The Agency for Healthcare Quality Research has defined quality in healthcare as “..… doing the right thing, at the right time, in the right way, for the right person—and having the best possible results” (18
). In this secondary analysis from RTOG 9704, we have observed that radiotherapy was not always administered in the prospectively defined “right” way, and when it was not, the treatment administered was associated with inferior survival () and was more likely to result in the occurrence of first failure (p=0.016) ().
For the gemcitabine arm deviation from recommended radiotherapy guidelines resulted in a trend toward increased acute toxicity, especially non-hematologic toxicity. Gemcitabine is a significantly more potent radiosensitizing agent than 5-FU and is also associated with radiotherapy recall (19
). The frequency of these deviations is consistent with the those seen in the German Hodgkins Disease Study Group for Study HD-10 (where radiotherapy was rated as suboptimal in 47% of cases) (21
), as well as in a number of other oncologic and non-oncologic studies (4
Additionally: 1. The impact on survival of a radiotherapy QA score of < PP remained significant upon multivariate analysis () 2. Arithmetically, the magnitude of effect on survival of RT QA score by itself was larger than that of treatment by itself (). Moreover, when the effect of RT QA score was taken into account by multivariate analysis, along with nodal involvement, this improved the precision of the estimate of the treatment effect between the two treatment arms and survival differences between the 2 treatment arms became significantly different for pancreatic head patients ().
We acknowledge that post treatment review can document but not prevent radiotherapy protocol variations. A mandated, rapid and efficient prospective method of review and intervention, as in now done through the Advanced Technology Committee of the RTOG, is required to prevent their inclusion in actual treatment (for more information please see www.rtog.org
). With this lesson in mind the current RTOG/SWOG/EORTC protocol for the adjuvant therapy of pancreatic adenocarcinoma (RTOG 0848) includes real time, prospective, mandated review and correction of deviations prior to the start of radiotherapy.
These observations result from a planned secondary analysis rather than a prospective assignment. There is no other way to study this issue ethically.
To our knowledge this analysis represents the first well documented association that radiotherapy quality, as defined by adherence to protocol specified guidelines, and survival may be strongly correlated in the management of any gastrointestinal malignancy, although our results relate specifically to pancreatic cancer. Speculatively, failure to fully appreciate this in past trials, may have contributed to the current uncertainty and controversy regarding the role of radiotherapy in this context (24
Although at the time we set out to examine these QA issues we were aware of accumulating experiences in more general medical situations that correlated guideline adherence with survival (12
). More recently, data have also become available from studies in oncologic contexts, both related and not related to the details of radiotherapeutic management, that confirm and reinforce the role of protocol adherence for optimal survival (23
It is acknowledged that radiation protocol violations could be associated with inferior survival without being the causative factor for inferior survival. Other possible associations with survival within these data were sought and not found.
Our data raise a number of questions. One of these is the mechanism by which QA deviation in radiotherapy might result in this outcome. To our minds, the most logical, possible explanation is that local regional radiotherapy is important for optimal survival in the context of adjuvant therapy for pancreatic adenocarcinoma. RTOG 9704 was designed from this perspective and both arms of management included radiation management. While acknowledging that the role of radiotherapy in this context has become more controversial since RTOG 9704 was designed over 13 years ago, it remains possible that this hypothesis is correct. RTOG 0848 has recently opened and is designed to address this question. That local regional radiotherapy would be important is consistent with some but not all reports examining this question (reviewed in ref 9
) and also consistent with the results of two randomized trials comparing radiotherapy plus chemotherapy to chemotherapy alone for locally unresectable patients (28
) and with data indicating that uncontrolled local regional disease is a frequent cause of death in pancreatic cancer (30
If radiotherapy is important for optimal survival, then inferior radiotherapy could logically be associated with inferior survival outcomes (23
). The appearance of the observed survival difference between PP and <PP treatment at12 and 18 months () mitigates against the cause being either acute or late radiotherapy toxicity. Additional support for our results can be inferred from: For malignancies with high frequencies of both nodal involvement and distant failure, a number of randomized, phase III trials have confirmed a survival advantage to chemotherapy and radiotherapy versus chemotherapy only (1
). Variation in surgery when done for local regional tumor management has also been documented to adversely impact on survival for a variety of tumors including pancreatic adenocarcinoma (37
). Because these differences generally correlate with operative experience or volumes, we looked for, but did not find, an association between outcome and number of patients enrolled per institution in our data.
A priori, one might expect that deviation from required radiotherapy parameters would have produced an increased incidence of first failure within the irradiated volume. However in both breast cancer and prostate cancer regional involvement often manifests first as systemic rather than regional failure (39
). Therefore, failure to identify a first failure difference within the irradiated volume of pancreatic cancer patients does not mitigate against the validity of our data, especially for a tumor where local regional failure patterns may be difficult to assess.