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 Table of Contents  
ORIGINAL ARTICLE
Year : 2022  |  Volume : 13  |  Issue : 2  |  Page : 41-47

A comparative study of planning and dosimetry in locally advanced head-and-neck cancer: sequential versus simultaneous integrated boost methods in intensity-modulated radiotherapy


1 Department of Radiotherapy, All India Institute of Medical Sciences, Patna, Bihar, India
2 Department of Radiotherapy, Bhagwan Mahavir Cancer Hospital and Research Centre, Jaipur, Rajasthan, India
3 Department of Radiotherapy, All India Institute of Medical Sciences, Jodhpur, Rajasthan, India
4 Department of Radiotherapy, SMS Medical College, Jaipur, Rajasthan, India
5 Department of Radiotherapy, Shalby Hospital, Jaipur, Rajasthan, India

Date of Submission12-Oct-2021
Date of Acceptance17-Dec-2021
Date of Web Publication20-Apr-2022

Correspondence Address:
Dr. Amrita Rakesh
Department of Radiotherapy, All India Institute of Medical Sciences, Patna, Bihar
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jrcr.jrcr_46_21

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  Abstract 

Objective: A head-and-neck cancer (HNC) comprises one-third load of India’s cancer burden. We aim to compare the target coverage and the normal tissue sparing between sequential intensity-modulated radiotherapy (IMRT) and simultaneously integrated boost (SIB)-IMRT plan for patients of locally advanced HNCs. We evaluate dosimetric parameters of two plans for a single patient and compare target coverage and conformity index (C. I.) and also assess the differences in dose received by organs at risk (OAR) by two plans. Materials and Methods: After recording the detailed history, performing a thorough clinical examination and the relevant investigations, the patients who were staged as locally advanced squamous cell carcinoma of oropharynx, hypopharynx, and supraglottic regions were chosen for the study. An informed consent was taken before enrolling them in study. Results: A total of 30 patients were enrolled in the study. Three patients were female, whereas the remaining 27 were male. Of the 30 patients 19 patients (63.34%) had oropharyngeal disease and 11 had hypopharyngeal disease (36.66%). The present study reported that 24 patients had moderately differentiated squamous cell carcinoma, two patients had well differentiated tumor, and in four patients, it was poorly differentiated carcinoma. The minimum dose, maximum dose, and the mean dose volumes of planning target volume (PTV) 1 and PTV2 which were designated as D100, Dmax and Dmean, respectively, were analyzed by both SIB and SEQ-B IMRT plans. The C. I. was derived by Radiation Therapy Oncology Group (RTOG) 90-05 (34). The C. I. for PTV1 and PTV2 by SEQ-B and SIB IMRT plans was 0.96 versus 0.95 and 0.97 versus 0.95, respectively. The mean maximum dose to brain stem was 4230.02 cGy with SEQ-B and 4305.52 cGy with SIB plan. On analyzing the mean maximum dose received by mandible, a statistically significant sparing was seen with SIB technique. Conclusion: In the present study, as no significant difference was observed in OAR sparing except mandible in both the plans. Hence, in view of the results and comparative studies, both the plans are clinically acceptable, although taking into account the tumor coverage, the sequential boost IMRT plan arm gave better results.

Keywords: Head-and-neck cancer, intensity-modulated radiotherapy, planning target volume 1, planning target volume 2, simultaneously integrated boost, squamous cell carcinoma


How to cite this article:
Rakesh A, Goyal J, Soni S, Abhilasha, Rastogi K. A comparative study of planning and dosimetry in locally advanced head-and-neck cancer: sequential versus simultaneous integrated boost methods in intensity-modulated radiotherapy. J Radiat Cancer Res 2022;13:41-7

How to cite this URL:
Rakesh A, Goyal J, Soni S, Abhilasha, Rastogi K. A comparative study of planning and dosimetry in locally advanced head-and-neck cancer: sequential versus simultaneous integrated boost methods in intensity-modulated radiotherapy. J Radiat Cancer Res [serial online] 2022 [cited 2022 Oct 1];13:41-7. Available from: https://www.journalrcr.org/text.asp?2022/13/2/41/343546


  Introduction Top


Head-and-neck cancers (HNCs) comprise one-third load of India's cancer burden. They account for 30% of cancers in males and about 13% in females. In males, the oral cavity and pharynx are the commonly affected site, followed by the larynx. In females, oral cavity is the predominant site.[1],[2],[3]

The Indian Council of Medical Research started a National Cancer Registry Program (NCRP) in the year 1982 with the main objective of generating reliable data on the magnitude and pattern of cancer in India. Recently, NCRP has published a report on Time Trends in Cancer Incidence Rates (NCRP 2009). This report depicts the changes in incidence rates of cancer from five urban registries and one rural registry of India. Tobacco is the most important identified cause of cancer and is responsible for 30%–50% of cancers in men and about 10%–15% of cancers in women, in different registry areas (NCRP-2008). In India, according to the GLOBOCON 2020 data, lip and oral cavity cancers rank second among all sites with 135 929 cases and cancers of oropharynx, larynx, and hypo pharynx are among the top 20 cancers by site.[4]

Definitive chemoradiation remains the standard of care for patients with locally advanced squamous cell carcinoma of the head and neck.[5] These patients were classically treated with three dimensional conformal radiotherapy where increasing radiation doses were delivered to higher risk areas of disease using sequential radiotherapy plans to treat smaller boost fields, better known as “shrinking field approach.” However, patients experienced severe acute and late toxicities in the form of mucositis, xerostomia, and skin reactions. As intensity-modulated radiotherapy (IMRT) techniques were introduced, it was possible to deliver more conformal doses along with dose escalation to higher risk areas with better sparing of organs at risk (OAR). IMRT allowed for planning and irradiation of different targets at different dose levels in a single treatment session.

Two kinds of planning target volume (PTV) are generally used for HNCs. PTV boost is generated by adding a margin to gross tumor volume (GTV) and PTV elective by including elective volumes. Recently, simultaneously integrated boost (SIB) which simultaneously delivers different doses to two PTVs with a single plan has become standard of IMRT. Because SIB uses equal fraction numbers for PTV boost and PTV elective, doses per fraction for the two PTVs must be different, i.e., fraction size for PTV boost is higher and lower for PTV elective. These fraction sizes are usually unconventional (2.0 Gy, 2.11 Gy and 2.2 Gy for PTV boost). SIB with greater fraction size involves a greater risk of late adverse effects. On the other hand, if fraction size for PTV boost is 2 Gy, the fraction size for PTV elective may be unconventionally low (<1.8 Gy) and thus radiobiologically ineffective even for controlling sub-clinical disease.[6]

One solution for this fraction size problem with SIB is two phase IMRT, which has two sequential plans. The first plan is for the treatment of PTV elective, including PTV–GTV and subsequent second plan is for PTV associated with GTV. Therefore, in this study, we aim to compare the target coverage and the normal tissue sparing between sequential IMRT and SIB-IMRT plan for patients of locally advanced HNCs.


  Materials and Methods Top


This is prospective, observational and comparative study conducted on locally advanced HNC patients between November 2016 and November 2017. The study was conducted in Department of Radiation Oncology at Bhagwan Mahaveer Cancer Hospital and Research Centre, Jaipur, Rajasthan, India. The ethical clearance was taken from Institutional Scientific Committee and Ethics Committee. An informed consent was taken before enrolling them in study. The sample for this study was 30 which has been calculated using below formula:

Sample size formula: N = (Z [2alpha] + Z [beta]) 2 × S2/delta2

(Where S = standard deviation; delta = difference of means to be detected; Zalpha = “Z” value of standard normal curve corresponding to alpha-error of 0.05; Zbeta = “Z” value of standard normal curve corresponding to beta-error of 0.02; Zalpha = 1.96; Zbeta = 1.99).

Patient evaluation and management

After recording the detailed history, performing a thorough clinical examination and the relevant investigations, the patients who were staged as locally advanced squamous cell carcinoma of oropharynx, hypo pharynx and supraglottic regions were chosen for the study.

Orfit casting and computed tomography-simulation

Patients were immobilized in the supine position using a 5 clamp customized thermoplastic mask on appropriate neck rest. A plain and contrast computed tomography (CT) scan for radiotherapy planning was done after immobilization in the treatment position as per the department protocol. The area from frontal sinus to 2 cm below clavicle was scanned and 3 mm contagious sections were obtained on “Phillips Brilliance CT Bigbore-16 slice G-XL-40830” machine.

Regions of interest

The DICOM images were transferred to the treatment planning system (TPS) through local area network. After importing the plain and contrast images, fusion was done automatically by the TPS. This was followed by target and OAR delineation on plain scan using contrast scan as reference thereby creating volume images as follows:

  1. The GTV
  2. The clinical target volume (CTV1 and CTV2)
  3. The PTV (PTV1 and PTV2)
  4. The left and right parotid glands
  5. Spinal cord
  6. Brainstem
  7. Mandible.


Volume delineation

Mandible was contoured as whole bone as seen on CT from temporomandibular joint to symphysis meant, bilaterally. The spinal cord as seen on CT scan or magnetic resonance imaging (MRI) which begins at the superior aspect of C1 vertebral body extending up to 2 cm below the lower margin of the PTV. Parotid glands were contoured with their cranial border from external auditory canal, mastoid process; caudally posterior part of submandibular space; posteriorly anterior belly of sternocleidomastoid muscle and lateral side upto posterior belly of the digastric muscle; laterally subcutaneous fat and platysma and medially posterior belly of digastric muscle, styloid process, and parapharyngeal space.[7] Brain stem was contoured from top of the posterior clinoid to an inferior extent up to superior aspect of C1 vertebral body.

Volume definitions were based on ICRU report 50, as follows

GTV[8]: The GTV denotes demonstrable tumor. It includes all known gross disease including abnormally enlarged lymph nodes. CTV[8]: The CTV denotes the GTV and subclinical disease (i.e., volume of tissue with suspected tumor). PTV[8]: The planning arget volume denotes the CTV and includes margins for geometric uncertainties. One also should account for variation in treatment setup and other anatomic motion during treatment such as respiration. OAR[8]:-are normal tissues, whose radiation sensitivity may significantly influence treatment planning and/or prescribed dose. The OAR in our study is brain stem, spinal cord, the left and right parotid glands, and mandible. Dose constraints for the OAR will be guided by quantitative analysis of normal tissue effects in the clinic (QUANTEC).[9] For all cases, two different CTVs were drawn based on RTOG guidelines[10],[11] Elective volume (CTV2) including tumor bed, lymph nodes and tissue at risk for subclinical or microscopic disease. Boost volume called CTV1 including tumor bed and high risk areas. All the patients received bilateral neck nodal radiotherapy. PTVs (PTV2/PTV1) were defined from CTV by adding a margin of 3 mm to take into account all uncertainties. The PTVs were cropped 1 mm inside the body contour automatically by the system. Target and OARs were drawn and checked by a single user. Fusion of MRI scan or positron emission tomography scan were done whenever feasible to aid target delineation.

Dose constraints and planning

For each patient, plans were generated by sequential and SIB IMRT method and dosimetric comparison was done for target coverage (PTV), conformity index (C. I.) and dose received by the OARs. SIB planning was done once at the start of radiotherapy with the prescription doses assigned to the PTV1 and PTV2. Sequential boost plans were done in two phases, first at the start of radiotherapy (phase I) and then coned down in Phase II.

Dose prescription to planning target volume

The dose prescribed in SIB-IMRT to PTV1 was 66 Gy in 30 fractions at the rate of 2.2 Gy per fraction and PTV2 was prescribed 54 Gy in 30 fractions at the rate of 1.8 Gy per fraction. The dose prescription for sequential IMRT plans was 50 Gy in 25 fractions at the rate of 2 Gy per fraction to the complete target area followed by 20 Gy boost in 10 fractions to the high risk areas at the rate of 2 Gy per fraction. Acceptable mean dose to PTVs was kept at 100% with maximum dose less than or equal to 107% and minimum dose more than or equal to 95%.

Intensity-modulated radiotherapy planning

IMRT plans were generated with sliding window technique using nine coplanar equidistant field of 6 MVenergy. Optimizations and dose calculations were done with Eclipse version 10.0.42 (Varian Medical System). The plan objectives were to achieve PTV volume receiving less than 95% (V <95) of the prescribed dose <1% and V >107 close to zero. The most important objective was to keep maximum dose to the spinal cord and brain stem below 44 Gy and 54 Gy, respectively. The second priority for OAR is to reduce the mean dose to parotids where possible to 26 Gy. Both the cold and hot spots on the PTVs were reduced to minimum by delineating them as virtual organs for further optimization.

After optimization, the dose calculation was performed in Eclipse TPS with anisotropic analytical algorithm using calculation grid of 2.5 mm.

Criteria for data-analysis

For comparison, all plans were normalized to the mean target dose. Dose volume histograms were generated for the PTV and all OARs and the following parameters were recorded for comparison:

  • Dmean-mean dose to the target PTV, usually dose to 50% volume of the PTV
  • Dmax-maximum dose to the target PTV, usually dose to 2% volume of PTV
  • D100-dose to 100% volume of the PTV
  • C. I. (as per RTOG 90-05) = Target volume (TV) covered by reference isodose/reference isodose volume.


CI of one indicates good conformity.

For the OAR, the following parameters were recorded for each planning method:

  • Dmean to left parotid: Mean dose to left parotid
  • Dmean to right parotid: Mean dose to right parotid
  • Dmax mandible: Maximum dose to mandible
  • Dmax to brain stem: Maximum dose to brainstem.
  • Dmax spinal cord: Maximum dose to spinal cord.


Plan evaluation and selection

After evaluating both the SIB and SEQ-B IMRT plans, the clinically superior plan was chosen for the treatment with quality assurance based on the following criteria:

  • PTV1 and PTV2 C. I. is close to unity
  • The doses to OAR based on constraints are respected.


Normal tissue dose constraints used both for SIB and SEQ-B were based upon QUANTEC guidelines [Table 1] as follows.[9]
Table 1: Quantitative Analysis of Normal Tissue Effects in the Clinic guidelines

Click here to view



  Results Top


A total of 30 patients were enrolled in the study from November 2016 to November 2017. The maximum number of patients 20/30 (66.67%) were in the sixth decade. Three patients were female (10%), whereas the remaining 27 were of male gender (90%) [Table 2].
Table 2: Demographic data among patients

Click here to view


Among 30 patients, 19 patients (63.34%) had oropharyngeal disease and 11 had hypopharyngeal disease (36.66%). The disease laterality was on the left for three patients (10%); on the right for three patients (10%) and bilateral disease in 24 (80%) patients [Figure 1].
Figure 1: Distribution of cases according to site

Click here to view


All tumors were histologically squamous cell carcinoma. Among the 30 patients, 24 (80%) patients had moderately differentiated squamous cell carcinoma; 2 (6.67%) patients had well differentiated tumor and in 4 patients (13.33%) it was poorly differentiated carcinoma. Regarding the clinical staging, 14/30 (46.67%) patients had cIII stage; 14/30 (46.67%) patients had cIVa stage and remaining 2/30 (6.67%) patients had cIVb disease [Figure 2] and [Figure 3].
Figure 2: Distribution of cases according to fine-needle aspiration cytology/biopsy

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Figure 3: Distribution of cases according to cTNM

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Target coverage of planning target volume 1 and planning target volume 2 by simultaneously integrated boost and SEQ-B intensity-modulated radiotherapy plans

The minimum dose, maximum dose, and the mean dose volumes of PTV1 and PTV2 which were designated as D100, Dmax, and Dmean, respectively, were analyzed by both SIB and SEQ-B IMRT plans. The C. I. was derived by RTOG 90-05 (34). The C. I. for PTV1 and PTV2 by SEQ-B and SIB IMRT plans were 0.96 versus 0.95 and 0.97 versus 0.95, respectively. On statistical analysis for both the planning techniques in regard to both PTV1 and PTV2, there was no significant difference noted [Table 3] and [Table 4].
Table 3: Target coverage of planning target volume 1 and planning target volume 2 by simultaneous integrated boost and sequential-B intensity-modulated radiation therapy plans

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Table 4: Comparison of conformity index for planning target volume 1 and planning target volume 2 by sequential-B and simultaneous integrated boost intensity-modulated radiation therapy plans

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Organs at risk

The mean maximum dose to brainstem was 4230.02 cGy with SEQ-B and 4305.52 cGy with SIB plan. It was observed with SIB plan, brainstem received 75.5 cGy more dose than with SEQ-B plan, but on statistical analysis, it was not found to be significant. The mean maximum dose received by spinal cord was 4429.88 cGy and 4424.02 cGy with both SEQ-B and SIB plans, respectively, with no significant statistical difference. The mean doses to parotids were recorded and analyzed irrespective of the disease laterality. The mean dose to both the parotid glands showed no significant statistical difference in both the planning techniques. On analysing the mean maximum dose received by mandible, a statistically significant sparing was seen with SIB technique (mean Dmax = 6953.97 cGy) as compared to the SEQ-B plan (mean Dmax = 7296.42 cGy) with a P value <0.001 [Table 5].
Table 5: Comparison of maximum dose to brain stem with Sequential-B and simultaneous integrated boost intensity-modulated radiation therapy plans

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  Discussion Top


HNCs comprises 30% load of India's cancer burden with 200,000 new HNC cases per year.[1] These cases have a distinct demographic profile, risk factors, food habits, family, and personal history.[12] HNCs are more common in males compared to females. This is mainly attributed to tobacco, areca nut, alcohol, etc., Oral cancers are most common among all head and neck squamous cell cancers (HNSCCs). HNC is the most common cancer in developing countries.[13] It is the most common cancer of males in India and fifth most common in females.[14] In India, nearly two-thirds of patients present with advanced stages.[15] The mean age of patients at presentation of HNCs is the fifth and early sixth decades in Asian populations compared with the seventh and eighth decades in the North American population.[16],[17]

Our study has 90% male population and 10% female population. Majority of the cases 66.67% were >60 years, 26.67% were in the age group 51–60 years, while a small number of cases (6.67%) were <50 years. Although most studies reveal oral carcinoma to be most prevalent, but in our study of the total cases taken 56.67% were of oropharynx and 40% cases of hypo pharynx. A small percentage of cases were of locally advanced oral cancers. This difference was observed as we included locally advanced HNC cases not amenable to surgery, while oral cavity cases amenable to surgery were operated first and thus not included in our study.

The vast majority (more than 90%) are squamous cell carcinomas, such that the term HNC is often used to describe all carcinomas arising from the epithelium lining the sinonasal tract, oral cavity, pharynx, and larynx and showing microscopic evidence of squamous differentiation. The microscopic appearance may vary as a function of tumor differentiation, but the prototypic HNSCC is moderately differentiated.[18] Our study also comprises of 80% cases of moderately differentiated followed by 13.33% of poorly differentiated and 6.67% of well differentiated carcinomas.

This study compared prospectively sequential (SEQ-B) and simultaneous integrated boost (SIB) IMRT plans in 30 patients with locally advanced squamous cell carcinoma of head and neck. IMRT has been accepted as the standard treatment technique in HNCs so as to spare the OAR effectively than the conventional radiotherapy techniques. Most of the studies comparing the planning techniques are retrospective, but in this study, we compared two plans of single patient prospectively and the dosimetrically superior plan was implemented for the treatment.

Stromberger et al.[19] compared sequential versus simultaneous integrated boost in HNC patients and showed clear do dosimetric differences in terms of coverage, conformity, and dose to PTVs between the two strategies with potential clinical implications. However, the data demonstrated that there were no significant or clinically relevant differences regarding classical OAR sparing. However Dogan et al.[20] found that a two dose level SIB IMRT provided better sparing of parotid glands as compared to sequential IMRT in a study on 5 HNCC patients.

In a study by Loo et al., interobserver variation in parotid gland delineation was studied in IMRT, and it was found to be significant.[21] Accurate delineation of TVs and OARs is essential for the success of IMRT. Interobserver variation in GTV is found to be large and clinically significant for many tumor types including HNSCC.[22]

A study by Dosoretz et al. determined the accuracy and variability in defining nodal TVs in the uninvolved neck for head and neck IMRT radiation therapy in a group of well trained but not head and neck expert physicians. This study demonstrates large variability in target volumes contoured by physicians. This phenomena is more marked at the most cephalic and caudal extent of the target volumes.[23]

In another study by Kuritzky et al.[24] investigated the dosimetric impact of inter observer contouring variation by examining the dose to tissue outside of the PTV. To determine the dose to tissue outside of the PTV70, they performed 0.5 cm and 1 cm expansions of the PTV70 followed by subtractions of the original PTV70 to generate axial 0.5 cm and 1 cm “rings of tissue” concentric around the PTV70. For the 0.5 cm rim of tissue surrounding the PTV70, the median dose to 95% of the volume (D95) was 61 Gy (range 50–60 Gy), while the median D50 was 68.3 Gy (range 67–70 Gy). For the 1 cm rim surrounding the PTV70, the median D95 and D50 were 54.7 Gy (50–60 Gy), and 68.3 Gy (67–70 Gy), respectively. This study concluded that this variability can result in potential marginal miss that can further translate itself to treatment failures.

In a international multi-institutional study by Hong et al. found a remarkable heterogeneity in head-and-neck IMRT design and practice technique between 20 institutions and presented notable challenges for comparative analysis of the same at global level. The authors found that for a similar identical tonsillar cancer patients, about two-thirds of responders would treat the primary and bilateral neck, whereas one third would treat only the primary tumor and ipsilateral neck.[25]

In our study, Dmean, D100 and Dmax for PTV1 was more with sequential boost IMRT with a significant P value (Dmean, P = 0.012; D100, P = 0.035; Dmax, P < 0.001) with Dmax being statistically most significant. The PTV2 also demonstrated statistically better results with the sequential boost plan for Dmean (P < 0.001) and Dmax (P < 0.001) but D100 being better for simultaneous integrated boost plan (P = 0.012). But it is clearly seen to obtain much significant values with the Dmean and Dmax in the sequential arm as compared to the simultaneous arm. Dmean can be surrogated for target coverage.[26] Increasing Dmax decreases C. I. but it doesn't compromise with tumor coverage. Therefore, in view of the results target coverage was superior with the sequential boost IMRT plan arm.

As far OAR and normal tissue sparing is concerned, in accordance to most of the studies, in our study also no significant difference was observed in doses to brain stem, spinal cord, left parotid gland and right parotid gland. A significant sparing of mandible was although seen with SIB technique (P < 0.001). Rest other structures also had somewhat lower doses with SIB technique as compared to sequential boost planning, but the P value was no significant. Hence, the results remain equivocal in both the cases.

The higher doses to the adjacent OAR and normal tissue with sequential-boost IMRT plans could be attributed to the phenomenon of “dose-spillage.” With SEQ-B as we cut of the low-risk area in the phase II plan, and deliver dose to the high risk area only, but as we consider PTV coverage by 95% iso-dose lines as optimum, the remaining dose fall off covers the adjacent region also, thereby, increasing dose to the adjacent tissues and increasing the chances of second malignancy in long term follow-ups.


  Conclusion Top


In the present study as no significant difference was observed in OAR sparing except mandible in both the plans, so acute toxicities and late-complications is thought not be much different. So, in view of the results and comparative studies, both the plans are clinically acceptable, although taking into account the tumor coverage, the sequential boost IMRT plan arm gave better results.

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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Abstract
Introduction
Materials and Me...
Results
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