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PLOS One logoLink to PLOS One
. 2024 Oct 10;19(10):e0311855. doi: 10.1371/journal.pone.0311855

Scalp dose analysis for transient and permanent alopecia following conventional cranial irradiation using Image Guided Radiotherapy (IGRT): A prospective study

Bongkot Jia-Mahasap 1,#, Wannapha Nobnop 1,‡, Patumrat Sripan 2,#, Ekkasit Tharavichitkul 1,‡, Somvilai Chakrabandhu 1,‡, Pitchayaponne Klunklin 1,‡, Wimrak Onchan 1,‡, Pooriwat Muangwong 1,‡, Imjai Chitapanarux 1,*
Editor: Li-Ping Liu3
PMCID: PMC11466407  PMID: 39388438

Abstract

Purpose

The dosimetry of scalp dose was prospectively studied and correlated with alopecia following conventional cranial irradiation in primary brain tumors patients.

Materials and methods

Patients with primary brain tumors who required conventional radiotherapy were enrolled. A hairline marker was applied to the patient’s scalp to identify the entire scalp region. The maximal dose to 2% volume of interest (D2) for the entire scalp region were obtained. The radiation dosages at the localized hair-loss areas were evaluated during the final week of RT (transient alopecia) and six months after completing RT (permanent alopecia). Kruskal-Wallis tests were used to compare the dosimetric parameter values with statistical significance set as p < 0.05.

Results

Forty-eight patients were included in the analysis. The prescribed radiation doses ranged from 50.4 to 60.0 Gy. Thirty-two patients experienced alopecia (27 transient and 5 permanent). The median D2 values adjusted for the entire scalp were higher in the alopecia group (38.40 Gy for transient alopecia and 47.84 Gy for permanent alopecia vs 11.90 Gy for no alopecia, p < 0.001). The D2 value was determined as a predictive parameter for alopecia. The threshold values for transient and permanent alopecia over the entire scalp were 22.15 Gy and 36.81 Gy, respectively. At the localized hair-loss areas, the D2 values for transient and permanent alopecia were higher at 44.82 Gy and 50.00 Gy, respectively. The radiation intensity at the localized hair-loss areas was also related to the severity of alopecia, with D2 values of 35.14 Gy and 46.39 Gy for clinically assigned grade 1 and grade 2 transient alopecia, respectively, with the D2 value being even higher for permanent alopecia.

Conclusions

The D2 parameter value could be used to predict the type and severity of alopecia.

Introduction

Radiotherapy (RT) is an important treatment for primary brain tumors. Typically, external-beam RT is utilized for intracranial lesions during which the radiation beam generated by a linear accelerator machine directly penetrates the cranium into the brain parenchyma to eradicate tumors and delivers a radiation dose from 45 to 60 Gy depending on the tumor subtype [1, 2]. Localized alopecia along the radiation path is a typical side effect of RT. Transient alopecia occurs approximately 2 to 3 weeks after commencing RT and usually resolves within 3–6 months [3]. RT-induced apoptosis of hair bulges containing stem cells can result in permanent alopecia, which can have deleterious psychological effects on quality of life and self-esteem [4].

Previous research has demonstrated a clinical correlation between alopecia and whole brain RT for the treatment of brain metastatic [5–8]. They all used a hypo-fractionated radiation dose regimen (ranging from 2.5 Gy to 4 Gy per fraction [Fx]) which typically delivers a greater absorbed radiation dose to healthy tissue. There were few investigations examining the relationship between focalized RT and hair loss in patient with primary brain tumors receiving 1.8–2.0 Gy per Fx [3, 9]. A notable study conducted by Lawenda and colleagues [9] found that hair follicles exposed to 43 Gy of radiation had a 50% chance of developing permanent alopecia [9]. However, they estimated hair follicle dosage by calculating the radiation dosage delivered by each radiation beam passing through the scalp region of interest using extremely complex calculations, which could be difficult to implement in practice. In other studies, hair follicles were identified by contouring tissue between skin and scalp at skin depths ranging from 3 to 7 mm after hypo-fractionated whole-brain RT [3, 5–8, 10].

The human hair follicle is traditionally divided into three sections: the infundibulum, the isthmus, and the inferior portion. The bulge region, which is located in the isthmus and inferior portion, is the most important subunit in which stem cells are pooled [11]. The length of the hair follicle from the epidermis is between 3.86 mm and 4.16 mm [11, 12]. Exploiting this crucial data, we decided to study the area of interest on the scalp by using automated tissue contouring to distinguish hair follicles from skin at a depth of 4 mm.

We hypothesize that permanent alopecia resulting from irreversible damage to the hair follicle after focal RT for primary brain tumors is directly proportional to the hair follicle radiation dose. A reduction in the scalp dose without compromising target coverage may reduce hair loss and thereby improve the quality of life of the patients. Therefore, the purpose of this prospective study was to determine the scalp dose that is associated with alopecia and to identify additional variables (such as age and gender) that may have an influence.

Materials and methods

This prospective study enrolled patients who met the following criteria: 1) Age 18 to 70 years, 2) Eastern Cooperative Oncology Group (ECOG) performance status 0–2 [13], 3) Primary intracranial solid tumors as determined by histopathology or classical imaging for benign brain tumors, 4) Radiation delivery using conventional fractionation scheme, and 5) Concurrent temozolomide chemotherapy was allowed, which has a low rate of chemotherapy-induced transient alopecia [14]. The exclusion criteria were patients 1) who had previously undergone cranial irradiation, 2) who were already showing signs of baldness, 3) who had received a radiation dose greater than 2.5 Gy/Fx, and/or 4) who had previously undergone chemotherapy. Ethical approval was granted by the Research Ethics Committee, Faculty of Medicine, Chiang Mai University (Grant no. 236/2019). Written consent was obtained from each of the participants.

Computed tomography (CT) simulation with 3-mm thick slices was conducted on the eligible patients. During this procedure, a thermoplastic mask with a hairline marker at the scalp was applied (Fig 1), which assisted in delineating the scalp region. After the simulation, the CT images were registered in an Oncentra master plan contouring system (Elekta, Sweden). Subsequently, the target volumes (gross tumor volume, GTV; clinical target volume, CTV; planned treatment volume, PTV) and critical structures (organs at risk, OARs) were defined based on the primary tumor type. The volume of the entire scalp was measured based on the hairline marker. Finally, an automated ring region with a maximum thickness of 4 mm was generated between the skin and the cranium at this location (Fig 2).

Fig 1. A hairline marker on a scalp before CT simulation.

Fig 1

Fig 2. The scalp volume (purple).

Fig 2

The yellow arrows point toward the pre-applied hairline marker. The blue arrows indicate the isocenter.

Radiation had been administered to the patients using image-guided RT (IGRT), which included volumetric arc therapy (VMAT) and helical tomotherapy (HT). Target dosages were evaluated in accordance with the International Commission on Radiation Units and Measurements (ICRU) 83 guidelines [15], which stipulate that the prescription radiation dose coverage must be over at least 50% of the PTV (D50). The maximum dosage applied to a 2% volume of the PTV (D2) needed to be less than 107% of the prescribed dose while the minimum dosage to a 98% volume of the PTV (D98) needed to be greater than 95% of the prescribed dose. The Quantitative Analysis of Normal Tissue Effects in the Clinic (QUANTEC) guidelines were employed to assess the irradiation of OARs [16]. For the scalp volume, we defined radiation dosage constraints without compromising the target coverage at three different doses: the primary constraint was D2 ≤ 20 Gy, followed by ≤ 30 Gy and ≤ 40 Gy as secondary and tertiary constraints, respectively. The mean (Dmean), median (D50), and D2 radiation doses to the scalp region, as well as the absolute scalp volumes receiving doses of 20 Gy (V20) and 40 Gy (V40) were obtained and recorded.

Alopecia assessment

Right lateral, left lateral, vertex, and occipital regions of the scalp were objectively photographed at five distinct time intervals: before beginning RT, during the final week of RT, and three, six, and 12 months after completing RT. Later, three independent investigators assigned alopecia grades to each photo. The Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 was used to assess the severity of alopecia (grade 1, hair loss < 50% of normal; grade 2, hair loss ≥ 50% of normal) [17]. The areas of localized hair loss that occurred during the final week of RT (designated as transient alopecia) and six months after completing RT (designated as permanent alopecia) had their radiation dosages re-evaluated by wiring a scalp marker to a thermoplastic mask, CT simulation of this wired mask, and assigning the images to their previous counterparts used for radiation planning by applying the isocenter as the matching point (Fig 3). RT research (CERR) software was used to analyze the dosimetric parameters for the region of interest using Dicom RTdose data from the prior treatment planning system that delivered radiation to the patient [18]. The radiation dosimetry was recorded as the Dmean, D50, D2, V20, and V40 values.

Fig 3. The CT simulation of a wired mask of the hair-loss region assigned by using previous CT images.

Fig 3

The blue arrows indicate the isocenter as the matching point. The pink arrows elucidate the correlated hairline marker for localized alopecia. The specific scalp region (green) could then be identified.

Sample size

This study sample size was determined according to Harris’s recommendation [19]; for 5 or fewer predictors, the number of subjects should exceed the number of independent variables by 50 (n > 50+m). We assessed the relationship between alopecia and three predictors: radiation dose, age, and gender. Consequently, the sample size needed to be 74 patients.

Statistical analysis

Descriptive analyses were summarized as medians with interquartile range (IQR) for continuous variables and as frequencies and proportions for categorical variables. The values of the dosimetric parameters (Dmean, D50, D2, V20, and V40.) were summarized using the medians and IQR. Kruskal-Wallis tests were performed to compare the medians for the dosimetric parameters for the entire scalp of patients without alopecia, or with transient (including different grades) or permanent alopecia. Pair-wise comparisons were conducted using Dunn’s Kruskal-Wallis Multiple Comparison tests. Wilcoxon rank-sum tests were used to compare the dosimetric parameter values for the localized hair-loss areas of patients with grade I or II transient alopecia and between those with and without alopecia. Associations between transient alopecia grade and permanent alopecia were analyzed using Fisher’s Exact tests. After plotting receiver operating characteristic (ROC) curves, relevant results including the area under the curve (AUC) with sensitivity and specificity were estimated to determine the diagnostic values of the dosimetry parameters. All statistical analyses were performed using Stata version 16 (StataCorp LP, College Station, TX, USA). Statistical significance for two-tailed tests was assessed using an alpha value of 0.05.

Result

Fifty-six patients satisfied the eligibility requirements. Among them, 8 did not undergo CT simulation, leaving 48 patients included in the analysis. Meningioma was the most prevalent tumor type (21 patients, 44%), followed by glioma (17 patients, 35%) and other types (10 patients, 21%). The median age was 51 (47–56 years) and the majority were female (37 patients, 77%). The median follow-up was 27 months (14–33 months). The prescribed RT doses ranged from 50.4 to 60.0 Gy (1.8–2.0 Gy/Fx). Thirty-two out of 48 patients (66.7%) experienced hair loss, with 27 experiencing transient alopecia and 5 experiencing permanent alopecia. Age, gender, RT technique, and scalp volume parameters were unrelated to hair loss, whereas the PTV volume and radiation intensities on the scalp region were statistically significantly associated with alopecia, as presented in Table 1.

Table 1. Characteristics of the participants.

Characteristics No alopecia Transient alopecia Permanent alopecia P-value
N = 16 N = 27 N = 5
Median age (IQR), year 51 (47–56) 52 (44–60) 56 (46–58) 0.890a
Gender, N (%) 0.171b
Male 2 (18.18) 9 (81.82) 0 (0.00)
Female 14 (37.84) 18 (48.65) 5 (13.51)
RT technique, N (%) 0.696b
VMAT 9 (39.13) 12 (52.17) 2 (8.70)
HT 7 (28.00) 15 (60.00) 3 (12.00)
Median PTV volume (IQR), cm3 34 207.89 164.63 <0.001a
(13.76–40.43) (97.31–355.43) (116.92–327.93)
Median scalp volume (IQR), cm3 226.08 224.62 201.97 0.531a
(209.98–250.36) (203.10–237.96) (190.37–236.87)
Median Dmean for the entire scalp (IQR), Gy 2.28 9.70 9.55 <0.001a
(1.67–3.42) (6.72–16.08) (9.43–15.10)
Median D50 for the entire scalp (IQR), Gy 0.42 7.61 6.81 <0.001a
(0.31–0.73) (2.43–14.91) (5.71–10.57)
Median D2 for the entire scalp (IQR), Gy 11.90 38.4 47.84 <0.001a
(10.68–15.80) (28.24–43.11) (36.81–48.21)
Median V20 for the entire scalp (IQR), cc 0.00 37.75 30.25 <0.001a
(0.00–0.12) (14.40–73.95) (28.48–55.62)
Median V40 for the entire scalp (IQR), cc 0.00 3.78 12.25 <0.001a
(0.00–0.00) (0.28–7.84) (3.63–17.83)

aDetermined using a Kruskal-Wallis test

bdetermined using a Fisher’s Exact test.

Radiation dosimetry and clinical alopecia correlation

The Dmean value for the entire scalp was substantially higher in the alopecia groups (9.70 Gy for transient alopecia and 9.55 Gy for permanent alopecia vs. 2.28 Gy for without alopecia, p < 0.001), as was the D50 value (7.61 Gy and 6.81 Gy vs. 0.42 Gy, respectively, p < 0.001), and the D2 value (38.40 Gy and 47.84 Gy vs. 11.90 Gy, respectively, p < 0.001). Furthermore, the V20 and V40 values were considerably higher in the alopecia group, as demonstrated in Table 1. The D2 and V20 values were also determined as predictive parameters of alopecia. The threshold values for transient and permanent alopecia were 22.15 Gy and 36.81 Gy for D2, and 6.63 cc and 16.36 cm3 for V20, respectively, as shown in Table 2. When measured at the site of localized hair loss, one patient who experienced transient alopecia did not undergo a re-evaluation of the localized hair-loss areas dosage. Therefore, the analyses were conducted on the scalp doses of 26 patients with transient alopecia, as shown in Table 3. The permanent alopecia group had greater values for all five dosimetric parameters. The median Dmean, D50, D2, V20, and V40 values were 31.07 Gy, 30.85 Gy, 50.00 Gy, 28.08 cm3, and 12.26 cm3, respectively.

Table 2. Median radiation dosimetry parameter values for the entire scalp volume.

Parameters Sensitivity (%) Specificity (%) AUC 95% CI (AUC) Cutoff value Youden’s index
Transient Alopecia
    Mean Dose 0.938 0.938 0.982 0.956–1.000 4.17 Gy 0.875
    D50 0.844 1.000 0.963 0.918–1.000 2.41 Gy 0.844
    D2 0.969 1.000 0.994 0.981–1.000 22.15 Gy 0.969
    V20 0.969 1.000 0.994 0.981–1.000 6.63 cc 0.969
    V40 0.875 0.938 0.922 0.854–0.990 0.18 cc 0.812
Permanent Alopecia
    Mean Dose 1.000 0.553 0.823 0.695–0.952 6.33 Gy 0.553
    D50 1.000 0.632 0.817 0.696–0.938 3.09 Gy 0.632
    D2 0.800 0.737 0.813 0.685–0.942 36.81 Gy 0.537
    V20 1.000 0.605 0.810 0.682–0.939 16.36 cc 0.605
    V40 0.900 0.658 0.776 0.616–0.937 1.62 cc 0.558

Table 3. Median radiation dosimetry parameter values for the localized hair-loss areas.

Parameters Transient Alopecia (N = 26) Permanent Alopecia (N = 5)
Median Dmean (IQR), Gy 24.70 (19.96–28.79) 31.07 (27.80–41.92)
Median D50, (IQR), Gy 25.28 (18.27–28.91) 30.85 (28.92–43.09)
Median D2, (IQR), Gy 44.82 (39.23–48.65) 50.00 (48.94–51.93)
Median V20 (IQR), cm3 27.78 (9.68–63.25) 28.08 (26.88–51.68)
Median V40 (IQR), cm3 3.68 (0.28–7.85) 12.26 (3.08–13.14)

Impact of radiation dose on the severity of alopecia

Grade 1 alopecia was diagnosed in 3 of the 32 patients who experienced hair loss following the completion of RT, while the remaining 29 patients were diagnosed with grade 2 alopecia. Medians of the dosimetry parameter values were used to determine any correlations between them and the severity of alopecia. The Dmean values for the entire scalp were substantially less in the group without alopecia than in the group with alopecia: 2.28 Gy vs. 9.02 Gy and 9.70 Gy for no alopecia vs. grades 1 and 2, respectively (p < 0.001) as were the D50 and D2 values (0.42 Gy vs. 5.00 Gy and 7.61 Gy, and 11.90 Gy vs. 34.15 and 38.52 Gy, respectively, p < 0.001), as presented in Table 4. Furthermore, the V20 and V40 values of the non-alopecia group were both 0.00 cm3, both of which were significantly greater for alopecia grades 1 and 2. The focal scalp dosage of radiation intensity at the localized hair-loss area was not re-evaluated for 1 patient with grade 1 alopecia but was for 2 cases of grade 1 alopecia and 29 cases of grade 2 alopecia: none of the dosimetric parameter values were statistically significantly different between the two grades (Dmean: 20.40 Gy vs. 25.75 Gy, p = 0.31; D50: 20.67 Gy vs. 26.45 Gy, p = 0.24; D2: 35.14 Gy vs. 46.39 Gy, p = 0.35; V20: 56.16 cm3 vs. 28.08 cm3, p = 0.748, and V40: 2.59 cm3 vs. 4.22 cm3, p = 0.421).

Table 4. Correlations between median radiation dosimetry parameter values and the severity of alopecia.

Parameters Severity of Alopecia P-value
No Alopecia Grade 1 Grade 2
N = 16 N = 3 N = 29
The entire scalp
Median Dmean (IQR), Gy 2.28 9.02 9.70 <0.001a
(1.67–3.42) (7.80–18.70) (6.72–15.96)
Median D50 (IQR), Gy 0.42 5.00 7.61 <0.001a
(0.31–0.73) (3.09–20.20) (2.91–14.34)
Median D2 (IQR), Gy 11.90 34.15 38.52 <0.001a
(10.68–15.80) (24.96–41.54) (34.81–45.51)
Median V20 (IQR), cm3 0.00 41.36 32.05 <0.001a
(0.00–0.12) (18.81–107.88) (16.36–72.04)
Median V40 (IQR), cm3 0.00 0.28 4.27 <0.001a
(0.00–0.00) (0.00–5.18) (1.36–11.76)
Localized hair-loss areas Grade 1 Grade 2
N = 2 N = 29
Median Dmean (IQR), Gy 20.40 25.75 0.310b
(15.89–24.92) (20.21–29.14)
Median D50 (IQR), Gy 20.67 26.45 0.241b
(16.27–25.07) (19.43–29.29)
Median D2 (IQR), Gy 35.14 46.39 0.348b
(24.67–45.61) (40.75–49.57)
Median V20 (IQR), cm3 56.16 28.08 0.748b
(6.29–106.02) (12.03–61.95)
Median V40 (IQR), cm3 2.59 4.22 0.421b
(0.00–5.18) (1.37–11.4)

aObtained using a Kruskal-Wallis test

bobtained using a Wilcoxon rank-sum test.

Discussion

Alopecia is a common side effect following conventional RT, as was also seen in 66.7% of patients in the present prospective study. Significant factors correlating with clinical alopecia included the radiation intensity in the scalp region. The median Dmean values for the entire scalp region were 9.70 and 9.55 Gy in the groups with transient and permanent alopecia, respectively, compared to 2.28 Gy in the group without alopecia. This is in concert with the results of a clinical investigation conducted in Italy [20], the authors of which reported Dmean value of 11.6 Gy and 14.1 Gy for the entire scalp of patients who developed transient or permanent alopecia after undergoing RT, respectively, compared to 3.1 Gy for patients without alopecia. Differences in race and the depth of hair follicle bulge definition (5 mm) might explain the higher radiation dose in the scalps of persons with RT-induced alopecia. Moreover, V20 > 5.2 cm3 for transient alopecia and V40 ≥ 2.2 cm3 for permanent alopecia were the strongest predictors in their study [20]. In the present study, the D2 and V20 values were determined to be potentially predictive parameters for alopecia. The threshold values for transient and permanent alopecia were 22.15 and 36.81 Gy for D2, and 6.63 and 16.36 cm3 for V20, respectively. However, regarding the correlation between radiation dose and the severity of alopecia, we found that a higher D2 value was associated with a greater severity grade of alopecia, whereas V20 was lower in the grade 2 alopecia group. This outcome could have been influenced by the limited number of patients with grade 1 alopecia, so we recommend conducting a future study with a greater number of patients to more accurately assess this correlation. Another European research group reported that an absolute radiation dose of 12.6 Gy to the hair follicle depth (4 mm) was associated with transient alopecia after conventional fractionation [21]. They measured visible alopecia in two directions using a ruler and applied it to a standardized picture of the human scalp. The absolute radiation dosage was automatically established at the site of alopecia by the specific treatment planning system. The potential discrepancy between the image and the actual region of hair loss might have restricted the data analysis in their report. Other factors, including chemotherapy, medication use, and mental stress levels are not predictive of radiation-induced alopecia [9, 21]. Lawenda et al. [9] applied an extremely complex formula to establish the radiation dosimetry associated with clinical focal hair loss in their study. The D50 value for hair follicle dose was 43 Gy, which was found to be correlated with 50% of patients who developed permanent alopecia. In contrast, we found that patients who developed permanent alopecia had a median D50 value for localized hair loss of 30.85 Gy. We also found correlations between the Dmean and D50 values for the localized hair-loss areas and the severity of alopecia: the Dmean values for grades 1 and 2 were 20.40 Gy and 25.75 Gy while the D50 values were 20.67 Gy and 26.45 Gy, respectively. Lawenda et al. [9] also found a correlation between higher radiation dosimetry values and alopecia grade severity: the Dmean values for grade 1 and grade 2 alopecia were 31.6 and 46.1 Gy while the D50 values were 32.9 and 48 Gy, respectively. In another study conducted in the US [22], the D50 values for grades 1 and 2 alopecia were 31.9 and 41.5 Gy, respectively, thereby suggesting that this is a significant parameter for predicting radiation-induced alopecia. Again, differences in ethnicity may explain the disparity in radiation intensity causing clinical alopecia. Additionally, we found that larger treatment volumes were also associated with clinical alopecia due to their potential to attach the scalp region.

The definition of permanent alopecia is a controversial topic. Persistent radiation-induced alopecia was defined by Phillips and colleagues [22] as incomplete hair regrowth six months after the completion of RT whereas Lawenda and colleagues [9] defined it as 12 months. We used the former definition in our investigation. We also reassessed the radiation dose at the permanent hair-loss region of the patients with permanent alopecia. Nevertheless, we also photographed the scalps of the patients with permanent alopecia for 12 months following the completion of RT and found that those with permanent alopecia at 6 months also had it after 12 months.

In our cancer-treatment center, IGRT is the preferred radiation therapy modality for patients receiving treatment for cranial tumors. Thus, all of the patients included in the present study had undergone IGRT. This technique enhances precision by ensuring that radiation is delivered accurately to the targeted area by accounting for any patient movements or anatomical changes. By targeting radiation more precisely, IGRT also helps minimize unnecessary radiation exposure to the scalp. Although IGRT did not show a significant improvement in tumor control or reduction of radiation-induced toxicity for intracranial RT, further research is needed to evaluate the potential benefits of IGRT compared to conventional IMRT.

This prospective study’s strength was the detailed evaluation of alopecia. We applied a hairline marker to identify the scalp region as well as the regions of alopecia. We also evaluated photographs of the scalp to assist researchers in better grading alopecia. In addition, we provided several dosimetric parameters for potentially predicting radiation-induced alopecia that are easy to calculate in clinical practice. Of them, a higher D2 value was correlated with localized hair loss. The median D2 values for transient and permanent alopecia were 38.40 and 47.84 Gy, respectively for the entire scalp but higher in the localized hair-loss areas (44.82 and 50.00 Gy, respectively). A higher D2 value was also detected in the higher alopecia grade (35.14 and 46.39 Gy for grades 1 and 2, respectively). Limitations of our analysis are not using a quality-of-life questionnaire assessment and not using advanced modeling to predict alopecia following conventional photon RT. For future research, a larger sample size would help to confirm which parameters are useful for predicting radiation-induced alopecia.

Conclusion

We discovered that all five dosimetric parameters investigated (Dmean, D50, D2, V20, and V40) were associated with radiation-induced alopecia. Among them, D2 proved to be the best for predicting the propensity and grade of alopecia post-RT: the greater the D2 value, the higher the alopecia grade.

Supporting information

S1 File. Contained the characteristics of each patient.

(XLSX)

pone.0311855.s001.xlsx (22.3KB, xlsx)

Data Availability

All relevant data are within the manuscript and its Supporting Information files.

Funding Statement

The author(s) received no specific funding for this work.

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Decision Letter 0

Li-Ping Liu

10 Jul 2024

PONE-D-23-41670Scalp dose analysis for transient and permanent alopecia following conventional cranial irradiation using Image Guided Radiotherapy (IGRT): A prospective studyPLOS ONE

Dear Dr. Chitapanarux,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

Please submit your revised manuscript by Aug 24 2024 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

  • A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.

  • A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.

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If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols. Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols.

We look forward to receiving your revised manuscript.

Kind regards,

Li-Ping Liu

Academic Editor

PLOS ONE

Journal requirements:

When submitting your revision, we need you to address these additional requirements.

1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

**********

2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

**********

3. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

**********

4. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

**********

5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: The manuscript is good interesting and good designed

Introduction is good written

Material and methods are good designed

Results are good written and illustrated

Discussion is good written and include the conclusion of the study

**********

6. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

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Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

**********

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PLoS One. 2024 Oct 10;19(10):e0311855. doi: 10.1371/journal.pone.0311855.r002

Author response to Decision Letter 0


11 Jul 2024

Reviewer #1

The manuscript is good interesting and good designed. Introduction is good written. Material and methods are good designed. Results are good written and illustrated. Discussion is good written and include the conclusion of the study.

Response: Thank you for your kind comments. Additionally, this manuscript has been revised in accordance with the formatting guidelines of PLOS ONE and stated the Ethics statement at the beginning of the Methods.

Attachment

Submitted filename: Response to Reviewers.docx

pone.0311855.s002.docx (15KB, docx)

Decision Letter 1

Li-Ping Liu

23 Jul 2024

PONE-D-23-41670R1Scalp dose analysis for transient and permanent alopecia following conventional cranial irradiation using Image Guided Radiotherapy (IGRT): A prospective studyPLOS ONE

Dear Dr. Chitapanarux,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

We apologize that due to a system error, the reviewer comments were not fully attached in the previous decision letter. I have included the comments below, and kindly request that you provide a comprehensive response letter addressing the feedback from all three reviewers. Additionally, please carefully proofread the revised manuscript to check for any grammatical issues.

Please submit your revised manuscript by Sep 05 2024 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

  • A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.

  • A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.

  • An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols. Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols.

We look forward to receiving your revised manuscript.

Kind regards,

Li-Ping Liu

Academic Editor

PLOS ONE

Journal Requirements:

REVIEWER COMMENTS

Reviewer 1

The manuscript is good interesting and good designed

Introduction is good written

Material and methods are good designed

Results are good written and illustrated

Discussion is good written and include the conclusion of the study.

Reviewer 2

Strengths

Study design:

The prospective study design is robust and the inclusion/exclusion criteria are well defined.

The use of detailed dosimetric analysis for both the entire scalp and localized areas of hair loss is commendable.

Results:

Clear and concise presentation of results with appropriate descriptive statistical analysis.

Differentiation between transient and permanent alopecia provides valuable insights.

Major review:

1. Definition of permanent alopecia:

The manuscript defines permanent alopecia as hair loss assessed at 6 months after RT.

However, permanent alopecia is typically defined as hair loss that persists for more than 9-12 months.

This discrepancy should be addressed in the discussion or the results should be modified taking into account the time cutoff.

2. I don't understand the "Sample size" paragraph, the only steady-state analyses performed are univariate so why did the authors bother to include Harris' recommendations for independent variables typically used for multivariate analyses?

3. Use of ROC curve analysis:

To define dose cutoffs, ROC curve analysis and AUC should be included in the study.

4. English careful proofreading and possibly professional editing is recommended to refine grammar and simplify complex sentences for better readability.

Minor review:

1. The manuscript does not clearly explain the specific advantages of IGRT over nonimage-guided radiotherapy.

It should be explicitly stated and explained in the context of alopecia minimization.

2. Median follow-up time should be entered

3. It would have been interesting to also include other factors that may justify influencing toxicity i.e., cigarette smoking, tumor target volume and RT techniques used (VMAT, IMRT etc)

Reviewer 3

In my opinion, this is an interesting prospective study with appropriate method and statical analysis. It is well written on general knowkedge and previous studies about this theme. Totally, this is a good manuscript. I have one comment about statical analysis.

In discussion, authors mentions the V20 and V40 of scalp. Have you considered obtaining these parameters and comparing them with D2, Dmean, and D50?

[Note: HTML markup is below. Please do not edit.]

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

PLoS One. 2024 Oct 10;19(10):e0311855. doi: 10.1371/journal.pone.0311855.r004

Author response to Decision Letter 1


23 Aug 2024

August 20, 2024

RE: PONE-D-23-41670

Dear Academic Editor PLOS ONE

I would like to thank you for sending the comments of the reviewers following the peer review of our Original Article entitled “Scalp dose analysis for transient and permanent alopecia following conventional cranial irradiation using Image Guided Radiotherapy (IGRT): A prospective study”

Please find attached the revised manuscript. We have addressed the reviewers’ comments in the order they were provided, the reviewer’s comments are in italic. All changes are highlighted. According to the changes the in manuscript, we have also modified tables as follows:

Table 2 has been revised to “The dosimetric parameter of the entire scalp volume that predicted the occurrence of alopecia” using ROC curve analysis.

We have converted the previous Table 2 to Table 3, and Table 3 to Table 4.

Review Comments to the Author

Reviewer 1

The manuscript is good interesting and good designed. Introduction is good written. Material and methods are good designed. Results are good written and illustrated. Discussion is good written and include the conclusion of the study.

Response: Thank you for your kind comments. Additionally, this manuscript has been revised in accordance with the formatting guidelines of PLOS ONE and stated the Ethics statement at the beginning of the Methods.

Reviewer 2

Strengths

Study design: The prospective study design is robust and the inclusion/exclusion criteria are well defined. The use of detailed dosimetric analysis for both the entire scalp and localized areas of hair loss is commendable.

Results: Clear and concise presentation of results with appropriate descriptive statistical analysis. Differentiation between transient and permanent alopecia provides valuable insights.

Major review:

1. Definition of permanent alopecia: The manuscript defines permanent alopecia as hair loss assessed at 6 months after RT. However, permanent alopecia is typically defined as hair loss that persists for more than 9-12 months. This discrepancy should be addressed in the discussion or the results should be modified taking into account the time cutoff.

Response: Thank you for your impressive advice. The definition of permanent alopecia has been discussed. Please see the discussion session [Page 16-17, Line 253-260].

2. I don't understand the "Sample size" paragraph, the only steady-state analyses performed are univariate so why did the authors bother to include Harris' recommendations for independent variables typically used for multivariate analyses?

Response: Thank you for your comment. Initially, we suspected that clinical alopecia may be influenced by a variety of factors. Subsequently, it is imperative to implement both univariate and multivariate analyses. Consequently, we determined the sample size in accordance with Harris' recommendations. However, after we analyzed all characteristics, only the radiation dose factor was associated with clinical alopecia. Therefore, this study did not implement any multivariable analysis.

3. Use of ROC curve analysis: To define dose cutoffs, ROC curve analysis and AUC should be included in the study.

Response: Thank you for this important recommendation. The ROC curve analysis has been implemented, as shown in Table 2 [Page 12]. We have also made modifications to the abstract, the statistical analysis section, the result, and the discussion in accordance with your advice.

4. English careful proofreading and possibly professional editing is recommended to refine grammar and simplify complex sentences for better readability.

Response: Thank you for your comment. We have revised English in this manuscript with professional editing.

Minor review:

1. The manuscript does not clearly explain the specific advantages of IGRT over nonimage-guided radiotherapy. It should be explicitly stated and explained in the context of alopecia minimization.

Response: Thank you for your comment. This critical issue has been addressed in the discussion session [Page 17, Line 261-269]. The radiation technique utilized in this research was IGRT, as it was implemented in all curative-intent radiotherapy at our center.

2. Median follow-up time should be entered

Response: Thank you for your suggestion. The median follow-up time has been stated in the result session [Page 10, Line 162].

3. It would have been interesting to also include other factors that may justify influencing toxicity i.e., cigarette smoking, tumor target volume and RT techniques used (VMAT, IMRT etc)

Response: Thank you for your advice. The tumor target volume and RT techniques have been examined. Please refer to Table 1 for the data. To our regret, the cigarette consumption was not document as a patient characteristic.

Reviewer 3

In my opinion, this is an interesting prospective study with appropriate method and statical analysis. It is well written on general knowkedge and previous studies about this theme. Totally, this is a good manuscript. I have one comment about statical analysis.

In discussion, authors mentions the V20 and V40 of scalp. Have you considered obtaining these parameters and comparing them with D2, Dmean, and D50?

Response: Thank you for your suggestion. V20 and V40 to the entire scalp have been further analyzed and discussed, following your advice. Please see the additional data in Tables 1 to 4, as well as the discussion [Page 15, Line 222-230] and the conclusion [Page 19, Line 285-286].

We thank you for your careful review.

Sincerely,

Imjai Chitapanarux

Attachment

Submitted filename: Response to Reviewers.docx

pone.0311855.s003.docx (19.4KB, docx)

Decision Letter 2

Li-Ping Liu

25 Sep 2024

Scalp dose analysis for transient and permanent alopecia following conventional cranial irradiation using Image Guided Radiotherapy (IGRT): A prospective study

PONE-D-23-41670R2

Dear Dr. Chitapanarux,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

An invoice will be generated when your article is formally accepted. Please note, if your institution has a publishing partnership with PLOS and your article meets the relevant criteria, all or part of your publication costs will be covered. Please make sure your user information is up-to-date by logging into Editorial Manager at Editorial Manager® and clicking the ‘Update My Information' link at the top of the page. If you have any questions relating to publication charges, please contact our Author Billing department directly at authorbilling@plos.org.

If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.

Kind regards,

Li-Ping Liu

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #2: All comments have been addressed

Reviewer #3: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #2: Yes

Reviewer #3: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #2: Yes

Reviewer #3: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #2: Yes

Reviewer #3: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #2: Yes

Reviewer #3: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #2: The authors have adequately addressed the revisions, making improvements to the manuscript where necessary. The changes implemented have enhanced the clarity and quality of the paper. In my opinion, the manuscript is now suitable for publication.

Reviewer #3: Thank you for addressing my suggestion regarding V20 and V40 of the scalp. I appreciate the additional analysis and the integration of these parameters in your manuscript. The updated tables and discussion have strengthened the overall analysis, providing more comprehensive insights. The manuscript is now even more robust, and I am pleased with the revisions.

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #2: No

Reviewer #3: No

**********

Acceptance letter

Li-Ping Liu

30 Sep 2024

PONE-D-23-41670R2

PLOS ONE

Dear Dr. Chitapanarux,

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now being handed over to our production team.

At this stage, our production department will prepare your paper for publication. This includes ensuring the following:

* All references, tables, and figures are properly cited

* All relevant supporting information is included in the manuscript submission,

* There are no issues that prevent the paper from being properly typeset

If revisions are needed, the production department will contact you directly to resolve them. If no revisions are needed, you will receive an email when the publication date has been set. At this time, we do not offer pre-publication proofs to authors during production of the accepted work. Please keep in mind that we are working through a large volume of accepted articles, so please give us a few weeks to review your paper and let you know the next and final steps.

Lastly, if your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.

If we can help with anything else, please email us at customercare@plos.org.

Thank you for submitting your work to PLOS ONE and supporting open access.

Kind regards,

PLOS ONE Editorial Office Staff

on behalf of

Dr. Li-Ping Liu

Academic Editor

PLOS ONE

Associated Data

    This section collects any data citations, data availability statements, or supplementary materials included in this article.

    Supplementary Materials

    S1 File. Contained the characteristics of each patient.

    (XLSX)

    pone.0311855.s001.xlsx (22.3KB, xlsx)
    Attachment

    Submitted filename: Response to Reviewers.docx

    pone.0311855.s002.docx (15KB, docx)
    Attachment

    Submitted filename: Response to Reviewers.docx

    pone.0311855.s003.docx (19.4KB, docx)

    Data Availability Statement

    All relevant data are within the manuscript and its Supporting Information files.


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