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  • Jonathan Abdelmalak1,2,3,
  • Simone I. Strasser4 and
  • Natalie L. Ngu4
  • et al.

Reviewer 1: Rafał Patryn Reviewer 2: Rajesh Selvaraj Reviewer 3: Giovanni Colonna Reviewer 4: Suvithanandhini Loganathan

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

It's worth considering whether this report provides facts and figures, but lacks a reason. It's important to know that the most common screening method for cancer detection is abdominal ultrasound (with diagnostic accuracy ranging from 58 to 89%/ss. 90%). It's worth investigating whether this method was unavailable or whether there was a lack of knowledge on the part of diagnosticians (?). 

Author Response

Reviewer 1

It's worth considering whether this report provides facts and figures, but lacks a reason. It's important to know that the most common screening method for cancer detection is abdominal ultrasound (with diagnostic accuracy ranging from 58 to 89%/ss. 90%). It's worth investigating whether this method was unavailable or whether there was a lack of knowledge on the part of diagnosticians (?). 

We have revised paragraph two of the discussion to read as follows: “Those living in rural and remote communities, especially First Nations Australians, are known to face systemic barriers in accessing HCC surveillance(19,20), reducing the likelihood that HCC will be diagnosed in early-stage where curative therapy is an option. HCC surveillance in Australia involves abdominal ultrasonography with or without serum alpha-fetoprotein testing and is clinician-driven, as no centralised surveillance program currently exists. HCC surveillance uptake in Australian primary care has historically been poor with one study reporting less than a third of chronic hepatitis B patients receiving appropriate surveillance(21) in contrast to those receiving specialist care where rates of uptake have been observed to be in excess of 80%(22). Furthermore, patients at risk for HCC, particularly those with non-viral cirrhosis, often go entirely unrecognised with one study demonstrating that up to a quarter of patients with HCC are only diagnosed with cirrhosis at the time of HCC diagnosis(23). Improving identification of those at-risk for HCC and access to HCC surveillance across Australia and similar other multicultural countries is a clear and urgent need and there has been a recent call for increased resourcing to identify those at-risk and for a national centralised surveillance program(10).”

Reviewer 2 Report

Comments and Suggestions for Authors
  1. Ethics for the study was approved by Monash Health Human Re- 116
    search Ethics Committee (HREC). - Approved number should be included.
  2. A total of 854 patients were included in this study, with 612 (72%) residing in metropolitan and 242 (18%) – Anything particular reason for choosing this much difference between the two groups.
  3. Non-metropolitan patients were significantly more likely to be Indigenous (5% vs 2%, p=0.001) – What indication those 2%? It is metropolitan. It should be clarify in the manuscript.
  4. Cox-proportional hazards logistic regression, with an overall median follow up time of 42.6 months (27.8 to 61.0 months) – Median or Mean?
  5. Abbreviation should be included in the manuscript.

Author Response

Reviewer 2

  1. Ethics for the study was approved by Monash Health Human Re- 116
    search Ethics Committee (HREC). - Approved number should be included.

This is now included (HREC Reference Number: HREC/80727/MonH−2022−302788(v3), 23 February 2022).

  1. A total of 854 patients were included in this study, with 612 (72%) residing in metropolitan and 242 (18%) – Anything particular reason for choosing this much difference between the two groups.

This was an observational study rather than an interventional study. The demography of our cohort represents that most patients managed at Australian tertiary centres with early-stage disease are residing in metropolitan areas. 

  1. Non-metropolitan patients were significantly more likely to be Indigenous (5% vs 2%, p=0.001) – What indication those 2%? It is metropolitan. It should be clarify in the manuscript.

For clarity, we have now modified the sentence to read: “Non-metropolitan patients, in comparison to metropolitan patients, were significantly more likely to be Indigenous (5% vs 2%, p=0.001).”

  1. Cox-proportional hazards logistic regression, with an overall median follow up time of 42.6 months (27.8 to 61.0 months) – Median or Mean?

Median.

  1. Abbreviation should be included in the manuscript.

Below tables and where abbreviations occur for the first time, we include the full written terms. If the editorial team of the journal would consider modifying their usual template, a full abbreviations section could be added that could include all abbreviations used in the manuscript.

Reviewer 3 Report

Comments and Suggestions for Authors

This report investigates the situation of Australian patients with early-stage liver cancer (HCC) treated at large hospitals, regardless of whether they reside in urban or rural areas. The authors studied 854 patients, mostly from cities and non-urban regions. After diagnosis, the study monitored the survival of these patients. The main finding is that survival rates are similar regardless of where patients live.

The manuscript explores whether geographic location affects survival outcomes in Australian patients with early-stage HCC treated at tertiary centers. Showing comparable survival between metropolitan and non-metropolitan areas suggests fair access or effective treatment strategies, which is valuable for health planning and policy. However, some points need clarification. The text does not specify adjustments for tumor characteristics, comorbidities, or treatment types that could influence survival. A mean follow-up of 42.6 months might not reveal long-term survival differences.

Since most patients (72%) live in metropolitan areas, the findings might not entirely reflect rural populations’ experiences. The sample may not wholly represent the entire population of early-stage HCC patients across Australia, especially those in rural or non-tertiary healthcare facilities. The data show that most patients are from metropolitan areas, while only 18% are from non-metropolitan regions. As the study focuses on patients treated at tertiary centers, it may exclude individuals managed in primary or secondary care or those with limited access to specialized treatment. This imbalance could lead to an overrepresentation of patients with better healthcare access, socioeconomic status, or health literacy—factors linked to better outcomes. Therefore, the survival results might not fully address disparities faced by rural populations, who often encounter barriers to care, delayed diagnoses, or limited treatment options. This potential bias in representation calls for caution when applying these findings to all Australian HCC patients, especially in resource-limited or non-tertiary settings. Future research should aim to include a broader range of healthcare environments to improve representativeness and address disparities more effectively. These aspects should be better explained to readers, and the manuscript should contain more details.

Author Response

Reviewer 3

  1. The text does not specify adjustments for tumor characteristics, comorbidities, or treatment types that could influence survival.

We do specify adjustments for tumour characteristics and comorbidities as described in the abstract, paragraph 3 of the results and Table 2. We did not adjust for treatment modality as systematic differences in treatment allocation may have been a mechanism for non-metropolitan patients to be disadvantaged.

 

  1. A mean follow-up of 42.6 months might not reveal long-term survival differences.

We have added this as a limitation in the final paragraph of the discussion as follows: “Secondly, statistical power is limited by the duration of follow-up and cohort size. Survival differences may have been observed with greater patient numbers or a longer duration of follow-up, particularly as non-metropolitan patients could be expected to receive systematically different longer-term care, such as reduced surveillance uptake which could theoretically delay the detection of late tumour recurrence and negatively affect long-term survival.”

  1. Since most patients (72%) live in metropolitan areas, the findings might not entirely reflect rural populations’ experiences. The sample may not wholly represent the entire population of early-stage HCC patients across Australia, especially those in rural or non-tertiary healthcare facilities. The data show that most patients are from metropolitan areas, while only 18% are from non-metropolitan regions. As the study focuses on patients treated at tertiary centers, it may exclude individuals managed in primary or secondary care or those with limited access to specialized treatment. This imbalance could lead to an overrepresentation of patients with better healthcare access, socioeconomic status, or health literacy—factors linked to better outcomes. Therefore, the survival results might not fully address disparities faced by rural populations, who often encounter barriers to care, delayed diagnoses, or limited treatment options. This potential bias in representation calls for caution when applying these findings to all Australian HCC patients, especially in resource-limited or non-tertiary settings. Future research should aim to include a broader range of healthcare environments to improve representativeness and address disparities more effectively. These aspects should be better explained to readers, and the manuscript should contain more details.

 

We have revised the final paragraph of the discussion as follows: “Importantly, our results are specific to a cohort of patients with early-stage disease at diagnosis who were referred to a metropolitan tertiary centre for management and therefore should not be generalised to all non-metropolitan patients with HCC, many of whom are diagnosed with more advanced disease or have limited access to tertiary care. Non-metropolitan Australian patients with HCC are not represented by the unique cohort described in our study and all available evidence suggests they face inferior survival outcomes compared to those living in metropolitan areas. The similarity in survival outcomes observed in our study suggests that early diagnosis and referral to expert multidisciplinary care are the two key factors needed in non-,metropolitan cohorts to achieve parity with metropolitan patients in HCC outcomes While we believe that our study provides compelling indirect evidence for stage at diagnosis and access to tertiary care as the likely explanations for the survival gap between metropolitan and non-metropolitan patients, direct evidence should be sought prospectively to definitively assess this, including direct comparisons between metropolitan and non-metropolitan by BCLC stage and by assessing differences in care between those referred to tertiary centres and those not referred.”

Reviewer 4 Report

Comments and Suggestions for Authors

The article is well written, clearly structured with sound methodology. The analysis addresses an important question and provides valuable real-world data between metropolitan and non-metropolitan residents. However, a few things need clarification and minor revisions to improve the interpretability of the data

 

  1. The study population is limited to patients with early-stage disease managed at tertiary centers. This is clearly acknowledged but should be more explicitly discussed as a key limitation. The findings cannot be extrapolated to the wider non-metropolitan population, many of whom may never reach tertiary services or are diagnosed at later stages.
  2. If possible, the authors should discuss how many non-metropolitan HCC patients are referred to tertiary centers annually.
  3. Clearly specify the primary outcome and the median follow up period in the abstract
  4. Include number at risk tables below Kaplan Meier plots for transparency.
  5. Table 1 is comprehensive but dense. Summarize key differences in the text rather than relying solely on table 1.
  6. The conclusion could highlight the practical implications for healthcare delivery (e.g., telemedicine, outreach programs).

Author Response

Reviewer 4

  1. The study population is limited to patients with early-stage disease managed at tertiary centers. This is clearly acknowledged but should be more explicitly discussed as a key limitation. The findings cannot be extrapolated to the wider non-metropolitan population, many of whom may never reach tertiary services or are diagnosed at later stages.

We have revised the final paragraph of the discussion as follows: “Importantly, our results are specific to a cohort of patients with early-stage disease at diagnosis who were referred to a metropolitan tertiary centre for management and therefore should not be generalised to all non-metropolitan patients with HCC, many of whom are diagnosed with more advanced disease or have limited access to tertiary care. Non-metropolitan Australian patients with HCC are not represented by the unique cohort described in our study and all available evidence suggests they face inferior survival outcomes compared to those living in metropolitan areas. The similarity in survival outcomes observed in our study suggests that early diagnosis and referral to expert multidisciplinary care are the two key factors needed in non-,metropolitan cohorts to achieve parity with metropolitan patients in HCC outcomes While we believe that our study provides compelling indirect evidence for stage at diagnosis and access to tertiary care as the likely explanations for the survival gap between metropolitan and non-metropolitan patients, direct evidence should be sought prospectively to definitively assess this, including direct comparisons between metropolitan and non-metropolitan by BCLC stage and by assessing differences in care between those referred to tertiary centres and those not referred.”

 

  1. If possible, the authors should discuss how many non-metropolitan HCC patients are referred to tertiary centers annually.

Unfortunately, we do not have this data available to include in this study.

  1. Clearly specify the primary outcome and the median follow up period in the abstract

We have added the sentence ‘The primary endpoint was adjusted all-cause mortality.’ Median follow-up time is outlined in line 58 in the third paragraph of the abstract.

  1. Include number at risk tables below Kaplan Meier plots for transparency.

The Kaplan Meier curves in Figure 2 include number at risk below the graph.

  1. Table 1 is comprehensive but dense. Summarize key differences in the text rather than relying solely on table 1.

Key differences are summarised in paragraph two of the results as follows: “Non-metropolitan patients, in comparison to metropolitan patients, were significantly more likely to be Indigenous (5% vs 2%, p=0.001), have cirrhosis (89% vs 81%, p=0.009), have lower platelet counts (median 119 x109/L vs 136 x109/L, p<0.001), less likely to be diagnosed on surveillance (74% vs 82%, p=0.017, remaining patients diagnosed incidentally on imaging performed for other indications) and more likely to be managed at a liver transplant centre (66% vs 45%, p<0.001) with corresponding differences in initial treatment strategy as previously described(11) with greater use of initial transarterial chemoembolization [TACE] (50% vs 39%) and lesser use of upfront ablation (16% vs 24%).  Metropolitan patients were much more likely to have chronic hepatitis B as an underlying cause of liver disease (16% vs 2%, p<0.001).  Age, sex, smoking, Charlson Comorbidity Index (CCI), Child Pugh Score, tumour burden and use of transplant over the course of follow-up did not significantly differ between the two groups.”

  1. The conclusion could highlight the practical implications for healthcare delivery (e.g., telemedicine, outreach programs).

We have concluded as follows: “Community-based models of care, ideally within the framework of a national centralised screening program, to improve identification of patients at risk for HCC and encourage adherence with semi-annual ultrasound surveillance are urgently needed and should be expected to reduce the gap in outcomes observed between Australians living in metropolitan and non-metropolitan areas.”

Round 2

Reviewer 3 Report

Comments and Suggestions for Authors

I appreciate the authors for clarifying the points I raised in the manuscript.