Review Reports - Stereotactic Body Radiation Therapy for Symptomatic Pancreatic Insulinoma: Two-Case Report and Literature Review

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

This case report demonstrates the potential of Stereotactic body radiation therapy (SBRT) in treating inoperable pancreatic insulinomas, making it a valuable clinical case study. The article has a certain degree of novelty and is of high quality, with a clear structure and detailed content. The case descriptions are thorough and logically coherent, the discussion is comprehensive, and the conclusions are strong. However, there are some details that can be improved.

1. The text mentions follow-up results but lacks detailed long-term follow-up data, such as changes in blood glucose levels, body weight, and other long-term trends. Providing more detailed follow-up data, including blood glucose levels, body weight, and symptom changes at multiple time points, would further demonstrate the long-term efficacy and safety of SBRT.

2. The case descriptions mention the alleviation of hypoglycemic symptoms but lack detailed symptom assessments and changes in quality of life. Including assessments of patient symptoms and quality of life during follow-up, using standardized scales, would provide a more comprehensive evaluation of efficacy.

3. Although the treatment process and dosage of SBRT are described, the planning process and technical details are not thoroughly explained. Clarifying the treatment planning process in detail, including the criteria for target area selection, dose distribution maps, and dose-volume histograms, would help readers better understand the implementation details and technical requirements of SBRT.

4. Although it is mentioned that no significant early or late toxicity was observed, specific monitoring and evaluation data are lacking. Detailing the monitoring process for complications and side effects during treatment and follow-up, including specific monitoring indicators, evaluation methods, and time points, would support the safety claims of SBRT.

5. Enhancing the discussion on differential diagnosis, explaining in detail how other potential diseases were ruled out, would improve diagnostic accuracy and credibility.

6. Expanding the discussion on potential side effects and complications during treatment, providing more data to ensure the safety of the treatment method, would be beneficial.

7. Further elaborating on the comparative analysis of other treatment methods (e.g., surgery, pharmacotherapy), highlighting the advantages and limitations of SBRT, would strengthen the discussion section.

Author Response

Thank you very much for your review and very helpful suggestion.

This case report demonstrates the potential of stereotactic body radiation therapy (SBRT) in treating inoperable pancreatic insulinomas, making it a valuable clinical case study. The article has a certain degree of novelty and is of high quality, with a clear structure and detailed content. The case descriptions are thorough and logically coherent, the discussion is comprehensive, and the conclusions are strong. However, there are some details that can be improved.

Comments 1. The text mentions follow-up results but lacks detailed long-term follow-up data, such as changes in blood glucose levels, body weight, and other long-term trends. Providing more detailed follow-up data, including blood glucose levels, body weight, and symptom changes at multiple time points, would further demonstrate the long-term efficacy and safety of SBRT.

Response 1.

Based on an interview with the patient during each follow-up visit, the patient's general condition was assessed and whether hypoglycemia incidents occurred. Glucose and insulin levels were measured, creatinine levels, electrolytes, TSH (first patient) were determined, and blood counts were examined. The change in glucose levels over time is shown in Figures 5 and 8.

There were no deviations in blood parameters that could result from toxicity of the treatment, only deviations related to insulinoma and concomitant diseases such as renal failure. Body weight was not measured, but the patients did not report any weight loss.

The reviewer's comment is very valid, and certainly body weight, blood parameters and symptom changes at multiple time points will be evaluated in the future, especially in the case of a prospective study.

Comments 2. The case descriptions mention the alleviation of hypoglycemic symptoms but lack detailed evaluations of symptoms and changes in quality of life. Including assessments of patient symptoms and quality of life during follow-up, using standardized scales, would provide a more comprehensive evaluation of efficacy.

Response 2.

We agree with the reviewer that detailed evaluation of quality of life would be important, but this was a retrospective study, therefore it was difficult to collect detailed information about the quality of life with available questionnaires as QLQ 30 and EORTC QLQ-PAN26.

Comments 3. Although the treatment process and SBRT dosage of SBRT are described, the planning process and technical details are not thoroughly explained. Clarifying the treatment planning process in detail, including the criteria for target area selection, dose distribution maps, and dose-volume histograms, would help readers better understand the implementation details and technical requirements of SBRT.

Response 3.

Additional information was added on SBRT planning.

GTV was delineated on PET/CT, MR and CT. To create PTV, a 5 mm margin to GTV was added.

Critical organs such as the kidney, liver, spinal canal, small intestine, large intestine, stomach, duodenum, and vessels were contoured. The total dose was 35 Gy in 5 fractions to limit the dose to the small intestine. The maximum dose to the small intestine was 31.73 Gy and according to the Timmerman's tables, a dose of 32 Gy was recommended. Dose distribution is shown on figure 2. Image-guided respiration-gated radiation therapy (IGRT) was used using cone beam computed tomography (CBCT).

In July 2016, the patient received image-guided respiration-gated radiation therapy to the pancreatic tumour with a fractional dose of 10 Gy to a total dose of 30 Gy (Fig.7) to limit the dose to the duodenum. GTV was determined based on CT and MRI. IGRT was performed using kV images therefore additional margins were used; CTV-GTV margins of 5 mm and PTV-CTV of 4 mm were added.

In both cases, we draw critical organs such as the kidney, liver, spinal canal, small intestine, large intestine, stomach and duodenum, and vessels. When the patients described in the publication were irradiated, we used the dose recommendations from available Timmerman's tables. We are currently relying on the update information from Timmerman's published recommendations.

The GTV was delineated on MR, CT and PET/CT in the first case. The added margin to the GTV depended on the type of verification before fraction-gated CBCT /kV. The total dose depended on the location of the critical organs.

Comments 4. Although it is mentioned that no significant early or late toxicity was observed, specific monitoring and evaluation data are lacking. Detailing the monitoring process for complications and side effects during treatment and follow-up, including specific monitoring indicators, evaluation methods, and time points, would support the safety claims of SBRT.

Response 4.

We added:

The first follow-up was 1 month after radiotherapy and after every 3 months for 6 months and every 3 to 8 months afterward.

The first follow-up was 1 month after SBRT, during the next year and half every 3 months and the last visit was after one year due to a compression fracture of the L1 vertebral body due to osteoporosis and the inability to return for a follow-up visit.

During the follow-up period of 2 years in the first case and 2 years and 9 months in the second case, there was no radiological or biochemical progression of the disease.

Comments 5. Enhancing the discussion of differential diagnosis, explaining in detail how other potential diseases were ruled out, would improve diagnostic accuracy and credibility.

Response 5.

Information was added:

Diagnosis of insulinoma is based on clinical picture and consistent biochemical tests, low glucose level (2.5 mmol/l) accompanied by high insulin level (more than 6 μU/ml). Other biochemical markers include elevated levels of C-peptide, proinsulin and β-hydroxybutyrate. Factitious hypoglycaemia should be ruled out with assessment of oral hypoglycaemic agents.

Wei et al. report that the detection rates for transabdominal ultrasound, CT, MRI, and EUS are 22%, 72%, 75%, and 80%, respectively. EUS in combination with fine needle aspiration biopsy (FNA) achieves sensitivity and specificity above 90%.

Some data suggest that insulinomas express highly glucagon-like peptide-1 receptors (GLP-1R) and thus are labelled with a GLP-1R agonist.

Comments 6. Expanding the discussion of potential side effects and complications during treatment, pro

Providing more data to ensure the safety of the treatment method, would be beneficial.

Response 6.

Information was added:

We use multifraction regimens in our patients due to concerns about gastrointestinal toxicity. Schellenberg et al. showed that the use of a single dose of 25 Gy in locally advanced pancreatic cancer resulted in an increased risk of duodenal ulcers, strictures and perforation. Pollom et al. compared single- versus multifraction stereotactic body radiation therapy for pancreatic adenocarcinoma and there were significantly fewer instances of toxicity grade ≥2 with multifraction SBRT.

Comments 7. Further elaborating on the comparative analysis of other treatment methods (eg surgery, pharmacotherapy), highlighting the advantages and limitations of SBRT, would strengthen the discussion section.

Response 7.

Thank you for this comment; we added:

Currently, enucleation is performed in 56% of patients, distal pancreatectomy in 32%, Whipple in 3%, subtotal pancreatectomy in less than 3%, while 0.5% of cases undergo exploratory laparotomy and biopsy. However, surgical treatment is associated with the risk of complications. Even with laparoscopic treatment, pancreatic fistula (7.2%), abscess (2%), diabetes mellitus (7.5%), pancreatitis (3.1%), and pulmonary embolism (1.8%) are observe. SBRT is not an invasive method that, as in our cases, can be safely applied in operable patients with major comorbidities to achieve stabilization of the disease with a decrease in drug intake.

Reviewer 2 Report

Comments and Suggestions for Authors

General comments:

This is a case report of two patients with insulinoma successfully treated with stereotactic body radiation therapy (SBRT). This report is interesting and shows that SBRT may be a promising treatment for patients with functional neuroendocrine tumors of the pancreas, such as insulinoma, particularly for patients with limited treatment options because of old age or severe comorbidities. It will give useful information to readers and add a new strategy to the treatment of pancreatic neuroendocrine tumors. However, there are some problems that the authors need to clarify and revise as mentioned in the specific comments below.

Specific comments:

1. Abstract, page 1

“…stereotactic radiotherapy (SBRT).” It should be stereotactic body radiotherapy, isn’t it? Please check it.

2. Introduction, page 1

“About 50% of well differentiated neuroendocrine are functional, and…” Is a word like “tumors” missing?

3. First case, page 2

In this patient, PET/CT was taken for diagnosis. Please specify the nuclide used for PET/CT.

A total dose of 35 Gy in 7 Gy fractions was delivered to the pancreatic tumor. Detailed information of SBRT, including the radiation technique (3DCRT or IMRT?), prescribed dose point (isodose, peripheral dose, or D₉₅?), and dose constraints for the organs at risk, needs to be given. Ditto in the second case.

This patient died of concomitant disease. What was the concomitant disease? The disease might be concretely shown to guarantee that it was not a therapy-related toxicity.

4. Second case, page 2

For this patient, a total dose of 30 Gy in 10 Gy fractions was used. What was the rationale to determine the dose fractionation used for the treatment of the first and second cases? It should be mentioned in the discussion section.

5. Figure 2, Figure legends, page 3

“Dose distribution in the transverse and sagittal planes.” Is it correct? They do not look like the dose distribution. If so, please denote %dose.

6. Figure 7, Figure legends, page 5

The abbreviation, “OAR” is used in the first appearance. It seems to be incomprehensible to non-radiation oncologists. Please spell it in the full.

Comments on the Quality of English Language

Overall, it seems good.

Author Response

Thank you very much for your review and very helpful suggestion.

Specific comments:

Abstract, page 1

“…stereotactic radiotherapy (SBRT).” It should be stereotactic body radiotherapy, isn’t it? Please check it.

Response 1.

Thank you for this remark, we changed it accordingly.

To prevent tumour growth and hormonal excess, stereotactic radiotherapy may be an alternative to surgical treatment. In our paper, we present 2 cases of patients with insulinoma treated successfully with stereotactic body radiation therapy (SBRT).

Keywords: pancreatic insulinoma; stereotactic body radiation therapy; local control

Introduction, page 1

“About 50% of well differentiated neuroendocrine are functional, and…” Is a word like “tumors” missing?

Response 2.

Thank you for this remark, we changed it accordingly.

Insulinoma is the most common functional neuroendocrine tumour of the pancreas with the main clinical symptom of hypoglycemia.

First case, page 2

In this patient, PET/CT was taken for diagnosis. Please specify the nuclide used for PET/CT.

A total dose of 35 Gy was delivered in 7 Gy fractions was delivered to the pancreatic tumor. Detailed information of SBRT, including the radiation technique (3DCRT or IMRT?), prescribed dose point (isodose, peripheral dose, or D₉₅?), and dose constraints for the organs at risk, needs to be given. Ditto in the second case.

This patient died of concomitant disease. What was the concomitant disease? The disease might be concretely shown to guarantee that it was not a therapy-related toxicity.

Response 3.

Information below was added in the text:

In September 2018 Ga68 PET/CT Ga68 Dotatate scan and in October abdominal contrast enhanced magnetic resonance imaging were performed and showed a pancreatic lesion (Fig. 1a) and a small (7x8 mm) peripancreatic lymph node. Tectrotide scintigraphy was also performed.

Additional information was added on SBRT planning.

GTV was delineated on PET/CT, MR and CT. To create PTV, a 5 mm margin to GTV was added. Critical organs such as the kidney, liver, spinal canal, small intestine, large intestine, stomach, duodenum, and vessels were contoured. The total dose was 35 Gy in 5 fractions to limit the dose to the small intestine. The maximum dose to the small intestine was 31.73 Gy and according to the Timmerman's tables, a dose of 32 Gy was recommended. Dose distribution is shown on figure 2. Image-guided respiration-gated radiation therapy (IGRT) was used using cone beam computed tomography (CBCT).

The patient was treated with volumetric arc therapy (VMAT). Dose distribution in the transverse and sagittal planes is shown as a dose wash colour. The minimum dose is set to 35 Gy. There was a dose decrease in the proximity of the intestine (the minimum dose in PTV was 30Gy). Colours legend: orange, liver; green, bowel, cyan – left kidney; blue, right kidney, magenta – vessels, red – GTV/PTV.

We add information:

The patient died in March 2019 due to comorbidities and deterioration of the general condition without symptoms of radiological or biochemical progression.

Second case, page 2

For this patient, a total dose of 30 Gy was used in 10 Gy fractions. What was the rationale to determine the dose fractionation used for the treatment of the first and second cases? It should be mentioned in the discussion section.

Response 4.

We added:

The total dose was 35 Gy in 5 fractions to limit the dose to the small intestine. The maximum dose to the small intestine was 31.73 Gy and according to the Timmerman's tables, a dose of 32 Gy was recommended.

Figure 2, Figure legends, page 3

’Dose distribution in the transverse and sagittal planes.” Is it correct? They do not look like the dose distribution. If so, please denote %dose.

We changed the description of the figure:

Response 5.

Figure 7, Figure legends, page 5

The abbreviation, “OAR” is used in the first appearance. It seems to be incomprehensible to non-radiation oncologists. Please spell it in the full.

Response 6.

Thank you for this comment. We add the explanation.

The dose is shown as a wash colours. The minimum dose is set at 28.5 Gy. Dose decrease in OAR (organ at risk) volume, such as intestines, duodenum, spinal cord, liver, and stomach, in line with international guidelines for doses to these organs. Colours legend: yellow/green – duodenum, blue bowel, magenta – stomach, red – GTV/CTV/PTV.

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

I think this version is eligible for publication.

Author Response

Thank you very much for your review.

Reviewer 2 Report

Comments and Suggestions for Authors

It was remarkably refined by the revision. However, there is still one point that should be corrected as mentioned below.

1. Figure 2

“…volumetric arc therapy (VMAT)…” It should be “volumetric modulated arc therapy”, shouldn’t it? Please correct it.

In addition, was the second case also treated with VMAT? Please clarify it.

Comments on the Quality of English Language

Overall, it seems good.

Author Response

Thank you very much for your review and very helpful suggestion.

Comments 1.

Figure 2

“…volumetric arc therapy (VMAT)…” It should be “volumetric modulated arc therapy”, shouldn’t it? Please correct it.

In addition, was the second case also treated with VMAT? Please clarify it.

Response 1.

We agree with this comment.

We changed : The patient was treated with volumetric modulated arc therapy (VMAT).

The second patient was also treated with VMAT and we added this in figure 7.