The objective of the present single-arm study was to demonstrate the clinical efficacy of the newly developed intratumoral thermotherapy using magnetic nanoparticles in conjunction with percutaneous irradiation for the treatment of recurrent GBM.
Because it is not randomized, this study specifically recognizes the potential for selection bias. A randomization would have been possible in theory but extremely difficult in practice because patients with recurrent glioblastoma are acutely aware of their impending mortality and therefore typically make a highly considered decision about any participation in trials of a new experimental therapy. Most would be loath to participate in a randomized study where they might only be receiving supportive treatment, and thus recruiting patients for randomized trials would have been difficult and considerably extended the time required for this study.
As with many other carcinomas, pre-therapeutic prognostic factors are major determinants of overall survival [37
], and survival may show greater correlation to these factors than any specific treatment. Selecting historical controls from past studies is thus not unproblematic since these frequently involve only small populations with differing prognostic factors (particularly KPS, age and prior treatment). For this reason, many studies have utilized the meta-analysis by Wong et al. [39
] as a baseline historical reference population. According to their study, the median survival for patients treated with chemotherapy following glioblastoma recurrence was 5.8 months. However, the recently published results of the EORTC-NCIC trial on primary glioblastoma by Stupp et al. [1
] reflect the more recent use of temozolomide as the current standard in the treatment of primary glioblastoma, and thus its results establish, in principle, a new baseline for survival data. Its OS-2 is particularly well suited to direct comparison with future study results because the primary therapy was conducted on a large patient population (n
= 287) using this currently prevailing standard treatment, while upon recurrence/progression, patients were treated at the local investigators’ discretion. The OS-2 data from this study may therefore be viewed as broadly representative of median survival using the range of salvage therapies currently available.
While recognizing the issues of data comparability between our’s and other studies, the extension of median OS-2 to 13.4 months in our study compared to 6.2 months in the Stupp study population [2
] can clearly be regarded as significant (using the statistical method of Simon [40
]). It should specifically be noted that it is not the results of the primary therapy being compared but rather survival following the best possible treatment upon tumor recurrence after standard first-line treatment.
Further evidence suggesting superiority of this new therapy is provided by the median secondary study endpoint OS-1, which at 23.2 months substantially exceeded the median 14.6 months in the reference group [1
]. In comparing the increase in median OS-2 of 7.2 months to the gain in OS-1 of 8.6 months, it is apparent that the great majority of the gain in overall survival followed recurrence and thus can be specifically attributed to the thermo-/radiotherapy. If one restricts the study group to only those patients who had not received any prior treatment following their first recurrence (n
= 35), the median OS-2 for this subset is shortened to 11.2 months but still much greater than 6.2 months. It may thus be inferred that the observed increase in survival is not attributable to any prior treatment of the recurrence before study entry. The remaining patients who had been previously treated (n
= 24) had a median OS-2 of 13.9 months.
The median age of the study population (56 years) was extremely close to the reference population (57 years), and median TTP-1 differed only modestly (8.0 vs 6.9 months), suggesting that the study results were not materially affected by patient selection and thus that they are clinically relevant. Data on other prognostic factors, such as tumor volume and KPS at recurrence, were unfortunately not available for the reference population.
In addition to examining the potential role of patient selection on survival, the extent to which the adjunct radiotherapy might have contributed to the increased survival must also be addressed. Prior studies of stereotactic fractionated radiotherapy following GBM recurrence, however, demonstrate only a lower increase in median survival, and in small patient groups. Hudes et al. [8
] and Vordermark et al. [13
] attained respective OS-2 of 10.5 months (n
= 19) and 7.9 months (n
= 14) using hypofractionated stereotactic radiotherapy, but both these studies involved relatively small tumor volumes. However, a retrospective study by Combs et al. involving similar tumor volumes in a comparable patient population (in terms of KPS and age) found a median survival of 8.1 months following fractionated stereotactic re-irradiation at a level of 36 Gy [12
The remarkable increase in overall survival in our study through the combination of thermotherapy with a lower radiotherapy dosage of 30 Gy thus indicates the efficacy of the applied heat, at least in this combination. It must be underscored that the studies of stereotactic radiosurgery involving tumors of significantly smaller volume do not necessarily offer a valid basis of comparison with our study results.
Even with deliberate selection of patients being treated for recurrent GBM using predefined criteria, Hau et al. [3
] could demonstrate only a modest increase in OS-2 to 7.6 months, although it must be noted that, with a median KPS of 70 and a TPP-1 of 6 months, the prognosis for their patient group was presumably slightly worse than for our own study population.
With regard to safety, intratumoral thermotherapy offers an approach to hyperthermia (or thermoablation) with only moderate side effects.
Two drawbacks of this new approach which warrant mention are, firstly, the need to remove all metal from within 40 cm of the treatment area (i.e., all dental work), and secondly, the indefinite exclusion of MRI for subsequent diagnosis of tumor progression. There remain, however, other effective methods beside CT to monitor disease progression including PET and SPECT, which can be regarded at least as good as MRI. Outside the area of nanoparticle deposits, conventional MRI according to current practice may still be used without any limitation. It should be noted that the exclusion of MRI for evaluating tumor progression arises not from the effects of MRI on the magnetic nanoparticles but, conversely, from the MRI artifacts resulting from the very high particle concentrations used. By comparison, iron-oxide nanoparticles are used in much lower concentrations for therapeutic targeting and MRI contrast enhancement of glioblastoma [41
In looking at the entirety of the observed side effects, intratumoral thermotherapy may be regarded as safe and well tolerated compared to other available treatment options. This study likewise demonstrates that, in the indicated patient group, this new therapeutic approach in conjunction with fractionated stereotactic radiotherapy is clinically effective. The increase in overall survival points to a clearly favorable risk–benefit ratio in patients with recurrent GBM.
Intratumoral thermotherapy may, in principle, be used in combination with any conventional therapy in order to amplify its effects and thus offers the potential for even greater potency. Because of the stability of the nanoparticle deposits, and in contrast to radiotherapy, which is subject to cumulative dosage limits, the thermotherapy sessions may be repeated or combined with other therapies without any inherent limit. The combination of intratumoral hyperthermia and chemotherapy (particularly temozolomide) presents a particularly promising approach which warrants further clinical investigation. The delivery of nanoparticles into the tumor using convection-enhanced delivery (CED) might be a potential alternative to direct intratumoral instillation and is thus also a potential subject for examination in future clinical studies.
Furthermore, because there are only marginal differences in temperature sensitivity between different body tissues [27
], one may suppose that patients with other solid tumors besides glioblastoma might benefit from this novel approach provided that sufficient temperatures can be safely attained in these tumors. This is the subject of other clinical studies currently in progress.