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ORIGINAL ARTICLE
Year : 2022  |  Volume : 18  |  Issue : 6  |  Page : 1498-1503

Relationship of irradiated bone marrow volume and neutropenia in patients undergoing concurrent chemoradiation therapy for cervical cancer


Department of Radiation Oncology, Amala Institute of Medical Sciences, Thrissur, Kerala, India

Date of Submission08-Jun-2021
Date of Decision01-Jul-2021
Date of Acceptance02-Jul-2021
Date of Web Publication03-Aug-2022

Correspondence Address:
Jomon Raphael Chalissery
Professor and Head, Department of Radiation Oncology, Amala Institute of Medical Sciences, Amala Nagar, Thrissur - 680 555, Kerala
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jcrt.jcrt_924_21

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 > Abstract 


Introduction: Concurrent chemoradiation therapy (CCRT) is the standard of care in the management of cervical cancer (International Federation of Gynecology and Obstetrics [FIGO] 2008 Stages IB2-IVA). Apart from the myelotoxic effects of chemotherapy, irradiation of pelvic bone marrow (BM) in the radiation field, can also contribute to hematological toxicity.
Objectives: We examined the relationship of irradiated BM volume and neutropenia in cervical cancer patients undergoing CCRT.
Materials and Methods: This prospective study was conducted in a tertiary cancer center with a longitudinal study design. A total of 43 patients undergoing CCRT for cervical cancer were included. Using auto bone segmentation, the external contour of pelvic bones from L4 vertebral body to ischial tuberosities were delineated as BM. The volume of BM receiving 10, 20, 40, 50 Gy was calculated. Complete blood counts were done weekly to evaluate the neutropenia and were graded according to Common Terminology Criteria for Adverse Events, version 3.0. The risk of developing neutropenia was analyzed using logistic regression.
Results: Twenty-seven patients (62.8%) received 5 cycles of chemotherapy, 14 patients (32.6%) received 4 cycles of chemotherapy and 2 patients (4.7%) received 3 cycles of chemotherapy. Overall, 22 patients (51.2%) experienced acute neutropenia. On multivariate analysis increased BM V50Gy had a statistically significantly odds of developing any grade of neutropenia (odds ratio [OR] =1.43; 95% confidence interval [CI], 1.03–1.97; P = 0.028). When comparing patients receiving BM V40Gy ≥40% with BM V40Gy <40% odds of any grade of neutropenia was increased (OR = 2.03; 95% CI, 0.55–7.42; P = 0.28). Moreover, when comparing patients receiving BM V50Gy ≥15% with BM V50Gy <15% odds of any grade of neutropenia was increased (OR = 2.13; 95% CI, 0.57–7.97; P = 0.26).
Conclusions: High-dose irradiation to the larger volume of BM prevents compensatory hyperplasia which leads to neutropenia in patients undergoing CCRT for cervical cancer.

Keywords: Bone marrow, cervical cancer, concurrent chemoradiation therapy, neutropenia


How to cite this article:
Antony F, Chalissery JR, Varghese K M, Gopu G P, Boban M. Relationship of irradiated bone marrow volume and neutropenia in patients undergoing concurrent chemoradiation therapy for cervical cancer. J Can Res Ther 2022;18:1498-503

How to cite this URL:
Antony F, Chalissery JR, Varghese K M, Gopu G P, Boban M. Relationship of irradiated bone marrow volume and neutropenia in patients undergoing concurrent chemoradiation therapy for cervical cancer. J Can Res Ther [serial online] 2022 [cited 2022 Dec 2];18:1498-503. Available from: https://www.cancerjournal.net/text.asp?2022/18/6/0/353343




 > Introduction Top


The current guidelines for the management of cervical cancer (FIGO Stage IB2-IVA) are concurrent chemo-radiation therapy (CCRT).[1] Cochrane metanalysis showed improved overall survival, reduced local and distant failure with CCRT.[2] CCRT maximizes tumor cell death by the inhibition of potentially lethal damage recovery and by radio sensitization of hypoxic tumor cells.[3],[4] However, combination therapy can also produce acute hematological toxicity (HT), particularly neutropenia.[5],[6]

Chemotherapeutic agents can cause bone marrow (BM) suppression. As BM is highly radiosensitive, pelvic irradiation that causes BM stem cells destruction also contributes to acute HT in pelvic radiation.[6]

HT can cause a delay in treatment, reduce the cycles of concurrent chemotherapy, and thus can affect the survival of the patient.[7] There are also trials looking into the role of systemic chemotherapy in carcinoma cervix after CCRT.[8],[9] This points to the importance of looking into the irradiated BM volume and its relationship with HT.

A series of publications from a single institution have studied the impact of whole-pelvis intensity-modulated radiation therapy (IMRT) and concurrent chemotherapy and showed a relationship between HT and volume of BM radiated to low doses (10, 20 Gy).[10],[11],[12] RTOG 0418 showed the relationship of HT and volume of BM radiated to higher doses (40 Gy).[13]

Different ways have been explained in the literature for contouring the BM, but the whole pelvic bone contouring using auto bone segmentation defined by Mell et al. is widely accepted.[10] As of now, there is no standard guidelines on dose constraints for BM in pelvic radiotherapy (RT).

Hence, we tried to examine the relationship of irradiated BM volume and neutropenia in patients undergoing CCRT for cervical cancer.


 > Materials and Methods Top


In this prospective longitudinal study, our primary objective was to find the relationship between irradiated BM volume and the development of neutropenia as well as the secondary objective was to define BM dose constraints. Sample size calculation was done by the incidence of Grade 1–4 neutropenia in cervical cancer as 70%. Significance level and relative precision were 5% and 20%, respectively. Based on this, the sample size calculated for this study was 43. From February 2017 to June 2018, patients receiving CCRT for cervical cancer at our institution were included in this study. Eligible patients had squamous cell carcinoma/adenocarcinoma/adenosquamous carcinoma of the cervix within 2008 FIGO Stages IB2–IIIB. Other eligibility criteria included <70 years of age, Eastern Cooperative Oncology Group performance status <2, calculated creatinine clearance >50 mL/min, and no previous chemotherapy or pelvic surgery. Those patients with para-aortic nodes who may require extended field RT were excluded. The study was approved by the institutional ethics committee (Ref. No: AIMSIEC/23/20I7 on 17/01/2017).

Study procedures

The procedures followed were in accordance with the Ethical Standards of the Responsible Committee on Human Experimentation (institutional or regional) and with the Helsinki Declaration of 1964, as revised in 2013. After getting informed consent, eligible patients were taken up for contrast-enhanced computed tomography (CT) scanning session for planning as per institutional bladder protocol. 3 mm slice thickness scans were acquired and transferred to the treatment planning system (Eclipse version 11.0). Organs at risk (OAR) - rectum, bladder, bowel bag, bilateral femoral heads, and BM were delineated on the CT images. In each patient, the external contour of whole bones from the L4 vertebral body to ischial tuberosities was contoured and delineated as BM [Figure 1]. The clinical target volume was delineated according to the consensus guidelines and planned target volume (PTV) was given according to institution protocol. An IMRT plan was generated, and normalization was done to obtain full coverage of the PTV with the 95% isodose curve and to achieve OAR dose constraints as per quantitative analyses of normal tissue effects in the clinic. Dose-volume histograms were generated for each structure based on the delivered IMRT plan. The volume of BM receiving 10, 20, 40, 50Gy were computed. These patients received IMRT (50.4Gy in 28 fractions) with concurrent cisplatin (40 mg/m2/week) for a total of preferably 5 cycles followed by high dose rate brachytherapy (21 Gy in 3 fractions) according to institutional practice. Complete blood counts were done weekly to evaluate the neutropenia and were graded according to Common Terminology Criteria for Adverse Events, version 3.0.
Figure 1: Delineation of bone marrow in one of our patients

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Statistics

Data collected were entered into Microsoft Excel sheet and analysis performed using IBM Corp. Released 2015. IBM SPSS Statistics for Windows, Version 23.0. Armonk, NY: IBM Corp. Results on continuous measurements were presented on the mean ± standard deviation and results on categorical measurements were presented in numbers and percentages. Significance was assessed at 5% level. The risk of developing any grade of neutropenia from the external beam RT dose was analyzed by logistic regression.


 > Results Top


A total of 43 patients were studied and [Table 1] summarizes the baseline characteristics of our patients. The mean age was 56.81 years (±10.07). 27 patients (62.8%) received 5 cycles of chemotherapy, 14 patients (32.6%) received 4 cycles of chemotherapy and 2 patients (4.7%) received 3 cycles of chemotherapy. None of the patients had delays or breaks in pelvic RT because of acute toxicity. Among the patients who had not completed 5 cycles of chemotherapy, 2 patients had 1 week break before the last cycle of chemotherapy.
Table 1: Patient characteristics

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Overall, 22 patients (51.2%) experienced acute neutropenia [Figure 2]. Maximum grade of neutropenia observed were Grade 1, Grade 2, Grade 3 in 14 patients (32.6%), 7 patients (16.3%), 1 patient (2.3%), respectively [Table 2]. 4 patients (18%) developed neutropenia in week 5, 18 patients (82%) developed neutropenia in week 6 [Figure 3].
Figure 2: Incidence of neutropenia during chemoradiotherapy

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Table 2: Haematological toxicity during concurrent chemoradiotherapy

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Figure 3: Incidence of neutropenia with respect to the time of onset and grade of neutropenia

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On multivariate analysis increased BM V50Gy had a statistically significant odds of developing any grade of neutropenia (odds ratio [OR] =1.43; 95% confidence interval [CI], 1.03–1.97; P = 0.028), when compared with V10Gy (OR = 0.99; 95% CI, 0.698–1.42; P = 0.99), V20Gy (OR = 0.99; 95% CI, 0.77–1.26; P = 0.94), V40Gy (OR = 0.84; 95% CI, 0.69–1.01; P = 0.070) [Table 3].
Table 3: Incidence of any grade of neutropenia with respect to bone marrow dose volumetric parameters

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The mean values of BM V10, V20, V40, V50Gy were calculated and was 90%, 80%, 40%, 15%, respectively [Table 4]. When comparing patients receiving BM V10Gy ≥90% with BM V10Gy <90% OR was 0.27 (95% CI, 0.06–1.17; P = 0.08) and those receiving BM V20Gy ≥80% with BM V20Gy <80% OR was 0.22 (95% CI, 0.05–0.94; P = 0.04). When patients receiving BM V40Gy ≥40% was compared with BM V40Gy <40% odds of any grade of neutropenia was increased (OR = 2.03; 95% CI, 0.55–7.42; P = 0.28). Similar observation was noted when patients with BM V50Gy ≥ 15% compared with BM V50Gy <15% (OR = 2.13; 95% CI, 0.57–7.97; P = 0.26).
Table 4: Incidence of any grade of neutropenia on comparing bone marrow volume and dosimetric parameters with respect to mean values

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For ≥Grade 2 neutropenia, the only dose volumetric parameter associated with increased likelihood was the BM V50Gy [Table 5]. When BM V50Gy was ≥15% the odds of ≥Grade 2 neutropenia was increased compared with patients with a BM V50Gy was <15% (OR, 16.296; 95% CI, 0.693–383.348; P = 0.083). [Table 6] summarises our analysis of the above dose-volumetric parameters correlated with any grade of neutropenia in those patients who have completed 5 cycles of chemotherapy. The only dose volumetric parameter associated with chemotherapy and any grade of neutropenia in the above analysis was BM V50Gy. Those with BM V50Gy ≥15% were more likely to have any grade of neutropenia than those with a BM V50Gy <15% (OR, 7.036; 95% CI, 0.516–95.887; P = 0.143).
Table 5: Incidence of≥grade 2 neutropenia on comparing bone marrow volume and dosimetric parameters with respect to mean values

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Table 6: Incidence of any grade of neutropenia on comparing bone marrow volume and dosimetric parameters with respect to mean values in patients who have completed 5 cycles of chemotherapy

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 > Discussion Top


BM is an important dose-limiting organ in pelvic RT with concurrent chemotherapy.[6] Direct injury to the hematopoietic cells or structural, functional damage to the stroma either of this can be considered as the mechanism of BM dysfunction in CCRT.[6] Acute marrow toxicity can be measured by granulocytopenia, thrombocytopenia, and anemia.

BM is highly radiosensitive that any dose of radiation will produce injury.[6] Pelvic bones hold 40% of the total-body BM reserve. After 30–40 Gy to large BM volumes, neutropenia occurs followed by thrombocytopenia and anemia. As chemotherapeutic agents act on immature cells, depression in peripheral blood counts is not apparent for the initial 1–3 weeks, which can be best explained by the kinetics of cell maturation in BM and life span of mature peripheral blood cells (granulocytes: 1–2 days, platelets: 10–12 days, erythrocytes: 120 days).[6] Hence, we considered neutropenia as the HT endpoint and was graded accordingly.

Whole pelvic bone contours using auto bone segmentation in CT images were considered as the surrogate of active BM by Mell et al.[10] Auto segmentation technique of bone contours also helps in decreasing the interobserver variation. The whole bone comprises of bone and the cavity, which has active and inactive yellow marrow. Mahantshetty et al. considered the cavity as the closest volume, that can be contoured on CT as a surrogate of active BM, hence freehand contours of the low-density regions inside the bone were considered as the surrogate for BM.[14] Other imaging modalities available to delineate the active BM include single-photon emission CT fluro thymidine-positron emission tomography and magnetic resonance imaging.[15],[16],[17] As these are usually not available for RT planning owing to logistics, whole bone contouring of BM is widely accepted, external contour of whole bones from L4 vertebral body to ischial tuberosities on CT were contoured and delineated as BM in our study.

Previous studies performed by Mell et al., have shown an association between the volume of BM receiving low-dose radiation and acute HT in cervical cancer patients receiving CCRT with IMRT technique (BM V10Gy ≥90% had higher rate of neutropenia).[10],[11] Similar study by Albuquerque et al. found that the volume of BM receiving low dose radiation predicted acute HT while using the three-dimensional conformal radiation therapy technique (BM V20Gy ≥80% had higher rate of neutropenia).[12] Both these studies could not find any association of HT to high dose receiving BM volume. In contrast with the above studies, RTOG 0418 study by Klopp et al. found an association with the volume of BM receiving high dose radiation and HT with IMRT technique (V40 Gy >37% had a higher rate of neutropenia).[13] Similar study by Huang et al. also found that efforts to maintain lumbosacral spine V10 Gy <87%, lumbosacral spine mean <39 Gy, and pelvic bone V40 Gy <28% concomitantly may reduce the risk of Grade 2 or higher HT.[18]

Our study looked into doses including 10, 20, 40, 50 Gy using the IMRT technique and found statistically significant increased odds of any grade of neutropenia with an increased V50Gy [P = 0.028; [Table 3]]. When comparing patients receiving BM V40Gy ≥40% with BM V40Gy <40% odds of any grade of neutropenia was increased (OR = 2.03; 95% CI, 0.55–7.42; P = 0.28). Moreover, when comparing patients receiving BM V50Gy ≥15% with BM V50Gy <15% odds of neutropenia was increased (OR = 2.13; 95% CI, 0.57–7.97; P = 0.26) [Table 4]. As the previous studies used ≥Grade 2 neutropenia, we also analyzed this separately [Table 5]. Due to the low incidence of ≥Grade 2 neutropenia (8 patients), statistical significance was not seen even though odds of ≥Grade 2 neutropenia was higher when BM V50Gy was ≥15%.

Our primary objective was to analyze the relationship of irradiated BM volume and the development of any grade of neutropenia. Apart from RT these patients also received cytotoxic chemotherapy (cisplatin). Hence, we also analyzed the dose volumetric parameters associated with chemotherapy and any grade of neutropenia in patients who completed all the planned cycles of chemotherapy [Table 6]. 27 patients (62.8%) received all the planned cycles of chemotherapy (5 cycles), hence statistical significance was not seen even though odds of any grade of neutropenia was higher when BM V50Gy was ≥15%.

Earlier studies have also demonstrated that when small fields are irradiated, the unexposed BM responds by increasing its population of progenitor cells meeting the demand of hematopoiesis.[6],[19],[20] Thus, acute effects are not seen unless very large fields containing a substantial portion of marrow is irradiated to prevent compensatory hyperplasia. In accordance with the above observation, we could also see that odds of neutropenia were increased when larger volumes were irradiated. The major difference between the findings of our study and the previous studies of Mell et al. and Albuquerque et al. is that the present analysis found that the volume of BM receiving higher doses resulted in HT. Hence, future studies with a higher sample size may be helpful for achieving clarity regarding this disparity.


 > Conclusions Top


Our present study concludes that high dose irradiation to the larger volume of BM prevents compensatory hyperplasia which leads to neutropenia in patients undergoing CCRT for cervical cancer. The odds of any neutropenia is 2 when BM V40Gy ≥40% and BM V50Gy ≥15%. Hence considering BM as an OAR is of great importance in these patients.

Acknowledgment:

The authors acknowledge with gratitude the immense help given by Mr. K Venkatesan, Dr. Sunu Cyriac, and radiotherapy team during all stages of the work.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
 > References Top

1.
NCCN Clinical Practice Guidelines in Oncology. Available from: https://www.nccn.org/professionals/physician_gls/default.aspx. [Last accessed on 2020 Apr 20].  Back to cited text no. 1
    
2.
Chemoradiotherapy for Cervical Cancer Meta-analysis Collaboration (CCCMAC). Reducing uncertainties about the effects of chemoradiotherapy for cervical cancer: Individual patient data meta-analysis. Cochrane Database Syst Rev 2010;2010:CD008285.  Back to cited text no. 2
    
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Carde P, Laval F. Effect of cis-dichlorodiammine platinum II and X rays on mammalian cell survival. Int J Radiat Oncol Biol Phys 1981;7:929-33.  Back to cited text no. 3
    
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Stratford IJ, Williamson C, Adams GE. Combination studies with misonidazole and a cis-platinum complex: Cytotoxicity and radiosensitization in vitro. Br J Cancer 1980;41:517-22.  Back to cited text no. 4
    
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Green JA, Kirwan JM, Tierney JF, Symonds P, Fresco L, Collingwood M, et al. Survival and recurrence after concomitant chemotherapy and radiotherapy for cancer of the uterine cervix: A systematic review and meta-analysis. Lancet 2001;358:781-6.  Back to cited text no. 5
    
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Mauch P, Constine L, Greenberger J, Knospe W, Sullivan J, Liesveld JL, et al. Hematopoietic stem cell compartment: Acute and late effects of radiation therapy and chemotherapy. Int J Radiat Oncol Biol Phys 1995;31:1319-39.  Back to cited text no. 6
    
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Lanciano RM, Pajak TF, Martz K, Hanks GE. The influence of treatment time on outcome for squamous cell cancer of the uterine cervix treated with radiation: A patterns-of-care study. Int J Radiat Oncol Biol Phys 1993;25:391-7.  Back to cited text no. 7
    
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Tang J, Tang Y, Yang J, Huang S. Chemoradiation and adjuvant chemotherapy in advanced cervical adenocarcinoma. Gynecol Oncol 2012;125:297-302.  Back to cited text no. 8
    
9.
Mileshkin LR, Narayan K, Moore KN, Rischin D, King M, Kolodziej I, et al. A phase III trial of adjuvant chemotherapy following chemoradiation as primary treatment for locally advanced cervical cancer compared to chemoradiation alone: Outback (ANZGOG0902/GOG0274/RTOG1174). J Clin Oncol 2014;32 (Suppl):15.  Back to cited text no. 9
    
10.
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.  Back to cited text no. 10
    
11.
Mell LK, Schomas DA, Salama JK, Devisetty K, Aydogan B, Miller RC, 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.  Back to cited text no. 11
    
12.
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.  Back to cited text no. 12
    
13.
Klopp AH, Moughan J, Portelance L, Miller BE, Salehpour MR, Hildebrandt E, 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.  Back to cited text no. 13
    
14.
Mahantshetty U, Krishnatry R, Chaudhari S, Kanaujia A, Engineer R, Chopra S, et al. Comparison of 2 contouring methods of bone marrow on CT and correlation with hematological toxicities in non-bone marrow-sparing pelvic intensity-modulated radiotherapy with concurrent cisplatin for cervical cancer. Int J Gynecol Cancer 2012;22:1427-34.  Back to cited text no. 14
    
15.
Hayman JA, Callahan JW, Herschtal A, Everitt S, Binns DS, Hicks RJ, 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.  Back to cited text no. 15
    
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Roeske JC, Lujan A, Reba RC, Penney BC, Diane Yamada S, Mundt AJ. Incorporation of SPECT bone marrow imaging into intensity modulated whole-pelvic radiation therapy treatment planning for gynecologic malignancies. Radiother Oncol 2005;77:11-7.  Back to cited text no. 16
    
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Blebea JS, Houseni M, Torigian DA, Fan C, Mavi A, Zhuge Y, et al. Structural and functional imaging of normal bone marrow and evaluation of its age-related changes. Semin Nucl Med 2007;37:185-94.  Back to cited text no. 17
    
18.
Huang J, Gu F, Ji T, Zhao J, Li G. Pelvic bone marrow sparing intensity modulated radiotherapy reduces the incidence of the hematologic toxicity of patients with cervical cancer receiving concurrent chemoradiotherapy: A single-center prospective randomized controlled trial. Radiat Oncol 2020;15:180.  Back to cited text no. 18
    
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Rubin P, Scarantino CW. The bone marrow organ: The critical structure in radiation-drug interaction. Sir Stanford Cade Memorial lecture. Int J Radiat Oncol Biol Phys 1978;4:3-23.  Back to cited text no. 19
    
20.
Scarantino CW, Rubin P, Constine LS 3rd. The paradoxes in patterns and mechanism of bone marrow regeneration after irradiation. 1. Different volumes and doses. Radiother Oncol 1984;2:215-25.  Back to cited text no. 20
    


    Figures

  [Figure 1], [Figure 2], [Figure 3]
 
 
    Tables

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