Clinical Outcomes of RTOG 9310 Protocol for Primary Central Nervous System Lymphoma: Single-Center Experience with 87 Patients

Round 1

Reviewer 1 Report

Reviewed changes....Adequate

This manuscript is a resubmission of an earlier submission. The following is a list of the peer review reports and author responses from that submission.

Round 1

Reviewer 1 Report

The authors present their results of treatment for Primary CNs Lymphoma following the guidelines of the RTOG 9310 protocol. They compared the results they obtained to the published results from the protocol.

They showed an encouraging improvement of Overall Survival and Progression Free Survival. In the discussion, the authors went to explain the differences between the two approaches in an attempt to justify the different outcomes. There is an overwhelming amount of graphs and tables (9 pages) and a very long discussion section (3 pages). This renders the manuscript discouraging to read as the readers become easily lost in details, which can at times be confusing.

Author Response

See details in the attachment.

Author Response File: Author Response.pdf

Reviewer 2 Report

Comments – major

1. The radiation dose is incorrectly stated. According to the Methods section patients received a whole brain dose of 45 Gy unless a complete response had occurred due to the chemotherapy, in which case the whole brain dose was 36 Gy. The radiation dosing provided in the abstract needs to be corrected. Instead of “Whole brain radiotherapy was followed by 45 Gy for residual tumors and 36 Gy for remitted tumors.” the authors should consider something like “Whole brain radiotherapy consisting of 45 Gy for patients with less than a complete response to the chemotherapy or 36 Gy for complete responders was started ___ weeks after the last dose of chemotherapy was administered.”
2. The chemotherapy description is incomplete. In addition to the doses of methotrexate, vincristine and procarbazine that are provided, according to the Methods, all patients also received high dose dexamethasone and some patients received high dose cytarabine. The chemotherapy description in the abstract needs to be corrected.
3. Table 1 is incomplete. It should include the cytarabine.
4. Patient enrolment (p 3) and patient characteristics (p 5 and 6). As the authors acknowledge interpretation of single arm clinical experiences such as is reported in this paper is always complicated by selection bias. It is very helpful to know that 13 of the 100 patients with primary CNS lymphoma who presented to this center during the study period 2007 to 2020 were excluded from the analysis.
5. p 6, last paragraph and Table 4. The histopathology description is confusing. Germinal center B-cell-like lymphoma is a type of diffuse large B-cell lymphoma. What does “others” mean in Table 4? A less confusing description of the histopathology should be provided.
6. p 11 Figure 2. Graph A appears to be mislabeled. I doubt that the younger patients had a much worse progression free survival.
7. Figures 2 and 3 graphs A. These results are difficult to believe. The first graph A estimates that almost 60% patients over age 60 experience a progression by 5 years and 90% by 10 years but the second graph A indicates this had very little impact on overall survival, which is projected to be approximately 80% at 5 years with no deaths are anticipated after that, implying that secondary treatments for disease progressing despite protocol treatment were extraordinarily effective, an experience strongly at variance with experience elsewhere. If this remarkable observation is correct it certainly requires explanation and description of the unexpectedly effective secondary treatment.
8. p 17, discussion. The authors claim that several clinical trials have proven that the addition of rituximab is beneficial but provide no citations validating this statement. The one citation is to a review article that in turn cites the IELSG32 trial, which actually only demonstrated that the addition of rituximab and thiotepa improved results. The claim about the benefit of rituximab should be softened.

 

Comments – minor

1. p 5-6. The sentence “The mean age of these patients at the time of the PCNSL diagnosis was 57.6 years (range, 32.4–81.2 years)” is confusingly placed, appearing to refer to the 13 patients who were excluded when, in fact, it refers to the 87 fully enrolled patients. This sentence should be moved to after the sentence “The study population included 45 men 237 (51.7%) and 42 women (48.3%).”
2. p 3. The timing of the leucovorin doses is imprecise. Was the leucovorin after the high dose methotrexate started 24 hours after the initiation of the methotrexate or 24 hours after the methotrexate was finished. When was the leucovorin after the intra-Ommaya injection of methotrexate started? “[T]he evening” is too vague. How many hours after the intra-Ommaya injection of methotrexate was the leucovorin started.
3. p 5. The first paragraph under Results should be removed. It is an instruction to the authors, not a part of the report.
4. p 6. 3^rd line from the bottom. The correct term is germinal center B-cell-like lymphoma, not germinal cell.

Author Response

see attachment

Author Response File: Author Response.pdf