Thema: TTF position paper
TTF position paper
DHH e.V.
13.05.2019 09:27:22
Patient representatives call for a controlled study
Treatment option evaluation G-BA
Advantages for patients need to be central concern
Health care in Germany is administered jointly by political and other bodies, and is subject to the Federal Joint Committee (G-BA), the highest decision-making body of the joint self-government of physicians, dentists, hospitals and health insurance funds in Germany. The commission issues directives and thus specifies which services in medical care are reimbursed by the statutory health insurance funds (Gesetzliche Krankenversicherung).
The evaluation subcommittee of the G-BA announced on 25 July 2018 its intention of evaluating the therapeutic use of “tumor treating fields” as a supplementary component to standard therapies in first-line treatment of Glioblastoma. Such an announcement requires the agency to consult professionals, whether individual researchers, associations or patient representatives, and invites these to present their point of view.
The Deutsche Hirntumorhilfe (DHH or German Brain Tumor Association) is pleased to submit its input as outlined below. The DHH is a nationwide organization, independently funded and managed for public benefit, which has the twin aims of improving patient care and of supporting research in neurooncology. The DHH is in contact with over 4000 brain-tumor patients and their family members each year. It offers a central information service and a number of public events throughout the year.
Patient representatives call for a controlled study on the use of tumor-treating field (TTF) devices in Glioblastoma
Experts in medical associations have questions that they say remain unanswered on the application of TTF alternating-current devices in the treatment of brain-tumor patients. The Deutsche Hirntumorhilfe advocates an independently funded clinical trial to clarify some of the points raised. The TTF device includes four transducer arrays, each consisting of nine insulated electrodes which are applied to the patient’s scalp to deliver low-intensity, intermediate-frequency (200 kHz) alternating electric fields. The device is known as Optune and is marketed by the company Novocure.
Since 2005 a standard protocol for first-line treatment of glioblastoma (GBM) has become established, consisting of surgical resection, followed by concurrent radiation/chemotherapy and six subsequent cycles of chemotherapy. Most recently, additional treatments have been experimentally added in an attempt to improve outcomes. One of these trials is the application of TTF.
One trial (EF-11) focusing on 120 patients with a recurrent GBM showed no benefit for the users. [1] A subsequent phase-III clinical trial (EF-14) looked at newly diagnosed GBM patients and applied the TTFs in addition to the standard therapy outlined above. Median overall survival times under this regime were 20.9 months, versus 16 months with Temozolomide alone. [2]
Doubts raised over reported outcomes in EF-14 study
Whether the TTFs actually produced the effects noted, and to what extent, remains unclear, as the specialist associations point out. These include the Neuroonkologische Arbeitsgemeinschaft (NOA), Deutsche Gesellschaft für Neurologie (DGN), Deutsche Gesellschaft für Neurochirurgie (DGNC), Deutsche Gesellschaft für Radioonkologie (DEGRO) and Deutsche Gesellschaft für Neuroradiologie (DGNR). They point out that the TTF-treated patients in the study – unlike those in the control group – received frequent specialist support from Novocure’s staff during their treatment. Such regular, qualified support is known in itself to lead to improvements in quality of life and indeed in overall survival. [3-7] Thus, the TTF device might not be solely responsible for the improvements seen; appropriate therapeutic, care-oriented, psychological and social support might have achieved comparable outcomes without the additional burden of the electronic equipment. Since the control group did not receive a TTF device, the study in any case falls short of the standards required for blinding of the experiment. A new study should be designed to include sham interventions to eliminate these potential causes of bias.
Controlled, independent study called for
While the published results of the EF-14 trial do show an improvement in overall survival, TTF treatment comes with significant compromises: a requirement that the head be shaved regularly, 18-hour application per day, an unmistakable sign for observers that the wearer has a head illness, the expectation of warmth and other electrical side-effects, not to mention the frequent support-personnel visits. In view of these and other concerns, the learned societies have demanded that an independent controlled study be initiated. The Deutsche Hirntumorhilfe supports this demand, since it feels unable to recommend the approach to its members or the public without meaningful research results to hand.
From the patient’s point of view, extending life at all costs is not the aim of treatment; quality of life is also a major consideration. Brain tumor patients should be able to achieve an acceptable quality of life over the final months and years. A current research project shows the majority of patients with advanced tumors rate their autonomy and quality of life as more important than length of life and progression-free survival. [8] Thus, while overall survival should indeed be an aim of treatment, prolonged acceptable quality of life, with limited neurocognitive deficits and no neurological limitations, is of equal importance to patients.
Limitations more significant than supposed
Patients undergoing TTF treatment may experience burdens that have not yet been assessed, and these should be explored in any evaluation of the method and equipment. The patient’s neurological status and quality of life should be improved under a new therapeutic approach. No data have yet been published to indicate any improvement in quality of life from the TTF helmet: the impacts are fundamentally palliative in nature.
To date, there is no published evidence that the TTF worsens quality of life. [9] However, within the scope of the DHH’s information service, some patients reported significant stress from the application of the TTF device. So, the charity has examined patient reports relating to TTF use in its 2018 records, with specific reference to quality-of-life impacts and treatment side effects. Patients were asked which of these effects they rated most significant and what might have motivated them to discontinue such treatment prematurely.
Fifty-two such GBM patients were questioned. Of these, 38% refused TTF use when it was first suggested. Of those who did use it, two thirds reported skin irritation and rashes at the stick-on contact points. One third reported pain in back or neck. All patients experienced one or more severe quality-of-life limitations in their daily life in the course of the treatment. These could be generalized restrictions (see below), constant need for assistance, persistent reminders of one’s illness, stigmatization through the appearance of the TTF helmet and the visibility of a brain/head complaint, electric shocks, vibrations, disagreeable oscillations and a perception that those around them were worried by electronic radiation.
The generalized restrictions reported by users related to the changing of adhesive contacts, restrictions on personal mobility, persistent irritation related to the wearing of the helmet or its wires, unpleasant levels of heat generation/sweating, limitations in work or hobby, as well as alarm and ventilator noise. Less frequent mention was made of weight gain through decreased physical activity levels, skin rashes, or the perception that the wiring needed for the helmet was in fact an indicator that the patient represented a security risk (eg at the airport, the Christmas market or on a museum visit).
Twenty-eight percent of the users reported that their TTF use had been abandoned prematurely. The most frequent reasons given were the intolerable side effects or restrictions imposed on daily life and its quality. Nor did the patients welcome the persistent reminder of their illness. Some reported that the doctor responsible for their treatment had little faith in the efficacy of the treatment.
In summary, patients’ responses to the application of the TTF device were wide ranging, and their assessment of the equipment’s side effects was also highly diverse. Nevertheless, for a majority of them, the limitations on their daily life were significant and were experienced as a major loss of quality of life. Those who used the TTF device did so while accepting these persistent limitations and losses. Helmet use brought on reductions in quality of life that tended to last throughout the therapy process, rather than the one-off discomforts that tumor patients generally suffer from treatments.
TTF helmets: who needs them?
The recently published results of the NOA-09 research study [10] on first-line treatment for GBM patients provide a useful point of reference to evaluate the EF-14 results with the TTF helmet. The NOA-09 research showed a significant improvement in overall survival from replacing the standard post-operative chemotherapy treatment with a combination of Lomustine and Temozolomide, from 31.4 months to 48.1 months, for patients with MGMT-promoter methylation. This improvement was largely not associated with a worsening of side effects. [11] In consequence, at least for this subgroup of patients, a new basis of comparison should be used. Does the helmet offer any advantages for such people? Its claimed benefits and known disadvantages for the patient’s daily life need to be offset, at least for the relevant group of MGMT-promoter-methylated patients, to produce a new cost-benefit comparison. Quality of life needs methodical scrutiny in a comparative study of this therapy protocol against the application of TTF helmets.
Belief in efficacy is not an argument
Patients diagnosed with GBM have few therapy options to date. Those who have faith in the claimed therapeutic benefits of the TTF helmet, and understand the likely implications for their quality of life during treatment, must accept the approach in the knowledge that no blind testing with a genuine control-group has taken place; the benefits must therefore count as unproven.
As a question of consumer protection, such a therapy approach implies a number of ethical questions. Faith alone is not enough. Patients need to know that the claimed benefits were observed in a single clinical trial with questionable scientific validity. If the medical profession is to live up to its own ethical standards, it should not allow the current unproven assertions of the TTF helmet marketing effort to go unchallenged.
Sources
[1] Stupp R, et al. Eur J Cancer. 2012 Sep ; 48(14) :2192-202 [sic]
[2] Stupp R, et al. JAMA. 2017 Dec 19;318(23):2306-2316
[3] Temel JS, et al. N Engl J Med. 2010 ; 363 :733-42
[4] Bakitas MA, et al. J Clin Oncol. 2015 ; 33 :1438-45
[5] Zimmermann C, et al. Lancet. 2014; 383:172-30 [sic]
[6] Higginson IJ, et al. Lancet Respir Med. 2014 ; 2 :979-87
[7] Dyar S, et al. J Palliat Med. 2012; 15:890-5
[8] Sullivan DR, et al. Lung Cancer. 2019 May ; 131 : 47-57
[9] Taphoorn MJB, et al. JAMA Oncol. 2018;4(4):495-504
[10] Herrlinger U, et al. Lancet 2019 Feb 16; 393 810172):678-688
[11] Weller J, et al. Brainstorm 2019 Feb; 1:2. SNO Abstract QoLP-20
Leipzig, 12.05.2019
Deutsche Hirntumorhilfe e.V.
German Brain Tumor Association
Karl-Heine-Str. 27
D-04229 Leipzig
Germany
Tel.: +49 341.590 93 96
Fax: +49 341.590 93 97
info@hirntumorhilfe.de
https://www.hirntumorhilfe.de
Donate now!
Donation account
Sparkasse Muldental
IBAN: DE83 8605 0200 1010 0369 00
BIC: SOLADES1GRM
Treatment option evaluation G-BA
Advantages for patients need to be central concern
Health care in Germany is administered jointly by political and other bodies, and is subject to the Federal Joint Committee (G-BA), the highest decision-making body of the joint self-government of physicians, dentists, hospitals and health insurance funds in Germany. The commission issues directives and thus specifies which services in medical care are reimbursed by the statutory health insurance funds (Gesetzliche Krankenversicherung).
The evaluation subcommittee of the G-BA announced on 25 July 2018 its intention of evaluating the therapeutic use of “tumor treating fields” as a supplementary component to standard therapies in first-line treatment of Glioblastoma. Such an announcement requires the agency to consult professionals, whether individual researchers, associations or patient representatives, and invites these to present their point of view.
The Deutsche Hirntumorhilfe (DHH or German Brain Tumor Association) is pleased to submit its input as outlined below. The DHH is a nationwide organization, independently funded and managed for public benefit, which has the twin aims of improving patient care and of supporting research in neurooncology. The DHH is in contact with over 4000 brain-tumor patients and their family members each year. It offers a central information service and a number of public events throughout the year.
Patient representatives call for a controlled study on the use of tumor-treating field (TTF) devices in Glioblastoma
Experts in medical associations have questions that they say remain unanswered on the application of TTF alternating-current devices in the treatment of brain-tumor patients. The Deutsche Hirntumorhilfe advocates an independently funded clinical trial to clarify some of the points raised. The TTF device includes four transducer arrays, each consisting of nine insulated electrodes which are applied to the patient’s scalp to deliver low-intensity, intermediate-frequency (200 kHz) alternating electric fields. The device is known as Optune and is marketed by the company Novocure.
Since 2005 a standard protocol for first-line treatment of glioblastoma (GBM) has become established, consisting of surgical resection, followed by concurrent radiation/chemotherapy and six subsequent cycles of chemotherapy. Most recently, additional treatments have been experimentally added in an attempt to improve outcomes. One of these trials is the application of TTF.
One trial (EF-11) focusing on 120 patients with a recurrent GBM showed no benefit for the users. [1] A subsequent phase-III clinical trial (EF-14) looked at newly diagnosed GBM patients and applied the TTFs in addition to the standard therapy outlined above. Median overall survival times under this regime were 20.9 months, versus 16 months with Temozolomide alone. [2]
Doubts raised over reported outcomes in EF-14 study
Whether the TTFs actually produced the effects noted, and to what extent, remains unclear, as the specialist associations point out. These include the Neuroonkologische Arbeitsgemeinschaft (NOA), Deutsche Gesellschaft für Neurologie (DGN), Deutsche Gesellschaft für Neurochirurgie (DGNC), Deutsche Gesellschaft für Radioonkologie (DEGRO) and Deutsche Gesellschaft für Neuroradiologie (DGNR). They point out that the TTF-treated patients in the study – unlike those in the control group – received frequent specialist support from Novocure’s staff during their treatment. Such regular, qualified support is known in itself to lead to improvements in quality of life and indeed in overall survival. [3-7] Thus, the TTF device might not be solely responsible for the improvements seen; appropriate therapeutic, care-oriented, psychological and social support might have achieved comparable outcomes without the additional burden of the electronic equipment. Since the control group did not receive a TTF device, the study in any case falls short of the standards required for blinding of the experiment. A new study should be designed to include sham interventions to eliminate these potential causes of bias.
Controlled, independent study called for
While the published results of the EF-14 trial do show an improvement in overall survival, TTF treatment comes with significant compromises: a requirement that the head be shaved regularly, 18-hour application per day, an unmistakable sign for observers that the wearer has a head illness, the expectation of warmth and other electrical side-effects, not to mention the frequent support-personnel visits. In view of these and other concerns, the learned societies have demanded that an independent controlled study be initiated. The Deutsche Hirntumorhilfe supports this demand, since it feels unable to recommend the approach to its members or the public without meaningful research results to hand.
From the patient’s point of view, extending life at all costs is not the aim of treatment; quality of life is also a major consideration. Brain tumor patients should be able to achieve an acceptable quality of life over the final months and years. A current research project shows the majority of patients with advanced tumors rate their autonomy and quality of life as more important than length of life and progression-free survival. [8] Thus, while overall survival should indeed be an aim of treatment, prolonged acceptable quality of life, with limited neurocognitive deficits and no neurological limitations, is of equal importance to patients.
Limitations more significant than supposed
Patients undergoing TTF treatment may experience burdens that have not yet been assessed, and these should be explored in any evaluation of the method and equipment. The patient’s neurological status and quality of life should be improved under a new therapeutic approach. No data have yet been published to indicate any improvement in quality of life from the TTF helmet: the impacts are fundamentally palliative in nature.
To date, there is no published evidence that the TTF worsens quality of life. [9] However, within the scope of the DHH’s information service, some patients reported significant stress from the application of the TTF device. So, the charity has examined patient reports relating to TTF use in its 2018 records, with specific reference to quality-of-life impacts and treatment side effects. Patients were asked which of these effects they rated most significant and what might have motivated them to discontinue such treatment prematurely.
Fifty-two such GBM patients were questioned. Of these, 38% refused TTF use when it was first suggested. Of those who did use it, two thirds reported skin irritation and rashes at the stick-on contact points. One third reported pain in back or neck. All patients experienced one or more severe quality-of-life limitations in their daily life in the course of the treatment. These could be generalized restrictions (see below), constant need for assistance, persistent reminders of one’s illness, stigmatization through the appearance of the TTF helmet and the visibility of a brain/head complaint, electric shocks, vibrations, disagreeable oscillations and a perception that those around them were worried by electronic radiation.
The generalized restrictions reported by users related to the changing of adhesive contacts, restrictions on personal mobility, persistent irritation related to the wearing of the helmet or its wires, unpleasant levels of heat generation/sweating, limitations in work or hobby, as well as alarm and ventilator noise. Less frequent mention was made of weight gain through decreased physical activity levels, skin rashes, or the perception that the wiring needed for the helmet was in fact an indicator that the patient represented a security risk (eg at the airport, the Christmas market or on a museum visit).
Twenty-eight percent of the users reported that their TTF use had been abandoned prematurely. The most frequent reasons given were the intolerable side effects or restrictions imposed on daily life and its quality. Nor did the patients welcome the persistent reminder of their illness. Some reported that the doctor responsible for their treatment had little faith in the efficacy of the treatment.
In summary, patients’ responses to the application of the TTF device were wide ranging, and their assessment of the equipment’s side effects was also highly diverse. Nevertheless, for a majority of them, the limitations on their daily life were significant and were experienced as a major loss of quality of life. Those who used the TTF device did so while accepting these persistent limitations and losses. Helmet use brought on reductions in quality of life that tended to last throughout the therapy process, rather than the one-off discomforts that tumor patients generally suffer from treatments.
TTF helmets: who needs them?
The recently published results of the NOA-09 research study [10] on first-line treatment for GBM patients provide a useful point of reference to evaluate the EF-14 results with the TTF helmet. The NOA-09 research showed a significant improvement in overall survival from replacing the standard post-operative chemotherapy treatment with a combination of Lomustine and Temozolomide, from 31.4 months to 48.1 months, for patients with MGMT-promoter methylation. This improvement was largely not associated with a worsening of side effects. [11] In consequence, at least for this subgroup of patients, a new basis of comparison should be used. Does the helmet offer any advantages for such people? Its claimed benefits and known disadvantages for the patient’s daily life need to be offset, at least for the relevant group of MGMT-promoter-methylated patients, to produce a new cost-benefit comparison. Quality of life needs methodical scrutiny in a comparative study of this therapy protocol against the application of TTF helmets.
Belief in efficacy is not an argument
Patients diagnosed with GBM have few therapy options to date. Those who have faith in the claimed therapeutic benefits of the TTF helmet, and understand the likely implications for their quality of life during treatment, must accept the approach in the knowledge that no blind testing with a genuine control-group has taken place; the benefits must therefore count as unproven.
As a question of consumer protection, such a therapy approach implies a number of ethical questions. Faith alone is not enough. Patients need to know that the claimed benefits were observed in a single clinical trial with questionable scientific validity. If the medical profession is to live up to its own ethical standards, it should not allow the current unproven assertions of the TTF helmet marketing effort to go unchallenged.
Sources
[1] Stupp R, et al. Eur J Cancer. 2012 Sep ; 48(14) :2192-202 [sic]
[2] Stupp R, et al. JAMA. 2017 Dec 19;318(23):2306-2316
[3] Temel JS, et al. N Engl J Med. 2010 ; 363 :733-42
[4] Bakitas MA, et al. J Clin Oncol. 2015 ; 33 :1438-45
[5] Zimmermann C, et al. Lancet. 2014; 383:172-30 [sic]
[6] Higginson IJ, et al. Lancet Respir Med. 2014 ; 2 :979-87
[7] Dyar S, et al. J Palliat Med. 2012; 15:890-5
[8] Sullivan DR, et al. Lung Cancer. 2019 May ; 131 : 47-57
[9] Taphoorn MJB, et al. JAMA Oncol. 2018;4(4):495-504
[10] Herrlinger U, et al. Lancet 2019 Feb 16; 393 810172):678-688
[11] Weller J, et al. Brainstorm 2019 Feb; 1:2. SNO Abstract QoLP-20
Leipzig, 12.05.2019
Deutsche Hirntumorhilfe e.V.
German Brain Tumor Association
Karl-Heine-Str. 27
D-04229 Leipzig
Germany
Tel.: +49 341.590 93 96
Fax: +49 341.590 93 97
info@hirntumorhilfe.de
https://www.hirntumorhilfe.de
Donate now!
Donation account
Sparkasse Muldental
IBAN: DE83 8605 0200 1010 0369 00
BIC: SOLADES1GRM
DHH e.V.
