|Year : 2021 | Volume
| Issue : 2 | Page : 70-76
Dosimetric analysis and acute toxicity comparison of bone marrow sparing intensity-modulated radiation therapy versus three-dimensional conformal therapy with concurrent chemotherapy for the treatment of cervical carcinoma: A prospective single institutional study
Ghritashee Bora1, Apurba Kumar Kalita2, Mouchumee Bhattacharyya2, Moirangthem Nara Singh2, Partha Pratim Medhi2, Shashi Bhushan Sharma2, Shashank Bansal2, Moumita Paul2
1 Registrar, Department of Radiation Oncology, Tezpur Medical College and Hospital, Tezpur, Assam, India
2 Department of Radiation Oncology, BBCI, Guwahati, Assam, India
|Date of Submission||05-Oct-2020|
|Date of Acceptance||15-Oct-2020|
|Date of Web Publication||26-Apr-2021|
Dr. Ghritashee Bora
Registrar, Department of Radiation Oncology, Tezpur Medical College and Hospital, Tezpur, Assam
Source of Support: None, Conflict of Interest: None
Background: The aim of the study was to compare the dosimetry and acute toxicities of bone marrow sparing intensity-modulated radiation therapy (BMS-IMRT) and three-dimensional conformal radiation techniques (3DCRT) in locally advanced cervical cancer. Materials and Methods: This is a hospital-based prospective randomized study and histologically proven locally advanced cervical carcinoma patients were selected for the analysis. A total of thirty patients were equally allocated in the two treatment arms: BMS-IMRT and 3DCRT. External beam radiation therapy was delivered to a dose of 50 Gy/25# followed by high dose rate brachytherapy along with concurrent chemotherapy. The target volumes and the organs at risks were delineated. The BM comprised pelvic BM (PBM); lumbosacral BM (LSBM); ilium BM (IBM) and Ischium, Pubis and Pelvic femora together constituting lower PBM (LPBM). Results: BMS-IMRT was superior to the 3DCRT arm in reducing the dose to the PBM, small bowel, rectum, and bladder. On comparison of the BM dose volume histogram, the P value was significant (BMS IMRT vs. 3DCRT) in the higher dose range (30 and 40 Gy) for the IBM, LPBM, and whole pelvis BM. However, the difference in the low-dose irradiation (10 and 20 Gy) region was not significant. Furthermore, in the LSBM region, BMS IMRT was superior at all dose levels with no significant P value. Acute toxicities were higher in the 3DCRT arm. Conclusion: Thus, BMS-IMRT resulted in significant reduction of dose to the PBM. This can help in reducing the hematologic toxicities associated with pelvic radiation.
Keywords: Bone marrow sparing intensity-modulated radiation therapy, cervical carcinoma, pelvic bone marrow, three-dimensional conformal radiation therapy
|How to cite this article:|
Bora G, Kalita AK, Bhattacharyya M, Singh MN, Medhi PP, Sharma SB, Bansal S, Paul M. Dosimetric analysis and acute toxicity comparison of bone marrow sparing intensity-modulated radiation therapy versus three-dimensional conformal therapy with concurrent chemotherapy for the treatment of cervical carcinoma: A prospective single institutional study. J Radiat Cancer Res 2021;12:70-6
|How to cite this URL:|
Bora G, Kalita AK, Bhattacharyya M, Singh MN, Medhi PP, Sharma SB, Bansal S, Paul M. Dosimetric analysis and acute toxicity comparison of bone marrow sparing intensity-modulated radiation therapy versus three-dimensional conformal therapy with concurrent chemotherapy for the treatment of cervical carcinoma: A prospective single institutional study. J Radiat Cancer Res [serial online] 2021 [cited 2021 Jul 28];12:70-6. Available from: https://www.journalrcr.org/text.asp?2021/12/2/70/314705
| Introduction|| |
C ervical cancer is the fourth most common malignancy in women worldwide with over 500,000 women globally developing this tumor. In developing countries, cervical cancer is the leading cause of cancer-related deaths and is more common in areas where women have less access to screening., According to GLOBOCAN 2018, the number of new cases of carcinoma cervix is 96,922 constituting 8.4% of all new cancer cases in both sexes.
Radiation therapy with concurrent cisplatin-based chemotherapy is considered the standard of care for locally advanced cervical cancer. This was in accordance with the National Cancer Institute Alert in February 1999, which stated “strong consideration should be given to the incorporation of concurrent cisplatin-based chemotherapy with radiation therapy in women who require radiation for treatment of cervical cancer. The basis of this statement was the publication of five prospective randomized clinical trials comparing radiotherapy with chemoradiation.,,,,
For radiation delivery, the use of intensity-modulated radiation therapy (IMRT) and highly conformal techniques are increasing in the present era due to its better dose conformality and also increased sparing of the normal structures than the conventional techniques., Furthermore, an important issue while irradiating the pelvic region is the radiosensitivity of the bone marrow (BM). It is known that 40% of the BM reserve lies within the pelvic bones and damage to the BM stromal cells can lead to chronic injury, thus reducing their ability of self-renewal., Moreover, the radiation therapy fields in the conventional techniques encompass a large volume of the hematopoietically active BM located in the pelvic and lower lumbar region, which might lead to increased rates of hematologic toxicity. IMRT though reduces the dose to normal tissues for whole pelvic radiation therapy; however, its ability to reduce the pelvic BM (PBM) dose has not been fully investigated.
Thus, this study is an attempt to ascertain the dosimetric benefits of BMS-IMRT keeping BM as a constraint compared with 3DCRT in the treatment of patients with cervical cancer.
| Materials and Methods|| |
Plan of study and accrual
This is a two-arm randomized prospective study which was carried out in the Department of Radiation Oncology, Dr. B. Borooah Cancer Institute – a tertiary cancer center in North East India. Histologically proven cervical carcinoma patients of Stage IIA to IVA, aged 18–65 years with Karnosffsky's Performance Scale >70 and with adequate BM, renal and hepatic function (Hb >10 g/dl, white blood cell 4000/mm3, absolute neutrophil count 1500 cells/mm3, platelets 100,000 cells/mm3, creatinine clearance 50 ml/min) considered eligible for concurrent chemoradiation were included in the study. Whereas patients who received prior pelvic radiation therapy, patients with serious comorbidities and who had bladder control problems (making it difficult for bladder filling protocols) were considered as exclusion criteria. Prior approval for conducting this study was obtained from the institutional ethics committee, and it was registered with the Clinical Trial Registry of India vide registration no. CTRI/2018/05/014118.
A total of thirty patients were enrolled during the study period of 1 year. Patients were randomized on 1:1 basis into the two study arms: 15 patients in each arm. Informed consent was obtained from each of the study participants. Data on patient demographics, tumor, treatment, and toxicity-related parameters were collected for each of them. Patient characteristics are shown in [Table 1], and consort diagram is depicted in [Figure 1].
Treatment procedure and evaluation
Radiotherapy was delivered to the patients as per the allocated treatment arms; Arm A – BM sparing-IMRT (BMS-IMRT); Arm B – three-dimensional conformal radiation technique (3DCRT).
Patients were placed supine with hands over chest using 4-clamp thermoplastic mold to immobilize the lower half of the body. After evacuation of bladder, patients were asked to drink half liter water, 1 h after which computed tomography (CT) simulation was done in PHILIPS Brilliance big bore CT Simulator. Intravenous ionic contrast injection was used for optimum differential tissue enhancement and proper delineation of vessels to assist contouring. For both the techniques, gross tumor volume, clinical target volume, planning target volume (PTV), and organs at risk (OAR) (urinary bladder, bowel, and rectum) were contoured on axial slices according to EMBRACE II protocol guidelines. For BM delineation, the external contour of all bones within the pelvis was contoured according to the method described by Mell et al. and Albuquerque et al. which comprised lumbosacral spine, ilium, ischium, pubis, and proximal femora. The axial images of the CT scan with contours have been depicted in [Figure 2].
|Figure 2: Axial computed tomography scan images showing bone marrow contours|
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External beam radiotherapy planning for both the techniques was done using CMS-XIO (Version 4.08) Version 4.08, Manufacturer is Elekta Company treatment planning system. The prescribed dose was 50 Gy in 25 fractions. For 3DCRT planning, four fields were used, and IMRT planning was done using seven fields. A plan approval criterion was: 95% of the PTV must be covered by 95% of the prescribed dose. Treatment was delivered using 6 Mv pPhotons in a Elekta Synergy Linear Accelerator with 40 pairs of Multi-Leaf Collimators (i2 leaves, width of 1 cm at isocentre). Treatment setup and daily verification were done using cone-beam CT. Concurrent weekly Inj. Cispaltin at 40 mg/m2 was given along with external beam radiation therapy (EBRT).
Following EBRT, high dose rate brachytherapy was given at a dose of 7 Gy per week for three fractions with iridium 192 stepping source. CT simulation was done for image guidance, and the dose was prescribed to point A. The dose received by 2 cc of the OARs (D2cc) for bladder, rectum, and sigmoid were recorded.
During the course of treatment, all patients were examined weekly to monitor treatment-related toxicities and general condition. After completion of treatment, follow-up was done 2 monthly for the next 6 months in the outpatient department. Follow-up included history and clinical examination. MRI pelvis was performed during the first follow-up. Acute toxicity was assessed as per CTCAE criteria (v4.03) and treatment response was evaluated according to response evaluation criteria in solid tumors (RECIST; version 1.1).
Student's t-test and Fisher's exact test or Chi-square test were performed to test the significance of this study at 5% level using GraphPad Prism and SPSS V19 software IBM Corp.in Armonk,NY. Pearson Chi-square test was performed for categorical values. A P < 0.05 was considered statistically significant at 95% confidence interval.
| Results|| |
Dose volume parameters of the different subvolumes of BM for each of the two techniques are represented in tabular and graphical form [Table 2] and [Figure 3].
|Table 2: Dose volume parameters for various locations of bone marrow with respect to treatment technique with statistical analysis for significance (significant P value shown in bold italics)|
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|Figure 3: Dose volume Histogram parameters comparing bone marrow subsites for Bone Marrow Sparing Intensity Modulated Radiotherapy (BMS IMRT) versus Three Dimensional Conformal Radiation Technique (3DCRT) a) Lumbo-Sacrum; b) Ilium ; c) Lower Pelvis; d) Whole Pelvis|
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On comparison of the BM dose volume histogram (DVH) in the various subsites, it was seen that the P value is significant (BMS-IMRT vs. 3DCRT) in the higher dose range (30 and 40 Gy) for the ilium BM (IBM), lower PBM (LPBM), and whole PBM. However, the low dose irradiation (10 and 20 Gy) although reduced, the difference was not statistically significant. Furthermore, it was found that, in the LSBM region, BMS IMRT was superior at all dose levels, but the P value was not significant (P > 0.05).
On evaluation of the DVH of the other OARs, it was seen that BMS-IMRT provided modest but nonsignificant reductions in the bladder, rectum, and bowel doses [Table 3].
|Table 3: Dose volume parameters for various organs at risk with respect to treatment technique with statistical analysis for significance (significant P values shown in bold italics)|
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Grade 2 hematologic toxicity was lower in the BMS IMRT arm compared to the other. Grade 2 diarrhea was found to be higher in the 3DCRT arm. Radiation-induced skin reaction was seen in all the patients of the two arms [Table 4].
| Discussion|| |
Radiotherapy treatment techniques in gynecologic malignancies have evolved from the era of conventional 2 field and 4 field box techniques to the present era of highly conformal therapy. There are limited data on the use of IMRT for the treatment of intact cervical carcinoma patients, but its role in the postoperative setting has been described in a prospective study by Portelance et al. Various retrospective studies have been conducted to show the dosimetric advantages of IMRT over conventional techniques. Lower rates of acute Grade 2 gastrointestinal (GI) toxicity were noted in studies conducted by Mundt et al., also another study by Brixey et al. found significantly lower rates of acute Grade 2 or more hematologic toxicity in patients treated with IMRT compared to 4 field box techniques., Kidd et al. in his retrospective study comparing IMRT to conventional techniques also reported lower rates of Grade 2 or more GI toxicity as well as lower rate of acute Grade 3 or more GU toxicity.
Radiation and chemotherapy both can cause myelosuppression, but the extent to which radiation contributes to hematologic toxicity in patients undergoing chemoradiation therapy is not well known. It is generally assumed that radiation causes apoptosis of BM stem cells and stromal damage, which can lead to characteristic pathologic and radiographic BM changes as well as result in myelosuppression. Furthermore, concomitant chemotherapy can lead to higher rates of hematologic toxicity compared to radiation alone. Various clinical studies have proved that BM injury induced by radiation depends on both dose and volume of BM irradiated. As the RT fields in the conventional techniques encompass, a large volume of the hematopoietically active BM located in the pelvic and lower lumbar region, this might lead to increased rates of hematologic toxicity. Thus, BMS-IMRT might prove to be beneficial in this area.
This study was conducted to know about the dosimetric advantages of BMS IMRT over 3DCRTand whether it results in reduction of the toxicities during treatment.
In our study, the BM was delineated by drawing the external contours of the bones; lumbosacral BM (LSBM), IBM, and ischium, pubis, and proximal femora LPBM., The whole pelvis was the combined structure of all these contours. The BM dosimetric constraint for BMS IMRT was the PBM V10Gy (%) and V20Gy (%) <90% and < 75%, respectively, according to validated normal tissue complication probability models.,
The BMS-IMRT plans reduced the V10Gy, V20Gy, V30Gy, V40Gy (Volumes in percentage receiving 10 Gy, 20 Gy, 30 Gy, and 40 Gy, respectively) of the whole PBM and lower pelvis BM to statistically significant level (P < 0.05) compared to the 3DCRT plans. The Iliac BM dose was also reduced, but it was significant only for the higher dose range (30 and 40 Gy). Lumbosacral BM volume irradiated was although reduced at all dose levels, but it was not found to be statistically significant. Mell et al. in their study found that BMS-IMRT and AP–PA plans reduced irradiation of the PBM compared with the four-field box techniques, in addition to reducing the high dose area in the lumbosacral region. They also demonstrated that, although BMS-IMRT reduced the PBM volume irradiated to high doses compared with the AP–PA plans, low-dose radiation was increased. In another study by Lujan et al., it was seen that IMRT without BMS also results in reduced irradiation of the BM, particularly within the Iliac crests.
Here, it was seen that the PTV V95% (PTV receiving 95% of the prescribed dose) was less with BMS IMRT compared to the four-field conformal technique, which serves as an indication that though the dosimetric benefits of BMS can be achieved this was at the cost of decreased coverage of the PTV. Thus, in this regard, functional BMS can be a valuable option, which might result in more accurate delineation of the active “red marrow.”
The INTERTECC-2 trial is the first prospective controlled study to test the hypothesis that reducing the radiation dose to functional BM can reduce hematologic toxicity. This study compared patients who underwent CT-based BMS-IMRT with those who underwent PET IG-IMRT and found that the later had lower rates of neutropenia, which was as per the previous studies.
In the IMRT arm of our study, the doses to the bladder (P < 0.05); rectum (P value not significant) and bowel (P value not significant) were reduced and the rate of Grade 2 GI toxicity was 0% compared to 27% in the 4-field arm which is as per other studies.
Another important aspect in this study was to demonstrate whether the dosimetric benefits of BMS translated into reduced rates of hematologic toxicity in the BMS-IMRT arm. In previous studies of cervical carcinoma patients treated with whole pelvic radiotherapy, the rates of acute Grade 3 hematologic toxicity were around 35%, while with IMRT Grade 3 toxicities were low.,, In this study, it was found that the rates of Grade 2 anemia were higher in the 4-field arm (40% vs 20%) than in the BMS IMRT arm (P value: not significant); similarly, the rates of Grade 2 neutropenia were 20% and 14% in the two arms, respectively, with no significant P value.
A study conducted by Albuquerque et al. using 3DCRT showed that when the V20Gy (%) of the whole pelvis exceeds 80%, the risk of Grade 2 hematologic toxicity increases by a factor of 4.5 (P < 0.05), but the other values did not show any correlation with the development of hematologic toxicity, which may be because the areas of low-dose regions are less with 3DCRT compared to IMRT. It was also demonstrated in a study by Mell et al., that the V10Gy and V20Gy of the pelvic BM and LSBM correlated well in the development of hematologic toxicities in cervical cancer and anal cancer patients who were treated with concurrent pelvic IMRT and weekly cisplatin. However, in our study, it was seen that, although the doses to the LSBM were reduced, the data were not found to be statistically significant.
Furthermore, BM is extremely radiosensitive, and its progressive damage can lead to a sequence of events such as chronic hematologic toxicities. Thus, with the help of newer imaging modalities, appropriate delineation can be done for accurate sparing of the active BM. However, there is a lack of definitive prospective data to emphasize on the beneficial effects of BMS IMRT and its outcomes, though studies are still ongoing to further answer this issue.
| Conclusion|| |
The main aim of this study was to assess the dosimetric benefits of BMS IMRT over 3DCRT. After evaluating the V10, V20, V30, and V40 of the Pelvic BM, Iliac BM, lower pelvis BM, and lumbosacral BM, it was found that these values are lower in the BMS IMT arm compared to the four field arm, with P value being statistically significant except for LSBM doses. Furthermore, the hematologic toxicities were lower in the BMS-IMRT arm. This study is thus an attempt to provide an insight into this emerging topic and its potential implications. The main limitation is less patient data and need of clinical follow-up. More prospective data to further validate the subject are essential.
Special thanks to Dr. Vikas Jagtap, Associate Professor and Head of Department of Radiation Oncology, NEIGRIHMS, Shillong for his constant guidance throughout our work and also to Mr. Manoj Kalita for helping us with the statistical analysis.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2], [Table 3], [Table 4]