Letter to the Editor. Predictors for radiation toxicity and tumor control

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TO THE EDITOR: We read with interest the work of Aiyama and colleagues1 investigating whether conformity and gradient indices are predictors for radiation toxicity and local tumor control (Aiyama H, Yamamoto M, Kawabe T, et al: Clinical significance of conformity index and gradient index in patients undergoing stereotactic radiosurgery for a single metastatic tumor. J Neurosurg 129 [Suppl 1]:103–110, December 2018). For decades, we have known that successful radiation treatments require these qualities, although the degree to which they need to be refined to further improve treatment is unknown. Their conclusion is that lower conformity is related to improved local control and the gradient index (GI) has no effect on toxicity.

This work is actually investigating the clinical significance of not two but three qualities, as the conformity index (CI), while being a single value, combines two very different parameters: target coverage (which might predict local control) and selectivity/spillage outside the target (which might cause complications). Therefore, looking at the overall CI as a predictor of either local control or toxicity is flawed.

Considering the large range of CIs and GIs, it is not surprising that no correlation with toxicity was detected. The lowest CI was 0.08 and the largest GI was 11.4. These values would be associated with treatment of very small metastases, which are safe to treat, even with a poor conformity.2 Conversely, large metastases are usually planned with great attention to conformity and gradient, but despite optimal planning, larger lesions are more prone to local failure and toxicity. This is shown in their data, i.e., their cumulative incidences of local progression were significantly lower in patients with CIs < 0.65 than in those with CIs ≥ 0.65. However, 66% of lesions < 5 cm3 in their study had poor CIs (<0.65), but for lesions ≥ 5 cm3, this dropped to just 26%.

In order to mitigate confounders, volumes were divided into two groups: < 5 cm3 vs ≥ 5 cm3. However, this method would not eliminate volume as a confounding factor; volumes in the < 5 cm3 group range from 0.01 cm3 to 5 cm3, so vary by a factor of 500. Sneed et al.,3 in their study investigating 2200 brain metastases, divided this range into four and found an increasing incidence of symptomatic radiation necrosis; < 1%, 1%, 3%, and 10% for target diameters 0.3–0.6 cm, 0.7–1.0 cm, 1.1–1.5 cm, and 1.6–2 cm, respectively. These four ranges all reside within the < 5 cm3 subdivision, demonstrating that further divisions of volume are required to eliminate bias.

Clearly the authors are not suggesting that the principles of conformity and gradient should be abandoned. Taken to the extreme, no one would suggest that a conformity of 0.01 for a 15-cm3 metastasis is acceptable (this is the CI of a whole brain treatment when the tumor volume is 15 cm3 and the brain volume is 1500 cm3). Similarly, a GI of 100 in a perfectly conformal plan of a 15-cm3 lesion, treated to 20 Gy, would yield a mean brain dose > 10 Gy and have potentially catastrophic effects. The question is, when does further refinement of a treatment plan matter? This has yet to be revealed by a clinical study. In the meantime, we have a duty of care to reduce extraneous dose to normal tissue where possible.

Disclosures

Mr. Paddick reports being a consultant for Elekta.

References

  • 1

    Aiyama HYamamoto MKawabe TWatanabe SKoiso TSato Y: Clinical significance of conformity index and gradient index in patients undergoing stereotactic radiosurgery for a single metastatic tumor. J Neurosurg 129 (Suppl 1):1031102018

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  • 2

    Nakamura JLVerhey LJSmith VPetti PLLambourn KRLarson DA: Dose conformity of Gamma Knife radiosurgery and risk factors for complications. Int J Radiat Oncol Biol Phys 51:131313192001

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  • 3

    Sneed PKMendez JVemer-van den Hoek JGMSeymour ZAMa LMolinaro AM: Adverse radiation effect after stereotactic radiosurgery for brain metastases: incidence, time course, and risk factors. J Neurosurg 123:3733862015

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INCLUDE WHEN CITING Published online June 21, 2019; DOI: 10.3171/2019.3.JNS19498.

Response

We thank Dr. Alexis Dimitriadis and Mr. Ian Paddick for their careful reading and analysis of our article. As they suggested, the CI is coverage multiplied by selectivity. With our treatment plan for brain metastases, target coverage ranges from 0.98 to 1.0, a range generally accepted by the Gamma Knife Radiosurgical Society. Thus, the CI reflects only selectivity. They stated that looking at the overall CI as a predictor of either local control or toxicity is flawed. However, we are uncertain as to why Mr. Paddick proposed CI as a parameter of good dose-planning.1,2

Dr. Dimitriadis and Mr. Paddick quoted an article written by Sneed and her colleagues.3 However, they did not describe the GI based on target diameters of 0.3–0.6 cm, 0.7–1.0 cm, 1.1–1.5 cm, and 1.6–2 cm. Furthermore, the most serious criticism of their article is that, as we discussed in our article, their cohort consisted of considerable numbers of patients who had multiple brain metastases. Although they did not explain the method applied to GI determination in patients with multiple brain metastases, Paddick’s GI cannot be correctly calculated in patients with multiple brain metastases. Nevertheless, according to the helpful suggestions made by Dr. Dimitriadis and Mr. Paddick, we investigated, using our own database, the relationship between tumor control/complications and the CI/GI, along with three tumor volume groups, i.e., < 1 cm3, ≥ 1.0 to < 3.0 cm3, and ≥ 3.0 to < 5.0 cm3, as shown in Table 1. We cannot as yet draw meaningful conclusions and must await the results of further studies using different, larger data sets, hopefully in the near future.

TABLE 1.

Analysis of complications and local recurrence after stereotactic radiosurgery

ComplicationLocal Recurrence
Vol (cm3)No. of PtsHR95% Confidence Intervalp ValueHR95% Confidence Intervalp Value
<1.0212
 CI <0.651950.2900.043–5.6860.330.8040.149–14.8930.84
 CI ≥0.6517
 GI <3.11111.2630.209–9.6000.802.1980.610–10.2070.23
 GI ≥3.1101
≥1.0 to <3.0146
 CI <0.65622.5660.018–4.0790.430.3000.069–0.9300.03
 CI ≥0.6584
 GI <3.1792.3320.496–3.3950.480.9670.345–2.5980.95
 GI ≥3.167
≥3.0 to <5.0126
 CI <0.65520.5490.080–2.3960.440.9820.260–3.1430.98
 CI ≥0.6574
 GI <3.1381.0030.146–4.4100.992.4190.712–7.6240.15
 GI ≥3.188

HR = hazard ratio; pts = patients.

References

  • 1

    Paddick I: A simple scoring ratio to index the conformity of radiosurgical treatment plans. Technical note. J Neurosurg 93 (Suppl 3):2192222000

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    • PubMed
    • Search Google Scholar
    • Export Citation
  • 2

    Paddick ILippitz B: A simple dose gradient measurement tool to complement the conformity index. J Neurosurg 105 Suppl:1942012006

  • 3

    Sneed PKMendez JVemer-van den Hoek JGMSeymour ZAMa LMolinaro AM: Adverse radiation effect after stereotactic radiosurgery for brain metastases: incidence, time course, and risk factors. J Neurosurg 123:3733862015

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation

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Article Information

Correspondence Ian Paddick: ian@physicsconsulting.co.uk.

INCLUDE WHEN CITING Published online June 21, 2019; DOI: 10.3171/2019.2.JNS19420.

Disclosures Mr. Paddick reports being a consultant for Elekta.

© AANS, except where prohibited by US copyright law.

Headings

References

  • 1

    Aiyama HYamamoto MKawabe TWatanabe SKoiso TSato Y: Clinical significance of conformity index and gradient index in patients undergoing stereotactic radiosurgery for a single metastatic tumor. J Neurosurg 129 (Suppl 1):1031102018

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 2

    Nakamura JLVerhey LJSmith VPetti PLLambourn KRLarson DA: Dose conformity of Gamma Knife radiosurgery and risk factors for complications. Int J Radiat Oncol Biol Phys 51:131313192001

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 3

    Sneed PKMendez JVemer-van den Hoek JGMSeymour ZAMa LMolinaro AM: Adverse radiation effect after stereotactic radiosurgery for brain metastases: incidence, time course, and risk factors. J Neurosurg 123:3733862015

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 1

    Paddick I: A simple scoring ratio to index the conformity of radiosurgical treatment plans. Technical note. J Neurosurg 93 (Suppl 3):2192222000

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 2

    Paddick ILippitz B: A simple dose gradient measurement tool to complement the conformity index. J Neurosurg 105 Suppl:1942012006

  • 3

    Sneed PKMendez JVemer-van den Hoek JGMSeymour ZAMa LMolinaro AM: Adverse radiation effect after stereotactic radiosurgery for brain metastases: incidence, time course, and risk factors. J Neurosurg 123:3733862015

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation

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