|Year : 2015 | Volume
| Issue : 4 | Page : 670-674
Dosimetric evaluation and clinical outcome in post-operative patients of carcinoma vulva treated with intensity-modulated radiotherapy
D Khosla, FD Patel, AK Shukla, B Rai, AS Oinam, SC Sharma
Department of Radiotherapy and Oncology, Regional Cancer Centre, Postgraduate Institute of Medical Education and Research, Chandigarh, India
|Date of Web Publication||10-Mar-2016|
Department of Radiotherapy and Oncology, Regional Cancer Centre, Postgraduate Institute of Medical Education and Research, Chandigarh
Source of Support: None, Conflict of Interest: None
BACKGROUND: To compare dosimetric parameters of intensity-modulated radiation therapy (IMRT) with 3D conformal radiotherapy (3DCRT) in post-operative patients of vulvar cancer and to assess clinical outcome and toxicity with IMRT. MATERIALS AND METHODS: A total of 8 post-operative patients of vulvar cancer were treated with IMRT. All patients were also planned by 3DCRT for comparison with IMRT. The two plans were compared in terms of conformity index, homogeneity index, tumor control probability (TCP) and normal tissue complication probability (NTCP) for the planning target volume and organs at risk (OAR). RESULTS: IMRT resulted in significantly lesser doses to rectum, bladder, bowel and femoral head as compared with 3DCRT plans. Mean conformity and homogeneity indices were better and within range with IMRT. The TCP was comparable between the two treatment plans and NTCP for rectum, bladder, bowel and femoral head was significantly less with IMRT as compared with 3DCRT. Treatment was well-tolerated and none of the patients developed Grade 3 or higher toxicity. CONCLUSION: IMRT yielded superior plans with respect to target coverage, homogeneity and conformality while lowering dose to adjacent OAR as compared with 3DCRT. Thus, IMRT offers a reduction in NTCP while maintaining TCP.
Keywords: Intensity modulated radiation therapy, normal tissue complication probability, tumor control probability, vulvar cancer, 3D conformal radiotherapy
|How to cite this article:|
Khosla D, Patel F D, Shukla A K, Rai B, Oinam A S, Sharma S C. Dosimetric evaluation and clinical outcome in post-operative patients of carcinoma vulva treated with intensity-modulated radiotherapy. Indian J Cancer 2015;52:670-4
|How to cite this URL:|
Khosla D, Patel F D, Shukla A K, Rai B, Oinam A S, Sharma S C. Dosimetric evaluation and clinical outcome in post-operative patients of carcinoma vulva treated with intensity-modulated radiotherapy. Indian J Cancer [serial online] 2015 [cited 2020 Aug 13];52:670-4. Available from: http://www.indianjcancer.com/text.asp?2015/52/4/670/178448
| » Introduction|| |
Vulvar cancer is a rare malignancy that represents only about 1-2% of all the cancers diagnosed in women and about 3-4% of all gynecologic neoplasms. Patients with moderately advanced disease, close or positive margins, deep invasion and/or lymphatic-vascular invasion or with inguinal lymph node metastasis should be considered for adjuvant radiation in order to reduce locoregional recurrence and improve survival., The treatment of carcinoma of the vulva is challenging for multiple reasons. In general, patients with this disease are older and have comorbidities. The tumor, by virtue of its location, can easily involve adjacent organs such as the bladder and the rectum and the frequency of nodal involvement is high. Because of its relatively low incidence, most published reports include rather small and heterogeneous groups of patients.
Most commonly used technique of radiation therapy consists of wide anterior photon field to encompass the entire target volume (pelvis, area of the primary tumor and inguinal nodes), a narrower posterior photon field covering only the pelvis and supplemental anterior electron fields to bring up the dose to inguinofemoral node areas that overlie femoral head and neck. This technique results in dose inhomogeneity with hot spots at the region of abutment of volumes encompassing primary tumor and nodes. Treatment with this technique further entails irradiation of considerable volumes of normal tissues with risk of increased skin toxicity and exposes patients to many treatment related toxicities. This toxicity can cause gaps or delay in treatment completion, further compromising therapeutic ratio and treatment response and can result in acute and long-term impairments in quality-of-life.
Recent reports described favorable preliminary results using intensity-modulated radiation therapy (IMRT) in the treatment of vulvar cancer. It has the potential of improved conformality with reduced doses to normal tissues and also eliminates dose inhomogeneity across the abutting regions.
The present article details a single institution's experience of eight post-operative patients with squamous cell cancer of the vulva who required adjuvant radiation and were treated with IMRT. This study was carried out to evaluate clinical outcome and toxicity and also to perform dosimetric comparison between IMRT and 3Dconformal radiotherapy (3DCRT). To analyze these two different techniques of radiotherapy, in this study, the target coverage and normal-tissue sparing for both IMRT and 3DCRT plans were compared in terms of dose-volume histograms (DVHs) using dose statistics for the planning target volume (PTV) and normal tissues. The two plans were also compared in terms of conformity index and homogeneity index. Simultaneously, the radiobiological effect of the two strategies on the tumor and normal tissues was also analyzed by comparing tumor control probability (TCP) and normal tissue complication probability (NTCP).
| » Materials and Methods|| |
Computed tomography (CT) simulation and target and organs at risk (OAR) delineation
This is a study of eight post-operative patients of carcinoma vulva treated at our institute from 2008 to 2011. To minimize set-up variability, patients were immobilized with vacuum-evacuated Vac-Lok bag (MEDTEC, OrangeCity, IA) fabricated in the supine position. All patients underwent a planning CT scan with triple contrast in the treatment position on the Light Speed VFX-16 CT simulator (GE Medical Systems, Waukesha, WI, USA). The clinical target volume (CTV) and critical organs were contoured on individual axial CT slices in all patients. CTV included bilateral external iliac, internal iliac and inguinofemoral nodal areas with 1 cm margin around the entire vulvar region. For the nodal groups, a margin of 1 cm around the blood vessel with editing was used for iliac nodes and about 2 cm with editing was used for inguinofemoral nodes. For the vulvar region, the entire vulva with a 1 cm margin was used for the CTV. The CTV was expanded by 1 cm for PTV to account for organ motion and set-up uncertainty. The superior border of the pelvic CTV was generally kept 1-2 cm below L5-S1, which resulted in the PTV being approximately around L5-S1. OAR was also contoured on the planning CT scan, which included small bowel, bladder, rectum and femoral heads. A bolus of 1 cm thickness was created for the vulvar region at the time of treatment planning and was also used for daily treatments. For in vivo dosimetry, thermoluminescent dosimetry chips were placed at vulvar tumor region.
Treatment planning was performed using Eclipse Planning System version 8.6 (Varian Medical Systems, Palo Alto, CA) and treatment was delivered with a Varian 2300 CD dual energy linear accelerator using the sliding window technique and patient specific IMRT quality assurance was performed using I'mRT MatriXX from Scanditronic Wellhover, Freiburg, Germany with the help of Omni Pro IMRT ® software, version 1.5 (Scandetronix Wellhofer, Germany) and found within 2%.
Dose constraints for IMRT planning were as follows: ≤35% of small bowel to receive ≤35 Gy, with a dose maximum of 50 Gy; ≤40% of the bladder to receive ≤40 Gy, with a dose maximum of 50 Gy; and ≤40% of the rectum to receive ≤40 Gy with a dose maximum of 50 Gy. The IMRT plans were optimized in order to minimize the volume of PTV receiving less than 95% of the prescribed dose and the volume receiving more than 110% of the prescribed dose. The prescription dose was normalized to the 95% isodose line.
All patients were also planned by 3DCRT for comparison with IMRT. 3DCRT planning was performed by use of the same planning system and the field arrangement was anteroposterior/posteroanterior (AP/PA), with 6-MV and 15-MV photons with matching electron fields (range, 9-20 MeV). Multileaf collimators were used to shape the fields. The anterior electron field was matched with the divergence of posterior pelvic field. The IMRT and 3DCRT plans are shown in [Figure 1] and [Figure 2].
|Figure 1: Field arrangement for intensity-modulated radiation therapy plan|
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Patient position verification
Electronic portal imaging of the patients were performed with Portal Vision LC 250 (Varian Medical System Palo Alto, CA). AP and left-right/right-left lateral double-exposed electronic portal images (EPIs) during the first three fractions of treatment course (day1-3) and then AP and lateral EPIs were acquired on a weekly basis. Each EPI was compared with the digitally reconstructed radiograph generated from the therapy CT scans, using ARIA 8.6 (Varian Medical Systems USA) and the action level was defined as 3 mm for the process.
Clinical and dosimetric analysis
Patients were analyzed for local control, toxicity and survival outcome. Toxicity was graded by use of radiation therapy oncology group (RTOG) morbidity-scoring criteria. Plans were compared according to DVH analysis in terms of PTV conformity index and homogeneity index as well as OAR dose and volume parameters.
Several definitions of conformity index are available, but the one used in our study was RTOG conformity index  (Eq. 1) as it is easy to interpret.
Conformity indexRTOG = VRI/TV (1)
Where VRI = Reference isodose volume and TV = Target volume.
A conformity index equal to 1 corresponds to ideal conformation. A conformity index greater than 1 indicates that the irradiated volume is greater than the target volume and conformity index less than 1 indicates that target volume is only partially irradiated. According to RTOG guidelines, ranges of conformity index values have been defined to determine the quality of conformation because a value of 1 is rarely obtained. If the conformity index is situated between 1 and 2, treatment is considered to comply with the treatment plan; an index between 2 and 2.5, or 0.9 and 1, is considered to be a minor violation and an index less than 0.9 or more than 2.5 is considered to be a major violation.
Similarly homogeneity index used was the one defined by RTOG  (Eq. 2).
Homogeneity indexRTOG = Imax/RI(2)
Where Imax = maximum isodose in the target, and RI = reference isodose.
If the “homogeneity index” (Eq. 2) is ≤2, treatment is in accordance with the protocol with the protocol. If this index is between 2 and 2.5, the protocol violation is considered to be minor, but when the index exceeds 2.5, the protocol violation is considered to be major, but may nevertheless be considered to be acceptable.
For radiobiological comparison
To predict the biological impact of the two treatment techniques (IMRT and 3DCRT) on the tumor and normal organs, the radiobiological models were used, which depend on an implicit estimation of TCP and NTCP arising from a given dose distribution using equivalent uniform dose (EUD). EUDs were calculated from differential DVHs with α = 8.33for the rectum and α=2 for bladder.
The TCP was calculated using the Poisson statistics given below (Eq. 3) with D50 and γ50 representing the two parameters describing the dose and normalized slope at the point of 50% probability of control.
The NTCP i.e., probability of complications in normal tissue was calculated for IMRT and 3DCRT plans using the phenomenologic Lyman-Kutcher-Burman (Eq. 4) model summarized below. Lyman's formula models the sigmoid-shaped dose response curve of NTCP as a function of dose (D) to a uniformly irradiated fractional reference volume (vref). The parameters used in this model are TD50/5 (dose at which probability of complication becomes 50% in 5 years), m (tissue-specific parameter inversely proportional to the slope of the response curve) and n parameter to find the EUD of inhomogeneous irradiation using DVH reduction method proposed by Kutcher-Burman model. NTCP was calculated for bladder, rectum, bowel and femoral heads for all patient treatment plans.
Where t is defined as
TD50 (v) = TD50 (1)·v–n(6)
As known, the parameters n, m and TD50/5 determine the volume dependence of NTCP, the slope of NTCP versus dose and the tolerance dose to the whole organ leading to a 50% complication probability, respectively. The TD50/5, n and m for rectum were 80 Gy, 0.12 and 0.15; for bladder were 80 Gy, 0.50 and 0.11; for bowel were 55 Gy, 0.15 and 0.16 and for femoral head were 65 Gy, 0.25 and 0.12, respectively.
Statistical analysis was performed using the statistical package for social sciences (SPSS) software v 15.0. Pairwise comparisons were performed using the Wilcoxon matched-pairs signed-rank test. All tests were two-tailed and P < 0.05 was considered to be significant.
| » Results|| |
Since 2008, eight post-operative patients of carcinoma vulva were treated with IMRT. The patients' ages ranged from 45 to 71 years, with a median of 65 years. The patient profile, surgery, stage and status are enumerated in [Table 1]. The treatment volume included both vulva and nodes in all patients. The mean PTV volume was 2327 cm 3. Dose ranged from 50 Gy to 54 Gy in 25-30 fractions.
PTV coverage was consistently superior with the IMRT plans as compared with the corresponding 3DCRT plans. Volume receiving 95% of the prescribed dose (V95) was 99.8% ± 0.11% with IMRT as compared with 97.6% ± 1.28% with 3DCRT which was statistically significant (P = 0.012). Mean conformity index was 1.4 ± 0.19 with IMRT and 2.7 ± 0.35 with 3DCRT, which means that IMRT plans were well within range and 3DCRT plans showed major violation. The mean homogeneity index was 1.1 ± 0.05 with IMRT and 1.6 ± 0.21 with 3DCRT.
The volume of each organ of interest (small bowel, bladder and rectum) receiving different doses was compared between IMRT and 3DCRT treatment plans. This is quantified at various dose levels in [Table 2]. Mean volume of the rectum that received doses in excess of 20 Gy and bladder in excess of 30 Gy was significantly reduced by IMRT as compared with 3DCRT plans. Similarly, mean volume of bowel that received doses in excess of 10 Gy was significantly reduced with IMRT as compared with 3DCRT plans. The mean dose to the femoral head was significantly less with IMRT plans in comparison with 3DCRT plans (43.99 ± 2.54 Gy vs. 47.18 ± 1.41 Gy, P = 0.01 respectively). The mean of maximum dose to the femoral head was 52.4 ± 1.46 Gy with IMRT and 57.71 ± 1.23 Gy with 3DCRT, which was statistically significant (P = 0.01). The comparative DVHs for rectum, bladder, bowel, femoral heads and PTV are shown in [Figure 3]. The results for TCP for PTV and NTCP for bladder, rectum, bowel and femoral head are summarized in [Table 3]. As calculated by Poisson statistics, TCP was comparable between the two treatment plans (91.57% with IMRT vs. 91.41% with 3DCRT, P = 0.67 respectively). As calculated by LKB models, NTCP for rectum, bladder, bowel and femoral head was significantly less with IMRT as compared with 3DCRT.
|Table 2: DVH differences between IMRT and 3DCRT for all critical structures evaluated, averaged over the eight patient cases (Average±Standard deviation). Statistical P values are listed for each corresponding DVH parameters|
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|Figure 3: Dose-volume histogram comparison of 3D conformal radiotherapy with intensity-modulated radiation therapy for organs at risk and planning target volume|
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Clinical outcome and toxicity
Patients were analyzed for local control and survival outcome. Follow-up from completion of radiation treatment ranged from 7 to 53 months, with a median of 27 months and no patient was lost to follow-up. Seven out of eight patients were disease free at last follow-up. Only one patient developed recurrence in the treatment field at a median time of 4.5 months, which was not salvageable and patient died of disease. The remaining seven patients were disease free and alive at last follow-up.
Toxicity was graded by use of RTOG morbidity-scoring criteria. Acute toxicity graded as per RTOG is summarized in [Table 4]. All patients experienced acute Grade 2 dermatitis, namely moist desquamation in the vulva. Three patients had treatment interruption (range 3-7 days). Two patients had late Grade 1 skin toxicity. No other late toxicity was seen. No patient has developed Grade 3 or higher acute or late toxicity in our study.
| » Discussion|| |
The management of vulvar carcinoma has undergone very significant change in the last few decades. The technical resources at our disposal allow us to treat the vulvar and inguinal regions more effectively and at the same time with less morbidity and sequelae.
The commonly used technique of radiation therapy consists of delivering the treatment with wide anterior and narrower posterior field. The difference in the dose to the inguinal field because the posterior field does not cover this area is made up with a direct anterior electron field to each of the inguinal areas. This approach not only presents a dosimetric challenge secondary to its abutting photon-electron field, but also poses the risk of increased skin toxicity as well as toxicity of small bowel, bladder, rectum and femoral heads thus contributing to patient morbidity and long-term complications. The daily set-up variation also contributes significantly to the inhomogeneity across the match line. IMRT has the advantage of eliminating dose inhomogeneity, thus producing a relatively homogenous dose distribution with sparing of vulnerable normal tissues. The depth of inguinal nodes is highly variable, ranging from 4 cm to 9 cm in our study. Moreover, with conventional techniques, the higher energy electrons required to reach inguinal nodal depths can result in severe skin reactions and lead to treatment breaks and extended treatment duration. Contrary to this, use of photons in IMRT decreases the dose to the groin skin, thus, reducing the risk of skin reaction. None of the patients in our study developed acute Grade 3 or above dermatitis. Similarly, in other studies using IMRT for treatment of vulvar cancer, none of the patients developed acute Grade 3 or higher skin toxicity.,,
There are few dosimetry studies, which have evaluated IMRT planning in patients with vulvar cancer undergoing pelvic-inguinal radiotherapy. In our study, IMRT technique significantly reduced treatment volumes for bladder, rectum, small bowel and femoral head as compared with 3DCRT. PTV coverage was comparable between two plans. Garofalo et al. evaluated IMRT planning in patients with vulvar cancer undergoing pelvic inguinal radiotherapy. In comparison with conventional treatment planning, IMRT reduced the volume of small bowel, bladder and rectum that received the prescription dose by 47%, 78% and35%, respectively. Significant sparing of the femoral heads was also achieved by use of IMRT. While on the contrary, Gilroy et al. found significantly excessive dose to portions of the central pelvic with IMRT planning. Ahmad et al. demonstrated the feasibility of inversely optimized IMRT of whole pelvis including inguinal-femoral nodes. Compared with modified segmental-boost technique, it produced a more uniform and conformal dose distribution in the entire target volume, while protecting the femurs from the risk of radiation-induced fracture. Beriwal et al. reported 15 patients treated with IMRT using a median of seven fields. This early experience yielded reasonable clinical response with 13 of 15 patients having no evidence of disease at last follow-up, improved dose conformality and resulted in lower doses to normal structures including rectum, bladder and small bowel. Only one patient had acute Grade 3 small-bowel toxicity. In the adjuvant group, two patients had recurrences in the treatment field. In our study, only one patient had recurrence in the treatment field and none of the patients developed Grade 3 or higher toxicity. Thus, the outcomes presented in our study are comparable with the outcomes reported in the literature.
Although the conformity index was first proposed in 1993 by the RTOG  and described in report 62 of the International Commission on Radiation Units and Measurements, it has not become part of routine practice. With the growth of conformal radiotherapy, the conformity index could logically be supposed to play an important role in the future. The conformity index constitutes an attractive tool, because it could facilitate decisions during analysis of various treatment plans proposed for conformal radiotherapy. Its advantages are its simplicity and the integration of multiple parameters. An ideal tool does not exist at the present time. Therefore, we have used the standard RTOG tool to compare the two treatment modalities. In our study, both conformity and homogeneity indices were better and within range with IMRT. The dosimetric data suggest improved dose conformity and homogeneity with IMRT. However, these indices should not be used as tools which can replace the utility of analysis of DVHs and checking the plan slice by the slice for detecting high or low dose points. It should only be used once a satisfactory plan has been achieved on the basis of dose gradients and dose distribution along the treatment volumes and normal structures. Prospective studies with a long follow-up may establish the relationship between these parameters and clinical outcomes.
In this article, we have addressed IMRT treatment planning issues by comparing physical dosimetry and radiobiological modeling of IMRT compared to conformal 3D planning for vulvar cancer. These plans were evaluated by calculating the TCP and NTCP of the treatment plans to determine the radiobiological ranking of different plans amongst them. However, the TCP was comparable between two treatment plans, but NTCP was significantly lower with IMRT as compared to 3DCRT.
To the best of our knowledge, this is the first study in post-operative patients of vulvar cancer that reports clinical outcome, physical dosimetric and radiobiological results with the use of IMRT. The treatment was well-tolerated, with acceptable toxicities. In our study, no patient had Grade 3 or higher acute and late toxicity. Our single-institution experience with a small number of patients shows promising results, with acceptable toxicity and dosimetric advantages of IMRT over 3DCRT.
The limitations of our study are its retrospective nature, short follow-up and a small number of patients. The incidence of vulvar carcinoma is low and it is difficult to do a meaningful prospective trial for any single institution. The strengths of our study is that it contains a homogenous group of post-operative patients of carcinoma vulva and detailed dosimetric comparison in terms of physical doses, conformity index, homogeneity index, TCP and NTCP. Based on the results of our study, we could conclude that IMRT compared with 3DCRT offers the best possibility to spare the critical surrounding organs in case of radiation treatment of patients with vulvar cancer. This study demonstrates that IMRT achieves superior normal tissue avoidance, especially for rectum, bladder, bowel and femoralheadscomparedwith 3DCRT, with comparable target dose. It is anticipated that this reduction in normal tissue irradiated volume and acute toxicity would translate into overall reduction in potentially late treatment-related toxicity.
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[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2], [Table 3], [Table 4]
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