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does anyone gives TMZ with hypofractionated schedule for GBM ( for ex 40Gy/15fr)?
concomitant TMZ with hypofractionated RT for GBM
- Thread starter Kroll2013
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You can do it. There are a number of Phase II trials and retrospective reports, who have done it. No increased toxicity.
One small "problem" is that you will be giving half the total dose of TMZ during RT, sicnce RT will be over after 3 and not 6 weeks. I've seen med oncs who prescribed the TMZ for a further 3 weeks after completion of RT in order to reach the Stupp-Trial dose. Others simply stopped it at completion of RT and waited to restart it in the maintenance phase.
The question you should be asking however is why to give concurrent TMZ and hypoFx RT in the first place? If you are planning to give hypoFx RT because the patient is old or frail, you could just give RT alone and give TMZ only at progression. The benefit of concurrent RT and TMZ is limited in elder and frail patients. And if you want to give TMZ because your patient has an MGMT-methylated tumor, then you could simply give TMZ alone and keep RT as an option at further progression. There is randomized evidence showing this to be a good approach in elder patients.
One small "problem" is that you will be giving half the total dose of TMZ during RT, sicnce RT will be over after 3 and not 6 weeks. I've seen med oncs who prescribed the TMZ for a further 3 weeks after completion of RT in order to reach the Stupp-Trial dose. Others simply stopped it at completion of RT and waited to restart it in the maintenance phase.
The question you should be asking however is why to give concurrent TMZ and hypoFx RT in the first place? If you are planning to give hypoFx RT because the patient is old or frail, you could just give RT alone and give TMZ only at progression. The benefit of concurrent RT and TMZ is limited in elder and frail patients. And if you want to give TMZ because your patient has an MGMT-methylated tumor, then you could simply give TMZ alone and keep RT as an option at further progression. There is randomized evidence showing this to be a good approach in elder patients.
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Agree with Palex. If I see a patient age > 70 or KPS < 70 who desires abbreviated treatment I tailor to hyofrac XRT alone for negative MGMT and TMZ alone for positive MGMT.
Occasionally a patient wants aggressive treatment with shorter XRT I which case both approaches may be combined.
Occasionally a patient wants aggressive treatment with shorter XRT I which case both approaches may be combined.
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Just looked up this article today from the Red Journal, in case you didn't see it: Hypofractionated Versus Standard Radiation Therapy With or Without Temozolomide for Older Glioblastoma Patients (Arvold et al Jun 2015, Joint Center). At least it appears to be safe and non-inferior in elderly patients.
Discussion
Age has long been considered one of the most important prognostic factors for patients with malignant glioma (2). Given the shorter OS times relative to that of younger patients, there have been efforts to de-intensify treatment in order to improve quality of life. Although the administration of radiation therapy has been shown to confer a survival benefit (5), the optimal radiation dose schedule is not well characterized, particularly in the setting of concurrent and adjuvant TMZ. In the absence of TMZ, the study by Roa et al (8) showed that 40 Gy in 15 daily fractions was similar to 60 Gy in 30 fractions for patients ≥60 years of age with KPS of ≥50. One caveat to these data is that it was a small, underpowered study that only ruled out a 13.7% absolute survival difference at 6 months. Nonetheless, the survival curves were almost entirely overlapping with a HR of 1.0 (95% CI: 0.65-1.53). The Nordic trial randomized patients ≥60 years of age with World Health Organization performance status (PS) of 0 to 2 to either TMZ alone, 34 Gy in 10 fractions over 2 weeks, or 60 Gy in 30 fractions over 6 weeks (7). In the overall cohort, there were no differences between the 2-week and 6-week course of radiation, but there was improved survival for the 2-week course in patients older than 70 years of age (7). It is unknown whether these data still apply in the setting of concurrent TMZ. One argument against this idea is that a 3-week course of daily TMZ is half the amount of TMZ given in standard course regimens. If daily TMZ has an independent effect from purely radiosensitization (perhaps overwhelming the MGMT enzyme in unmethylated patients), then patients may be getting less chemotherapy than is optimal. Furthermore, if there is a benefit from radiosensitization, it may require longer concurrent treatment.
Multiple noncomparative studies have reported on clinical outcomes following HRT + TMZ in the elderly, with median survival ranging between 6.9 and 12.4 months (9, 10, 11, 12, 13, 14, 15), but there are no randomized data to guide decision making. A single-arm phase 2 study demonstrated that the approach was safe and tolerable (15), although the lack of a control arm limits any further conclusions. In a retrospective observational study of patients between 65 and 75 years of age, Gzell et al (16) showed that patients receiving 60 Gy with TMZ had longer OS than those receiving 40 Gy with TMZ, although the numbers were quite small (less than 10 patients in both groups), and controls for potential confounding prognostic factors due to selection bias were not incorporated. Our institutional data showed that 40 Gy in 15 fractions was generally administered to older patients and/or those with lower performance status. Patients receiving HRT alone had the lowest median baseline KPS (score of 50) of the treatment cohorts and did particularly poorly, with a median survival of only approximately 4 months. Although the study by Roa et al (8) allowed patients with baseline KPS as low as 50 in the trial, low performance status was not an inclusion criterion, and the median KPS in that trial was 70 (range: 60-80). Furthermore, although the Nordic trial showed an interaction between treatment arm and age, there was no such relationship between treatment arm and performance score (7). The imbalances demonstrated in our data are evidence for significant bias in selecting patients for hypofractionated regimens, likely due to lack of direct data showing similar outcomes for these regimens in the setting of TMZ or enrollment in clinical trials that use standard fractionation. It is worth noting that when patients enrolled in clinical trials were excluded, the imbalances of age and performance status remained statistically significant (data not shown). These selection biases show that more definitive data for hypofractionated regimens in the setting of concurrent and adjuvant TMZ may have a significant impact on practice patterns among centers with similar selection practices as our institution. These biases make retrospective head-to-head comparison of treatment regimens more difficult, however.
Although only randomization can control for unknown prognostic variables, propensity scores have been useful to help control for known prognostic variables when comparing treatment regimens. The propensity score is the conditional probability of receiving a specific treatment, given the individual's covariates, and is used to mitigate bias in observational studies (17). Following adjustment using the propensity score model, we did not find a statistically significant difference in OS between HRT + TMZ and SRT + TMZ. This could be related to power (the difference between treatment groups was not significant on univariate analysis either) or be model-specific, but the HR for treatment group was substantially mitigated once controls for prognostic variables were included.
There was clearly bias in selection of patients for hypofractionated regimens, and once this bias was controlled for, there was no longer a trend toward worse OS for HRT + TMZ. Our results are hypothesis-generating, and although the results of the NCIC CTG CE.6, EORTC 26062-22061, and TROG 08.02 studies may provide the answer to whether the addition of TMZ to HRT is better than HRT alone and thereby reduce selection bias and treatment variation, the question of SRT + TMZ versus HRT + TMZ will still remain. It remains possible that SRT + TMZ could result in better outcomes due to TMZ treatment intensification (doubling of daily exposure) and/or longer time for adequate radiosensitization. Alternatively, HRT + TMZ may have several benefits to the patient, particularly from the quality-of-life standpoint, and if HRT + TMZ truly affords the same survival as a longer course of radiation therapy, the shorter course would be preferable. Furthermore, if longer concurrent treatment does not influence the degree of radiosensitization and daily TMZ functions purely as a radiosensitizer, halving the amount of total TMZ may result in improved toxicity profiles. Any future clinical trials attempting to answer this question would therefore certainly benefit from the use of several patient-centric endpoints, in addition to OS, to quantify such benefits.
Conclusions
HRT for newly diagnosed GBM in the elderly is often administered to the oldest patients and those with lower performance status. Controlling for this selection bias, we observed no OS differences between SRT and HRT when given with concurrent TMZ. Previous and ongoing trials of HRT among older patients with GBM have not compared outcomes to the standard regimen of SRT + TMZ. Although a randomized trial of SRT + TMZ versus HRT + TMZ may be the most clinically useful in defining optimal management for elderly patients, the amount of patients required for an appropriately powered noninferiority trial may limit interest, necessitating reliance on developing other sources of data and analytical methods such as population-based studies or multi-institutional registries (18).
Discussion
Age has long been considered one of the most important prognostic factors for patients with malignant glioma (2). Given the shorter OS times relative to that of younger patients, there have been efforts to de-intensify treatment in order to improve quality of life. Although the administration of radiation therapy has been shown to confer a survival benefit (5), the optimal radiation dose schedule is not well characterized, particularly in the setting of concurrent and adjuvant TMZ. In the absence of TMZ, the study by Roa et al (8) showed that 40 Gy in 15 daily fractions was similar to 60 Gy in 30 fractions for patients ≥60 years of age with KPS of ≥50. One caveat to these data is that it was a small, underpowered study that only ruled out a 13.7% absolute survival difference at 6 months. Nonetheless, the survival curves were almost entirely overlapping with a HR of 1.0 (95% CI: 0.65-1.53). The Nordic trial randomized patients ≥60 years of age with World Health Organization performance status (PS) of 0 to 2 to either TMZ alone, 34 Gy in 10 fractions over 2 weeks, or 60 Gy in 30 fractions over 6 weeks (7). In the overall cohort, there were no differences between the 2-week and 6-week course of radiation, but there was improved survival for the 2-week course in patients older than 70 years of age (7). It is unknown whether these data still apply in the setting of concurrent TMZ. One argument against this idea is that a 3-week course of daily TMZ is half the amount of TMZ given in standard course regimens. If daily TMZ has an independent effect from purely radiosensitization (perhaps overwhelming the MGMT enzyme in unmethylated patients), then patients may be getting less chemotherapy than is optimal. Furthermore, if there is a benefit from radiosensitization, it may require longer concurrent treatment.
Multiple noncomparative studies have reported on clinical outcomes following HRT + TMZ in the elderly, with median survival ranging between 6.9 and 12.4 months (9, 10, 11, 12, 13, 14, 15), but there are no randomized data to guide decision making. A single-arm phase 2 study demonstrated that the approach was safe and tolerable (15), although the lack of a control arm limits any further conclusions. In a retrospective observational study of patients between 65 and 75 years of age, Gzell et al (16) showed that patients receiving 60 Gy with TMZ had longer OS than those receiving 40 Gy with TMZ, although the numbers were quite small (less than 10 patients in both groups), and controls for potential confounding prognostic factors due to selection bias were not incorporated. Our institutional data showed that 40 Gy in 15 fractions was generally administered to older patients and/or those with lower performance status. Patients receiving HRT alone had the lowest median baseline KPS (score of 50) of the treatment cohorts and did particularly poorly, with a median survival of only approximately 4 months. Although the study by Roa et al (8) allowed patients with baseline KPS as low as 50 in the trial, low performance status was not an inclusion criterion, and the median KPS in that trial was 70 (range: 60-80). Furthermore, although the Nordic trial showed an interaction between treatment arm and age, there was no such relationship between treatment arm and performance score (7). The imbalances demonstrated in our data are evidence for significant bias in selecting patients for hypofractionated regimens, likely due to lack of direct data showing similar outcomes for these regimens in the setting of TMZ or enrollment in clinical trials that use standard fractionation. It is worth noting that when patients enrolled in clinical trials were excluded, the imbalances of age and performance status remained statistically significant (data not shown). These selection biases show that more definitive data for hypofractionated regimens in the setting of concurrent and adjuvant TMZ may have a significant impact on practice patterns among centers with similar selection practices as our institution. These biases make retrospective head-to-head comparison of treatment regimens more difficult, however.
Although only randomization can control for unknown prognostic variables, propensity scores have been useful to help control for known prognostic variables when comparing treatment regimens. The propensity score is the conditional probability of receiving a specific treatment, given the individual's covariates, and is used to mitigate bias in observational studies (17). Following adjustment using the propensity score model, we did not find a statistically significant difference in OS between HRT + TMZ and SRT + TMZ. This could be related to power (the difference between treatment groups was not significant on univariate analysis either) or be model-specific, but the HR for treatment group was substantially mitigated once controls for prognostic variables were included.
There was clearly bias in selection of patients for hypofractionated regimens, and once this bias was controlled for, there was no longer a trend toward worse OS for HRT + TMZ. Our results are hypothesis-generating, and although the results of the NCIC CTG CE.6, EORTC 26062-22061, and TROG 08.02 studies may provide the answer to whether the addition of TMZ to HRT is better than HRT alone and thereby reduce selection bias and treatment variation, the question of SRT + TMZ versus HRT + TMZ will still remain. It remains possible that SRT + TMZ could result in better outcomes due to TMZ treatment intensification (doubling of daily exposure) and/or longer time for adequate radiosensitization. Alternatively, HRT + TMZ may have several benefits to the patient, particularly from the quality-of-life standpoint, and if HRT + TMZ truly affords the same survival as a longer course of radiation therapy, the shorter course would be preferable. Furthermore, if longer concurrent treatment does not influence the degree of radiosensitization and daily TMZ functions purely as a radiosensitizer, halving the amount of total TMZ may result in improved toxicity profiles. Any future clinical trials attempting to answer this question would therefore certainly benefit from the use of several patient-centric endpoints, in addition to OS, to quantify such benefits.
Conclusions
HRT for newly diagnosed GBM in the elderly is often administered to the oldest patients and those with lower performance status. Controlling for this selection bias, we observed no OS differences between SRT and HRT when given with concurrent TMZ. Previous and ongoing trials of HRT among older patients with GBM have not compared outcomes to the standard regimen of SRT + TMZ. Although a randomized trial of SRT + TMZ versus HRT + TMZ may be the most clinically useful in defining optimal management for elderly patients, the amount of patients required for an appropriately powered noninferiority trial may limit interest, necessitating reliance on developing other sources of data and analytical methods such as population-based studies or multi-institutional registries (18).
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I opted for hypofrx though it is a pt of 56yo bcz he has very agressive infiltrative multifocal dz , rapidly progressing. So i was thinking of starting the first part of the trt as hypofx then continue the boost in 2Gy/fx.
