ≥61 days  4  6  Adjuvant chemotherapy before chemoradiotherapy   Yes  38  53   No  34  47  Concurrent chemoradiotherapy   Yes  67  93   No  5  7  Chemoradiotherapy with oxaliplatin   Yes  17  24   No  55  76  Chemoradiotherapy with Irinotecan   Yes  8  11   No  64  99    Median  Q1–Q3  Interval between surgery and radiotherapy (days)  75  63–83  Duration of radiotherapy (days)  38  37–42  Dose to PTVM (cGy)  4500  4500  Dose to PTVH (cGy)  5040  5040  Bowel bag V45 (cc)  282  196–361  Bone marrow volume (cc)  933  808–1087  Mean marrow dose (cGy)  2990  2934–3249  Bone marrow V40 (%)  29  25–35  Survival and pattern of failure Median follow-up time was 4.36 years (range 0.16–8.49 years). Overall survival and disease-free survival at 3 year was 79% (95% CI: 66–87%) and 70% (95% CI: 57–80%), respectively (Figs 1 and 2, respectively). Overall, 18 patient died during follow-up. Three deaths were unrelated to their primary disease: two as results of cardiovascular event and one succumbed to second primary hepatocellular carcinoma. Distant metastasis was the primary form of treatment failure, cumulative incidence of distant metastasis was 21% at 3 years (Fig. 3). Local failure was rare. Of the 72 patients in this cohort, only three local failures were identified during follow-up (Fig. 4). Local failure at 3 years follow-up was 5%. One regional failure subsequently developed after local failure in one patient. Figure 1. View largeDownload slide Kaplan–Meier survival analysis for OS (overall survival) of patients treated for resected rectal cancer (n = 72). Three-year OS rate was 79% (95% CI: 66.4–87.3%). Figure 1. View largeDownload slide Kaplan–Meier survival analysis for OS (overall survival) of patients treated for resected rectal cancer (n = 72). Three-year OS rate was 79% (95% CI: 66.4–87.3%). Figure 2. View largeDownload slide Kaplan–Meier survival analysis for DFS (disease-free survival) of patients treated for resected rectal cancer (n = 72). Three-year DFS rate was 70% (95% CI: 56.6–79.6%). Figure 2. View largeDownload slide Kaplan–Meier survival analysis for DFS (disease-free survival) of patients treated for resected rectal cancer (n = 72). Three-year DFS rate was 70% (95% CI: 56.6–79.6%). Figure 3. View largeDownload slide For patients who had IMRT based adjuvant radiotherapy for resected rectal cancer, distant metastasis was the primary form of treatment failure. Three-year cumulative rate of distant metastasis was 21%. Figure 3. View largeDownload slide For patients who had IMRT based adjuvant radiotherapy for resected rectal cancer, distant metastasis was the primary form of treatment failure. Three-year cumulative rate of distant metastasis was 21%. Figure 4. View largeDownload slide Local recurrence was a rare event following IMRT based adjuvant radiotherapy. Only three local failures were identified during follow-up. None of the patients with microscopic disease at surgical margins developed local failure. Figure 4. View largeDownload slide Local recurrence was a rare event following IMRT based adjuvant radiotherapy. Only three local failures were identified during follow-up. None of the patients with microscopic disease at surgical margins developed local failure. Acute toxicity Table 3 demonstrates the frequency of different acute toxicities. Most were self-limited. No Grade 5 toxicity was encountered. None but five patients had premature termination of adjuvant radiotherapy relating to acute toxicity, with three encountering dose limiting toxicities (one Grade 4 neutropenia and two Grade 3 gastrointestinal toxicity), two declining further treatment at Grade 2 gastrointestinal toxicity. The most commonly encountered limiting toxicities were primarily gastrointestinal and hematologic: 58% of patients had ≥Grade 2 diarrhea, of which four were Grade 3 (6%) and none were Grade 4. Twenty-five (36%) patients had ≥Grade 2 neutropenia, of which, 14 (19%) Grade 3 hematologic toxicities and two (3%) Grade 4 neutropenia were identified. Most ≥Grade 2 neutropenias were manageable with either dose adjustment or discontinuation of chemotherapy. Two patients withdrew themselves from treatment at third and fifth fraction of radiotherapy, respectively. Table 3. Summary of acute treatment toxicities   Toxicity grade  0  1  2  3  4  5  Nausea and vomiting  69  3  0  0  0  0  Diarrhea  13  17  38  4  0  0  Skin reaction  0  19  0  0  0  0  Anemia  52  10  8  2  0  0  Neutropenia  43  4  9  14  2  0  Thrombocytopenia  0  0  0  0  0  0  Cystitis  67  5  0  0  0  0    Toxicity grade  0  1  2  3  4  5  Nausea and vomiting  69  3  0  0  0  0  Diarrhea  13  17  38  4  0  0  Skin reaction  0  19  0  0  0  0  Anemia  52  10  8  2  0  0  Neutropenia  43  4  9  14  2  0  Thrombocytopenia  0  0  0  0  0  0  Cystitis  67  5  0  0  0  0  Table 3. Summary of acute treatment toxicities   Toxicity grade  0  1  2  3  4  5  Nausea and vomiting  69  3  0  0  0  0  Diarrhea  13  17  38  4  0  0  Skin reaction  0  19  0  0  0  0  Anemia  52  10  8  2  0  0  Neutropenia  43  4  9  14  2  0  Thrombocytopenia  0  0  0  0  0  0  Cystitis  67  5  0  0  0  0    Toxicity grade  0  1  2  3  4  5  Nausea and vomiting  69  3  0  0  0  0  Diarrhea  13  17  38  4  0  0  Skin reaction  0  19  0  0  0  0  Anemia  52  10  8  2  0  0  Neutropenia  43  4  9  14  2  0  Thrombocytopenia  0  0  0  0  0  0  Cystitis  67  5  0  0  0  0  Patient demographics, dosimetry data and treatment related factors were assessed for association to increased treatment-related gastrointestinal and hematologic toxicity (Table 4). None of the factors were associated with greater odds to ≥Grade 2 diarrhea was identified. On the other hand, patient who had any form of concomitant chemotherapy at the time of radiotherapy had 25.44 (CI 1.58–408.86) times greater odds of developing ≥Grade 2 grade neutropenia (Table 5). Table 4. Predisposing factors on acute diarrhea   Univariable  Multivariable  Crude OR (95% CI)  P value  Adjusted OR (95% CI)  P value  Age  1.00 (0.96–1.03)  0.838  0.98 (0.93–1.04)  0.502  Gender    0.655    0.567   Female  1.00 (Reference)    1.00 (Reference)     Male  0.81 (0.31–2.09)    1.55 (0.35–6.94)    BMI  0.99 (0.89–1.11)  0.867  1.02 (0.87–1.19)  0.809  Bowel bag V45 (cc)  1.00 (0.997–1.002)  0.762  1 (1–1.01)  0.824  Volume of bone marrow (cc)  1 (1)  0.145  1 (0.99–1)  0.071  Mean marrow dose (cGy)  1 (1)  0.477  1 (1)  0.590  Bone marrow V40 (%)  0.97 (0.92–1.02)  0.261  0.96 (0.88–1.04)  0.298  PS    0.523    0.800   0  1.00 (Reference)    1.00 (Reference)     1–2  1.50 (0.43–5.20)    1.23 (0.25–6.11)    Body weight loss at presentation    0.667    0.657   No  1.00 (Reference)    1.00 (Reference)     Yes  0.68 (0.12–3.97)    0.63 (0.08–4.96)    Anemia    0.566    0.551   No  1.00 (Reference)    1.00 (Reference)     Yes  1.48 (0.39–5.65)    1.74 (0.28–10.89)    Anal preservation surgery    0.766    0.819   No  1.00 (Reference)    1.00 (Reference)     Yes  1.45 (0.13–16.76)    1.46 (0.06–36.26)    Chemotherapy before CCRT    0.775    0.222   No  1.00 (Reference)    1.00 (Reference)     Yes  1.15 (0.44–3.03)    2.16 (0.63–7.46)    Chemotherapy at CCRT   No chemotherapy  1.00 (Reference)    1.00 (Reference)     CCRT with chemotherapy  1.36 (0.21–9.02)  0.748  0.61 (0.06–5.96)  0.669   CCRT with oxaplatin  0.32 (0.04–2.85)  0.308  0.11 (0.01–1.57)  0.103   CRT regimen with Irinotecan  2.50 (0.25–3.99)  0.433  2.2 (0.12–41.08)  0.597    Univariable  Multivariable  Crude OR (95% CI)  P value  Adjusted OR (95% CI)  P value  Age  1.00 (0.96–1.03)  0.838  0.98 (0.93–1.04)  0.502  Gender    0.655    0.567   Female  1.00 (Reference)    1.00 (Reference)     Male  0.81 (0.31–2.09)    1.55 (0.35–6.94)    BMI  0.99 (0.89–1.11)  0.867  1.02 (0.87–1.19)  0.809  Bowel bag V45 (cc)  1.00 (0.997–1.002)  0.762  1 (1–1.01)  0.824  Volume of bone marrow (cc)  1 (1)  0.145  1 (0.99–1)  0.071  Mean marrow dose (cGy)  1 (1)  0.477  1 (1)  0.590  Bone marrow V40 (%)  0.97 (0.92–1.02)  0.261  0.96 (0.88–1.04)  0.298  PS    0.523    0.800   0  1.00 (Reference)    1.00 (Reference)     1–2  1.50 (0.43–5.20)    1.23 (0.25–6.11)    Body weight loss at presentation    0.667    0.657   No  1.00 (Reference)    1.00 (Reference)     Yes  0.68 (0.12–3.97)    0.63 (0.08–4.96)    Anemia    0.566    0.551   No  1.00 (Reference)    1.00 (Reference)     Yes  1.48 (0.39–5.65)    1.74 (0.28–10.89)    Anal preservation surgery    0.766    0.819   No  1.00 (Reference)    1.00 (Reference)     Yes  1.45 (0.13–16.76)    1.46 (0.06–36.26)    Chemotherapy before CCRT    0.775    0.222   No  1.00 (Reference)    1.00 (Reference)     Yes  1.15 (0.44–3.03)    2.16 (0.63–7.46)    Chemotherapy at CCRT   No chemotherapy  1.00 (Reference)    1.00 (Reference)     CCRT with chemotherapy  1.36 (0.21–9.02)  0.748  0.61 (0.06–5.96)  0.669   CCRT with oxaplatin  0.32 (0.04–2.85)  0.308  0.11 (0.01–1.57)  0.103   CRT regimen with Irinotecan  2.50 (0.25–3.99)  0.433  2.2 (0.12–41.08)  0.597  BMI, body mass index; CCRT, concurrent chemoradiotherapy; CI, confidence interval; OR, odds ratio. Table 4. Predisposing factors on acute diarrhea   Univariable  Multivariable  Crude OR (95% CI)  P value  Adjusted OR (95% CI)  P value  Age  1.00 (0.96–1.03)  0.838  0.98 (0.93–1.04)  0.502  Gender    0.655    0.567   Female  1.00 (Reference)    1.00 (Reference)     Male  0.81 (0.31–2.09)    1.55 (0.35–6.94)    BMI  0.99 (0.89–1.11)  0.867  1.02 (0.87–1.19)  0.809  Bowel bag V45 (cc)  1.00 (0.997–1.002)  0.762  1 (1–1.01)  0.824  Volume of bone marrow (cc)  1 (1)  0.145  1 (0.99–1)  0.071  Mean marrow dose (cGy)  1 (1)  0.477  1 (1)  0.590  Bone marrow V40 (%)  0.97 (0.92–1.02)  0.261  0.96 (0.88–1.04)  0.298  PS    0.523    0.800   0  1.00 (Reference)    1.00 (Reference)     1–2  1.50 (0.43–5.20)    1.23 (0.25–6.11)    Body weight loss at presentation    0.667    0.657   No  1.00 (Reference)    1.00 (Reference)     Yes  0.68 (0.12–3.97)    0.63 (0.08–4.96)    Anemia    0.566    0.551   No  1.00 (Reference)    1.00 (Reference)     Yes  1.48 (0.39–5.65)    1.74 (0.28–10.89)    Anal preservation surgery    0.766    0.819   No  1.00 (Reference)    1.00 (Reference)     Yes  1.45 (0.13–16.76)    1.46 (0.06–36.26)    Chemotherapy before CCRT    0.775    0.222   No  1.00 (Reference)    1.00 (Reference)     Yes  1.15 (0.44–3.03)    2.16 (0.63–7.46)    Chemotherapy at CCRT   No chemotherapy  1.00 (Reference)    1.00 (Reference)     CCRT with chemotherapy  1.36 (0.21–9.02)  0.748  0.61 (0.06–5.96)  0.669   CCRT with oxaplatin  0.32 (0.04–2.85)  0.308  0.11 (0.01–1.57)  0.103   CRT regimen with Irinotecan  2.50 (0.25–3.99)  0.433  2.2 (0.12–41.08)  0.597    Univariable  Multivariable  Crude OR (95% CI)  P value  Adjusted OR (95% CI)  P value  Age  1.00 (0.96–1.03)  0.838  0.98 (0.93–1.04)  0.502  Gender    0.655    0.567   Female  1.00 (Reference)    1.00 (Reference)     Male  0.81 (0.31–2.09)    1.55 (0.35–6.94)    BMI  0.99 (0.89–1.11)  0.867  1.02 (0.87–1.19)  0.809  Bowel bag V45 (cc)  1.00 (0.997–1.002)  0.762  1 (1–1.01)  0.824  Volume of bone marrow (cc)  1 (1)  0.145  1 (0.99–1)  0.071  Mean marrow dose (cGy)  1 (1)  0.477  1 (1)  0.590  Bone marrow V40 (%)  0.97 (0.92–1.02)  0.261  0.96 (0.88–1.04)  0.298  PS    0.523    0.800   0  1.00 (Reference)    1.00 (Reference)     1–2  1.50 (0.43–5.20)    1.23 (0.25–6.11)    Body weight loss at presentation    0.667    0.657   No  1.00 (Reference)    1.00 (Reference)     Yes  0.68 (0.12–3.97)    0.63 (0.08–4.96)    Anemia    0.566    0.551   No  1.00 (Reference)    1.00 (Reference)     Yes  1.48 (0.39–5.65)    1.74 (0.28–10.89)    Anal preservation surgery    0.766    0.819   No  1.00 (Reference)    1.00 (Reference)     Yes  1.45 (0.13–16.76)    1.46 (0.06–36.26)    Chemotherapy before CCRT    0.775    0.222   No  1.00 (Reference)    1.00 (Reference)     Yes  1.15 (0.44–3.03)    2.16 (0.63–7.46)    Chemotherapy at CCRT   No chemotherapy  1.00 (Reference)    1.00 (Reference)     CCRT with chemotherapy  1.36 (0.21–9.02)  0.748  0.61 (0.06–5.96)  0.669   CCRT with oxaplatin  0.32 (0.04–2.85)  0.308  0.11 (0.01–1.57)  0.103   CRT regimen with Irinotecan  2.50 (0.25–3.99)  0.433  2.2 (0.12–41.08)  0.597  BMI, body mass index; CCRT, concurrent chemoradiotherapy; CI, confidence interval; OR, odds ratio. Table 5. Predictor factors on acute neutropenia   Univariate  Multivariate  Crude OR (95% CI)  P value  Adjusted OR (95% CI)  P value  Age  1.02 (0.99–1.07)  0.221  1.03 (0.97–1.09)  0.345  Gender    0.142    0.582   Female  1.00 (Reference)    1.00 (Reference)     Male  2.10 (0.78–5.65)    1.6 (0.3–8.44)    BMI  1.11 (0.97–1.26)  0.129  1.14 (0.93–1.4)  0.196  Bowel bag V45 (cc)  1 (1)  0.119  1 (0.99–1)  0.298  Volume of bone marrow (cc)  1 (1)  0.586  1 (1)  0.731  Mean marrow dose (cGy)  1 (1)  0.777  1 (1)  0.656  Bone marrow V40 (%)  0.96 (0.91–1.02)  0.151  0.94 (0.86–1.03)  0.188  PS    0.912    0.825   0  1.00 (Reference)    1.00 (Reference)     1–2  1.08 (0.29–4.00)    0.81 (0.13–5.23)    Body weight loss at presentation    0.941    0.814   No  1.00 (Reference)    1.00 (Reference)     Yes  1.07 (0.18–6.29)    1.39 (0.09–22.18)    Anemia    0.706    0.951   No  1.00 (Reference)    1.00 (Reference)     Yes  0.77 (0.20–3.02)    0.94 (0.12–7.21)    Anal preservation surgery    –    –   No  1.00 (Reference)    1.00 (Reference)     Yes  NA    NA    Chemotherapy before CCRT    0.912    0.529   No  1.00 (Reference)    1.00 (Reference)     Yes  1.06 (0.39–2.86)    0.63 (0.15–2.64)    Chemotherapy at CCRT   No chemotherapy  1.00 (Reference)    1.00 (Reference)     CCRT with chemotherapy  6.38 (0.91−44.72)  0.062  25.44 (1.58−408.86)  0.022   CCRT with oxaplatin  1.69 (0.22−12.81)  0.613  6.05 (0.32−114.33)  0.230   CRT regimen with Irinotecan  0.50 (0.05−5.51)  0.571  1.75 (0.07−46.68)  0.738    Univariate  Multivariate  Crude OR (95% CI)  P value  Adjusted OR (95% CI)  P value  Age  1.02 (0.99–1.07)  0.221  1.03 (0.97–1.09)  0.345  Gender    0.142    0.582   Female  1.00 (Reference)    1.00 (Reference)     Male  2.10 (0.78–5.65)    1.6 (0.3–8.44)    BMI  1.11 (0.97–1.26)  0.129  1.14 (0.93–1.4)  0.196  Bowel bag V45 (cc)  1 (1)  0.119  1 (0.99–1)  0.298  Volume of bone marrow (cc)  1 (1)  0.586  1 (1)  0.731  Mean marrow dose (cGy)  1 (1)  0.777  1 (1)  0.656  Bone marrow V40 (%)  0.96 (0.91–1.02)  0.151  0.94 (0.86–1.03)  0.188  PS    0.912    0.825   0  1.00 (Reference)    1.00 (Reference)     1–2  1.08 (0.29–4.00)    0.81 (0.13–5.23)    Body weight loss at presentation    0.941    0.814   No  1.00 (Reference)    1.00 (Reference)     Yes  1.07 (0.18–6.29)    1.39 (0.09–22.18)    Anemia    0.706    0.951   No  1.00 (Reference)    1.00 (Reference)     Yes  0.77 (0.20–3.02)    0.94 (0.12–7.21)    Anal preservation surgery    –    –   No  1.00 (Reference)    1.00 (Reference)     Yes  NA    NA    Chemotherapy before CCRT    0.912    0.529   No  1.00 (Reference)    1.00 (Reference)     Yes  1.06 (0.39–2.86)    0.63 (0.15–2.64)    Chemotherapy at CCRT   No chemotherapy  1.00 (Reference)    1.00 (Reference)     CCRT with chemotherapy  6.38 (0.91−44.72)  0.062  25.44 (1.58−408.86)  0.022   CCRT with oxaplatin  1.69 (0.22−12.81)  0.613  6.05 (0.32−114.33)  0.230   CRT regimen with Irinotecan  0.50 (0.05−5.51)  0.571  1.75 (0.07−46.68)  0.738  BMI, body mass index; CCRT, concurrent chemoradiotherapy; CI, confidence interval; OR, odds ratio. Table 5. Predictor factors on acute neutropenia   Univariate  Multivariate  Crude OR (95% CI)  P value  Adjusted OR (95% CI)  P value  Age  1.02 (0.99–1.07)  0.221  1.03 (0.97–1.09)  0.345  Gender    0.142    0.582   Female  1.00 (Reference)    1.00 (Reference)     Male  2.10 (0.78–5.65)    1.6 (0.3–8.44)    BMI  1.11 (0.97–1.26)  0.129  1.14 (0.93–1.4)  0.196  Bowel bag V45 (cc)  1 (1)  0.119  1 (0.99–1)  0.298  Volume of bone marrow (cc)  1 (1)  0.586  1 (1)  0.731  Mean marrow dose (cGy)  1 (1)  0.777  1 (1)  0.656  Bone marrow V40 (%)  0.96 (0.91–1.02)  0.151  0.94 (0.86–1.03)  0.188  PS    0.912    0.825   0  1.00 (Reference)    1.00 (Reference)     1–2  1.08 (0.29–4.00)    0.81 (0.13–5.23)    Body weight loss at presentation    0.941    0.814   No  1.00 (Reference)    1.00 (Reference)     Yes  1.07 (0.18–6.29)    1.39 (0.09–22.18)    Anemia    0.706    0.951   No  1.00 (Reference)    1.00 (Reference)     Yes  0.77 (0.20–3.02)    0.94 (0.12–7.21)    Anal preservation surgery    –    –   No  1.00 (Reference)    1.00 (Reference)     Yes  NA    NA    Chemotherapy before CCRT    0.912    0.529   No  1.00 (Reference)    1.00 (Reference)     Yes  1.06 (0.39–2.86)    0.63 (0.15–2.64)    Chemotherapy at CCRT   No chemotherapy  1.00 (Reference)    1.00 (Reference)     CCRT with chemotherapy  6.38 (0.91−44.72)  0.062  25.44 (1.58−408.86)  0.022   CCRT with oxaplatin  1.69 (0.22−12.81)  0.613  6.05 (0.32−114.33)  0.230   CRT regimen with Irinotecan  0.50 (0.05−5.51)  0.571  1.75 (0.07−46.68)  0.738    Univariate  Multivariate  Crude OR (95% CI)  P value  Adjusted OR (95% CI)  P value  Age  1.02 (0.99–1.07)  0.221  1.03 (0.97–1.09)  0.345  Gender    0.142    0.582   Female  1.00 (Reference)    1.00 (Reference)     Male  2.10 (0.78–5.65)    1.6 (0.3–8.44)    BMI  1.11 (0.97–1.26)  0.129  1.14 (0.93–1.4)  0.196  Bowel bag V45 (cc)  1 (1)  0.119  1 (0.99–1)  0.298  Volume of bone marrow (cc)  1 (1)  0.586  1 (1)  0.731  Mean marrow dose (cGy)  1 (1)  0.777  1 (1)  0.656  Bone marrow V40 (%)  0.96 (0.91–1.02)  0.151  0.94 (0.86–1.03)  0.188  PS    0.912    0.825   0  1.00 (Reference)    1.00 (Reference)     1–2  1.08 (0.29–4.00)    0.81 (0.13–5.23)    Body weight loss at presentation    0.941    0.814   No  1.00 (Reference)    1.00 (Reference)     Yes  1.07 (0.18–6.29)    1.39 (0.09–22.18)    Anemia    0.706    0.951   No  1.00 (Reference)    1.00 (Reference)     Yes  0.77 (0.20–3.02)    0.94 (0.12–7.21)    Anal preservation surgery    –    –   No  1.00 (Reference)    1.00 (Reference)     Yes  NA    NA    Chemotherapy before CCRT    0.912    0.529   No  1.00 (Reference)    1.00 (Reference)     Yes  1.06 (0.39–2.86)    0.63 (0.15–2.64)    Chemotherapy at CCRT   No chemotherapy  1.00 (Reference)    1.00 (Reference)     CCRT with chemotherapy  6.38 (0.91−44.72)  0.062  25.44 (1.58−408.86)  0.022   CCRT with oxaplatin  1.69 (0.22−12.81)  0.613  6.05 (0.32−114.33)  0.230   CRT regimen with Irinotecan  0.50 (0.05−5.51)  0.571  1.75 (0.07−46.68)  0.738  BMI, body mass index; CCRT, concurrent chemoradiotherapy; CI, confidence interval; OR, odds ratio. Discussion This study demonstrated that IMRT yielded adequate oncologic outcomes in the adjuvant treatment of locally advanced rectal cancer. Local control was competitive in this study. None of those who had microscopic residual disease developed local failure in this study. Only three local recurrences were identified during follow-up. This incidence was much lower than that reported by Sauer et al. in a randomized controlled trial comparing preoperative to postoperative chemoradiotherapy for rectal cancer (20). Of the 349 assigned to postoperative chemoradiotherapy, 36 local recurrences were identified, resulting in a cumulative 5-year local recurrence rate of 13%, as compared with the 5% incidence in this study. Our results also compared favorably to that in another large randomized controlled trial, in which both preoperative and postoperative arms had 10.7% incidence of locoregional recurrence (9). Nevertheless, distant failure remained problematic in the treatment of locally advanced rectal cancer, accounting for the majority of treatment failures in our study. As an attempt to improve the treatment outcome, more than a half of our patients (53%) had chemotherapy preceding adjuvant radiotherapy. Yet the delay in the start of radiotherapy does not seem to impact local control in a negative way. The incidence of acute ≥Grade 2 neutropenia was 36%, most of which were manageable with treatment breaks and/or modification of chemotherapy. Nevertheless, the combined incidence of dose limiting (Grade 3/4) neutropenia was 22%. A great body of literature has emphasized on the bone marrow sparing of advanced technology. Experiences with IMRT in the adjuvant treatments of gynecologic and anal cancers have shown promises in improving the therapeutic ratio (21,22), however, minimizing the radiation induced bone marrow suppression may only be a small part of the story. First of all, most studies on bone marrow parameters were retrospective and unplanned (23–25). A universal dose constraint is yet to be identified. For example, the bone marrow V40 was predictive of hematologic toxicity, as demonstrated in an unplanned analysis of RTOG 0418 (23). In our study, the median bone marrow V40 was 29%, well below the 37% described in RTOG 0418. Yet the incidence of neutropenia remained considerable in this study. Next, using bone marrow dose as sole predictor of acute bone marrow toxicity may be limiting. The use of combination chemotherapy in our study may have an impact on the incidence of serious neutropenia. Both irinotecan and oxaliplatin are known to predispose to increased incidence of serious (Grade 3/4) neutropenia, with incidence up to 40% (19). The incidence of serious neutropenia in this study was approximate half of that, reflecting the proportion of patients who had combination chemotherapy (29%). In addition to that, cumulative toxicities of individual chemotherapeutic agents and their combinations may be of significant importance as more than half of our patient got chemotherapy prior to radiotherapy as an attempt to initiate adjuvant chemotherapy as early as possible. Although not reaching statistical significance in our study, senile patients are known to be susceptible to cumulated toxicities of chemotherapy (26). Moreover, as Hayman et al. has demonstrated in their elaborated study with 18F-fluoro-l-deoxythymidine, significant proportions of proliferating bone marrow is not only found in pelvic bone marrow, but also in thoracolumbar spine (27), which is generally not included in the treatment field. Our study echoes on their findings by demonstrating that any form of chemotherapy at time of radiotherapy increases the odds of Grade 2 and higher neutropenia (OR 25.44, 95% CI [1.58, 408.89]). In terms of gastrointestinal toxicity, 58% of the patients developed ≤Grade 2 diarrhea. However, only 10% of these toxicities were Grade 3 and none Grade 4. Most patients were able to complete chemoradiotherapy between 37 and 42 days. In the era when 3DRT and adjuvant chemoradiotherapy were the norm, the reported rates of Grade 3–4 diarrhea were close to 20%, which compared unfavorably to our results (7). When compared with contemporary reports, in which preoperative chemoradiotherapy with IMRT is the prevalent form of treatment, the incidence of Grade 2 or greater gastrointestinal toxicity in our study still remained competitive. The increased incidence of Grade 2 diarrhea in our study may result from the combination of dosimetric and pharmacologic factors. The mean bowel bag V45 in this study is 282 ml, in excess of the widely accepted volume of 190 ml in the neoadjuvant chemoradiotherapy (28). The strong dose–volume relationship of irradiated small bowel to acute diarrhea has already been demonstrated (29). If the patient were treated in prone position with belly board, the volume of irradiated bowel bag might have been further reduced. In addition to that, resection of rectal mass might have attributed to the amount of exposed bowel bag. As the inferior end of the bowel bag extends with the surgical resection of rectum, the volume of bowel bag exposed will inevitably increase. Next, in this study, 25 patients had combination chemotherapy at the time of chemoradiotherapy. The overlapping gastrointestinal toxicity of oxaliplatin and irinotecan to fluorouracil based chemoradiotherapy may also have added toxicity to the standard chemoradiotherapy (19). RTOG 0822, a prospective study on preoperative chemoradiation using IMRT in combination with capacetibine and oxaliplatin, reported 51.5% incidence of ≥2 gastrointestinal toxicity (47% with ≥2 diarrhea), in which 17.6% experience Grade 3–4 diarrhea (29), while most retrospective studies on IMRT preceding RTOG 0822 had only fluorouracil as part of preoperative chemoradiation and showed much lower incidences of ≥2 GI toxicity (4,5). Without a comparison to the conventional 3DCRT technique, the value of this study may be undermined. It was institutional practice to provide IMRT for patients when it has become available. Meanwhile, the standard of patient care has also evolved, leaving such comparison less reliable. Investigation on the type chemotherapy preceding chemoradiotherapy and its relation to hematologic toxicity may be unyielding because of the limited number of patients in this study. Conclusion In summary, adjuvant IMRT produced competitive local control. Survival outcomes were comparable to contemporary preoperative treatments. Most treatment related toxicities were tolerable. One should practice care when concurrent chemotherapy is given, as the marrow sparing property of IMRT does not negate the inherent hematotoxicity. Acknowledgements All authors contributed to the study and provided more than general help. Conflict of interest statement All authors declare having no conflict of interest related to the content of this manuscript. Funding This study had no sponsor. Ethical considerations This work has been carried out in accordance with The Code of Ethics of the World Medical Association (Declaration of Helsinki) for experiments involving humans. It has been approved by the Institution Review Board at Chia-Yi Christian hospital (CYCH-IRB 105060). References 1 Fisher B, Wolmark N, Rockette H, et al.  . Postoperative adjuvant chemotherapy or radiation therapy for rectal cancer: results from NSABP protocol R-01. J Natl Cancer Inst  1988; 80: 21– 9. Google Scholar CrossRef Search ADS PubMed  2 Krook JE, Moertel CG, Gunderson LL, et al.  . Effective surgical adjuvant therapy for high-risk rectal carcinoma. N Engl J Med  1991; 324: 709– 15. Google Scholar CrossRef Search ADS PubMed  3 Parekh A, Truong MT, Pashtan I, et al.  . Acute gastrointestinal toxicity and tumor response with preoperative intensity modulated radiation therapy for rectal cancer. Gastrointest Cancer Res: GCR  2013; 6: 137. 4 Ng SY, Colborn KL, Cambridge L, et al.  . Acute toxicity with intensity modulated radiotherapy versus 3-dimensional conformal radiotherapy during preoperative chemoradiation for locally advanced rectal cancer. Radiother Oncol  2016; 121: 252– 7. Google Scholar CrossRef Search ADS PubMed  5 Samuelian JM, Callister MD, Ashman JB, et al.  . Reduced acute bowel toxicity in patients treated with intensity-modulated radiotherapy for rectal cancer. Int J Radiat Oncol Biol Phys  2012; 82: 1981– 7. Google Scholar CrossRef Search ADS PubMed  6 Jabbour SK, Patel S, Herman JM, et al.  . Intensity-modulated radiation therapy for rectal carcinoma can reduce treatment breaks and emergency department visits. Int J Surg Oncol  2012; 2012: 891067. Google Scholar PubMed  7 Sauer R, Liersch T, Merkel S, et al.  . Preoperative versus postoperative chemoradiotherapy for locally advanced rectal cancer: results of the German CAO/ARO/AIO-94 randomized phase III trial after a median follow-up of 11 years. J Clin Oncol  2012; 30: 1926– 33. Google Scholar CrossRef Search ADS PubMed  8 Tapan U, Ozbayrak M, Tatli S. MRI in local staging of rectal cancer: an update. Diagn Interv Radiol  2014; 20: 390– 8. Google Scholar CrossRef Search ADS PubMed  9 Roh MS, Colangelo LH, O'Connell MJ, et al.  . Preoperative multimodality therapy improves disease-free survival in patients with carcinoma of the rectum: NSABP R-03. J Clin Oncol  2009; 27: 5124– 30. 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RTOG 0529: a phase 2 evaluation of dose-painted intensity modulated radiation therapy in combination with 5-fluorouracil and mitomycin-C for the reduction of acute morbidity in carcinoma of the anal canal. Int J Radiat Oncol Biol Phys  2013; 86: 27– 33. Google Scholar CrossRef Search ADS PubMed  22 Klopp AH, Moughan J, Portelance L, et al.  . Hematologic toxicity in RTOG 0418: a phase 2 study of postoperative IMRT for gynecologic cancer. Int J Radiat Oncol Biol Phys  2013; 86: 83– 90. Google Scholar CrossRef Search ADS PubMed  23 Albuquerque K, Giangreco D, Morrison C, et al.  . Radiation-related predictors of hematologic toxicity after concurrent chemoradiation for cervical cancer and implications for bone marrow-sparing pelvic IMRT. Int J Radiat Oncol Biol Phys  2011; 79: 1043– 7. Google Scholar CrossRef Search ADS PubMed  24 Mell LK, Tiryaki H, Ahn KH, et al.  . Dosimetric comparison of bone marrow-sparing intensity-modulated radiotherapy versus conventional techniques for treatment of cervical cancer. Int J Radiat Oncol Biol Phys  2008; 71: 1504– 10. Google Scholar CrossRef Search ADS PubMed  25 Mell LK, Schomas DA, Salama JK, et al.  . Association between bone marrow dosimetric parameters and acute hematologic toxicity in anal cancer patients treated with concurrent chemotherapy and intensity-modulated radiotherapy. Int J Radiat Oncol Biol Phys  2008; 70: 1431– 7. Google Scholar CrossRef Search ADS PubMed  26 Kim JH, Kim JW, Kim SH, et al.  . Predicting cumulative incidence of chemotherapy toxicity in older patients with cancer: Korean Cancer Study Group prospective cohort study (KCSG) PC 13-09. J Clin Oncol  2017; 35: e21539– 39. 27 Hayman JA, Callahan JW, Herschtal A, et al.  . Distribution of proliferating bone marrow in adult cancer patients determined using FLT-PET imaging. Int J Radiat Oncol Biol Phys  2011; 79: 847– 52. 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For permissions, please e-mail: journals.permissions@oup.com This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Japanese Journal of Clinical Oncology Oxford University Press

Intensity modulated radiotherapy delivers competitive local control rate with limited acute toxicity in the adjuvant treatment of rectal cancer

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Abstract

Abstract Background Intensity-modulated radiotherapy (IMRT) has yet to show its capability in the adjuvant treatment of locally advanced rectal cancer. The purpose of this study is to evaluate the clinical efficacy and safety profile of IMRT in the adjuvant treatment of rectal cancer. Method Consecutive patients with resected locally advanced rectal cancer who had IMRT as part of adjuvant treatment between 2008 and 2014 were identified. The medical records and dosimetric parameters of 72 patients were retrospectively examined. Results The median follow-up time was 4.36 years (range 0.16–8.49 years). Overall survival rate and disease-free survival rate at 3 year was 79% (95% CI: 66.4–7.3%) and 70% (95% CI: 56.6–79.6%), respectively. Local control rate was 95%. The median bowel bag V45 was 282 ml (249–458 ml) and bone marrow V40 was 29%. Most acute toxicities were self-limited. Concurrent use of chemotherapy was associated with greater odds of ≥Grade 2 acute neutropenia (OR 25.44, P = 0.022). Conclusion Integration of IMRT in the adjuvant treatment of rectal cancer is promising with competitive local control rate. Acute toxicities are mostly self-limited. rectal cancer, adjuvant treatment, intensity modulated radiotherapy, neutropenia Introduction Radiotherapy has been an integral part of rectal cancer treatment. In the past few decades, radiotherapy has been consistently improving the outcome of rectal cancer treatment (1,2). Intensity modulated radiotherapy (IMRT), with the combination of inverse planning and multileaf collimator, has made possible not only the intended delivering target coverage, but also reduction of undesired dose to neighboring organs. To date, most existing literatures on IMRT focused on the preoperative management of rectal cancer (3–6), yet this approach is not without caveats. First, in the absence of reliable preoperative imaging, a 10th of patients who were initially diagnosed with locally advanced rectal cancer might have had unnecessary chemoradiotherapy, as shown in the German study (7). Moreover, advances in imaging technology has yet to completely solve this dilemma (8). Secondly, although preoperative chemoradiotherapy has shown to increase sphinter saving surgeries (7), this may only apply to a specific subgroup of patients, as sphinter saving surgery may be unnecessary and sometimes unavoidable even with chemoradiotherapy. In addition to that, the toxicity profile superiority of preoperative chemoradiotherapy may be controversial, as one large American study has shown (9). Lastly, the superiority in survival outcome of preoperative chemoradiotherapy has not been shown in two major randomized controlled trials (7,9). The need for toxicity reducing technology is never an understatement, especially when early introduction of systemic therapy is of paramount importance (10,11). As Kang et al. pointed out, early initiation of adjuvant chemotherapy may have a positive impact on the relapse free survival and overall survival of colorectal cancer (12). Kang’s finding on survival outcome was supported by a large meta-analysis, in which 14 studies were included (13). Meticulous works on combination systemic therapy have lead to improvement in the survival outcomes (14–17), yet with increased toxicity profile. As Braun et al. has pointed out, up to 40% of patient on combination chemotherapy such as FOLFOX are at risk of serious hematotoxicity (18). The added toxicity of combination chemotherapy have made chemoradiotherapy challenging. To meet these demands, clinical experiences on the adjuvant IMRT on locally advanced rectal cancer is urgently needed. This study aimed to examine the toxicities, oncologic outcomes and interaction of radiotherapy with fluorouracil (5-Fu)-based regimen in the adjuvant treatment of locally advanced rectal cancer with IMRT. Material and method Patient selection Seventy-two patients with rectal cancer treated with adjuvant IMRT were identified at our department. Patients with limited number of metastatic lesions at time of diagnosis were included. Electronic medical records and dose–volume–histogram (DVH) were meticulous reviewed. All pathologic findings were re-staged on the eighth AJCC staging manual. This study was approved by the Institution Review board at Chia-Yi Christian hospital. Treatment Surgery All patients had total mesorectal excision (TME) prior to chemotherapy and/or chemoradiotherapy. Surgeons had the ultimate decision in the preservation of anus. Extended Lymph node dissection was indicated for clinically suspected nodes. Radiotherapy Indications for adjuvant RT were in line with the guideline propose by the National Comprehensive Cancer Network (NCCN). The indications included T3-4N0 and any T + N1-2 diseases. T1-2N0 with unfavorable features, such as lymphovascular extension and close margin were also offered adjuvant RT. All patients had computed tomography (CT) based procedure in the supine position with full bladder. Immobilization with body foam is the practice at our institution. Body markers were used to position the patient on treatment couch. Gross tumor volumes (GTV) were reconstructed by registrating the preoperative CT/magnetic resonance imaging (MRI) images to their simulation counterparts. The intermediate risk clinical target volume (CTV-M) included the remaining rectum, if present, the mesorectum, and the internal iliac lymph nodes. CTV-M would also included and the external iliac lymph nodes if tumoral invasion of anterior pelvic organs was identified on pathologic record. PTV4500 is a 5 mm expansion of CTV-M. The longitudinal extends of high risk clinical target volumes (CTV-H) included the parts of the remaining rectum that was within 2-cm longitude to the surgical anastomosis, whereas the circumferential extent of CTV-H included the mesorectal bed and terminates at uninvolved muscle, bone or air. For ≤T3 lesions, an 5 mm expansion of the CTV-H yielded PTV5040, whereas T4 lesions got expanded 5 mm to yield PTV5400. All PTVs were treated at 1.8 Gy fractions. The available IMRT system at our institution consisted of Eclipse treatment planning system (Eclipse, Varian Medical Systems, Palo Alto, CA) and Clinac iX (Eclipse, Varian Medical Systems, Palo Alto, CA). Coverage of the PTV by at least 95% of the prescribed dose was mandatory. All treatment plans has coplanar beams. 6-MV and 15-MV photon were available for radiation delivery. For the inverse planning, the organs at risk included the urinary bladder, femoral heads, cauda equina, and bowel bag. All organs at risk were re-assessed with reference to the publication by Gay et al. (19). The bone marrow was not intentionally constructed at the time of planning, but was reconstructed for analysis. Chemotherapy Fluorouracil, in either intravenous or oral form, was the backbone of chemotherapy. For those considered at high risk of developing distant metastasis, adjuvant chemotherapy could precede chemoradiotherapy. Combination regimens, such as FOLFOX and FOLFIRI were allowed during chemoradiotherapy. Of note, oxaliplatin and irinotecan were not universally reimbursed by the National Health Insurance program until early 2009. Chemotherapy preceded radiotherapy when the time between surgery and RT exceeded 30 days, unless contraindicated. Toxicity assessment The treating clinician evaluated patients weekly at the time of adjuvant radiotherapy and made records on acute toxicities. Chart review was performed and toxicity data collected. Acute toxicities were revised according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) v4.0. Follow-up Patients were followed at our institution at 3-month interval after completing the scheduled treatment. Radiological studies such as CT/MRI were arranged at 3-month intervals and as clinically indicated. Tumor markers were examined if they correlated with the patient’s clinical course. Local failures were identified as recurrence in the PTV5040/5400, regional failures as that within PTV4500. Recurrence beyond the pelvic region was considered distant failure. Statistical analysis All statistical analyses were performed by using the SPSS software for Windows (version 21.0; IBM Corporation, Somers, NY, USA). To investigate risk factors of limiting toxicities, we calculated odds ratios (ORs) and 95% confidence intervals (CIs) by using logistic regression model. A two-tailed P value less than 0.05 was considered statistically significant. We also used R (version 3.2.1, R foundation for Statistical Computing, Vienna, Austria), with the KMsurv, survfit and survival packages to measure the death and/or treatment failures rates in this study with Kaplan–Meier analysis. The occurrence of death was considered an event in the overall survival curve. Death and/or treatment failures were considered events in disease-free survival. Results Patient, tumor and treatment characteristics Relevant clinicopathologic factors are summarized in Table 1. Median body mass index was 23 kg/m2 (Q1–Q3: 20–25) whereas the median distance of the tumor from the anal verge was 10 cm (Q1–Q3: 5–15). Locally advanced rectal cancers, defined as T3/4N0 and Tany + N1-2 constituted the majority of study population. There were three T1N0s and one T2N0 lesions. Indications for adjuvant radiotherapy included very close proximity (<2 cm) to anal verge in addition to LVI in one T2N0, close margin (close longitudinal margin or severe dysplasia on longitudinal margin) in two T1N0s, limited surgery from previous pelvic procedure in one T1N0 Table 1. Patient and tumor characteristics   Number  %  Gender   Female  29  40   Male  43  60  Age, years   <65  37  51   ≥65  35  49  Performance status   0  11  15   1  49  68   2  12  17  Bleeding   Yes  52  72   No  20  28  Abdominal pain   Yes  16  22   No  56  78  Obstruction   Yes  31  43   No  41  57  Body weight loss   Yes  6  8   No  66  92  Anemia   Yes  10  14    No  62  86  Distance from anal verge, cm   0–≤5  18  25   5–≤5  22  31   >10  32  44  Anal preservation surgery   Yes  69  96   No  3  4  pT   1  3  4   2  9  13   3  53  74   4a  6  8   4b  1  1  pN   0  24  33   1  16  22   2  32  44  pM   0  69  96   1  3  4  Histology   Adenocarcinoma  69  96   Mucinous adenocarcinoma  3  4  Grading   Well differentiated  1  1   Moderately differentiated  67  93   Poorly differentiated  2  2   Not available  2  2  Lymphovascular invasion   Yes  58  81   No  14  19  Perineural invasion   Yes  27  38   No  45  62  Extend of resection   R0  69  96   R1  3  4   R0  0  0    Number  %  Gender   Female  29  40   Male  43  60  Age, years   <65  37  51   ≥65  35  49  Performance status   0  11  15   1  49  68   2  12  17  Bleeding   Yes  52  72   No  20  28  Abdominal pain   Yes  16  22   No  56  78  Obstruction   Yes  31  43   No  41  57  Body weight loss   Yes  6  8   No  66  92  Anemia   Yes  10  14    No  62  86  Distance from anal verge, cm   0–≤5  18  25   5–≤5  22  31   >10  32  44  Anal preservation surgery   Yes  69  96   No  3  4  pT   1  3  4   2  9  13   3  53  74   4a  6  8   4b  1  1  pN   0  24  33   1  16  22   2  32  44  pM   0  69  96   1  3  4  Histology   Adenocarcinoma  69  96   Mucinous adenocarcinoma  3  4  Grading   Well differentiated  1  1   Moderately differentiated  67  93   Poorly differentiated  2  2   Not available  2  2  Lymphovascular invasion   Yes  58  81   No  14  19  Perineural invasion   Yes  27  38   No  45  62  Extend of resection   R0  69  96   R1  3  4   R0  0  0  Table 1. Patient and tumor characteristics   Number  %  Gender   Female  29  40   Male  43  60  Age, years   <65  37  51   ≥65  35  49  Performance status   0  11  15   1  49  68   2  12  17  Bleeding   Yes  52  72   No  20  28  Abdominal pain   Yes  16  22   No  56  78  Obstruction   Yes  31  43   No  41  57  Body weight loss   Yes  6  8   No  66  92  Anemia   Yes  10  14    No  62  86  Distance from anal verge, cm   0–≤5  18  25   5–≤5  22  31   >10  32  44  Anal preservation surgery   Yes  69  96   No  3  4  pT   1  3  4   2  9  13   3  53  74   4a  6  8   4b  1  1  pN   0  24  33   1  16  22   2  32  44  pM   0  69  96   1  3  4  Histology   Adenocarcinoma  69  96   Mucinous adenocarcinoma  3  4  Grading   Well differentiated  1  1   Moderately differentiated  67  93   Poorly differentiated  2  2   Not available  2  2  Lymphovascular invasion   Yes  58  81   No  14  19  Perineural invasion   Yes  27  38   No  45  62  Extend of resection   R0  69  96   R1  3  4   R0  0  0    Number  %  Gender   Female  29  40   Male  43  60  Age, years   <65  37  51   ≥65  35  49  Performance status   0  11  15   1  49  68   2  12  17  Bleeding   Yes  52  72   No  20  28  Abdominal pain   Yes  16  22   No  56  78  Obstruction   Yes  31  43   No  41  57  Body weight loss   Yes  6  8   No  66  92  Anemia   Yes  10  14    No  62  86  Distance from anal verge, cm   0–≤5  18  25   5–≤5  22  31   >10  32  44  Anal preservation surgery   Yes  69  96   No  3  4  pT   1  3  4   2  9  13   3  53  74   4a  6  8   4b  1  1  pN   0  24  33   1  16  22   2  32  44  pM   0  69  96   1  3  4  Histology   Adenocarcinoma  69  96   Mucinous adenocarcinoma  3  4  Grading   Well differentiated  1  1   Moderately differentiated  67  93   Poorly differentiated  2  2   Not available  2  2  Lymphovascular invasion   Yes  58  81   No  14  19  Perineural invasion   Yes  27  38   No  45  62  Extend of resection   R0  69  96   R1  3  4   R0  0  0  Three patients had resectable metastasis at time of surgery. Those metastatic lesions were located in the lung, liver and in para-aortic lymph nodes. All but three patients had sphinter saving surgeries. Table 2 illustrates the relevant treatment parameters, dosimetric data were also included. Thirty-eight (53%) of all patients had adjuvant chemotherapy before radiotherapy. The median interval between surgery and radiotherapy was 75 days (Q1–Q3:63–83 days). PTVH alone was treated because of previously existing gastrointestinal conditions in two patients. All but five were reluctant to concurrent chemotherapy at the time of radiotherapy. Two patients withdrew themselves from treatment within first week into treatment with personal considerations. Both were above the age of 70. Table 2. Treatment related factors   Number  %  Completion of assigned treatment   Yes  65  90   Withdrew within first week for personal considerations  2  3   Premature termination due to treatment related toxicity  5  7  Period between surgery and RT   ≤30 days  29  40   31–60 days  39  54   ≥61 days  4  6  Adjuvant chemotherapy before chemoradiotherapy   Yes  38  53   No  34  47  Concurrent chemoradiotherapy   Yes  67  93   No  5  7  Chemoradiotherapy with oxaliplatin   Yes  17  24   No  55  76  Chemoradiotherapy with Irinotecan   Yes  8  11   No  64  99    Median  Q1–Q3  Interval between surgery and radiotherapy (days)  75  63–83  Duration of radiotherapy (days)  38  37–42  Dose to PTVM (cGy)  4500  4500  Dose to PTVH (cGy)  5040  5040  Bowel bag V45 (cc)  282  196–361  Bone marrow volume (cc)  933  808–1087  Mean marrow dose (cGy)  2990  2934–3249  Bone marrow V40 (%)  29  25–35    Number  %  Completion of assigned treatment   Yes  65  90   Withdrew within first week for personal considerations  2  3   Premature termination due to treatment related toxicity  5  7  Period between surgery and RT   ≤30 days  29  40   31–60 days  39  54   ≥61 days  4  6  Adjuvant chemotherapy before chemoradiotherapy   Yes  38  53   No  34  47  Concurrent chemoradiotherapy   Yes  67  93   No  5  7  Chemoradiotherapy with oxaliplatin   Yes  17  24   No  55  76  Chemoradiotherapy with Irinotecan   Yes  8  11   No  64  99    Median  Q1–Q3  Interval between surgery and radiotherapy (days)  75  63–83  Duration of radiotherapy (days)  38  37–42  Dose to PTVM (cGy)  4500  4500  Dose to PTVH (cGy)  5040  5040  Bowel bag V45 (cc)  282  196–361  Bone marrow volume (cc)  933  808–1087  Mean marrow dose (cGy)  2990  2934–3249  Bone marrow V40 (%)  29  25–35  Table 2. Treatment related factors   Number  %  Completion of assigned treatment   Yes  65  90   Withdrew within first week for personal considerations  2  3   Premature termination due to treatment related toxicity  5  7  Period between surgery and RT   ≤30 days  29  40   31–60 days  39  54   ≥61 days  4  6  Adjuvant chemotherapy before chemoradiotherapy   Yes  38  53   No  34  47  Concurrent chemoradiotherapy   Yes  67  93   No  5  7  Chemoradiotherapy with oxaliplatin   Yes  17  24   No  55  76  Chemoradiotherapy with Irinotecan   Yes  8  11   No  64  99    Median  Q1–Q3  Interval between surgery and radiotherapy (days)  75  63–83  Duration of radiotherapy (days)  38  37–42  Dose to PTVM (cGy)  4500  4500  Dose to PTVH (cGy)  5040  5040  Bowel bag V45 (cc)  282  196–361  Bone marrow volume (cc)  933  808–1087  Mean marrow dose (cGy)  2990  2934–3249  Bone marrow V40 (%)  29  25–35    Number  %  Completion of assigned treatment   Yes  65  90   Withdrew within first week for personal considerations  2  3   Premature termination due to treatment related toxicity  5  7  Period between surgery and RT   ≤30 days  29  40   31–60 days  39  54   ≥61 days  4  6  Adjuvant chemotherapy before chemoradiotherapy   Yes  38  53   No  34  47  Concurrent chemoradiotherapy   Yes  67  93   No  5  7  Chemoradiotherapy with oxaliplatin   Yes  17  24   No  55  76  Chemoradiotherapy with Irinotecan   Yes  8  11   No  64  99    Median  Q1–Q3  Interval between surgery and radiotherapy (days)  75  63–83  Duration of radiotherapy (days)  38  37–42  Dose to PTVM (cGy)  4500  4500  Dose to PTVH (cGy)  5040  5040  Bowel bag V45 (cc)  282  196–361  Bone marrow volume (cc)  933  808–1087  Mean marrow dose (cGy)  2990  2934–3249  Bone marrow V40 (%)  29  25–35  Survival and pattern of failure Median follow-up time was 4.36 years (range 0.16–8.49 years). Overall survival and disease-free survival at 3 year was 79% (95% CI: 66–87%) and 70% (95% CI: 57–80%), respectively (Figs 1 and 2, respectively). Overall, 18 patient died during follow-up. Three deaths were unrelated to their primary disease: two as results of cardiovascular event and one succumbed to second primary hepatocellular carcinoma. Distant metastasis was the primary form of treatment failure, cumulative incidence of distant metastasis was 21% at 3 years (Fig. 3). Local failure was rare. Of the 72 patients in this cohort, only three local failures were identified during follow-up (Fig. 4). Local failure at 3 years follow-up was 5%. One regional failure subsequently developed after local failure in one patient. Figure 1. View largeDownload slide Kaplan–Meier survival analysis for OS (overall survival) of patients treated for resected rectal cancer (n = 72). Three-year OS rate was 79% (95% CI: 66.4–87.3%). Figure 1. View largeDownload slide Kaplan–Meier survival analysis for OS (overall survival) of patients treated for resected rectal cancer (n = 72). Three-year OS rate was 79% (95% CI: 66.4–87.3%). Figure 2. View largeDownload slide Kaplan–Meier survival analysis for DFS (disease-free survival) of patients treated for resected rectal cancer (n = 72). Three-year DFS rate was 70% (95% CI: 56.6–79.6%). Figure 2. View largeDownload slide Kaplan–Meier survival analysis for DFS (disease-free survival) of patients treated for resected rectal cancer (n = 72). Three-year DFS rate was 70% (95% CI: 56.6–79.6%). Figure 3. View largeDownload slide For patients who had IMRT based adjuvant radiotherapy for resected rectal cancer, distant metastasis was the primary form of treatment failure. Three-year cumulative rate of distant metastasis was 21%. Figure 3. View largeDownload slide For patients who had IMRT based adjuvant radiotherapy for resected rectal cancer, distant metastasis was the primary form of treatment failure. Three-year cumulative rate of distant metastasis was 21%. Figure 4. View largeDownload slide Local recurrence was a rare event following IMRT based adjuvant radiotherapy. Only three local failures were identified during follow-up. None of the patients with microscopic disease at surgical margins developed local failure. Figure 4. View largeDownload slide Local recurrence was a rare event following IMRT based adjuvant radiotherapy. Only three local failures were identified during follow-up. None of the patients with microscopic disease at surgical margins developed local failure. Acute toxicity Table 3 demonstrates the frequency of different acute toxicities. Most were self-limited. No Grade 5 toxicity was encountered. None but five patients had premature termination of adjuvant radiotherapy relating to acute toxicity, with three encountering dose limiting toxicities (one Grade 4 neutropenia and two Grade 3 gastrointestinal toxicity), two declining further treatment at Grade 2 gastrointestinal toxicity. The most commonly encountered limiting toxicities were primarily gastrointestinal and hematologic: 58% of patients had ≥Grade 2 diarrhea, of which four were Grade 3 (6%) and none were Grade 4. Twenty-five (36%) patients had ≥Grade 2 neutropenia, of which, 14 (19%) Grade 3 hematologic toxicities and two (3%) Grade 4 neutropenia were identified. Most ≥Grade 2 neutropenias were manageable with either dose adjustment or discontinuation of chemotherapy. Two patients withdrew themselves from treatment at third and fifth fraction of radiotherapy, respectively. Table 3. Summary of acute treatment toxicities   Toxicity grade  0  1  2  3  4  5  Nausea and vomiting  69  3  0  0  0  0  Diarrhea  13  17  38  4  0  0  Skin reaction  0  19  0  0  0  0  Anemia  52  10  8  2  0  0  Neutropenia  43  4  9  14  2  0  Thrombocytopenia  0  0  0  0  0  0  Cystitis  67  5  0  0  0  0    Toxicity grade  0  1  2  3  4  5  Nausea and vomiting  69  3  0  0  0  0  Diarrhea  13  17  38  4  0  0  Skin reaction  0  19  0  0  0  0  Anemia  52  10  8  2  0  0  Neutropenia  43  4  9  14  2  0  Thrombocytopenia  0  0  0  0  0  0  Cystitis  67  5  0  0  0  0  Table 3. Summary of acute treatment toxicities   Toxicity grade  0  1  2  3  4  5  Nausea and vomiting  69  3  0  0  0  0  Diarrhea  13  17  38  4  0  0  Skin reaction  0  19  0  0  0  0  Anemia  52  10  8  2  0  0  Neutropenia  43  4  9  14  2  0  Thrombocytopenia  0  0  0  0  0  0  Cystitis  67  5  0  0  0  0    Toxicity grade  0  1  2  3  4  5  Nausea and vomiting  69  3  0  0  0  0  Diarrhea  13  17  38  4  0  0  Skin reaction  0  19  0  0  0  0  Anemia  52  10  8  2  0  0  Neutropenia  43  4  9  14  2  0  Thrombocytopenia  0  0  0  0  0  0  Cystitis  67  5  0  0  0  0  Patient demographics, dosimetry data and treatment related factors were assessed for association to increased treatment-related gastrointestinal and hematologic toxicity (Table 4). None of the factors were associated with greater odds to ≥Grade 2 diarrhea was identified. On the other hand, patient who had any form of concomitant chemotherapy at the time of radiotherapy had 25.44 (CI 1.58–408.86) times greater odds of developing ≥Grade 2 grade neutropenia (Table 5). Table 4. Predisposing factors on acute diarrhea   Univariable  Multivariable  Crude OR (95% CI)  P value  Adjusted OR (95% CI)  P value  Age  1.00 (0.96–1.03)  0.838  0.98 (0.93–1.04)  0.502  Gender    0.655    0.567   Female  1.00 (Reference)    1.00 (Reference)     Male  0.81 (0.31–2.09)    1.55 (0.35–6.94)    BMI  0.99 (0.89–1.11)  0.867  1.02 (0.87–1.19)  0.809  Bowel bag V45 (cc)  1.00 (0.997–1.002)  0.762  1 (1–1.01)  0.824  Volume of bone marrow (cc)  1 (1)  0.145  1 (0.99–1)  0.071  Mean marrow dose (cGy)  1 (1)  0.477  1 (1)  0.590  Bone marrow V40 (%)  0.97 (0.92–1.02)  0.261  0.96 (0.88–1.04)  0.298  PS    0.523    0.800   0  1.00 (Reference)    1.00 (Reference)     1–2  1.50 (0.43–5.20)    1.23 (0.25–6.11)    Body weight loss at presentation    0.667    0.657   No  1.00 (Reference)    1.00 (Reference)     Yes  0.68 (0.12–3.97)    0.63 (0.08–4.96)    Anemia    0.566    0.551   No  1.00 (Reference)    1.00 (Reference)     Yes  1.48 (0.39–5.65)    1.74 (0.28–10.89)    Anal preservation surgery    0.766    0.819   No  1.00 (Reference)    1.00 (Reference)     Yes  1.45 (0.13–16.76)    1.46 (0.06–36.26)    Chemotherapy before CCRT    0.775    0.222   No  1.00 (Reference)    1.00 (Reference)     Yes  1.15 (0.44–3.03)    2.16 (0.63–7.46)    Chemotherapy at CCRT   No chemotherapy  1.00 (Reference)    1.00 (Reference)     CCRT with chemotherapy  1.36 (0.21–9.02)  0.748  0.61 (0.06–5.96)  0.669   CCRT with oxaplatin  0.32 (0.04–2.85)  0.308  0.11 (0.01–1.57)  0.103   CRT regimen with Irinotecan  2.50 (0.25–3.99)  0.433  2.2 (0.12–41.08)  0.597    Univariable  Multivariable  Crude OR (95% CI)  P value  Adjusted OR (95% CI)  P value  Age  1.00 (0.96–1.03)  0.838  0.98 (0.93–1.04)  0.502  Gender    0.655    0.567   Female  1.00 (Reference)    1.00 (Reference)     Male  0.81 (0.31–2.09)    1.55 (0.35–6.94)    BMI  0.99 (0.89–1.11)  0.867  1.02 (0.87–1.19)  0.809  Bowel bag V45 (cc)  1.00 (0.997–1.002)  0.762  1 (1–1.01)  0.824  Volume of bone marrow (cc)  1 (1)  0.145  1 (0.99–1)  0.071  Mean marrow dose (cGy)  1 (1)  0.477  1 (1)  0.590  Bone marrow V40 (%)  0.97 (0.92–1.02)  0.261  0.96 (0.88–1.04)  0.298  PS    0.523    0.800   0  1.00 (Reference)    1.00 (Reference)     1–2  1.50 (0.43–5.20)    1.23 (0.25–6.11)    Body weight loss at presentation    0.667    0.657   No  1.00 (Reference)    1.00 (Reference)     Yes  0.68 (0.12–3.97)    0.63 (0.08–4.96)    Anemia    0.566    0.551   No  1.00 (Reference)    1.00 (Reference)     Yes  1.48 (0.39–5.65)    1.74 (0.28–10.89)    Anal preservation surgery    0.766    0.819   No  1.00 (Reference)    1.00 (Reference)     Yes  1.45 (0.13–16.76)    1.46 (0.06–36.26)    Chemotherapy before CCRT    0.775    0.222   No  1.00 (Reference)    1.00 (Reference)     Yes  1.15 (0.44–3.03)    2.16 (0.63–7.46)    Chemotherapy at CCRT   No chemotherapy  1.00 (Reference)    1.00 (Reference)     CCRT with chemotherapy  1.36 (0.21–9.02)  0.748  0.61 (0.06–5.96)  0.669   CCRT with oxaplatin  0.32 (0.04–2.85)  0.308  0.11 (0.01–1.57)  0.103   CRT regimen with Irinotecan  2.50 (0.25–3.99)  0.433  2.2 (0.12–41.08)  0.597  BMI, body mass index; CCRT, concurrent chemoradiotherapy; CI, confidence interval; OR, odds ratio. Table 4. Predisposing factors on acute diarrhea   Univariable  Multivariable  Crude OR (95% CI)  P value  Adjusted OR (95% CI)  P value  Age  1.00 (0.96–1.03)  0.838  0.98 (0.93–1.04)  0.502  Gender    0.655    0.567   Female  1.00 (Reference)    1.00 (Reference)     Male  0.81 (0.31–2.09)    1.55 (0.35–6.94)    BMI  0.99 (0.89–1.11)  0.867  1.02 (0.87–1.19)  0.809  Bowel bag V45 (cc)  1.00 (0.997–1.002)  0.762  1 (1–1.01)  0.824  Volume of bone marrow (cc)  1 (1)  0.145  1 (0.99–1)  0.071  Mean marrow dose (cGy)  1 (1)  0.477  1 (1)  0.590  Bone marrow V40 (%)  0.97 (0.92–1.02)  0.261  0.96 (0.88–1.04)  0.298  PS    0.523    0.800   0  1.00 (Reference)    1.00 (Reference)     1–2  1.50 (0.43–5.20)    1.23 (0.25–6.11)    Body weight loss at presentation    0.667    0.657   No  1.00 (Reference)    1.00 (Reference)     Yes  0.68 (0.12–3.97)    0.63 (0.08–4.96)    Anemia    0.566    0.551   No  1.00 (Reference)    1.00 (Reference)     Yes  1.48 (0.39–5.65)    1.74 (0.28–10.89)    Anal preservation surgery    0.766    0.819   No  1.00 (Reference)    1.00 (Reference)     Yes  1.45 (0.13–16.76)    1.46 (0.06–36.26)    Chemotherapy before CCRT    0.775    0.222   No  1.00 (Reference)    1.00 (Reference)     Yes  1.15 (0.44–3.03)    2.16 (0.63–7.46)    Chemotherapy at CCRT   No chemotherapy  1.00 (Reference)    1.00 (Reference)     CCRT with chemotherapy  1.36 (0.21–9.02)  0.748  0.61 (0.06–5.96)  0.669   CCRT with oxaplatin  0.32 (0.04–2.85)  0.308  0.11 (0.01–1.57)  0.103   CRT regimen with Irinotecan  2.50 (0.25–3.99)  0.433  2.2 (0.12–41.08)  0.597    Univariable  Multivariable  Crude OR (95% CI)  P value  Adjusted OR (95% CI)  P value  Age  1.00 (0.96–1.03)  0.838  0.98 (0.93–1.04)  0.502  Gender    0.655    0.567   Female  1.00 (Reference)    1.00 (Reference)     Male  0.81 (0.31–2.09)    1.55 (0.35–6.94)    BMI  0.99 (0.89–1.11)  0.867  1.02 (0.87–1.19)  0.809  Bowel bag V45 (cc)  1.00 (0.997–1.002)  0.762  1 (1–1.01)  0.824  Volume of bone marrow (cc)  1 (1)  0.145  1 (0.99–1)  0.071  Mean marrow dose (cGy)  1 (1)  0.477  1 (1)  0.590  Bone marrow V40 (%)  0.97 (0.92–1.02)  0.261  0.96 (0.88–1.04)  0.298  PS    0.523    0.800   0  1.00 (Reference)    1.00 (Reference)     1–2  1.50 (0.43–5.20)    1.23 (0.25–6.11)    Body weight loss at presentation    0.667    0.657   No  1.00 (Reference)    1.00 (Reference)     Yes  0.68 (0.12–3.97)    0.63 (0.08–4.96)    Anemia    0.566    0.551   No  1.00 (Reference)    1.00 (Reference)     Yes  1.48 (0.39–5.65)    1.74 (0.28–10.89)    Anal preservation surgery    0.766    0.819   No  1.00 (Reference)    1.00 (Reference)     Yes  1.45 (0.13–16.76)    1.46 (0.06–36.26)    Chemotherapy before CCRT    0.775    0.222   No  1.00 (Reference)    1.00 (Reference)     Yes  1.15 (0.44–3.03)    2.16 (0.63–7.46)    Chemotherapy at CCRT   No chemotherapy  1.00 (Reference)    1.00 (Reference)     CCRT with chemotherapy  1.36 (0.21–9.02)  0.748  0.61 (0.06–5.96)  0.669   CCRT with oxaplatin  0.32 (0.04–2.85)  0.308  0.11 (0.01–1.57)  0.103   CRT regimen with Irinotecan  2.50 (0.25–3.99)  0.433  2.2 (0.12–41.08)  0.597  BMI, body mass index; CCRT, concurrent chemoradiotherapy; CI, confidence interval; OR, odds ratio. Table 5. Predictor factors on acute neutropenia   Univariate  Multivariate  Crude OR (95% CI)  P value  Adjusted OR (95% CI)  P value  Age  1.02 (0.99–1.07)  0.221  1.03 (0.97–1.09)  0.345  Gender    0.142    0.582   Female  1.00 (Reference)    1.00 (Reference)     Male  2.10 (0.78–5.65)    1.6 (0.3–8.44)    BMI  1.11 (0.97–1.26)  0.129  1.14 (0.93–1.4)  0.196  Bowel bag V45 (cc)  1 (1)  0.119  1 (0.99–1)  0.298  Volume of bone marrow (cc)  1 (1)  0.586  1 (1)  0.731  Mean marrow dose (cGy)  1 (1)  0.777  1 (1)  0.656  Bone marrow V40 (%)  0.96 (0.91–1.02)  0.151  0.94 (0.86–1.03)  0.188  PS    0.912    0.825   0  1.00 (Reference)    1.00 (Reference)     1–2  1.08 (0.29–4.00)    0.81 (0.13–5.23)    Body weight loss at presentation    0.941    0.814   No  1.00 (Reference)    1.00 (Reference)     Yes  1.07 (0.18–6.29)    1.39 (0.09–22.18)    Anemia    0.706    0.951   No  1.00 (Reference)    1.00 (Reference)     Yes  0.77 (0.20–3.02)    0.94 (0.12–7.21)    Anal preservation surgery    –    –   No  1.00 (Reference)    1.00 (Reference)     Yes  NA    NA    Chemotherapy before CCRT    0.912    0.529   No  1.00 (Reference)    1.00 (Reference)     Yes  1.06 (0.39–2.86)    0.63 (0.15–2.64)    Chemotherapy at CCRT   No chemotherapy  1.00 (Reference)    1.00 (Reference)     CCRT with chemotherapy  6.38 (0.91−44.72)  0.062  25.44 (1.58−408.86)  0.022   CCRT with oxaplatin  1.69 (0.22−12.81)  0.613  6.05 (0.32−114.33)  0.230   CRT regimen with Irinotecan  0.50 (0.05−5.51)  0.571  1.75 (0.07−46.68)  0.738    Univariate  Multivariate  Crude OR (95% CI)  P value  Adjusted OR (95% CI)  P value  Age  1.02 (0.99–1.07)  0.221  1.03 (0.97–1.09)  0.345  Gender    0.142    0.582   Female  1.00 (Reference)    1.00 (Reference)     Male  2.10 (0.78–5.65)    1.6 (0.3–8.44)    BMI  1.11 (0.97–1.26)  0.129  1.14 (0.93–1.4)  0.196  Bowel bag V45 (cc)  1 (1)  0.119  1 (0.99–1)  0.298  Volume of bone marrow (cc)  1 (1)  0.586  1 (1)  0.731  Mean marrow dose (cGy)  1 (1)  0.777  1 (1)  0.656  Bone marrow V40 (%)  0.96 (0.91–1.02)  0.151  0.94 (0.86–1.03)  0.188  PS    0.912    0.825   0  1.00 (Reference)    1.00 (Reference)     1–2  1.08 (0.29–4.00)    0.81 (0.13–5.23)    Body weight loss at presentation    0.941    0.814   No  1.00 (Reference)    1.00 (Reference)     Yes  1.07 (0.18–6.29)    1.39 (0.09–22.18)    Anemia    0.706    0.951   No  1.00 (Reference)    1.00 (Reference)     Yes  0.77 (0.20–3.02)    0.94 (0.12–7.21)    Anal preservation surgery    –    –   No  1.00 (Reference)    1.00 (Reference)     Yes  NA    NA    Chemotherapy before CCRT    0.912    0.529   No  1.00 (Reference)    1.00 (Reference)     Yes  1.06 (0.39–2.86)    0.63 (0.15–2.64)    Chemotherapy at CCRT   No chemotherapy  1.00 (Reference)    1.00 (Reference)     CCRT with chemotherapy  6.38 (0.91−44.72)  0.062  25.44 (1.58−408.86)  0.022   CCRT with oxaplatin  1.69 (0.22−12.81)  0.613  6.05 (0.32−114.33)  0.230   CRT regimen with Irinotecan  0.50 (0.05−5.51)  0.571  1.75 (0.07−46.68)  0.738  BMI, body mass index; CCRT, concurrent chemoradiotherapy; CI, confidence interval; OR, odds ratio. Table 5. Predictor factors on acute neutropenia   Univariate  Multivariate  Crude OR (95% CI)  P value  Adjusted OR (95% CI)  P value  Age  1.02 (0.99–1.07)  0.221  1.03 (0.97–1.09)  0.345  Gender    0.142    0.582   Female  1.00 (Reference)    1.00 (Reference)     Male  2.10 (0.78–5.65)    1.6 (0.3–8.44)    BMI  1.11 (0.97–1.26)  0.129  1.14 (0.93–1.4)  0.196  Bowel bag V45 (cc)  1 (1)  0.119  1 (0.99–1)  0.298  Volume of bone marrow (cc)  1 (1)  0.586  1 (1)  0.731  Mean marrow dose (cGy)  1 (1)  0.777  1 (1)  0.656  Bone marrow V40 (%)  0.96 (0.91–1.02)  0.151  0.94 (0.86–1.03)  0.188  PS    0.912    0.825   0  1.00 (Reference)    1.00 (Reference)     1–2  1.08 (0.29–4.00)    0.81 (0.13–5.23)    Body weight loss at presentation    0.941    0.814   No  1.00 (Reference)    1.00 (Reference)     Yes  1.07 (0.18–6.29)    1.39 (0.09–22.18)    Anemia    0.706    0.951   No  1.00 (Reference)    1.00 (Reference)     Yes  0.77 (0.20–3.02)    0.94 (0.12–7.21)    Anal preservation surgery    –    –   No  1.00 (Reference)    1.00 (Reference)     Yes  NA    NA    Chemotherapy before CCRT    0.912    0.529   No  1.00 (Reference)    1.00 (Reference)     Yes  1.06 (0.39–2.86)    0.63 (0.15–2.64)    Chemotherapy at CCRT   No chemotherapy  1.00 (Reference)    1.00 (Reference)     CCRT with chemotherapy  6.38 (0.91−44.72)  0.062  25.44 (1.58−408.86)  0.022   CCRT with oxaplatin  1.69 (0.22−12.81)  0.613  6.05 (0.32−114.33)  0.230   CRT regimen with Irinotecan  0.50 (0.05−5.51)  0.571  1.75 (0.07−46.68)  0.738    Univariate  Multivariate  Crude OR (95% CI)  P value  Adjusted OR (95% CI)  P value  Age  1.02 (0.99–1.07)  0.221  1.03 (0.97–1.09)  0.345  Gender    0.142    0.582   Female  1.00 (Reference)    1.00 (Reference)     Male  2.10 (0.78–5.65)    1.6 (0.3–8.44)    BMI  1.11 (0.97–1.26)  0.129  1.14 (0.93–1.4)  0.196  Bowel bag V45 (cc)  1 (1)  0.119  1 (0.99–1)  0.298  Volume of bone marrow (cc)  1 (1)  0.586  1 (1)  0.731  Mean marrow dose (cGy)  1 (1)  0.777  1 (1)  0.656  Bone marrow V40 (%)  0.96 (0.91–1.02)  0.151  0.94 (0.86–1.03)  0.188  PS    0.912    0.825   0  1.00 (Reference)    1.00 (Reference)     1–2  1.08 (0.29–4.00)    0.81 (0.13–5.23)    Body weight loss at presentation    0.941    0.814   No  1.00 (Reference)    1.00 (Reference)     Yes  1.07 (0.18–6.29)    1.39 (0.09–22.18)    Anemia    0.706    0.951   No  1.00 (Reference)    1.00 (Reference)     Yes  0.77 (0.20–3.02)    0.94 (0.12–7.21)    Anal preservation surgery    –    –   No  1.00 (Reference)    1.00 (Reference)     Yes  NA    NA    Chemotherapy before CCRT    0.912    0.529   No  1.00 (Reference)    1.00 (Reference)     Yes  1.06 (0.39–2.86)    0.63 (0.15–2.64)    Chemotherapy at CCRT   No chemotherapy  1.00 (Reference)    1.00 (Reference)     CCRT with chemotherapy  6.38 (0.91−44.72)  0.062  25.44 (1.58−408.86)  0.022   CCRT with oxaplatin  1.69 (0.22−12.81)  0.613  6.05 (0.32−114.33)  0.230   CRT regimen with Irinotecan  0.50 (0.05−5.51)  0.571  1.75 (0.07−46.68)  0.738  BMI, body mass index; CCRT, concurrent chemoradiotherapy; CI, confidence interval; OR, odds ratio. Discussion This study demonstrated that IMRT yielded adequate oncologic outcomes in the adjuvant treatment of locally advanced rectal cancer. Local control was competitive in this study. None of those who had microscopic residual disease developed local failure in this study. Only three local recurrences were identified during follow-up. This incidence was much lower than that reported by Sauer et al. in a randomized controlled trial comparing preoperative to postoperative chemoradiotherapy for rectal cancer (20). Of the 349 assigned to postoperative chemoradiotherapy, 36 local recurrences were identified, resulting in a cumulative 5-year local recurrence rate of 13%, as compared with the 5% incidence in this study. Our results also compared favorably to that in another large randomized controlled trial, in which both preoperative and postoperative arms had 10.7% incidence of locoregional recurrence (9). Nevertheless, distant failure remained problematic in the treatment of locally advanced rectal cancer, accounting for the majority of treatment failures in our study. As an attempt to improve the treatment outcome, more than a half of our patients (53%) had chemotherapy preceding adjuvant radiotherapy. Yet the delay in the start of radiotherapy does not seem to impact local control in a negative way. The incidence of acute ≥Grade 2 neutropenia was 36%, most of which were manageable with treatment breaks and/or modification of chemotherapy. Nevertheless, the combined incidence of dose limiting (Grade 3/4) neutropenia was 22%. A great body of literature has emphasized on the bone marrow sparing of advanced technology. Experiences with IMRT in the adjuvant treatments of gynecologic and anal cancers have shown promises in improving the therapeutic ratio (21,22), however, minimizing the radiation induced bone marrow suppression may only be a small part of the story. First of all, most studies on bone marrow parameters were retrospective and unplanned (23–25). A universal dose constraint is yet to be identified. For example, the bone marrow V40 was predictive of hematologic toxicity, as demonstrated in an unplanned analysis of RTOG 0418 (23). In our study, the median bone marrow V40 was 29%, well below the 37% described in RTOG 0418. Yet the incidence of neutropenia remained considerable in this study. Next, using bone marrow dose as sole predictor of acute bone marrow toxicity may be limiting. The use of combination chemotherapy in our study may have an impact on the incidence of serious neutropenia. Both irinotecan and oxaliplatin are known to predispose to increased incidence of serious (Grade 3/4) neutropenia, with incidence up to 40% (19). The incidence of serious neutropenia in this study was approximate half of that, reflecting the proportion of patients who had combination chemotherapy (29%). In addition to that, cumulative toxicities of individual chemotherapeutic agents and their combinations may be of significant importance as more than half of our patient got chemotherapy prior to radiotherapy as an attempt to initiate adjuvant chemotherapy as early as possible. Although not reaching statistical significance in our study, senile patients are known to be susceptible to cumulated toxicities of chemotherapy (26). Moreover, as Hayman et al. has demonstrated in their elaborated study with 18F-fluoro-l-deoxythymidine, significant proportions of proliferating bone marrow is not only found in pelvic bone marrow, but also in thoracolumbar spine (27), which is generally not included in the treatment field. Our study echoes on their findings by demonstrating that any form of chemotherapy at time of radiotherapy increases the odds of Grade 2 and higher neutropenia (OR 25.44, 95% CI [1.58, 408.89]). In terms of gastrointestinal toxicity, 58% of the patients developed ≤Grade 2 diarrhea. However, only 10% of these toxicities were Grade 3 and none Grade 4. Most patients were able to complete chemoradiotherapy between 37 and 42 days. In the era when 3DRT and adjuvant chemoradiotherapy were the norm, the reported rates of Grade 3–4 diarrhea were close to 20%, which compared unfavorably to our results (7). When compared with contemporary reports, in which preoperative chemoradiotherapy with IMRT is the prevalent form of treatment, the incidence of Grade 2 or greater gastrointestinal toxicity in our study still remained competitive. The increased incidence of Grade 2 diarrhea in our study may result from the combination of dosimetric and pharmacologic factors. The mean bowel bag V45 in this study is 282 ml, in excess of the widely accepted volume of 190 ml in the neoadjuvant chemoradiotherapy (28). The strong dose–volume relationship of irradiated small bowel to acute diarrhea has already been demonstrated (29). If the patient were treated in prone position with belly board, the volume of irradiated bowel bag might have been further reduced. In addition to that, resection of rectal mass might have attributed to the amount of exposed bowel bag. As the inferior end of the bowel bag extends with the surgical resection of rectum, the volume of bowel bag exposed will inevitably increase. Next, in this study, 25 patients had combination chemotherapy at the time of chemoradiotherapy. The overlapping gastrointestinal toxicity of oxaliplatin and irinotecan to fluorouracil based chemoradiotherapy may also have added toxicity to the standard chemoradiotherapy (19). RTOG 0822, a prospective study on preoperative chemoradiation using IMRT in combination with capacetibine and oxaliplatin, reported 51.5% incidence of ≥2 gastrointestinal toxicity (47% with ≥2 diarrhea), in which 17.6% experience Grade 3–4 diarrhea (29), while most retrospective studies on IMRT preceding RTOG 0822 had only fluorouracil as part of preoperative chemoradiation and showed much lower incidences of ≥2 GI toxicity (4,5). Without a comparison to the conventional 3DCRT technique, the value of this study may be undermined. It was institutional practice to provide IMRT for patients when it has become available. Meanwhile, the standard of patient care has also evolved, leaving such comparison less reliable. Investigation on the type chemotherapy preceding chemoradiotherapy and its relation to hematologic toxicity may be unyielding because of the limited number of patients in this study. Conclusion In summary, adjuvant IMRT produced competitive local control. Survival outcomes were comparable to contemporary preoperative treatments. Most treatment related toxicities were tolerable. One should practice care when concurrent chemotherapy is given, as the marrow sparing property of IMRT does not negate the inherent hematotoxicity. Acknowledgements All authors contributed to the study and provided more than general help. Conflict of interest statement All authors declare having no conflict of interest related to the content of this manuscript. Funding This study had no sponsor. Ethical considerations This work has been carried out in accordance with The Code of Ethics of the World Medical Association (Declaration of Helsinki) for experiments involving humans. It has been approved by the Institution Review Board at Chia-Yi Christian hospital (CYCH-IRB 105060). References 1 Fisher B, Wolmark N, Rockette H, et al.  . Postoperative adjuvant chemotherapy or radiation therapy for rectal cancer: results from NSABP protocol R-01. 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Japanese Journal of Clinical OncologyOxford University Press

Published: Jun 4, 2018

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