Κυριακή, 3 Απριλίου 2016


The use of immunotherapy is increasing in cancer care, but more research is needed to measure the effectiveness of treatment, researchers write in a report published in the Journal of Clinical Oncology.
Determining clinical efficacy can be challenging because of pseudoprogression and other distinct immune-related patterns of response that have been observed with these therapies.
The WHO and the RECIST Group have traditionally provided standard guidelines for defining tumor response to therapy, note authors Victoria L. Chiou, MD, and Mauricio Burotto, MD, both from the National Cancer Institute.
Although not perfect, the RECIST criteria are an accepted platform for defining "the moment of disease progression." For years, these criteria have guided clinician determination of tumor response and driven the subsequent approval of drugs.
However, the phenomenon of pseudoprogression, which can involve a temporary increase in tumor size and the development of new lesions, could be prematurely diagnosed as progressive disease with the RECIST or WHO criteria.
These unique immune responses prompted the development of the immune-related response criteria in 2009, which provided a basis for assessing response to immunotherapeutic agents (Clin Cancer Res2009;15:7412-7420).
However, the authors argue that the patterns of immune-related responses need to be better characterized.
"My main point is that because immune-related responses are low and we still don't have enough information about the dynamics of immune responses, we have to use the traditional RECIST criteria in real-world settings," said Dr Burotto.
"Moreover, if we tend to use immune-related responses, we could be overtreating patients who are not receiving any benefit from immunotherapy," he told Medscape Medical News.
Using the Immune Response Criteria
An example illustrating this point comes from a trial of pembrolizumab (Keytruda, Merck) in patients with melanoma, Drs Chiou and Burotto explain. In that study, 12% of the 411 patients were classified as responders or as having stable disease with immune-response criteria, but these patients would have been classified as having progressive disease with RECIST criteria (J Clin Oncol2014[suppl 15s]:32,abstr 3006).
This subgroup of patients classified as responders with the immune-response criteria also showed improved overall survival, compared with those who met the criteria for progressive disease with both the immune-response and RECIST criteria.
The authors note that a number of recent clinical trials involving PD-1 and PD-L1 inhibitors, which are used to treat a variety of advanced solid tumors, have enabled a "broader evaluation of pseudoprogression across solid tumors."
However, immune-response criteria are not widely integrated into these studies
The primary response end points for the studies included the RECIST 1.0, RECIST 1.1, and modified WHO criteria, and the majority used immune-response criteria, determined by investigator, as a corollary to the RECIST criteria.
In some of the studies, these criteria were used to help make clinical decisions in the event of a mixed response, such as a decrease in target lesions or the development of new nontarget lesions, the authors write.
In others, the immune-related response criteria were used as an exploratory end point. "Immune-related response criteria were not used in the reporting of objective response rates in 71% of the studies (10 of 14 studies)," they note.
Additionally, a head-to-head comparison of RECIST criteria and immune-related response criteria was performed in less than a third of the studies (four of 14 studies), with similar response rates.
"Increased reporting of immune-related response phenomena in ongoing trials is necessary to determine whether pseudoprogression is a surrogate for clinical benefit and increased survival and to further elucidate the complex dynamics of tumor interactions with the immune system," the authors conclude.
"We hope that every immunotherapy trial will be capturing this," Dr Burotto commented.
Immunotherapy in Palliative Care
In a letter published online February 29 that referenced this report, Annie Wong, MD, and her colleagues from the Peter MacCallum Cancer Centre in East Melbourne, Australia, highlight the "urgent need for more quality-of-life, palliative care, and survivorship research as we enter the era of immuno-oncology."
There is a notable lack of information regarding immunotherapy in the palliative care setting and at the end of life, Dr Wong's team notes.
"Traditionally, therapeutic decisions and end-of-life discussions are framed by a guarded prognosis measured in months," they write. "However, increasing availability of immune-based approaches that can yield rapid, dramatic, and durable responses — albeit in a minority of patients — has resulted in these lines being blurred."
"Divergence between providing therapies that potentially afford long-term responses in a subset of patients while also meeting the palliative care needs of the majority creates significant challenges," Dr Wong and colleagues note.
For example, a patient who has progressed according to standard RECIST criteria early in their immune therapy treatment could potentially still have a response to an immunotherapy. But decisions to treat beyond disease progression to "accommodate the possibility of a delayed response" could result in the prolongation of futile treatment.
This would delay transition to the next line of therapy, and continuing with immunotherapy in this setting could result in restrictions of supportive medications, such as steroids, the authors explain.
Overall, the advent of these agents raises a number of questions for the clinician, they write. For instance, how aggressively should a patient with metastatic disease be managed, given that they now have a chance of a durable response?
Questions about health resources also come into play, as these new agents could impose significant financial pressure on patients and their families, they point out.
But so far, the literature is lacking when it comes to guidance for clinicians who are faced with the option of immunotherapy in a patient receiving palliative care, commented Odette Spruyt, MBChB, a coauthor of the letter.
"At Peter MacCallum, we are auditing the response of patients treated over the past 5 years to see if we can retrospectively identify predictors of response, to help guide clinicians caring for patients with advanced disease," Dr Spruyt told Medscape Medical News.
There is also little information about responses in patients with a poor performance status, because these patients are generally excluded from clinical trials. It is very difficult to recruit patients with poor performance status into clinical trials," she said, "so we do the best we can at this stage."
And in Response...
In a reply to the letter, Drs Chiou and Burotto say they agree that these issues need to be addressed, especially as patients continue to gain wider access to these drugs.
"These novel therapies, with distinct mechanisms of action and immune-related patterns of response, have opened the door for further critical conversations for patients with cancer," they write in their response.
Patients are increasingly active advocates when evaluating their treatment options, and no matter where they are in the disease paradigm, they will approach their provider teams for guidance when deciding whether to pursue novel and/or experimental therapies, the authors note.
"Oncologists and palliative care providers perform a pivotal role in increasing awareness of immune-related patterns of response and guiding transitions to survivorship follow-up, next treatments, and supportive care," say Drs Chiou and Burotto.
As the number of patients treated with immunotherapy increases, emerging information about responders with a range of solid tumor types will expand knowledge about survivorship.
"In the field of immunotherapy, there are many stakeholders," they add. "Together, clinicians, investigators, regulatory agencies, drug developers, and ultimately our patients, are driving important ongoing conversations to improve cancer care."
The report was supported by the Intramural Program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health. Dr Spruyt reports a relationship with Teva Pharmaceuticals. Several of her coauthors report relationships with pharmaceutical companies, as detailed in the letter. Dr Chiou, Dr Burotto, and Dr Wong have disclosed no relevant financial relationships.
J Clin Oncol. 2015;33:3541-3543. Full text
J Clin Oncol. Published online February 29, 2106

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