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    -  Pruthi DS
    -  Nagpal P
    -  Pandey M
    -  Singh H

 
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ORIGINAL ARTICLE
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Dosimetric correlation of bone marrow irradiation with acute hematological toxicity in concurrent chemoradiation of cervical carcinoma patients


 Department of Radiation Oncology, Action Cancer Hospital, New Delhi, India

Date of Submission02-Jun-2020
Date of Decision26-Jul-2020
Date of Acceptance19-Oct-2020
Date of Web Publication02-Aug-2022

Correspondence Address:
Puneet Nagpal,
Department of Radiation Oncology, Action Cancer Hospital, New Delhi
India
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ijc.IJC_585_20

  Abstract 


Background: Many acute toxicities are associated with concurrent chemoradiation in cervical carcinoma, which includes burning micturition, burning defecation, pain lower abdomen, increased frequency of stools along with Acute Hematological Toxicity (AHT). AHT is often an expected adverse effect, which can lead to treatment interruptions and decreased response rates. The purpose of this study is to analyze if there are any dosimetric constraints on the volume of bone marrow irradiated with AHT in cervical carcinoma patients treated with concurrent chemoradiation.
Material and Methods: In this retrospective study of 215 patients, a total of 180 patients were eligible for analysis. Multiple parameters of bone marrow volumes (whole pelvis bone marrow and its sub-volumes––ilium, lower pelvis, and lumbosacral spine) which were contoured individually for all patients were assessed to have any statistically significant association with AHT.
Results: The median age of the cohort was 57 years and majority of cases were locally advanced (stage IIB-IVA: 88.3%). Grade I, II, III leukopenia was seen in 44, 25, and 6 patients, respectively. A statistically significant correlation between grade 2+ and 3+ leukopenia was seen if bone marrow V10, V20, V30, and V40 were more than 95%, 82%, 62%, and 38%, respectively. In subvolume analysis, volumes of lumbosacral spine V20, V30, and V40 more than 95%, 90%, and 65%, respectively, were statistically significant for AHT.
Conclusion: Bone marrow volumes should also be given a constraint and should be tried to be achieved so that it leads to minimal treatment breaks due to AHT.


Keywords: Acute hematological toxicity, bone marrow irradiation, cervical carcinoma



How to cite this URL:
Pruthi DS, Nagpal P, Pandey M, Singh H. Dosimetric correlation of bone marrow irradiation with acute hematological toxicity in concurrent chemoradiation of cervical carcinoma patients. Indian J Cancer [Epub ahead of print] [cited 2022 Dec 5]. Available from: https://www.indianjcancer.com/preprintarticle.asp?id=353186





  Introduction Top


Cervical carcinoma is one of the most common malignancies in females. As per GLOBOCAN 2018, cervical carcinoma is the fourth most common cancer in females in the world and a total of 569,847 new cases of cervical carcinoma were diagnosed in the year 2018.[1] In India, it is the second most common malignancy in females after breast cancer.[2]

Staging of cervical carcinoma is done clinically by using the International Federation of Gynecology and Obstetrics (FIGO) staging system.[3] Locally advanced cervical carcinoma usually includes stage IIB, III, and IVA[4] and the standard treatment for locally advanced cervical carcinoma is concurrent chemoradiation followed by brachytherapy.[5],[6]

During the last few decades, there has been a significant improvement in the techniques of external beam radiotherapy treatment from the two-dimensional conventional technique or three-dimensional conformal radiotherapy to the current era of intensity-modulated (IMRT)/image-guided (IGRT) or volumetric arc radiotherapy (VMAT) which reduces the dose to the normal tissues irradiated like bladder and rectum and hence decrease in side effects.[7],[8] Dosimetric studies have suggested that IMRT/VMAT could decrease the dose to bladder, rectum as well as the pelvic bone marrow without compromising on the Planning Target Volume (PTV).[9] This treatment is associated with a few acute side effects like vomiting, loose stools, and burning defecation.

However, one of the most commonly observed side effects, which are usually considered to occur is acute hematological toxicity or bone marrow suppression. This is because in adults, pelvic bone is the primary site of hematopoiesis. It is estimated that >50% of proliferating bone marrow is located in the pelvic region, including the lumbar spine.[10] AHT has many implications like multiple infections, canceled chemotherapy cycles, and multiple treatment breaks resulting in an increase in overall treatment time and hence reduced response.[11]

There is a significant correlation between overall treatment time and treatment outcome in cervical carcinoma.[12] EMBRACE I study also showed significantly more systemic relapses in node-positive and advanced-stage patients who received ≤4 chemotherapy cycles compared with the patients who received ≥5 cycles.[13] This makes the hematopoietic system in the lower lumbar spine and pelvis a potential Organ at Risk (OAR) during the radiotherapy treatment. Potential bone marrow sparing in patients of pelvic irradiation has been discussed since the last two decades yet no fixed constraints and guidelines are available.

A correlation between the volume of whole pelvic bone marrow receiving 20 Gy (V20) and grade 2+ AHT has been reported.[14] In patients treated with IMRT, some authors have shown a correlation between the pelvic bone dosimetric parameters (V10 Gy > 95% and V20 > 76%) and grade 3 leukopenia probability.[15] Among subvolumes in the pelvic bone marrow, lumbosacral spine (V40 Gy) was associated with clinically significant grade ≥2 hematologic toxicity.[16]

This retrospective study was conducted to examine the correlations between pelvic bone marrow dose/volume parameters and AHT incidence of our patients of cervical carcinoma treated with chemoradiation.


  Material and Methods Top


After due clearance from the ethical committee of the institution, we retrospectively analyzed 215 patients of FIGO (International Federation of Gynecology and Obstetrics) stage IB-IVB cervical carcinoma treated with concurrent chemoradiation from January 2016 to January 2019. All patients were treated with a curative intent.

Patients who did not receive concurrent chemotherapy due to medical co-morbidities or who received less than 5 cycles of chemotherapy were excluded (30 patients). Patients who underwent extended field radiotherapy (5 patients) were also excluded from the study. No patient received neoadjuvant chemotherapy.

The total number of patients eligible for the study was divided into two groups: Those who developed AHT and those who did not develop AHT.

Acute Hematological Toxicity was defined as per RTOG criteria. In this leukopenia (which is the main factor taken into consideration in this study) is defined in four grades in which grade I is 3000-3999 × 109/L, grade II is 2000-2999 × 109//L, grade III is 1000-1999 × 109//L and grade IV is less than 1000 × 109//L.[17] Neutropenia was considered if any Complete Blood Count (CBC) during concurrent chemoradiation had the above-said values.

Treatment details

All patients underwent Computed Tomography (CT) based planning in supine position and thermoplastic pelvic cast was made for immobilization. Bladder and rectal protocol were followed as per departmental protocol. A radio-opaque vaginal marker was placed at the introitus or the lowest extent of disease prior to simulation.

Target delineation was done as per the standard guidelines[18],[19],[20] in which Clinical Target Volume (CTV) nodal areas contained common iliac, internal iliac, external iliac, obturator and presacral nodes (started at aortic bifurcation). The CTV nodal was drawn by taking a uniform margin of 7 mm around blood vessels. The bones and psoas muscles were excluded. CTV tumor was drawn on axial slices including the whole cervix, vagina (lower border of ischial tuberosity or 2 cm caudal to lowermost disease extent), bilateral parametrium. A Planning Target Volume (PTV) of 0.5 cm was taken as per departmental protocol to account for setup uncertainties.

All patients received radiotherapy to a dose of 50.4 Gy in 28 fractions over 5 1/2 weeks treated using Rapid Arc technique on Varian Clinac iX.

The dose constraints used to optimize and validate the treatment followed the International Commission of Radiation Units and Measurements (ICRU) 89 in terms of PTV and organs at risk dose constraints.[21] The planning goal was to deliver 95% of the dose to at least 95% of the PTV without exceeding OARs dose constraints.

Concurrent chemotherapy was administered weekly by the medical oncology department with cisplatin to a dose of 40 mg/m2 with adequate hydration. Hydration was given using IV fluids followed by cisplatin infusion over 2 hours.

All bone marrow contours were retrospectively delineated manually in each cervical cancer patient individually [Figure 1]. Bone Marrow (BM) was contoured as per Loren Mell et al. in which the entire bone marrow was delineated manually on bony window and divided into three subvolumes as following.[22]
Figure 1: Shows the contouring of the bone marrow and its various sub-volumes - Ilium (red), Lower Pelvis (green) and Lumbo Sacral Spine (blue)

Click here to view


  • Ilium (I) which included iliac crests extending to the superior border of femoral heads.
  • Lower Pelvis (LP) included the pubic bone, ischia, acetabula and proximal femur extending from the superior border of femoral heads to inferior border of ischial tuberosities.
  • Lumbosacral Spine (LSS) which extended from the most superior vertebral body contained in the PTV to include the entire sacrum inferiorly.


All patients had undergone baseline hematological profile (complete blood count) and the tests were conducted once a week during the course of treatment. In complete blood count the parameters noted were hemoglobin, total leucocyte count, absolute neutrophil count and platelet count. The hematological toxicity was assessed using RTOG toxicity criteria.

Statistical analysis

Statistical analysis was conducted utilizing SPSS software version 22 (Corp, Armonk, NY, USA).

Based on the bone marrow delineation, the relative dose-volume histograms (DVHs) were calculated. Bone marrow volumes receiving 10, 20, 30, 40, and 50 Gy (V10, V20, V30, V40, V50, respectively) were calculated. Similarly, bone marrow volumes receiving 10, 20, 30, 40, and 50 Gy for individual subsites i.e., ilium, lower pelvis and lumbosacral spine were also calculated. Brachytherapy dose to the pelvic bone was not considered in our study, as the last AHT assessment was done prior to brachytherapy. For each patient, incidence of AHT was examined for each blood cell line separately and scored from grade 1 to grade 4.

The Chi-square test was used to compare rates of AHT with bone marrow dose metrics i.e., between the amount of bone marrow irradiated from 10–50 Gy and hematological toxicity for patients treated with chemoradiation. Receiver operating characteristic curve (ROC) analysis was performed for determining the optimal cut-off values for the dosimetric parameters. Further univariate logistic regression was used to identify potential associations between AHT and DVHs parameters. Odds ratio and correlation analysis were also performed. A value of P < 0.05 was considered to be statistically significant.


  Results Top


We retrospectively analyzed 215 patients of cervical carcinoma who were treated between January 2016 to January 2019. Of these 35 patients were excluded as they did not receive concurrent chemotherapy (due to medical reasons or refusal) or were treated using extended field radiotherapy. Finally, 180 patients were analyzed. The characteristics of the patient population are described in [Table 1].
Table 1: Describes the characteristics of our study population (N=180)

Click here to view


Radiotherapy and chemotherapy details

All patients underwent radiotherapy using Rapid Arc technique to a median dose of 50.4 Gy in 28 fractions which was followed by intracavitary brachytherapy as per departmental protocol. The mean percentages volumes of bone marrow receiving 10, 20, 30, 40 and 50 Gy for all patients were 95.5%, 81.5%, 61.1%, 37.1% and 11.5%, respectively. The mean dose to the bone marrow and lumbosacral spine for those who developed and did not develop hematological toxicity was 42.3 Gy and 34 Gy, 39 Gy and 32 Gy, respectively.

The patients had received concurrent chemotherapy with cisplatin at a dose of 40 mg/m2 with a median number of 5 cycles of concurrent chemotherapy.

Hematological toxicity

The mean baseline white blood cells (WBC), hemoglobin, and platelet counts were 7 × 109/L, 11 g/dL, and 172 × 109/L, respectively. Of 180 patients, 75 patients (41.6%) developed any form of hematological toxicity. Grade I, II, and III anemia were seen in 34, 33, and 2 patients, respectively. Grade l, ll and lll leukopenia was seen in 44, 25, and 6 patients, respectively. Grade l and ll thrombocytopenia was seen in 42 and 5 patients, respectively [Table 2].
Table 2: Showing the various forms and grades of hematological toxicity

Click here to view


A total number of 33 patients (44%) required administration of colony-stimulating factors during the treatment as no dose reduction of chemotherapy was done. 3 patients required interruption of treatment.

Increased V10, V20, V30, and V40 (irradiated bone marrow) were associated with increased hematological toxicity during chemoradiation.

The patients receiving chemoradiation with V10 > 95%, V20 > 82%, V30 > 62%, V40 > 38% and V50 > 11% had higher rates of grade 2+ toxicity with V10, V20, V30 and V40 having statistically significant results [Figure 2]. Similar findings were noted when the individual subsite of lumbosacral spine was studied in which V20 > 95%, V30 > 90%, and V40 > 65% showed statistically significant results. Irradiation of ilium and lower pelvis did not have any significant difference in terms of hematological toxicity [Table 3] and [Table 4].
Table 3: Shows the comparison of rates of AHT with bone marrow dose metrics for all pelvic Bone Marrow (BM) and Lumbosacral Spine (LSS) using chi square test

Click here to view
Table 4: Shows the odds ratio, correlation coefficient and respective p values for various bone marrow and subsite parameters for those patients who developed grade 2+ hematological toxicity

Click here to view
Figure 2: Shows line diagram comparing the dosimetric parameters of whole bone marrow (a) and its sub volumes (b-lower pelvis; c-lumbosacral spine; d- ilium) in patients who did and did not develop AHT, Blue: Developed AHT; Red: Did not develop AHT

Click here to view


Overall increasing BM V20, V30, V40, and LSS V20, V30, V40 were associated with a decreased WBC count on analysis and their associations were statistically significant. Statistically significant correlation was not observed between other parameters and hematological toxicity.

The univariate regression analysis showed that the factors of age, co-morbidities, and histology were not significantly associated with the development of hematological toxicity. Any significant correlation was not seen between the number of cycles of concurrent chemotherapy and hematological toxicity.


  Discussion Top


The established treatment of locally advanced cervical carcinoma has been and will be concurrent chemoradiation.[5],[6],[7] Apart from acute side effects like nausea, loose motions, pain abdomen; acute hematological toxicity is a very important side effect that can hamper treatment duration and outcome. For example, acute hematological toxicity can interrupt radiotherapy, chemotherapy, lead to the need of growth factors and occasionally may cause serious infections. This has a negative impact on local control and overall survival.[23],[24],[25] Thus, there is an imperative need to identify and reduce the hematological toxicity. IMRT and VMAT has helped us in reducing the dose to normal structures like bladder, rectum and bowel but there is a need to reduce the bone marrow side effects as well.

There have been a lot of studies done on the possible correlation between the volume of bone marrow irradiated and hematological toxicity but still there are no fixed constraints, which may be used during planning.

The contouring in our study was done according to Mell et al.[22] where the entire bone marrow and its subsites were contoured on the bony window. In their study, 20 patients with increased low-dose volumes, i.e., V10 and V20 were associated with decreased WBC counts. Radiation dose to the sacral vertebrae and low dose pelvic regions was linked to hematological toxicity. In our study, we found that if V10 was more than 95% there was a threefold chance of developing leukopenia as compared if V10 was less than 95% but it is not statically significant.

Similarly, Albuquerque et al.[14] and Rose et al.[15] showed that BM V20 > 80% and BM V20 > 76%, respectively, was significant which is similar to our study wherein V20 > 82% was found to be significant. RTOG 0418 has shown that V40 is the best predictor of acute hematological toxicity in concurrent pelvic chemoradiation. In that study V40 > 37% was associated with AHT.[26] When we compare that with our study again it's concordant with V40 > 38%.

In a study done by Mahantshetty et al., 4 patients of cervical carcinoma were prospectively studied and they divided pelvic bone marrow contour into two sets i.e., whole bone (WB) and freehand (FH) inner cavity of bone. Various subvolumes were also made in each set—ilium, ischium, lower pelvis, lumbosacral spine, sacrum, and whole pelvis. In their study, they found freehand bone marrow V40 > 40% to be significantly correlated with AHT.[27] Despite that our findings are similar to the above-mentioned study with V40 > 38% being significant.

In the past, there have been various methods adopted for bone marrow contouring with the incorporation of functional imaging. Liang et al. hypothesized that IMRT can reduce radiation dose to functional bone marrow identified with the help of the positron emission tomography (PET-CT) scan.[28] They divided their patients into two groups: functional bone marrow and total bone marrow. The mean functional bone marrow V10 and V20 were 85% and 70%, respectively, as compared to 94% and 82% in total bone marrow sparing. However, the usage of PET CT Scan in routine contouring of bone marrow may not be feasible at all centers due to non-availability.

So, no standard dose constraints have been achieved in various studies but V20 > 80%–82% and V40 > 38% are the most consistent surrogates for bone marrow suppression which should be contoured and evaluated for each patient of cervical carcinoma undergoing chemoradiation.

The limitation of our study was that it was retrospective in nature. Also, the contouring of the whole bone marrow was done and not the functional bone marrow as seen by Single Photon Emission Computerized Tomography (SPECT) scan. Nutritional status was not assessed but is one factor, which may play a role in the development of hematological toxicity and should be evaluated.

To conclude, bone marrow should be considered regularly as an OAR equally important while contouring for locally advanced cervical carcinoma. Bone marrow volume should be given a dose constraint of V20 < 82%, V30 < 62%, V40 < 38% as found in our study but not at the expense of PTV coverage. Bone marrow dosimetric parameters can help identify patients who will be at risk for developing bone marrow toxicity. Further prospective studies need to be done to evaluate its actual relevance.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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    Figures

  [Figure 1], [Figure 2]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4]



 

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