We appreciate the opportunity to reply to the points criticized. In the following, we will address each point individually and name the authors of the matching correspondence items in brackets.
1. Blinding, double publication (Hübner, Neubauer, Meyer, Schmacke, Wörmann): 1. Overall Survival (OS) was the primary endpoint (1). For this, FDA guidelines do not require blinding (2) since no placebo effect is expected and an observer bias with regard to the time of death is not possible. The quality-of-life results published in Deutsches Ärzteblatt are consistent with the OS treatment effects (1). In the context of OS studies, it is common to provide secondary publications of quality-of-life data collected under non-blinded conditions (3, 4).
2. Phase III declaration, single-center design, concealment of randomization (Meyer, Neubauer, Schmacke): Phase III characteristics are to plan the number of cases and to conduct a confirmatory analysis according to the guidelines of the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use; multi-center design is not a requirement in the good clinical practice (GCP) guidelines. Selection/performance bias is unlikely: The patients who participated in the study came from all oncology centers in Serbia and received no study-specific intervention after admission to the treatment. The randomization procedure is in line with CONSORT (“Enclosing assignments in sequentially numbered, opaque, sealed envelopes can be a good allocation concealment mechanism”) (5).
3. Termination of the study/overestimation of the treatment effect (Schmacke, Meyer): Since confirmatory significance levels for the OS superiority of the mistletoe group (α-level = 0.0042) were achieved, the group-sequential interim analysis allowed a protocol-compliant termination by the IDMC (Prof. Volker Diehl, Dr. Patrick Mansky, Prof. Ulrich Mansmann). An overestimation of the treatment effect is unlikely as the observed survival advantage is in line with those found in earlier studies (6).
4. No biopsy (Hübner, Neubauer, Wörmann): The current recommendations of the International Study Group of Pancreatic Surgery only require a biopsy proof of the diagnosis in cases in which the result is relevant to the management of the patient (7). Many patients in this study had unambiguous intraoperative or repeatedly progressive CT scan findings; consequently, a biopsy was often not required.
5. Statistical analysis, imbalances, distortions (Meyer, Neubauer, Wörmann): The current CONSORT statement 2010 differentiates the term “ITT“: “We replaced mention of “intention to treat“ analysis, a widely misused term, by a more explicit request for information about retaining participants in their original assigned groups.“ (8) Accordingly, the patient sub-groups with and without quality of live follow-up regarding QoL were compared (Tables 1 and 2 of the DÄ publication). In addition, the relevant literature on the measurement of quality of life in dying patient populations (9–11) was taken into consideration, as after 3 months already half and at the final visit already 86% of patients had died: Sensitivity analyses with “worst/ last values“ stratified by time of death were presented in the e-Supplement. According to Alshurafa (12), this is a valid analysis. A “last observation carried forward“ (LOCF) analysis does not reveal any qualitative differences compared with the published group differences (mean, [95% confidence interval]): “Global quality of health“ 24 (20 to 27); “physical function“ 18 [13 to 22]; “role function“ 14 [9 to 19]; ”emotional function“ 16 [11 to 21]; “cognitive function“ 14 [8 to 20]; “fatigue“ –26 [–31 to –21]; “nausea/vomiting“ –11 [–16 to –7]; “pain“ –20 [–25 to –14]; “insomnia“ –31 [–39 to –24]; “appetite loss“ –37 [–43 to –30]; body weight 6% [5 to 7] (all p < 0.0001 after Bonferroni correction). “Social function“ 8 [3 to 14]; p = 0.01 showed in the original analyses a minor difference too and “dyspnoea“ is not relevant to this disease. This LOCF analysis avoids imbalances; however, it distorts differences between means in a conservative direction and thus underestimates the true effect of the treatment.
6. Treatment standard, prior treatments/aftercare, best supportive care (BSC), (Hübner, Neubauer, Schmacke): The study arms are equivalent at baseline with regard to all studied sociodemographic and efficacy parameters; therefore, doubts relating to the successful randomization and consequently to the equal distribution of prior treatments are unfounded. Since the study was conducted as a centralized trial in Belgrade, it was possible to standardize the BSC options and offer them to all study patients.
7. Best palliative care (Hübner, Neubauer): Relative to survival time, the control patients, not the mistletoe patients, had more frequent contacts with the investigators. Patients with mistletoe treatment typically received only the initial mistletoe extract injections when they were admitted to the study center or the local health center; subsequently, the patients themselves or their relatives injected the mistletoe extract according to the instructions in the study protocol and documented each injection in the patient diaries.
8. Other mistletoe product for comparison (Meyer): The intention of this study was the proof of concept for mistletoe treatment versus BSC treatment alone.
9. Composition of (no interdisciplinary tumor conference) und decisions (no palliative chemotherapy, no revision) of the tumor board (Neubauer, Wörmann): Permanent members of the CCS’s tumor conference are pathologists, medical and gastrointestinal oncologists, radiologists, radiation therapists, and HBP surgeons; this composition fulfills the requirements for German oncology centers; its decision criteria were described in the DÄ publication.
10. Weight gain, financial situation (Hübner): Body weight stabilization or increase are frequently observed effects of mistletoe treatment and have been noted for several decades. In this trial, they were documented for the first time under standardized conditions. The mistletoe patients may have been more positive about their financial situation as the result of the reduced need for concomitant treatments.
11. Mistletoe treatment not known in Serbia (Meyer): Prior to the study, the investigators were informed about the mistletoe treatment; this did not change their neutral attitude towards mistletoe treatment.
12. Transferability to the German setting (Wörmann): In Germany, the proportion of patients who received no treatment other than BSC for various reasons is comparable in size (13). Therapies such as FOLFIRINOX are for patients in Germany just as little an option as for patients in Serbia.
13. Conflict of interest (Schmacke): It was made transparent that this study was financed by an interested party. With regard to the authors’ conflict of interest, please refer to the following statement.
In our opinion, the criticism expressed in the correspondence items cannot diminish the validity of the results of this study (14).
On behalf of the authors:
Dr. rer. nat. Wilfried Tröger
Conflict of interest statement
For all authors the following conflict of interest applies:
This trial was financially supported by the Swiss Cancer Research Association (Verein für Krebsforschung e. V. (VfK), Schweiz). The VfK receives license fees for the preparation of the active substance for the commercially available mistletoe drug Iscador from Weleda AG, the company that obtained approval for the drug. Weleda AG produced the trial drug as a separate lot and invoiced it to the VfK e.V. Wilfried Tröger, Marcus Reif, and Agnes Schumann are also involved in the conduct of other studies for the VfK.
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