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Can dosimetric parameters predict acute hematologic toxicity in rectal cancer patients treated with intensity-modulated pelvic radiotherapy?

Abstract

Background

To identify dosimetric parameters associated with acute hematologic toxicity (HT) in rectal cancer patients undergoing concurrent chemotherapy and intensity-modulated pelvic radiotherapy.

Methods

Ninety-three rectal cancer patients receiving concurrent capecitabine and pelvic intensity-modulated radiation therapy (IMRT) were analyzed. Pelvic bone marrow (PBM) was contoured for each patient and divided into three subsites: lumbosacral spine (LSS), ilium, and lower pelvis (LP). The volume of each site receiving 5–40 Gy (V 5, V10, V15, V20, V30, and V40, respectively) as well as patient baseline clinical characteristics was calculated. The endpoint for hematologic toxicity was grade ≥ 2 (HT2+) leukopenia, neutropenia, anemia or thrombocytopenia. Logistic regression was used to analyze correlation between dosimetric parameters and grade ≥ 2 hematologic toxicity.

Results

Twenty-four in ninety-three patients experienced grade ≥ 2 hematologic toxicity. Only the dosimetric parameter V40 of lumbosacral spine was correlated with grade ≥ 2 hematologic toxicity. Increased pelvic lumbosacral spine V40 (LSS-V40) was associated with an increased grade ≥ 2 hematologic toxicity (p = 0.041). Patients with LSS-V40 ≥ 60 % had higher rates of grade ≥ 2 hematologic toxicity than did patients with lumbosacral spine V40 < 60 % (38.3 %, 18/47 vs.13 %, 6/46, p =0.005). On univariate and multivariate logistic regression analysis, lumbosacral spine V40 and gender was also the variable associated with grade ≥ 2 hematologic toxicity. Female patients were observed more likely to have grade ≥ 2 hematologic toxicity than male ones (46.9 %, 15/32 vs 14.8 %, 9/61, p =0.001).

Conclusions

Lumbosacral spine -V40 was associated with clinically significant grade ≥ 2 hematologic toxicity. Keeping the lumbosacral spine -V40 < 60 % was associated with a 13 % risk of grade ≥ 2 hematologic toxicity in rectal cancer patients undergoing concurrent chemoradiotherapy.

Introduction

Preoperative chemoradiotherapy (CRT) followed by total mesorectal excision is the standard of care for patients with locally advanced rectal cancer (LARC) [3, 10, 19, 20]. The delivery of 5-Fluorouracil (5-FU) based chemotherapy with radiotherapy reduces 5-year incidence of local recurrence compared with radiotherapy (RT) alone [11]. Park et al. demonstrated tumor response to neoadjuvant CRT was associated with 5-year recurrence free survival (RFS) [18]. However, myelosuppression is a major common side effect of CRT that could lead to treatment interruptions [9, 25]. Thus, the reduction of hematologic toxicity (HT) is an important goal.

Pelvic radiotherapy may contribute to the development of HT. More than one-half of the body’s bone marrow is located in the os coxae, sacrum, proximal femora, and lower lumbar spine. Therefore, reducing pelvic bone marrow (PBM) irradiation may reduce HT, enabling improved delivery of chemotherapy, and, consequently, treatment efficacy.

Several studies demonstrated a correlation between PBM dosimetric parameters with HT in patients with anal cancer and cervical cancer. Thus, recommended dose constraints to the LSS are V10 ≤ 80 %, and keeping the mean PBM dose < 22.5 Gy and <25 Gy is associated with a 5 % and 10 % risk of HT, respectively, in patients with anal cancer [5, 7]. Data from cervical cancer suggest that patients with PBM-V10 ≥ 90 % had higher rates of Grade 2 HT than did patients with PBM-V10 < 90 % [16].

The clinical significance and optimal technique of PBM sparing in rectal cancer patients, however, are still unknown. Here, we set out to identify PBM dosimetric parameters that correlate with HT in patients treated with CRT for rectal cancer.

Materials and methods

We conducted a retrospective review of 93 patients with LARC (cT3-T4 and/or cN+) who were treated with neoadjuvant CRT at our institution between September 2013 and August 2014. The study was approved by the Fudan University Shanghai Cancer Center Institutional Review Board.

Combined chemoradiotherapy

Radiotherapy

Patients were immobilized in the prone or supine position and underwent a non-contrast planning CT scan with a 5-mm slices from the L3-L4 junction to 2 cm below the perineum. The image datasets were transferred to the PINNACLE planning system (Philips Radiation Oncology Systems, Milpitas, CA). The gross tumor volume (GTV) was defined as all known gross disease determined from CT and MRI. The clinical target volume (CTV) was defined as the GTV plus areas considered at significant risk of harboring microscopic disease, including the mesorectum (perirectal fascia), presacral region, and internal iliac lymph node region. Based on our institution set-up data, the planning target volume (PTV) was generated by adding a 6-mm margin around the CTV in lateral and anterior-posterior directions, and an 8-mm margin in the superiorinferior direction [26] (Fig. 1). The critical normal organs at risk (OARs) outlined were the bladder, femoral heads, and small bowel.

Fig. 1
figure 1

IMRT isodose distribution of representative axial (a) and sagittal (b) slice. PTV is shown in red. Blue, purple, and aurantium isodose lines represent 50, 47.5, and 40 Gy, respectively

The PTV was prescribed with a total of 50 Gy in 2Gy fractions. The intensity-modulated radiation therapy (IMRT) plans were generated using the inverse planning module of PINNACLE for a 6-MV linear accelerator, with seven coplanar fields. The D2 %, D50 %, and D98 % to PTV were set at 52.5 Gy, 50 Gy and 47.5 Gy, respectively. The dose of the OARs was set as low as possible and had to at least meet the following constraints: bladder, V45 ≤ 15 % and V40 ≤ 40 %; femoral heads, V45 ≤ 25 % and V40 ≤ 40 %; small bowel, V45 ≤ 65 cc, V40 ≤ 100 cc, and V35 ≤ 180 cc.

Concurrent chemotherapy

Capecitabine combined was administered concurrently with pelvic radiation. Capecitabine was given at a dose of 825 mg/m2 twice daily from Monday to Friday throughout the whole course of IMRT. Guidelines for capecitabine usage were as follows: for grade ≥ 2 toxicity (as defined by NCI CTCAE version 4.0), capecitabine was held, and appropriate symptomatic treatment was administered. Once toxicity resolved to grade 0 or 1, treatment was resumed.

Pelvic bone marrow delineation

For each patient, the external contour of all bones within the pelvis was used as a surrogate for PBM, and the PBM was further divided into three subsites, as described by Mell et al.: (1) ilium—including the iliac crests extending to the superior border of the femoral heads; (2) lower pelvis (LP)—consisting of the pubes, ischia, acetabula, and proximal femora, extending from the superior border of the femoral heads to the inferior border of the ischial tuberosities; and (3) lumbosacral spine (LSS)—extending from the most superior vertebral body contained in the planning treatment volume (usually L5) inferiorly to include the entire sacrum [16] (Fig. 2). Dose-volume Histograms (DVHs) were then generated, and the following parameters were recorded for the PBM and each subsite: volume, mean dose, and volume of each region receiving at least 5, 10, 15, 20, 30, and 40 Gy (V5, V10, V15, V20, V30, and V40, respectively).

Fig. 2
figure 2

Coronal section illustrating delineation of iliac (yellow), lumbosacral (green), and lower pelvic (blue) bone marrow

Hematologic toxicity

The HT was graded according to the Common Terminology Criteria for Adverse Events, version 4.0. The highest-grade toxicity for white blood count, absolute neutrophil count, hemoglobin, and platelets were recorded, with HT of grade ≥2 noted as an event (HT2+).

Statistical analysis

Age and dosimetric parameters were coded as continuous variables. Categorical variables included gender. Univariate logistic regression was used to test the correlation between clinical and dosimetric parameters with HT2+. Multivariate logistic regression models were then used to examine the effect of significant dosimetric parameters on HT2+. The incidence of HT2+ between male and female was compared by Pearson’s chi-square test.

Results

Patient characteristics

Baseline characteristics of the cohort are shown in Table 1. The median age at diagnosis was 57 years, with a male predominance. The majority of patients had clinical stage III tumors (79.6 %).

Table 1 Patient characteristics (n = 93)

Bone marrow dosimetric parameters

Table 2 summarizes the PBM dosimetric parameters. The median PBM mean dose was 29 Gy. The LSS was the smallest subsite of the PBM (22 %), and the LP was the largest subsite (46 %).

Table 2 Descriptive statistics of pelvic bone marrow dosimetric parameters

Hematologic toxicity

Overall, 51 patients (51/93, 54.8 %) experienced leukopenia during treatment. The percentage of patients developing acute neutropenia, anemia, and thrombocytopenia was 25.8 %, 6.5 %, and 6.5 %, respectively. The percentage of patients with grade 2 or worse leukopenia, neutropenia, anemia, and thrombocytopenia was 25.8 %, 16.1 %, 2.2 %, and 1.1 %, respectively (Table 3). 24 patients (24/93, 25.8 %) experienced HT2+ during chemoradiotherapy. 21 patients (21/24, 87.5 %) experienced only grade 2 or worse leukopenia and/or neutropenia. 2 patients experienced (2/24, 8.3 %) both grade 2 or worse leukopenia/ neutropenia and anemia and 1 patients (1/24, 4.2 %) experienced both grade 2 or worse leukopenia and thrombocytopenia. HT2+ was frequently observed in females (male/female: 46.9/14.8 %) (p-value =0.001) (Table 4).

Table 3 Acute hematologic toxicity during chemoradiotherapy
Table 4 Acute HT2+ during chemoradiotherapy

Predictors of hematologic toxicity

On univariate analysis, LSS-V40 and gender were associated with HT2+ (Table 5). Patients with LSS-V40 ≥ 60 % had higher rates of HT2+ than did patients with LSS-V40 < 60 % (38.3 %, 18/47 vs.13 %, 6/46, p =0.005). The incidence of HT2+ was higher in female patients (46.9 %, 15/32) than in male patients (14.8 %, 9/61) (p-value =0.001). On multivariate analysis, LSS-V40 and gender retained statistical significance (Table 6).

Table 5 Univariate logistic regression analysis of factors associated with the development of HT2+
Table 6 Multivariate logistic regression analysis

Discussion

To our knowledge, this is the second study to predict acute HT in patients with rectal cancer receiving CRT. Yang TJ et al. found that coxal BM V45 and sacral BM V45 were associated with lower WBC and ANC nadirs [25]. In this study we demonstrated that LSS-V40 was associated with the development of HT2+ following chemoradiation to the pelvic. Additionally, HT2+ was more likely to occur in women.

There have been several studies investigating the dosimetric parameters of PBM that correlate with the risk of HT on cervical and anal cancer [1, 4, 7, 16, 21]. Mell et al. found patients with PBM-V10 ≥ 90 % had higher rates of Grade 2 or worse leukopenia and neutropenia than did patients with BM-V10 < 90 % [16]. Rose et al. found V10 ≥ 95 % were more likely to experience Grade ≥ 3 leukopenia than were patients with V20 > 76 % in a similar patient cohort [21]. Albuquerque et al. studied 40 women who received CRT to treat cervical cancer and found the risk of HT2+ developing increases by a factor (odds ratio) of 4.5 if the V20 of the whole pelvis exceeds 80 % [1]. For patients with anal cancer, Cheng et al. demonstrated mean dose and low-dose radiation parameters (V5, V10, V15, V20) of whole bone or bone cavities of LSS were correlated most significantly with HT3+. An LSS mean dose of 23.5 Gy is associated with a 10 % risk of HT. Thus, recommended dose constraints to the LSS are V10 ≤ 80 % [7].

In our study we found LSS-V40 and gender were correlated with the risk of HT2+. Patients with LSS-V40 ≥ 60 % had higher rates of HT2+ than did patients with LSS-V40 < 60 % (38.3 %, 18/47 vs. 13 %, 6/46, p =0.005). The incidence of HT2+ was higher in female patients (46.9 %, 15/32) than in male patients (14.8 %, 9/61) (p-value =0.001). Tait et al. also found sex was the variable associated with any cardiac toxicity and pericardial effusion with multivariable logistic regression analysis in patients treated with chemoradiation therapy for esophageal carcinoma [23].

Given the evidence presented in this article for the existence of a sex-dependent hematologic toxicity difference, it is reasonable to seek explanations for potential mechanisms. Overall, it has been reported previously that women have a higher risk of myelotoxicity compared with men [2, 8, 12, 13]. This increased risk may likely be due to sex differences in pharmacokinetics and in pharmacodynamics [6, 24]. Makihara et al. found grade 4 neutropenia was frequently observed in females and gender could be considered as one of the important predictive factors associated with grade 4 neutropenia in patients receiving amrubicin monotherapy [15]. Milano et al. suggested that women were particularly prone to dihydropyrimidine dehydrogenase deficiency and there are data showing that the area under the curve, a measurement of plasma 5-FU level, is increased in women compared with men [14, 17]. Sloan et al. also reported women receiving 5-FU-based chemotherapy in a 5-day bolus schedule experience toxicity more frequently and with more severity than men [22].

In summary, there are no easy answers to the causes of increased hematologic toxicity of CRT in women and the reasons for this finding are likely multifactorial. Future studies should be directed to determine the mechanism behind the significant amount of women experiencing HT following CRT for rectal carcinoma. Based on our analysis, this specific finding was independent of the dose-volume relationship with toxicity and women did not demonstrate a significant difference in the dose of PBM compared with men. Potential analyses should investigate the rationale behind the lower tolerance of treatment in women versus men.

This study had some limitations because of the nature of retrospective studies, the small sample size and the small number of female patients. Our findings will need to be validated in a larger, prospectively collected group of data. In addition, all patients were treated with IMRT, and the results may not be applicable to patients being treated with conventional radiation therapy techniques. Finally, we contoured the entire bone as opposed to the actual bone marrow. However, there are currently no readily available imaging studies that would help delineate active bone marrow.

Conclusion

In conclusion, this is the second study, to our knowledge, to identify dosimetric parameters associated with acute hematologic toxicity in rectal cancer patients undergoing chemoradiotherapy. Lumbosacral spine V40 was associated with clinically significant grade ≥ 2 hematologic toxicity. Keeping the lumbosacral spine V40 < 60 % was associated with a 13 % risk of grade ≥ 2 hematologic toxicity in rectal cancer patients undergoing concurrent chemoradiotherapy.

Consent

Written informed consent was obtained from the patient for the publication of this report and any accompanying images.

Abbreviations

LARC:

Locally advanced rectal cancer

CRT:

Chemoradiotherapy

HT:

Hematologic toxicity

HT2+:

Hematologic toxicity of grade ≥2

PBM:

Pelvic bone marrow

LP:

Lower pelvis

LSS:

Lumbosacral spine

IMRT:

Intensity-modulated radiation therapy

P-IMRT:

Pelvic intensity modulated radiation therapy

References

  1. Albuquerque K, Giangreco D, Morrison C, Siddiqui M, Sinacore J, Potkul R, 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.

    Article  PubMed  Google Scholar 

  2. Armstrong TS, Cao Y, Scheurer ME, Vera-Bolaños E, Manning R, Okcu MF, et al. Risk analysis of severe myelotoxicity with temozolomide: the effects of clinical and genetic factors. Neuro Oncol. 2009;11:825–32.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  3. Aschele C, Cionini L, Lonardi S, Pinto C, Cordio S, Rosati G, et al. Primary tumor response to preoperative chemoradiation with or without oxaliplatin in locally advancedrectal cancer: pathologic results of the STAR-01 randomized phase III trial. J Clin Oncol. 2011;29:2773–80.

    Article  CAS  PubMed  Google Scholar 

  4. Bazan JG, Luxton G, Kozak MM, Anderson EM, Hancock SL, Kapp DS, et al. Impact of chemotherapy on normal tissue complication probability modelsof acute hematologic toxicity in patients receiving pelvic intensity modulated radiation therapy. Int J Radiat Oncol Biol Phys. 2013;87:983–91.

    Article  CAS  PubMed  Google Scholar 

  5. Bazan JG, Luxton G, Mok EC, Koong AC, Chang DT. Normal tissue complication probability modeling of acute hematologictoxicity in patients treated with intensity-modulated radiation therapy for squamous cell carcinoma of the anal canal. Int J Radiat Oncol Biol Phys. 2012;84:700–6.

    Article  PubMed  Google Scholar 

  6. Burchell B, Brierley CH, Rance D. Specificity of human UDP glucuronosyltransferases and xenobiotic glucuronidation. Life Sci. 1995;57:1819–31.

    Article  CAS  PubMed  Google Scholar 

  7. Cheng JC, Bazan JG, Wu JK, Koong AC, Chang DT. Lumbosacral spine and marrow cavity modeling of acute hematologictoxicity in patients treated with intensity modulated radiation therapy for squamous cell carcinoma of the anal canal. Pract Radiat Oncol. 2014;4:198–206.

    Article  PubMed  Google Scholar 

  8. Dixit S, Baker L, Walmsley V, Hingorani M. Temozolomide-related idiosyncratic and other uncommon toxicities: a systematic review. Anticancer Drugs. 2012;23:1099–106.

    Article  CAS  PubMed  Google Scholar 

  9. Fernández-Martos C, Pericay C, Aparicio J, Salud A, Safont M, Massuti B, et al. Phase II, randomized study of concomitant chemoradiotherapy followed by surgery and adjuvantcapecitabine plus oxaliplatin (CAPOX) compared with induction CAPOX followed by concomitantchemoradiotherapy and surgery in magnetic resonance imaging-defined, locally advanced rectal cancer: Grupo cancer de recto 3 study. J Clin Oncol. 2010;28:859–65.

    Article  PubMed  Google Scholar 

  10. Gérard JP, Azria D, Gourgou-Bourgade S, Martel-Laffay I, Hennequin C, Etienne PL, et al. Comparison of two neoadjuvant chemoradiotherapy regimens for locally advanced rectal cancer: results of the phase III trial ACCORD 12/0405-Prodige 2. J Clin Oncol. 2010;28:1638–44.

    Article  PubMed  Google Scholar 

  11. Gérard JP, Conroy T, Bonnetain F, Bouché O, Chapet O, Closon-Dejardin MT, et al. Preoperative radiotherapy with or without concurrent fluorouracil and leucovorin in T3-4 rectal cancers: results of FFCD 9203. J Clin Oncol. 2006;24:4620–5.

    Article  PubMed  Google Scholar 

  12. Gerber DE, Grossman SA, Zeltzman M, Parisi MA, Kleinberg L. The impact of thrombocytopenia from temozolomide and radiation in newly diagnosed adults with high-grade gliomas. Neuro Oncol. 2007;9:47–52.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  13. Lombardi G, Rumiato E, Bertorelle R, Saggioro D, Farina P, Della Puppa A, et al. Clinical and Genetic Factors Associated With Severe Hematological Toxicity in Glioblastoma Patients During Radiation Plus Temozolomide Treatment: A Prospective Study. Am J Clin Oncol. 2013 Sep 21 [Epub ahead of print].

  14. Macdonald JS. Vive la difference: sex and fluorouracil toxicity. J Clin Oncol. 2002;20:1439–41.

    PubMed  Google Scholar 

  15. Makihara RA, Makino Y, Yamamoto N, Yokote N, Nokihara H, Sekine I, et al. Gender difference in hematological toxicity among lung cancer patients receiving amrubicin monotherapy. Jpn J Clin Oncol. 2012;42:1187–91.

    Article  PubMed  Google Scholar 

  16. Mell LK, Kochanski JD, Roeske JC, Haslam JJ, Mehta N, Yamada SD, et al. Dosimetric predictors of acute hematologic toxicity in cervical cancer patients treated with concurrent cisplatin and intensity-modulated pelvic radiotherapy. Int J Radiat Oncol Biol Phys. 2006;66:1356–65.

    Article  PubMed  Google Scholar 

  17. Milano G, Etienne MC, Pierrefite V, Barberi-Heyob M, Deporte-Fety R, Renée N. Dihydropyrimidine dehydrogenase deficiency and fluorouracil-related toxicity. Br J Cancer. 1999;79:627–30.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  18. Park IJ, You YN, Agarwal A, Skibber JM, Rodriguez-Bigas MA, Eng C, et al. Neoadjuvant treatment response as an early response indicator for patients with rectal cancer. J Clin Oncol. 2012;30:1770–6.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  19. Rödel C, Liersch T, Becker H, Fietkau R, Hohenberger W, Hothorn T, et al. Preoperative chemoradiotherapy and postoperative chemotherapy with fluorouracil and oxaliplatin versus fluorouracil alone in locally advanced rectal cancer: initial results of the German CAO/ARO/AIO-04 randomised phase 3 trial. Lancet Oncol. 2012;13:679–87.

    Article  PubMed  Google Scholar 

  20. Roh M, Yothers GA, O’Connell M, Yothers G, Ko CY, Arora A, et al. The impact of capecitabine and oxaliplatin in the preoperative multimodality treatment in patients with carcinoma of the rectum: NSABP R-04. J Clin Oncol. 2011;29:221s. suppl; abstr 3503.

    Google Scholar 

  21. Rose BS, Aydogan B, Liang Y, Yeginer M, Hasselle MD, Dandekar V, et al. Normal tissue complication probability modeling of acute hematologic toxicity in cervical cancer patients treated with chemoradiotherapy. Int J Radiat Oncol Biol Phys. 2011;79:800–7.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  22. Sloan JA, Goldberg RM, Sargent DJ, Vargas-Chanes D, Nair S, Cha SS, et al. Women experience greater toxicity with fluorouracil-based chemotherapy for colorectal cancer. J Clin Oncol. 2002;20:1491–8.

    Article  CAS  PubMed  Google Scholar 

  23. Tait LM, Meyer JE, McSpadden E, Cheng JD, Baciewicz FA, Meropol NJ, et al. Women at increased risk for cardiac toxicity following chemoradiation therapy for esophageal carcinoma. Pract Radiat Oncol. 2013;3:e149–55.

    Article  PubMed  Google Scholar 

  24. Wrighton SA, Stevens JC. The human hepatic cytochromes P450 involved in drug metabolism. Crit Rev Toxicol. 1992;22:1–21.

    Article  CAS  PubMed  Google Scholar 

  25. Yang TJ, Oh JH, Apte A, Son CH, Deasy JO, Goodman KA. Clinical and dosimetric predictors of acute hematologic toxicity in rectal cancer patients undergoingchemoradiotherapy. Radiother Oncol. 2014;113:29–34.

    Article  PubMed  Google Scholar 

  26. Zhu J, Liu F, Gu W, Lian P, Sheng W, Xu J, et al. Concomitant boost IMRT-based neoadjuvant chemoradiotherapy for clinical stage II/III rectaladenocarcinoma: results of a phase II study. Radiat Oncol. 2014;9:70.

    Article  PubMed Central  PubMed  Google Scholar 

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Correspondence to Zhen Zhang.

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The authors declare that they have no competing interests.

Authors’ contributions

JFW was responsible for the primary concept and the design of the study; JFW, KTL, KXL and GCL performed the data capture and analysis. JFW and ZZ drafted the manuscript; all authors revised the manuscript. All authors have read and approved the final manuscript.

Juefeng Wan, Kaitai Liu and Kaixuan Li contributed equally to this work.

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Wan, J., Liu, K., Li, K. et al. Can dosimetric parameters predict acute hematologic toxicity in rectal cancer patients treated with intensity-modulated pelvic radiotherapy?. Radiat Oncol 10, 162 (2015). https://doi.org/10.1186/s13014-015-0454-0

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