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ORIGINAL ARTICLE
Ahead of print publication  

A randomized study for dosimetric assessment and clinical impact of bone marrow sparing intensity-modulated radiation therapy versus 3-dimensional conformal radiation therapy on hematological and gastrointestinal toxicities in cervical cancer


1 Department of Radiation Oncology, Jupiter Hospital, Thane, Maharashtra, India
2 Department of Radiation Oncology, National Cancer Institute, Jhajjar, Haryana, India
3 Department of Medical Physics, Jupiter Hospital, Thane, Maharashtra, India

Date of Submission25-Aug-2020
Date of Decision03-Oct-2020
Date of Acceptance01-Jan-2021
Date of Web Publication25-Oct-2021

Correspondence Address:
Ankita Rungta Kapoor,
Jupiter Lifeline Hospital, Off Eastern Express Highway, Thane - 400 601, Maharashtra
India
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jcrt.JCRT_1242_20

 > Abstract 


Background: Cervical cancer requires multimodality therapy, resulting in acute toxicities. Intensity-modulated radiation therapy (IMRT) is postulated to spare bone marrow (BM) and bowel to reduce acute hematological and gastrointestinal (GI) toxicities of chemoradiotherapy.
Patients and Methods: This is a prospective randomized phase III study enrolling patients with Stage IB to IVA cervical carcinoma in two arms receiving either three-dimensional conformal radiotherapy (3DCRT) or IMRT from December 2017 to December 2019. The primary objective was to compare the hematologic toxicities (Grade 2 or more neutropenia as the primary factor) and the secondary objectives were to compare GI toxicities, and dosimetric analysis for volumes of BM, and bowel irradiated. SPSS version 20 was used for all statistical calculations.
Results: Eighty patients with histopathologically confirmed cervical cancer were randomized to receive IMRT or 3DCRT (40 in each arm). The median age of the patients was 56.5 (36–67) and 59.5 (37–68) years, respectively, in IMRT and 3DCRT arms. The median dose of external radiation was 50 Gy in 25 fractions, and of brachytherapy was 24 Gy in 3 fractions in both the arms. The incidence of grade ≥2 neutropenia was 42.5% and 15% in the 3DCRT and IMRT arms, respectively (P < 0.001). All patients received concurrent chemotherapy with cisplatin, with the median number of cycles being 5 (range 3–5) in both the arms. All five cycles of concurrent chemotherapy could be completed in 25 (62.5%) patients in the IMRT arm and 24 (60%) patients in the 3DCRT arm.
Conclusions: IMRT significantly reduces acute hematologic and GI toxicities compared with 3DCRT with a better dosimetry profile.

Keywords: Conformal radiotherapy, intensity-modulated radiotherapy, radiation dosimetry, uterine cervical neoplasms



How to cite this URL:
Kapoor AR, Bhalavat RL, Chandra M, Pareek V, Moosa Z, Markana S, Nandakumar P, Bauskar P, Shincy N V. A randomized study for dosimetric assessment and clinical impact of bone marrow sparing intensity-modulated radiation therapy versus 3-dimensional conformal radiation therapy on hematological and gastrointestinal toxicities in cervical cancer. J Can Res Ther [Epub ahead of print] [cited 2021 Dec 7]. Available from: https://www.cancerjournal.net/preprintarticle.asp?id=329186




 > Background Top


Cervical cancer is the most common cause of cancer-related death in women from developing countries,[1] the peak age being 55–59 years in India.[2] According to the GLOBOCAN 2018, cervical cancer ranks fourth in incidence and mortality.[3] Several prospective, randomized studies have been performed by The Gynecologic Oncology Group to evaluate the benefits of concurrent chemotherapy with radiotherapy in patients with locally advanced cervical cancer.[4] This combined modality approach leads to improvement in local disease control, disease-free survival, and overall survival but is also associated with significant toxicities in the form of hematological, gastrointestinal (GI), and genitourinary side effects. It is reported that around 30% of patients develop acute grade ≥3 toxicities.[5],[6],[7],[8],[9],[10],[11],[12] The patients experience unique group of toxicities due to the anatomic location of the tumor with proximity with organs-at-risk.[13] Furthermore, higher doses of external beam radiation are expected to lead to chronic myelosuppressive effects and poor tolerance to subsequent chemotherapy by damaging the bone marrow (BM) microenvironment.[13]

The extent of radiation-induced BM injury depends on both radiation dose, and volume of BM irradiated.[14] It is important to note that more than half of the active BM is located in the lumbar vertebra, pelvic bones, sacrum, and proximal femur, and these bones are bound to receive entry and exit dose during pelvic radiotherapy.[15] As a result of hematologic toxicities, the patient is predisposed to infections, and the need for transfusions and growth factors which can lead to hospitalizations and reduced quality of life. At the same time, the toxicities can lead to delayed or missed chemotherapy cycles and treatment breaks, which might lead to suboptimal disease control.[13],[16]

Three-dimensional conformal radiotherapy (3DCRT) and intensity-modulated radiation therapy (IMRT) are two techniques currently used for the delivery of radiotherapy for pelvic cancers.[17] IMRT has the potential to deliver adequate dose to the target structures while reducing the dose to organs at risk with favorable outcomes in cervical cancer.[11],[18] Thus, we conducted this prospective randomized study with the primary objective to compare the hematologic toxicities (Grade 2 or more neutropenia as the primary factor) in patients of cervical cancer treated with 3DCRT and IMRT. The secondary objectives of the study were to compare GI toxicities and dosimetry of the two groups.


 > Patients and Methods Top


Trial design and conduct

This is a prospective, randomized, single-center phase III study with 1:1 allocation, conducted in the Radiation Oncology department of our hospital. The patients underwent contrast-enhanced computed tomography (CT) scan of the abdomen and pelvis for staging. Patients underwent cystoscopy and/or sigmoidoscopy if clinically indicated. Furthermore, chest X-ray was performed in all patients as part of the metastatic workup. Written informed consent was obtained from all the participants. The study was approved by the Institutional Review Board and Ethics Committee. The study was conducted as per the Declaration of Helsinki and local guidelines of the Indian Council of Medical Research.

The study population comprised patients diagnosed with carcinoma cervix FIGO Stage IB to IVA from December 2017 to December 2019. The inclusion criteria were patients undergoing definitive concurrent chemoradiation followed by brachytherapy with intracavitary radiation therapy, FIGO Stage IB to IVA, squamous or adenocarcinoma or adenosquamous histology, age 18–70 years, Karnofsky performance score >70%, and willing to give consent for participation in the study. The patients who had undergone hysterectomy/had received radiotherapy or chemotherapy previously, or had hematological derangement before start of the therapy were excluded from the study. Furthermore, patients with gross para-aortic or pelvic node on radiology, or any contraindications of concurrent chemotherapy were excluded.

Interventions

The patients were planned for definitive treatment with external beam radiation therapy (EBRT) either with IMRT or 3D CRT delivering 50 Gy in 25 fractions over 5 weeks with concurrent cisplatin 40 mg/m2 weekly after assessing the renal profile followed by 3 or 4 fractions of high dose rate brachytherapy. All patients underwent CT simulation with immobilization in the supine position using a customized thermoplastic mold. Bladder filling protocol with a consistent bladder filling state was followed for every patient on the day of CT Simulation, and thereafter daily before treatment. Patients were asked first to empty the bladder followed by 500 cc water intake over 10–15 min, and then they were taken for treatment after 30 min. Treatment planning involved contrast-enhanced planning CT scan of the area of interest with 2.5 mm slices followed by the delineation of various target volumes such as gross tumor volume (GTV), clinical target volume (CTV), planning target volume (PTV), and organ at risk volumes contoured on each slice. The delineation of the various volumes was done as per consensus guidelines.[19] For the CTV nodal, iliac vessels were contoured starting from the aortic bifurcation till the appearance of the femoral head. A uniform margin of 7mm was given around the pelvic vessels. For CTV primary, GTV of the primary tumor (GTV primary), uterine cervix, uterine corpus, parametrium, vagina, and ovaries. An isometric margin of 5 mm was provided to the CTV for the final PTV. The CTV was defined as the gross tumor plus areas containing the potential microscopic disease, including the cervix and uterus, the superior third of the vagina, the parametria, and the regional lymph nodes. Box field was used for 3DCRT plans with gantry angles of 0°, 90°, 180°, and 270° using 15 MV energy and prescription at the isocenter, which is kept at the center of PTV. IMRT plans consisted of 7–9 coplanar fields or 2–3 coplanar arcs and were designed to optimize bowel and pelvic BM sparing while maintaining PTV coverage with a 10 mm margin to CTV. Weekly cone-beam CT was taken for patients with IMRT plan to ensure the target coverage. Depending on the location of the tumor, the OARs were drawn, which included the rectum, urinary bladder, both femur, BM of the pelvis and lower lumbar spine and bowel bag (BB). BB, as well as BM, was contoured beginning from the axial slice situated 1 cm superior to the superior-most slice containing the PTV, continuing to its most inferior extent in the pelvis. Individual loops of bowel were not contoured separately. Rectum was contoured separately from the bowel. BM was contoured with CT-based freehand contouring of the inner hypo-enhancing area of pelvic bones in the bone window [Figure 1].
Figure 1: Delineation of bone marrow as an organ at risk in axial section (a), body reconstruction (b), coronal section (c), sagittal section (d), and bone marrow contour in three-dimensions (e)

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The assessment of toxicities was done according to the National Cancer Institute Common terminology criteria for adverse events (NCI CTCAE) version 5.0. Patients on treatment were evaluated after every five radiations for acute hematological and GI toxicities. Complete blood counts were recorded after every concurrent chemotherapy cycle. Patients with absolute neutrophil count <1000/mm3 were administered filgrastim (5 mcg/kg/day) till the count recovery.

For BM, Dmax, Dmin, Dmean, V5, V10, V20, V30, V40, V50 and for BB, V5, V15, V25, V30, V40, V45, V50 were assessed. Dose constraints for BM were V5 <95%, V10 <88%, V20 <80%, V30 <65% and V40 <45%. V45 for BB was kept <195 cc and 30% of entire bowel received <40 Gy (V40 <30%). For rectum, Dmax, Dmin, and Dmean were assessed, and for the target coverage, CTV total (CTV + CTV1), D95, D97, and D99 were assessed.

Statistical analysis

Assuming Grade 2 or more neutropenia in the 3D CRT to be 75% in accordance with the previously published study,[20] we assumed it to be reduced to 40% in the IMRT arm with two-sided alpha of 5% and power of 90%, a sample size of 80 patients was required. Simple randomization plan was generated from online software, available from http://www.randomization.com. Mann–Whitney U test was used to test for differences in the highest grade of toxicities (anemia, neutropenia, thrombocytopenia and diarrhea) between IMRT and 3D CRT arms. Binomial logistic regression was performed to ascertain the effect of 3D CRT versus IMRT on the likelihood of developing Grade 2 or more neutropenia and diarrhea. Correlation between BM volumes and grade ≥2 neutropenia was calculated using binomial logistic regression analysis. Correlation between BB volumes and the probability of grade ≥2 diarrhea was also assessed using the same method. SPSS version 20.0 for Windows (Armonk, NY, US) was used for all statistical calculations.


 > Results Top


One hundred and two patients with histopathologically confirmed cervical cancer were evaluated for this study; 22 were excluded [Figure 2]. Thus, 80 patients were randomized to receive IMRT or 3DCRT (40 in each arm) and were included in the analysis. The median age was 56.5 (36–67) and 59.5 (37–68) years in the IMRT and 3DCRT arms, respectively. The baseline characteristics of the patients in the two arms are depicted in [Table 1]. All patients received concurrent chemotherapy with cisplatin, with the median number of cycles being 5 (range 3–5) in both IMRT and 3DCRT arms. All five cycles of concurrent chemotherapy could be completed in 25 (62.5%) patients in the IMRT arm and 24 (60%) patients in the 3DCRT arm. The median overall treatment time (OTT) in patients receiving IMRT was 57 days (range 56–85) whereas, it was 57.5 days (range 49–88) in the 3D CRT arm.
Figure 2: Consort diagram of the study

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Table 1: Baseline characteristics of patients included in the study

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[Table 2] shows the dosimetry of organs-at-risk and CTV and [Figure 3] shows the colorwash for the 3DCRT and IMRT plans. In the IMRT arm, the mean volume of BM was 301.9 cc with mean values of Dmax, Dmin, and Dmean being 51.6 Gy, 3.9 Gy, and 32.2 Gy, respectively. In the 3DCRT arm, the mean volume of BM was 294.8 cc with mean values of Dmax, Dmin, and Dmean being 50.9 Gy, 4.7 Gy, and 40 Gy, respectively. There was a statistically significant difference in BM V10, V20, V30, V40, and V50 with comparable BM volumes in both study groups. BM volumes V20 (P = 0.011), V30 (P = 0.003), V40 (P = 0.009), and V50 (P = 0.015) showed positive correlation with grade ≥2 neutropenia.
Table 2: Dosimetric profile (organs-at-risk and target) of patients receiving three-dimensional conformal radiotherapy versus intensity modulated radiotherapy

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Figure 3: Colorwash for three-dimensional conformal radiotherapy (a) and IMRT (b) plans (Color represents the dose received by the particular volume). (2a) white- 50 Gy, orange- 40 Gy, red- 35 Gy, pink- 30 Gy. (2b) red- 50 Gy, yellow- 42 Gy, cyan- 32 Gy, blue- 25 Gy

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The mean volume of BB was 1948.6 cc and 1717.7 cc in IMRT and 3DCRT arm, respectively. The mean values of V45 were 187.8 cc and 251.2 cc in IMRT versus 3DCRT arm, respectively. There was a statistically significant difference in V45 and V50 in IMRT versus the 3DCRT arm. Mean BB volumes were comparable in the two groups with no significant difference.

In the IMRT arm, mean values of maximum, minimum, and mean dose to rectum were 52.1 Gy, 28.8 Gy, and 48.1 Gy, respectively, whereas, in the 3DCRT arm, these values were 50.9 Gy, 30.4 Gy, and 48.6 Gy, respectively. CTV volumes in both the arms were comparable, that is, 661.1 cc and 695.6 cc, respectively, in IMRT and 3DCRT arms.

The baseline blood counts were comparable in the two arms [Table 1]. In the IMRT arm, grade ≥2 anemia, grade ≥2 leukopenia, grade ≥2 neutropenia and grade ≥2 thrombocytopenia was seen in 45%, 17.5%, 15%, and 0%, respectively. In 3DCRT arm, grade ≥2 anemia, grade ≥2 leucopenia, grade ≥2 neutropenia and grade ≥2 thrombocytopenia was seen in 50%, 50%, 42.5%, and 0%, respectively [Table 3]. We found a statistically significant difference in the two groups of patients having diarrhea. Grade 2 diarrhea was lower in the IMRT group (35% versus 52.5%). Grade 3 diarrhea was seen in 7.5% versus 37.5% in IMRT versus 3DCRT arms, respectively. There was no grade 4 diarrhea in patients receiving either of the two treatment techniques. Statistically significant correlation was seen between BB volumes V25 (cc) and V30 (cc) and the probability of grade ≥ 2 diarrhea (P = 0.005 and 0.001, respectively). Median of the highest grade of neutropenia was statistically significantly higher in 3D CRT (1) than in IMRT (0), U = 1153, z = 3.742, P < 0.001. Similarly, the median of the highest grade of diarrhea was statistically significantly higher in 3D CRT (1) than in IMRT (2), U = 153.5, z = 4.68, P < 0.001. As per the binomial logistic regression model, the odds ratio for developing Grade 2 or more neutropenia in patients undergoing 3D CRT was 4.2 (95% confidence interval [CI]: 1.4–12.2) as compared to IMRT (P = 0.009). The odds ratio for developing Grade 2 or more diarrhea 12.2 (95% CI: 3.6–40.7) with 3D CRT as compared to IMRT (P < 0.001).
Table 3: Grades of hematological and gastrointestinal toxicities in three-dimensional conformal radiotherapy and intensity-modulated radiotherapy arms

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 > Discussion Top


Radiotherapy planning in cervical cancer must consider the potential impact on surrounding critical structures, such as the rectum, bladder, sigmoid, small bowel, and bone. Acute effects such as diarrhea, bladder irritation, fatigue occur in most of the patients undergoing radiation but are increased by combining concurrent chemotherapy.[21] Adult BM comprises hematopoietically active, red marrow, and inactive yellow marrow.[22] Magnetic resonance imaging, positron-emission tomography (PET), and single-photon emission CT have revealed that red BM is concentrated in specific sub-regions in the pelvis, like in the vertebrae and ilium.[23],[24],[25] This study was done to study the advantage of IMRT over 3DCRT in sparing pelvic BM and the bowel bag and their clinical implications on blood counts and diarrhea in patients receiving radiation for cervical cancer.

Mell et al. found hematologic tolerance was significantly improved with less grade 3–4 toxicity by reducing the dose to the BM.[26] They found statistically significant reduction in V5, V10, V20, V30, V40 in IMRT group as compared to four-field box technique (90.4% vs. 99.6%, 76.5% vs. 97.3%, 57.5% vs. 92.7%, 46.1% vs. 59.9% and 33.7% vs. 48.9%, respectively). Hui et al. studied 20 patients receiving 3DCRT or IMRT and four weekly doses of cisplatin.[20] The BM volumes V30, V40, and V50 were found to be lower in the IMRT group than in the 3DCRT group (62.93% vs. 76.91%, 31.36% vs. 39.60%, and 9.79% vs. 15.44%, respectively). There was no statistical difference for both V10 and V20. Acute hematologic toxicity was observed in both groups but was more frequent in the 3DCRT group. Grade 2 and worse leukopenia and neutropenia was seen in 90% and 80% in the 3DCRT group, whereas it was 80% and 40% in the IMRT group. In our study, V30, V40, and V50 were also found to be lower in the IMRT group (59.1% vs. 79.3, 37.1 vs. 59.3, and 3.2 vs. 26.9%, respectively). We found a statistically significant difference for all volumes of BM. The percentage of patients with grade 2 and worse leukopenia and neutropenia was 50% and 35% in the 3DCRT group, whereas it was 17.5% and 2.5% in the IMRT group. In a study done by Erpolat et al., Grade 2 or greater acute anemia, leukopenia, neutropenia, thrombocytopenia was observed in 21%, 41.5%, 12%, and 0% in the 3DCRT group and 27%, 53%, 24.5%, and 4.5% in IMRT group, respectively.[17] In our study, grade 2 or greater acute anemia, leukopenia, neutropenia was observed in 50%, 50%, and 35% in the 3DCRT group and 45%, 17.5%, and 2.5% in the IMRT group, respectively. There was no grade 2 or worse thrombocytopenia in our study. In a study by Klopp et al., the volume of BM receiving 40 Gy and the median dose to BM correlated with higher rates of grade ≥2 toxicity among cervical cancer patients who received weekly cisplatin.[27] Comparison of toxicities and dosimetry of these studies has been compared with that of our study in [Table 4] and [Table 5].
Table 4: Comparison of hematological toxicities in our study with that of previous studies

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Table 5: Comparison of bone marrow dosimetry in our study with that of previous studies

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As we found a positive correlation between BM volumes V20, V30, V40, V50, and grade ≥2 neutropenia, it is essential to achieve the target dose constraints while sparing the BM. In the recent study, INTERTECC 2 by Mell et al., PET-based BM contouring was done in 83 cervical cancer patients with Stage IB-IVA.[28] They found that, compared to patients treated with CT-based BM sparing IMRT, patients treated with PET-guided IG-IMRT had lower rates of neutropenia.

Early retrospective studies by Mundt et al. showed a significant reduction in acute Grade 2 GI toxicity from 91 to 60%, with the use of IMRT rather than a 4-field box.[29] A meta-analysis by Lin et al. included five studies and the results suggested that patients in the IMRT group had a lower incidence of grade ≥3 acute GI toxicity than did those in the 2D-RT or 3D-CRT group.[30] In our study, grade ≥2 diarrhea was seen in 42.5% in IMRT versus 90% in the 3DCRT arm. We also assessed the correlation between BB volumes and grade ≥2 diarrhea, but it did not show any significant correlation.

The American Brachytherapy Society recommends limiting the overall treatment duration below 8 weeks.[31] As per our institutional protocol, brachytherapy is started 1 week after completion of EBRT, and each session of brachytherapy is given at an interval of 1 week, which makes the treatment duration to a minimum of 56 days.[32] This practice led to slightly prolonged OTT. However, the median OTT was close to 8 weeks in both the arms. Since this study does not incorporate survival outcomes, the OTT would not have any significant impact on the primary endpoints of this study. Though all the above studies have shown a significant benefit of using IMRT over 3D CRT to reduce hematological as well as GI toxicities, yet there is a paucity of literature where BM has been delineated as an important organ at risk, and hematological toxicities have been assessed while radiating the pelvis as a part of multimodality treatment for locally advanced cervical cancer. There is still no standard protocol for BM delineation. Different studies have used various methods for delineation of BM from CT based freehand contouring to PET-based active marrow contouring. We could not incorporate PET-CT for contouring in our patients due to cost constraints, which is a limitation of our study. However, CT based approach is convenient for institutions with limited resources, and it resulted in significant improvement in both dosimetry and acute toxicities. There are data on the use of atlas-based active BM contouring for IMRT in cervical cancer and these studies provide an acceptable alternative to PET based contouring for the same.[33],[34] Furthermore, the main drawback of freehand CT based contouring is inter-observer variability in the delineation of BM. In our study, the delineation was performed by the same group of radiation oncologists from a single institute, which minimized the variation in contouring. Another limitation is the lack of quality of life data in the present study.


 > Conclusions Top


This study found a significant improvement in BM volumes irradiated with IMRT along with adequate target coverage. It also showed benefits in terms of less neutropenia and diarrhea, which is a serious problem in patients receiving concurrent chemoradiation for cervical cancer, consistent with previous findings from non-randomized studies. BM sparing IMRT is beneficial over 3D CRT in sparing of both BM and bowel bag with reduced acute toxicities. However, the clinical impact of IMRT was non-evident as the acute toxicities did not result in a significant prolongation of overall treatment time in the 3DCRT arm.

Acknowledgment

The authors would like to acknowledge the work and support of the nursing staff: Mrs. Uma Ambekar, Mrs. Sunu John and Mrs. Dayana Jain, physicist Mr. Deepak, and colleagues Dr. Amrita Srivastava, Dr. Darshana Kawale, and Dr. Rajesh Natte. We also acknowledge Dr. Akhil Kapoor for helping in the statistical analysis.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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    Figures

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

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5]



 

 
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