The overall goal is to update the healthcare professional’s knowledge of cancer detection and prevention and to understand current and new research regarding state-of-the-art care for those with or at risk for cancer.
Intended for advanced practice nurses, registered nurses, and other healthcare professionals who care for cancer patients.
Upon completion, participants should be able to:
Dannemiller is approved by the California Board of Registered Nursing, Provider Number 4229, for 1.0 contact hour. CBRN credit is not accepted by the Michigan and Utah State licensing boards.
The planners and authors of this CE activity have disclosed no relevant financial relationships with any commercial companies pertaining to this activity.
This activity is provided free of charge to participants.
Cognitive behavioral therapy for insomnia (CBT-I) and mindfulness-based stress reduction (MBSR) can improve sleep for patients with cancer, but CBT-I continues to be the best nonpharmacologic option, according to findings of a study directly comparing the two (J Clin Oncol. 2014;32(5):449-457).
Although medications are available for the treatment of insomnia, many cancer patients do not want to add to the already long list of medications they must take and also worry over possible side effects, drug interactions, and developing dependence.
For the study, 111 adults who received treatment at a Canadian tertiary cancer center for nonmetastatic cancer were randomly assigned to receive either CBT-I (n = 47) or MBSR (n = 64). The CBT-I protocol involved stimulus control, sleep restriction, cognitive therapy, and relaxation training. The MBSR program offered a psychoeducational component explaining the link between stress and health, accompanied by the practice of meditation techniques and gentle yoga. Both cohorts received 90-minute interventions weekly for 8 weeks. The MBSR group also participated in a 6-hour weekend retreat.
The study’s primary outcome, insomnia severity, was measured by the Insomnia Severity Index (ISI), a sevenitem questionnaire which assesses difficulties with sleep onset and sleep maintenance, the extent to which sleep problems interfere with daily function, and distress levels elicited by insomnia. The researchers set a four-point noninferiority margin for comparing the two interventions.
Secondary outcomes of the study included sleep quality, sleep beliefs, mood, and stress. Patient sleep diaries and actigraphy monitoring were used to determine sleep efficiency, sleep onset latency, wake after sleep onset, and total sleep time.
Patients were assessed at baseline, at the end of the program, and at 5 months. After completing the 8-week programs, both CBT-I and MBSR resulted in reduced insomnia severity; the CBT-I cohort experienced more rapid results, whereas MBSR led to a more gradual improvement. At the 5-month follow-up, MBSR met the established noninferiority criterion.
Sleep onset latency was reduced by 22 minutes in the CBT-I cohort and by 14 minutes for those receiving the MBSR. Total sleep time increased by 0.60 hours with CBT-I and 0.75 hours with MBSR. Both groups experienced a reduction in the time it took to fall asleep and return to sleep during the night, as well as improvements in mood and stress-related symptoms.
“If not properly addressed, sleep disturbances can negatively influence therapeutic and supportive care measures for these patients, so it’s critical that clinicians can offer patients reliable, effective, and tailored interventions,” said lead study author Sheila Garland, PhD, a Clinical Psychology Post-Doctoral Fellow in Integrative Oncology and Behavioral Sleep Medicine at Penn’s Abramson Cancer Center. “This study suggests that we should not apply a ‘one-size-fits-all’ model to the treatment of insomnia and emphasizes the need to individualize treatment based on patient characteristics and preferences.”
Assessment of insomnia is difficult because it usually is not the most important focus of my patient visit, but it no doubt impacts patient care. When I first reviewed the article above I was worried about my assessment skills for insomnia. After reviewing the Insomnia Severity Index (ISI), I feel a bit better about how I approach patients. Usually I try to focus on what part of their sleep they are having trouble with: falling asleep, staying asleep, or waking up early. The second half of the ISI focuses on how this impacts the patient. Here is where we as providers may not always get accurate or current information.
Finding out about patients’ sleep patterns is important, and we know this because half of all cancer patients suffer from this. I agree completely with the study that a majority of my patients do not want another “pill” to take for this diagnosis. Offering patients an intervention like cognitive behavioral therapy (CBT) or mindfulness-based stress reduction is a refreshing way to be able to offer a solution. One can see from the study above that both are effective interventions.
One limitation to this that we may run into in daily practice is that patients often do not want another appointment with another specialist. It is important to use these data to support our referrals to therapists for patients. Reminding them that help can benefit the quality of their sleep along with their sleep beliefs and sleep efficiency may help encourage them to seek assistance.
I see this intervention helping mainly in the population of patients who had trouble with insomnia prior to their cancer diagnosis. I am not sure they identified the duration of insomnia in patients’ in this trial. Patients with new-onset insomnia due to anxiety from their cancer, in my opinion, may just need short-term oral medication therapy. Another point mentioned in the article is that treatment of insomnia is individual, so being able to identify which patients would benefit from CBT and which from oral medication is what makes us great providers.
Breast cancer patients whose chemotherapy is initiated more than 60 days following surgery experience worse survival outcomes, and the impact of treatment delay is greatest among patients with stage III or triple-negative breast cancer and those whose HER2-positive tumors have been treated with trastuzumab, according to findings of a large, retrospective review of patient medical records conducted by researchers at the UT MD Anderson Cancer Center in Houston, Texas. ( [published online ahead of print January 27, 2014]. J Clin Oncol. doi:10.1200/JCO.2013.49.7693).
Most adjuvant breast cancer chemotherapy begins within a few weeks of surgery; however, previous research results differ on the impact longer time to chemotherapy (TTC) might have on survival. Treatment delays also have been reported to occur more frequently among lowincome groups, racial minorities, and Medicare patients.
To further investigate on the impact of TTC overall and on specific breast cancer subtypes, in particular, researchers analyzed the records of 6827 patients diagnosed with stage I-III invasive primary breast cancer who received treatment at the cancer center between 1997 and 2011, which, the authors noted, represents one of the largest single-institution cohorts to be evaluated for breast cancer outcomes associated with TTC. Most patients (84.3%) had stage I / II disease, and 15.5% stage had stage III disease.
Patient medical records were divided into three groups based on the number of days between completion of surgery and start of chemotherapy: ≤30 days (n = 2716), 31 to 60 days (n = 2994), and ≥61 days (n = 1117). Overall survival (OS), relapse-free survival (RFS), and distant relapse-free survival (DRFS) were assessed for the study population as a whole and also according to breast cancer subtype, with a median follow-up of 59.3 months.
and adjusted for confounders to estimate 5-year OS, RFS, and DRFS for all patients based on TTC and other patient characteristics. They determined that when compared with patients who had adjuvant chemotherapy ≤30 days after surgery, patients whose TTC was ≥61 days postsurgery had a 19% increased risk of death (HR = 1.19; 95% CI, 1.02-1.38).
Although TTC was not significantly linked to outcome in patients with stage I disease, the risk of distant relapse was estimated to increase by 18% in stage II patients whose chemotherapy started 31-60 days after surgery, and by 20% in the ≥61 days cohort. For patients with stage III disease who started chemotherapy ≥61 days after surgery, the risk of death was increased by 76%, the risk of relapse by 34%, and the risk of distant relapse by 36%, when compared with patients whose TTC was ≤30 days.
The impact of TTC on survival and relapse also varied according to breast cancer subtype. Patients with hormone receptor (HR)-positive tumors receiving chemotherapy ≥61 days after surgery had a 29% increased risk of death (HR = 1.29; 95% CI, 1.02-1.64). HR-positive patients who received chemotherapy 31 to 60 days after surgery were estimated to have a 15% increased risk of relapse and a 18% increased risk of distant relapse compared with patients whose TTC was ≤30 days, the researchers reported.
The magnitude of risk was more pronounced when the researchers looked at the records of patients with triple-negative breast cancer (TNBC) and those who were HER2-positive and treated with trastuzumab.
Patients with TNBC who received chemotherapy either 31 to 60 days or ≥61 days after surgery had a 74% and 54% increased risk of death, respectively, compared with the ≤30 days group, but RFS and DRFS were not impacted by TTC in these patients.
For patients whose tumors were HER2-positive but not treated with trastuzumab (n = 551), outcomes were not adversely affected by longer TTC, but a statistically significant increase in death risk was observed in the trastuzumabtreated group (n = 591) when chemotherapy was initiated ≥61 days after surgery versus ≤30 days (HR = 3.09; 95% CI, 1.49-6.39). A trend toward worse RFS and DRFS was also reported for this group.
The researchers concluded that for patients with stage II and III breast cancer, those with TNBC, and those with HER2-positive tumors, “Every effort should be made to avoid postponing the initiation of adjuvant chemotherapy. This may lead to an improvement in outcomes for these subsets of patients.”
The study performed by de Melo Gagliato et al was a large retrospective study examining the association between the initiation of adjuvant chemotherapy and survival outcomes among different breast cancer subtypes and stage of diagnosis. The authors concluded that those with a more advanced breast cancer stage at diagnosis experienced worse outcomes with delayed initiation of adjuvant chemotherapy, specifically those with stage II or III breast cancers and those with triple-negative and HER2-positive subtypes.
This study brings to light not only the importance of initiating adjuvant chemotherapy in newly diagnosed breast cancer patients, but also the possible reasons surrounding the delay of treatment. Reasons for delay of chemotherapy may include personal, work, insurance, or even organizational issues. Personal reasons may include fear or anxiety of starting chemotherapy. For these individuals, referral to counseling services, chaplaincy, or a support group may be necessary in order to allay these emotions. Insurance barriers may be overcome with the assistance of financial counselors. Organizational barriers may include wait times before being able to see a medical oncologist. A nurse case manager may be of assistance to these individuals experiencing this type of delay.
After definitive surgery, a multidisciplinary effort would be an optimum approach to care in order to assist this population of patients’ smooth transition to a medical oncologist’s care so that adjuvant chemotherapy can be started as promptly as possible.
Extended follow-up of patients with castration-resistant prostate cancer (CRPC) and bone metastases randomized to radium-223 dichloride in the phase III ALSYMPCA study revealed a continued low incidence of myelosuppression and no association with secondary malignancies. The data were presented at the 2014 Genitourinary Cancers Symposium by Sten Nilsson, MD. Abstract 9
The ALSYMPCA study compared the efficacy and safety of radium-223 with placebo in 921 patients with CRPC and symptomatic bone metastases, demonstrating a 3.6-month improvement in overall survival in the radium-223 arm. The incidence of hematologic adverse events at the 2-year follow-up was low in the radium-223 group.
“What we found in the ALSYMPCA trial, and also in the phase I and II trials, is that radium-223 has a very benign safety profile, but I think it’s important to find out if this benign safety profile exists in the long-term follow-up,” said Nilsson, professor of Oncology at the Karolinska University Hospital in Stockholm, Sweden. “It could be that a new drug could give rise to second malignancies or new disease.”
The safety population consisted of 901 of the 921 patients enrolled in ALSYMPCA. Of the 901 participants in the safety analysis, 571 (404 randomized to radium-223 and 167 randomized to placebo) entered a designated long-term follow-up that lasted until 3 years after their first injection of radium-223. Eighty-three percent of the radium-223 group and 71% of the placebo group who entered the follow-up period completed all six injections of the study treatment. The median follow-up durations at the time of the analysis (about 1.5 years after the patient’s last injection) were 10.4 months in patients randomized to radium- 223 and 7.6 months for placebo recipients.
“The very benign safety profile we saw in previous studies and the ALSYMPCA study remained,” said Nilsson. “There were very few side effects with respect to hematologic parameters and also with nonhematologic parameters.”
Treatment-related adverse events reported during follow-up occurred in 25 of the 404 radium- 223 patients (6%) and 8 of the 167 placebo patients (5%). The most common adverse events in the radium-223 group were hematologic: anemia (3%), aplastic anemia (<1%), leukopenia (<1%), neutropenia (1%), and thrombocytopenia (1%). Grade 3/4 hematologic adverse events in the radium-223 cohort included anemia (1%), aplastic anemia (<1%), leukopenia (<1%), and neutropenia (1%).
The one patient with aplastic anemia in the radium-223 group was diagnosed based on bone marrow biopsy. This patient had been treated previously with chemotherapy and repeated external beam radiotherapy due to bone metastatic disease, said Nilsson. Three percent of the placebo group experienced anemia and 1% had grade 3/4 anemia.
There were no reports of acute myelogenous leukemia, myelodysplastic syndrome, or primary bone cancer. Primary cancers in other organs developed in two radium-223 treated patients and three placebo patients, and were deemed by the investigators not to be related to the study drug.
Nonhematologic toxicities were rare in the radium- 223 group, with the most common occurring in <1% of patients for each adverse event (general physical health deterioration, multiorgan failure, pneumonia, weight loss, anorexia, musculoskeletal pain, pathologic fracture, and dizziness).
“Radium-223 is a good drug that prolongs life and the safety profile is very benign and keeps being so,” Nilsson said. The findings support the evaluation of combining radium-223 with other agents for the treatment of patients with CRPC and symptomatic bone metastases.
The full 3-year follow-up data will be presented at the 2014 meeting of the American Society of Clinical Oncology in Chicago in June.
In the study presented here, no differences in severe toxicities were found between the prednisone and the nonprednisone groups. In the mCRPC regimens included, steroid use does not appear to lead to directly poor outcomes. Not a definitive study in and of itself, and further studies should aim at the research questions posed by Dr. Galsky, exploring the role of prednisone beyond just safety, but more its efficacy and taking into account other clinical aspects. We step closer to personalized medicine by answering the question, “Which patients exactly could be helped (or harmed) with prednisone as part of their regimen?”
Regarding an emerging technology in mCRPC treatment, another study reported here supports the promising role of Radium-223. The findings show a low incidence of myelosuppression and no association with secondary malignancies, addressing the main concerns in patients using radiopharmaceuticals.
Still, these follow-up data have been compiled over a relatively short period of time—encouraging for now, but long-term data to follow hopefully will build upon the evidence in support of Radium-223, as yet another tool in mCRPC treatment.
In educating and advising our patients dealing with mCRPC, we can use studies like these in our practice to help understand the known versus the unknown, with respect to the ever-developing treatment agents and regimens. There may be no absolute right or wrong answer for the questions that come up about mCRC treatments and their outcomes, but at least, as oncology nurses, we can help our patients make well thought-out treatment decisions that foster overall quality of life.
Prednisone, when used in concert with other therapies for the treatment of metastatic castration-resistant prostate cancer (mCRPC), does not raise the risk for severe toxicities, nor does it affect overall survival (OS), researchers found in a meta-analysis presented during the 10th Annual Genitourinary Cancers Symposium held January 30-February 1, 2014 in San Francisco, California.1
In prostate cancer, the corticosteroid, an antiinflammatory that also suppresses the immune system, is routinely given with chemotherapy drugs docetaxel, cabazitaxel, and mitoxantrone, as well as with abiraterone, a recently approved androgen biosynthesis inhibitor, in which prednisone can mitigate side effects such as hypertension.
Prednisone is used in prostate cancer for its direct and indirect anticancer effects, including the lowering of prostate-specific antigen; for its quality-of-life benefits, including appetite stimulation; and because it was historically used to accompany mitoxantrone, and the practice was carried over to treatment with docetaxel when that drug was later approved for use in the disease, according to two authors of the study, Matthew D. Galsky, MD, and William K. Oh, MD.
Galsky, associate professor of Medicine at Mount Sinai’s Icahn School of Medicine in New York City and director of the Genitourinary Medical Oncology Program at the Tisch Cancer Institute, said that he and his co-investigators initiated the study because the role of prednisone in the treatment of men with advanced prostate cancer has been controversial, and it remains unclear whether steroids are needed, or provide benefit, in this group.
Further, Galsky said, prior biologic evidence showed that prednisone might be harmful in certain populations of men with prostate cancer. He gave as an example a recent preclinical study by Arora et al,2 which demonstrated that steroids given with certain inhibitors of the androgen receptor could actually drive tumor growth in some prostate cancers.
The meta-analysis by Galsky and colleagues includes five randomized trials that investigated grade ≥3 toxicities and survival outcomes associated with prostate cancer treatment regimens administered with and without prednisone. The studies were conducted between January 1996 and June 2013.
One trial compared docetaxel/prednisone against docetaxel/DN101; another compared docetaxel/prednisone against GVAX; and a third pitted docetaxel/prednisone against docetaxel/ GVAX. A fourth trial compared prednisone against flutamide, and the fifth compared mitoxantrone/ prednisone against docetaxel/estramustine phosphate.
In all, there were 2939 patients in those studies, about half of them receiving prednisone. All five studies were rolled into the analysis of toxicities, and four were included in the OS analysis; the flutamide study was excluded because it did not have the required parameters.
The investigators found no difference between the prednisone and nonprednisone groups when it came to severe toxicities, and patients in both groups faced the same risk of discontinuing therapy due to toxicities, the authors reported. The nonprednisone groups demonstrated no difference in OS compared to the prednisone groups. The results do not exclude the possibility that prednisone had a favorable palliative benefit for patients, the authors wrote.
“We showed that giving steroids doesn’t clearly lead to a detriment in outcomes in men with prostate cancer in the specific clinical disease states tested. That doesn’t mean that a subset of patients, based on the mechanism by which their tumors are progressing, might not be harmed by steroids,” Galsky pointed out. “That needs to be the subject of further studies to identify: 1) Are there any patients who actually benefit from the steroid use, aside from side-effect mitigation with abiraterone, and 2) Can we identify patients whom we are actually hurting by giving prednisone?”
Patients with comorbidities such as diabetes, fluid retention, or congestive heart failure might be among those whose conditions could be worsened by prednisone, noted Oh, professor of Medicine, Hematology, and Medical Oncology at Mount Sinai Hospital. “But that said, I don’t think that, by itself, prednisone is necessarily a dangerous drug,” he said, “and it has some positive effects we have to be aware of.”
Still, Galsky cautioned, there are more questions to be answered about the issue.
“Whether or not giving steroids with drugs in different disease settings is harmful at all is not clear,” he said. “In general, whether or not steroids help, hurt, or do neither depends on the individual patient and the individual tumor biology, and is much more complex than we initially thought.”
Metastatic cancer . . . Two words that no one wants to hear. As oncology nurses, our care of patients and families dealing with metastatic cancer can be intense, stressful, and scary for all involved—patients, family, and providers. Men with metastatic castrateresistant prostate cancer (mCRPC) have often already been through many treatments, ranging from surgery and radiation for localized disease, to the mixture of pills and injections that make up androgen deprivation therapy (ADT) for biochemical recurrence. Through this phase of the prostate cancer continuum, treatment decision-making strategies are far from simple, but the overarching goal is cure.
In mCRPC, our attention changes from cure to less concrete terms, like “palliation” and “quality of life.” There are still plenty of tools available for the treatment of mCRPC, but each has its own assortment of side effects and expected outcomes. The oncology nurse’s role here usually is to educate patients about all the pros and cons, ideally using the latest research and evidence to guide treatment decision-making. As compared to localized prostate cancer, the database of knowledge on treatments for mCRPC is not as large, with studies revolving around very basic safety and efficacy of new pharmaceutical agents, or even established medication regimens, like the two studies included here—important steps in building evidencebased practice.
Corticosteroids are commonly included in treatment regimens for mCRPC, potentially reducing side effects of other medications given concurrently, perhaps even having some direct effect on reducing pain and improving appetite. Medication interactions and possible toxicities are a main concern, given the mixture of agents given in mCRPC.
An analysis of phase III, second-line data found that RAS mutations beyond KRAS exon 2 are negative predictive biomarkers for the EGFR-inhibitor panitumumab (Vectibix) in metastatic colorectal cancer (mCRC). These findings are consistent with previously reported data in first-line mCRC. Combined, the results support the use of more comprehensive RAS testing in determining the appropriate patient population for panitumumab. Abstract LBA387
“These results confirm that it is RAS status that matters, not just KRAS, when determining if panitumumab could be beneficial,” said lead author Marc Peeters, MD, PhD, a professor of Oncology at Antwerp University Hospital in Edegem, Belgium, in presenting the research as part of the 2014 Gastrointestinal (GI) Cancers Symposium held January 16-18, 2014, in San Francisco.
In the primary analysis of the phase III 20050181 study (J Clin Oncol. 2010;28:4706– 4713), second-line panitumumab plus FOLFIRI was shown to significantly improve progressionfree survival (PFS) versus FOLFIRI alone in patients with wild-type (WT)-KRAS mCRC (5.9 months vs 3.9 months; hazard ratio [HR] = 0.73; P = .004), and also led to a non-statistically significant improvement in overall survival (OS; 14.5 months vs 12.5 months; HR = 0.85; P = .12). However, there was no benefit with panitumumab in patients with KRAS mutations.
The prospective-retrospective 20050181 mutational analysis presented at the GI Symposium examined the impact of additional RAS mutations (KRAS and NRAS, exons 2, 3, and 4) on the efficacy of panitumumab. The researchers were able to determine the RAS status of 85% of the primary study population (1008/1186).
The WT-RAS data showed improvement in PFS and OS outcomes with panitumumab compared with the WT-KRAS data from the primary analysis. In patients with WT RAS, PFS was 6.4 months in the panitumumab arm versus 4.4 months with chemotherapy alone (HR = 0.695; P = .006). OS was 16.2 months with panitumumab versus 13.9 months with chemotherapy alone. Adding panitumumab to chemotherapy did not result in a significant PFS or OS benefit in patients with RAS mutations.
Further, the analysis found that 18% of WTKRAS exon 2 patients had other RAS mutations. Without additional RAS testing, patients such as these will likely receive panitumumab, which would be ineffective. “For patients with a RAS mutation, these findings will spare them the costs and side effects of a treatment that will not improve their outcomes,” Peeters said.
The second-line RAS analysis presented at the GI Symposium corroborated similar research in the first-line mCRC setting from the phase III PRIME trial. In the primary study, combination treatment with panitumumab and FOLFOX4 chemotherapy significantly improved PFS (hazard ratio [HR] = 0.80; P = .02), with a trend toward improved OS, versus FOLFOX4 alone in patients with WT-KRAS exon 2 tumors (Douillard et al. J Clin Oncol. 2010;28:4697–4705). However, in patients with mutant KRAS, PFS and OS were worse in the panitumumab arm versus chemotherapy alone.
A recently published prospective-retrospective analysis of the PRIME study found that additional RAS mutations (KRAS exon 3 or 4; NRAS exon 2, 3, or 4) were also biomarkers for negative outcomes with panitumumab in mCRC (N Engl J Med. 2013;369:1023–1034). In patients with WT-RAS tumors (n = 512), PFS improved by 2.2 months (HR = 0.72; P = .004) and OS improved by 5.8 months (HR = 0.78; P = .04) with first-line panitumumab/FOLFOX4 versus FOLFOX4 alone. In patients with WT-KRAS exon 2 who had other RAS mutations (n = 108), PFS and OS were inferior with panitumumab versus chemotherapy alone.
As many oncology nurses may remember, initially we looked at epidermal growth factor receptor (EGFR) overexpression in order to determine whether a patient with metastatic colorectal cancer (mCRC) might benefit from the EGFR-targeted therapies (initially only cetuximab was available; later panitumumab became available). The prevailing thought at that time was that the more EGFR was overexpressed, the better the response to EGFR-targeted therapy would be. Unfortunately, this did not turn out to be the case.
Subsequent research revealed that it was not EGFR overexpression, but KRAS status which was important. Specifically, those patients who had a mutated KRAS would not respond to EGFR-targeted therapy and, in fact, could potentially have accelerated progression of their cancer. As approximately only 50% of colorectal tumors are not mutated, that is KRAS wild-type, this limits the therapy for KRAS-mutant patients, but was cause for much hope and excitement in the KRAS wild-type patients. And, we were not disappointed in about half of these patients. As predicted, their cancer responded extremely well to the EGFR therapy with diminution of their cancer and many were rendered NED (no evidence of disease). But, there was still a population of wild-type KRAS patients who did not respond to EGFR therapy and this was both puzzling and disappointing, both to the patients and to those of us who care for them.
This newly published prospective-retrospective analysis of the PRIME study has identified additional RAS mutations which are biomarkers for negative outcomes with panitumumab in mCRC. So what does this mean now? Rather than just KRAS testing, physicians will need to order RAS testing in order to identify if any of these particular mutations exist. Those patients would then not be candidates for EGFR therapy. This helps us understand why some patients did not respond to EGFR therapy, despite being KRAS wild-type. It is also helpful as there is no benefit to giving a patient a treatment which will not be effective. However, as there is no alternative therapy available at this time it is somewhat disheartening. We can hope that some of the therapies being looked at in clinical trials might turn out to be effective for these patients, and as oncology nurses we should strongly encourage our appropriate patients to enroll.
Combining two specific anticancer vaccines, rather than administering one as monotherapy, doubles the 1-year survival probability in patients with metastatic pancreatic ductal adenocarcinoma (PDAC), according to the results of a phase II study at the 2014 Gastrointestinal Cancers Symposium. Abstract 177
Adding the immunotherapy CRS-207 to GVAX Pancreas, rather than giving GVAX alone, sparked the improvement, most markedly in patients who received at least two doses of GVAX and at least one dose of CRS-207, and in those who had received two or more prior treatment regimens, the study’s researchers found in the randomized study.
“This is the first time a randomized study has shown that immunotherapy is effective in pancreatic cancer. This study is just a first step, and we believe we’ll be able to take this approach further,” said lead study author Dung T. Le, MD, an assistant professor of Medicine at the Johns Hopkins University Sidney Kimmel Comprehensive Cancer Center in Baltimore, Maryland
“Various chemotherapy drugs are used, but there are no standard treatment options for second- or third-line therapy in this setting. We’re excited these patients may soon have an alternative to chemotherapy that could come with fewer side effects.”
The new study tested an innovative strategy designed to stimulate an immune response against pancreas tumor cells, potentially improving outcomes for such patients with a regimen that appears to be better tolerated than chemotherapy. GVAX is made from two pancreatic cancer cell lines that are irradiated so that they secrete the protein GM-CSF, which stimulates the immune system. The drug is given intradermally after lowdose cyclophosphamide (CY), which inhibits regulatory T cells, Le explained. CRS-207 is composed of live-attenuated Listeria monocytogenes engineered to stimulate an immune response against the protein mesothelin, which is present at high levels on pancreatic cancer cells.
The study by Le et al included 90 patients with metastatic PDAC, the most common form of pancreatic cancer, who were randomly assigned 2:1 to treatment with two doses of CY/GVAX followed by four doses of CRS-207 (arm A), all 3 weeks apart for a 20-week course of treatment; or six doses of CY/GVAX every 3 weeks (arm B). Courses could be repeated. The primary endpoint was overall survival (OS), and secondary endpoints were safety and clinical and immune responses. Nearly all patients had received at least one prior course of chemotherapy, and 51% of them had received two or more prior regimens.
At a planned interim analysis, with a median follow-up of 7.8 months, the median OS was 6.1 months for the two-vaccine therapy compared with 3.9 months for therapy with GVAX. About 24% of patients in arm A were still alive after 1 year, compared with 12% in arm B, Le said. Among patieadnts who had received at least three doses of vaccine (about 70% of all patients), those in arm A who received two doses of GVAX and at least one dose of CRS-207 had a median OS of 9.7 months compared to 4.6 months for those who took three or more doses of CY/GVAX alone. Based on the benefit observed at this interim analysis, the study was stopped and patients were allowed to cross over from arm B to arm A.
The side effects of the vaccine were relatively mild, resolved quickly, and did not get worse with each dose of treatment. The side effects included local reactions after GVAX, and transient fevers, rigors, and lymphopenia after CRS-207, according to the authors.
“CY/GVAX followed by CRS-207 shows extended survival with manageable toxicity in previously treated metastatic PDA and warrants further study,” the authors concluded.
Single-agent neoadjuvant capecitabine combined with radiation therapy demonstrated similar outcomes as previously established standards of care for patients with stage II or stage III rectal cancer, according to findings from the four-arm phase III NSABP R-04 trial presented the 2014 Gastrointestinal Cancers Symposium. Abstract 390
The single-agent oral chemotherapy capecitabine was compared to 5-fluorouracil (5-FU), 5-FU plus oxaliplatin, and capecitabine plus oxaliplatin. Overall, a significant difference between treatments arms was not observed for local-regional control (LRC), disease-free survival (DFS), or overall survival (OS). Moreover, when oxaliplatin was added to either regimen, it did not provide additional clinical benefit but increased overall treatment toxicity, including diarrhea and fatigue. Infusional 5-FU and capecitabine had similar side effects.
“This study definitively establishes capecitabine as a new standard of care in this setting,” said Carmen Joseph Allegra, MD, the lead author and a professor of Medicine at the University of Florida in Gainesville.
In the four-arm trial, 1608 patients were randomly assigned to receive 5 weeks of radiation therapy at 46 Gy plus boost plus either 5-FU (477 patients; continuous intravenous infusion 225 mg/m2, 5 days a week), 5-FU and oxaliplatin (329 patients; 50 mg/m2); capecitabine (472 patients, 825 mg/m2, twice daily); or capecitabine plus oxaliplatin (330 patients). Patients received treatment for 5 weeks and then underwent surgery to remove the tumor.
LRC rates ranged from 87.4% to 88.2%. Local recurrence occurred in 2% to 4% of stage II patients and 4%–11% of stage III patients after undergoing surgery in which the tumor was completely removed and no traces of microscopic disease were detected. In each of the treatment arms, about 80% of patients were still alive 5 years after surgery.
The researchers noted that although capecitabine is more expensive than 5-FU, the cost differential for the two treatments also depends on the cost of placing and maintaining the port and pump for 5-FU infusion. Ease of administration and convenience for patients are other factors in favor of oral capecitabine.
“Doctors should feel reassured that they are not giving less effective therapy if they prescribe capecitabine,” said Allegra.