ASCO 2008: An Update for Nurses
ASCO 2008: An Update for Nurses
Every year, at the American Society for Clinical Oncology annual meeting, physicians present findings from research studies that change or clarify the way we treat patients with cancer. Unfortunately, nurses don’t always get this information right away, but often times our many internet-savy patients do. This continuing education module is designed to provide nurses in practice the latest information on select topics presented at ASCO 2008.
ACOSG ZO531: Report on a Multicenter, Phase II Trial for Adjuvant Therapy of Resected Pancreatic Cancer Using Cisplatin, 5-FU, and Alpha-Interferon
Surgery is considered the only curative therapy for pancreatic cancer. However, 50-80% of patients will develop recurrence after surgery. For this reason, patients also receive adjuvant (meaning postoperative) chemotherapy, either with or without radiation therapy. While this therapy improves survival, it only results in a 10-20% 5- year survival. Previous studies have shown that the addition of interferon alpha may make cisplatin chemotherapy work better in making tissues sensitive to radiation (radiosensitizing) and in improving survival.
This study gave all participants 5-FU, cisplatin, and alpha interferon. The study hoped to enroll 93 patients, but was stopped early with 89 participants due to high rates of toxicities. Overall survival (OS) was 69% at 20 months and 58% at 2 years. 96% of patients had a grade 3 or 4 (on a scale of 0-4, 4 being the most severe). The toxicities most commonly seen were anorexia (loss of appetite), dehydration, diarrhea and nausea. These toxicities were significant, but manageable with supportive care.
There are now three studies evaluating the efficacy of cisplatin, 5-FU, alpha interferon, and radiation. These studies include the Virginia Mason study (Picozzi V.J. et al., ACSO Annual Meeting 2003), the CapRI study (Knaebel H.P. et al., BMC Cancer, 2005; presently under analysis), and the present study. Data is available for over 174 patients from these studies, and they have consistently demonstrated a 2-year OS of greater than 50%. The CapRI study is the only randomized trial, and results are pending. It is important to note that the patients in this study were highly selected, and there is the potential for bias regarding patient enrollment.
The greatest problem with this regimen is the toxicity related to treatment, as seen now in multiple studies. The majority of these toxicities were related to anorexia and dehydration. It is unclear what supportive care patients received, such as whether feeding tubes were placed and used, the use of IV fluids, monitoring of patient weight during treatment, and use of pre-albumin levels. Without this information, it is difficult to know if there was adequate supportive care to get patients safely through treatment. The inability to complete treatment was associated with worse outcome and this was likely affected by the high toxicity associated with treatment. However, despite this toxicity and the significant number of patients who could not complete therapy, the outcomes were quite good compared with historical controls. Hence, if the tolerability of this treatment could be improved, such as through better supportive care, outcomes might improve as well.
Bortezomib/dexamethasone versus VAD as Induction Prior to Autologous Stem Cell Transplant (ASCT) in Previously Untreated Multiple Myeloma (MM): Updated Data from IFM 2005/01 Trial
The use of autologous stem cell transplant in treating multiple myeloma patients over 65 years of age has become standard therapy. Traditionally, the VAD chemotherapy regimen was used as first line induction therapy. This study looked at using bortezomib and dexamethasone (BD) as induction therapy, compared with VAD. This was based on the theory that both bortezomib and dexamethasone inhibit different peptides, resulting in a blockade of important cell pathways that are necessary for growth and replication. It is hoped that this interference will lead to greater cell death.
Patients were randomly assigned to one of the following therapies:
BD alone (4 cycles), VAD alone (4 cycles), BD followed by consolidation therapy with 2 cycles of dexamethasone, cyclophosphamide, etoposide, and platinum (DCEP), or VAD followed by 2 cycles of DCEP. 442 patients were evaluated.
BD had superior response rates in low-, intermediate-, and high-risk patients. Patients with high and low levels of beta2 microglobulin and patients with and without deletion of chromosome 13 all benefited from BD therapy. The responses were classified as complete and near complete (8.3% in VAD arm vs. 21.3% in BD arm) and "more than a very good partial response" (18.6% in the VAD arm vs. 46.7% in the BD arm). These patients went on to have stem cell transplants, and the superior response in the BD arm was still present after transplant. The addition of DCEP did not increase response rates. The BD superiority did not translate into improved survival rates at 18 months, but longer follow up is needed.
Side effects varied, with neuropathy and thrombocytopenia being higher in the BD arm and neutropenia and anemia being higher in the VAD arm.
Although this study does suggest great potential for this induction therapy regimen, it is not yet the standard of care. Longer follow-up is needed, and there should ideally be a true improvement in quality of life, overall survival, and/or cost of treatment (with equivalence of effect) prior to accepting this regimen as the standard of care for induction prior to ASCT.
BRCA1 mRNA expression in patients with bladder cancer treated with neoadjuvant cisplatin-based chemotherapy
Improved overall survival has been demonstrated with the use of cisplatin-based chemotherapy given prior to radical cystectomy in patients with locally advanced bladder cancer, as compared to radical cystectomy alone (Lancet, 2003). Although the majority of patients who are planned to undergo radical cystectomy receive cisplatin-based chemotherapy, no tumor or clinical marker currently exists to predict whether they will benefit from this treatment. Avoidance of platinum-based chemotherapy in patients with a decreased likelihood of benefit from these agents would be helpful.
Mutations in the BRCA1 gene (breast cancer susceptibility gene 1) have been associated with both increased risk of development of certain cancers, and resistance to chemotherapy. Overexpression of BRCA1 mRNA has recently been demonstrated to be predictive of in vitro (in the laboratory) sensitivity to cisplatin and docetaxel in metastatic lung, gastric and ovarian cancers. This study evaluates the role of overexpression of BRCA1 mRNA in bladder cancer patients with regard to response to treatment, disease-free survival, and overall survival.
98 patients with varying stages of disease were evaluated. Tumor tissue was tested and BRCA1 mRNA levels were found to be low in 35% of patients, intermediate in 32%, and high in 32%. Response to the chemotherapy was seen in 66% of patients with low or intermediate levels but only 23% of patients with high levels. Disease-free survival (that is, survival without any recurrence) was strongly correlated to the BRCA1 mRNA levels. DFS was 120 months in patients with low BRCA1 mRNA levels, 184 months in those with intermediate levels, and 14 months in those with high levels. Five-year overall survival (that is, survival with or without recurrence) was 63% in patients with low or intermediate BRCA1 mRNA expression, and 23% in those with high levels.
While this study suggests that BRCA1 mRNA levels can be used to predict response to cisplatin therapy, a randomized trial could be indicated to evaluate this as well as the response to taxane therapy for those with high expression levels.
Cancer-related fatigue interferes with activities of daily living among 753 patients receiving chemotherapy: A URCC CCOP study
Cancer-related fatigue is unfortunately a very common problem with few to no effective solutions. This study looked to evaluate rates of fatigue and how they interfere with activities of daily living (ADLs) (such as work, bathing, dressing, walking) in 700 patients. Assessment of fatigue was performed one week after the first cycle of chemotherapy and one week after the second cycle.
Researchers found that fatigue was present as soon as 1 week after the first chemotherapy cycle (this was the first time point they assessed). Fatigue interfered significantly with many essential ADLs, and most significantly with walking, completing household chores, and running errands. Of the 11 ADLs researchers asked about, 9 were reported to be affected after the first cycle and 10 after the second cycle of chemotherapy.
Although this study demonstrated that fatigue affects ADLs, there was no baseline assessment of fatigue, and the testing period was quite short. The study adds to the body of knowledge regarding fatigue, but does not offer any interventions for relief.
CONKO-001: Final Results of the Randomized, Prospective, Multicenter Phase III Trial of Adjuvant Chemotherapy with Gemcitabine vs. Observation in Patients with Resected Pancreatic Cancer (PC)
This study has previously reported (Oettle H., et al. JAMA 2007) that the use of post-operative gemcitabine in patients with pancreatic cancer significantly delays the development of recurrent disease after complete resection and is generally well tolerated. This presentation is an update of their previously published results.
354 patients were randomly assigned to receive gemcitabine for 6 months after surgical resection or no therapy after surgical resection. Median overall survival was 22.8 months in the chemotherapy arm (arm A) versus 20.2 months in the supportive care arm (Arm B). The survival difference increased over time:
The findings from this study suggest that gemcitabine is safe and effective in the postoperative setting, and its use should be considered. It is important to keep in mind that the patient population enrolled in this study was a highly selected one, in that the postoperative CA 19-9 levels had to be less than 2.5 times the upper limit of normal. This is a requirement that might rule out many postoperative pancreatic cancer patients.
The optimal postoperative management regimen continues to be studied by several groups. The use of combined regimens and whether or not to include radiation therapy are among the treatments being studied. Hopefully these studies will help determine the optimal regimen for postoperative use.
Effect of intravenous calcium and magnesium (IV CaMg) on oxaliplatin-induced sensory neurotoxicity (sNT) in adjuvant colon cancer: Results of the phase III placebo-controlled, double blind NCCTG trial N04C7
The addition of oxaliplatin to the arsenal of therapies for GI cancers has had a profound effect on survival, but not without additional side effects. In particular, neuropathy has resulted in delays and reduction in doses and more importantly, resulted in poor quality of life for those affected. Researchers have determined that oxaliplatin-related neuropathy resembles muscle abnormalities such as mytonia and tetany, which are thought to be related to a decrease in calcium (Ca) and magnesium (Mg) levels. Small studies used Ca and Mg intravenous infusions to prevent oxaliplatin-induced neuropathy with some success. This presentation reviewed a large phase III study in which Ca and Mg infusions were used in the hopes of preventing this side effect.
The study was ultimately closed early, with 102 of a planned 300 patients being evaluated. The study was closed because another trial suggested that Ca and Mg infusions may decrease the efficacy of oxaliplatin. Participants received either Ca/Mg infusion or placebo along with standard chemotherapy. Patients were assessed using an NCI scale, a scale specific to oxaliplatin related neuropathy and a quality of life scale. The infusion group performed better on both side effect scales. Percent of participants with grade 2 or higher neuropathy on the NCI scale: 22% for Ca/Mg group versus 41% for the placebo group. On the oxaliplatin specific scale, grade 2 or higher neuropathy was seen in 28% for Ca/Mg group versus 51% for the placebo group. As for quality of life ratings, there was a trend towards improved swallowing and muscle cramps in the Ca/Mg group, but these differences were not yet statistically significant, which may be due to the smaller-than-expected sample size.
The suggestion that the addition of Ca/Mg may affect response rates by the CONCEPT study has dampened the results of this study, but there were some questions of how response was evaluated in the study. Further studies are needed to clarify this issue as this study has clearly shown that Ca/Mg infusions can provide benefit and could possibly lead to fewer dose reductions.
Effect of paroxetine on depression and insomnia in 547 fatigued cancer patients undergoing chemotherapy
Depression and insomnia are two common issues in people with cancer. Studies have found that approximately 30% of people with cancer report insomnia and they are 2.5 times as likely to have insomnia compared with the general population. This study was carried out in order to determine the effectiveness of paroxetine in treatment of both depression and insomnia in patients undergoing treatment for cancer.
Patients were enrolled prior to beginning cancer treatment, and patient depression, insomnia, and fatigue levels were assessed at the time of each of the first four chemotherapy sessions. Following the second cycle of chemotherapy, 547 patients who reported cancer-related fatigue were randomized to receive paroxetine, 20 mg orally daily, versus placebo.
Patients randomized to paroxetine experienced significantly decreased rates of depression (p < 0.05) when compared to the control arm. A trend towards improvement in insomnia was noted in patients randomized to paroxetine, but this was not statistically significant. No impact on fatigue was seen in patients randomized to paroxetine versus those taking placebo. The researchers concluded that although the paroxetine improved depression, it did not improve insomnia or fatigue. This study is a well-designed trial that raises awareness of the need to consider insomnia as a separate entity from, and not an entity caused by, depression in cancer patients.
Effects of aerobic exercise training on physical performance during myeloablative therapy
The benefits of exercise for people undergoing cancer therapy have been shown in previous studies. These include improvements in lung and heart function, increased strength and improvements in fatigue levels. The purpose of this study was to evaluate effects of anaerobic exercise training on physical performance of patients with hematologic malignancies or solid tumors during myeloablative therapy or high-dose chemotherapy followed by autologous peripheral blood stem cell transplant.
The questions to be answered by the authors were:
1) Is exercise feasible in this group of patients?
2) What happens to physical performance in these patients if they do exercise?
The study included 85 participants undergoing high dose chemotherapy, who were randomly assigned to a 30 minute a day, 5 days a week exercise regimen or no exercise regimen. Both groups completed daily questionnaires on side effects and quality of life. Exercise was held when platelets or hemoglobin were low, for infection, fever or if the patient was in the ICU.
The primary endpoint was change in physical performance between the beginning and end of treatment, measured in Watts (W). There was a significant increase in physical performance in the exercise group (8.96 +/-24 W) and a decrease in the control group (-7.24 +/- 20 W). The exercise group had improvement in lung function and an increase in their physical functioning score. Patients tended to be fitter and feel better at discharge if they performed exercise.
The exercise regimen during myeloablative therapy appears to be achievable, effective, and safe, and may help to preserve physical function in these patients. Ultimately, this can reduce the risk for limitations and disabilities in patients later in life.
Epidemiology study of never-smokers with non-small cell lung cancer (NSCLC): High percentages of Asian and Hispanic female never-smokers and the significance of Asian ethnicity
Non-small cell lung cancer (NSCLC) remains the number one cause of cancer death in both men and women in the United States. The greatly increased risk of NSCLC development in tobacco users has been well recognized for several decades. More recently, a sharp rise has been seen in NSCLC among never smokers and this cancer has been found to be biologically different from that of a NSCLC in a current of former smoker. Common features of never-smokers with NSCLC have been identified, including East Asian ethnicity, female sex, adenocarcinoma (specifically bronchoalveolar) pathology, and an increased likelihood of EGFR mutations, which may result in different therapy choices. This study attempted to increase the understanding of the epidemiology (the occurrence and distribution) of NSCLC in never smokers and to look at the affect of ethnicity on prognosis.
Utilizing a southern California database that included smoking status, 2240 never smokers were identified with a NSCLC diagnosis (and compared with 22964 current and former smokers). Never smokers had significantly improved survival when compared with smokers. Never smokers responded better to chemotherapy, with an 8 month median survival in never-smokers versus 6 month median survival in smokers with metastatic disease receiving chemotherapy. Response to radiation therapy also appears to be better.
When the never smokers (NS) were compared to the smokers (SK), the NS group contained more females, their tumors were more likely to be adenocarcinoma and more specifically, bronchoaveolar. When looking at ethnicity, 13% of Caucasian women were NS, 45% of Asian women were NS, and 25% of Hispanic women were NS. Of women born in North America, 11% of women born in Canada and 12% of women born in the United States with NSCLC were never-smokers. Thirty percent of women born in Mexico with NSCLC were never smokers. Of women born in Asian countries with NSCLC, 53% of Philippine women, 64% of Vietnamese women, 17% of Japanese women, and 61% of Chinese women were never-smokers.
Being of Asian ethnicity was a favorable prognostic sign for both NSs and SKs. Other groups have demonstrated improved responses among Asian women to certain therapies. While the information from this study is interesting, actual treatments were not considered and the population was limited to one geographic area. It is unclear what is driving the rise in these ethnic groups. Further studies must look at exposures and genetics as possible causes and evaluate how ethnic factors play into treatment decisions.
Evaluation of chromosome 17 (Chr-17) polysomy in Her2 FISH-negative metastatic breast cancer (MBC) patients enrolled in a randomized phase III study of paclitaxel and lapatinib
Researchers believe that having multiple copies of a cromosome (i.e. 3 or more, a condition known as polysomy), specifically of chromosome 17, may result in higher expression of Her-2, thus leading to a greater response when treated with Her-2 inhibitors, such as lapatinib. This study evaluated whether women with Her-2 negative tumors who had chromosome 17 polysomy would derive a benefit from lapatinib.
Unfortunately, no statistically significant difference in progression-free survival was seen between the various groups. The authors conclude that women with Her-2 negative tumors will not derive any benefit from Her-2 inhibitors, regardless of the status of chromosome 17.
Intermittent oxaliplatin (oxali) administration and time-to-treatment failure (TTF) in metastatic colorectal cancer (mCRC): Final results of the phase III CONCEPT trial
The CONCEPT trial (Combined Oxaliplatin Neuropathy Prevention Trial) was designed to study patients with mCRC receiving Oxaliplatin/ Bevacizumab as 1 st line treatment, and to evaluate whether giving oxaliplatin intermittently (IO) in a regimen of FOLFOX/Bevicizumab would reduce cumulative neurotoxicity, and therefore allow patients to stay on treatment longer than those receiving a conventional Oxali schedule (CO). The authors also explored the impact of calcium and magnesium (CaMg) administration on neurotoxicity.
Patients were randomly assigned to receive either standard FOLFOX given every 2 weeks (CO) or FOLFOX alternating with 5-FU/Leucovorin and bevacizumab (IO group). Each group was further divided so that half received calcium (Ca) and magnesium (Mg) infusions and half received a placebo in an attempt to decrease neurotoxicity.
Many studies do a review of the results partway through, so that the study can be stopped if one group is doing much better. This study was stopped early because the investigators felt that the groups receiving Ca/Mg were having poorer responses to therapy. Critics have pointed out that the evaluation of response was not confirmed and was done by the investigator, who may have been biased. While the study has been stopped, further analysis continues into the responses.
Despite stopping early and having a smaller-than-planned sample size; the group receiving intermittent (IO) oxaliplatin did have better responses to therapy. Progression-free survival (that is, survival with no recurrence) was 12 months in the IO group versus 7.3 months in the CO group. In addition, the incidence of severe neurotoxicity was improved, 24% (CO) versus 10% (IO). And this toxicity also corresponded with a need for dose reductions, leading to more dose reductions in the CO group.
Despite the early termination of the study, the IO regimen appears to achieve the goal of keeping patients on therapy longer, and the Ca/Mg infusions appear to reduce neurotoxicity, also leading to better treatment adherence. Further study is needed to determine if the study was stopped prematurely, so stay tuned.
FLEX: A randomized,multicenter, phase III study of cetuximab in combination with cisplatin/ vinorelbine (CV) versus CV alone in the first-line treatment of patients with advanced non-small cell lung cancer (NSCLC)
Epidermal growth factor (EGFR) is over expressed in 80% of lung cancers. Cetuximab is a monoclonal antibody that interferes with EGFR. A previous randomized phase II FLEX (First-Line Treatment for Patients with EGFR-expressing Advanced NSCLC) trial compared cisplatin and vinorelbine (CV) to cisplatin, vinorelbine, and cetuximab (CV+C) in patients with advanced NSCLC. Forty-three patients were randomized to each arm. Improvement in outcomes were seen with the addition of cetuximab; tumor response was improved from 28% to 35% with addition of cetuximab, progression-free survival was improved from 4.6 months to 5 months, and overall survival was improved from 7.3 to 8.3 months (Rosell, 2008).
Data from the FLEX phase II trial prompted the design of the FLEX phase III trial a larger trial utilizing the same therapies as FLEX II in more patients to evaluate survival benefit.
1125 patients participated in the study, with 94% having stage IV disease. Median overall survival* (OS) was 11.3 months in the CV + C arm, versus 10.1 months in the CV arm. One-year OS was 47% and 42% in the CV + C arm versus CV arm, respectively, which was statistically significant. As far as variation in side effects in the two groups, as expected, 10% patients receiving cetuximab developed rash, while virtually no one in the CV arm developed rash. Neutropenic fever was seen in 22% of those receiving CV+C versus 15% in the CV arm.
The authors point out the survival benefit, which is quite small, as reason to change standard therapy, but one must consider the cost of adding cetuximab to all regimens. Patients with adenocarcinoma appeared to derive the most benefit from the addition of cetuximab. Further research may determine a way to better classify which patients will derive the most benefit. In the meantime, this trial demonstrates a modest but real survival advantage for patients with advanced NSCLC treated with cetuximab added to conventional chemotherapy versus chemotherapy alone. This data is interesting and supports findings in head and neck and colorectal cancer that cetuximab is effective and safe when utilized concurrently with conventional chemotherapy. These findings are clinically important, and are an important contribution to the literature regarding treatment of patients with NSCLC.
* The median is the "middle of the pack", where half of the patients have had more years since treatment and half have had less. For instance, if the patients were 2, 4, 6, 10.8, 12, 12 and 14 years since treatment, 10.8 is the mid point, or the median. It is different from the mean, which would be the average time since treatment.
KRAS Status and Efficacy in the First –Line Treatment of Patients with Metastatic Colorectal Cancer (mCRC) Treated with FOLFIRI with or without Cetuximab: The Crystal Experience
Cetuximab is a targeted therapy agent that blocks epidermal growth factor receptor (EGFR) and that is used in the treatment of colon cancers. EGFR has several targets, including one called k-ras. K-ras is a protein that is activated when bound to GTP. GTP can then convert to GDP, which turns off k-ras. However, if k-ras is mutated, it can remain constantly active. So, if the k-ras is mutated, it no longer relies on EGFR to work, and therefore may be less likely to be affected by a therapy that blocks EGFR (i.e. cetuximab). Researchers refer to unmutated k-ras as "wild type", and feel that this wild type may be more responsive to cetuximab.
The CRYSTAL trial (Van Custem E., et al., ASCO Annual Meeting , 2007) was a large, randomized, phase III trial which investigated the use of FOLFIRI (Arm A) versus FOLFIRI plus cetuximab (Arm B) as first-line treatment in EGFR-expressing advanced colorectal cancers. Results demonstrated an increase in both response rate (RR), median progression-free survival (PFS), and curative surgery rates in the arm with cetuximab. This presentation was an analysis of patients in whom k-ras status was available (about half of the original study participants).
Mutated k-ras (MT) was present in 35.6% of these patients and wild type (WT) in 64.4%. Patients with WT k-ras improved with the addition of cetuximab: median* survival was 9.9 months for patients in arm B versus 8.7 months for patients in arm A. Outcomes for patients with mutant k-ras were not affected by the addition of cetuximab: median survival was 7.6 months for arm B versus 8.1 months for arm A.
Response to FOLFIRI was similar for patients with WT and mutant k-ras. The duration of treatment was longer in patients with WT k-ras, likely reflecting their better outcome and longer survival. There was no difference in toxicity seen between patients with WT and those with mutant k-ras. In the original CRYSTAL study, there was more grade 3 or greater toxicity in the cetuximab arm. This held true for patients with WT and mutant k-ras in the present study (both groups had more grade 3 or higher toxicity with cetuximab).
Based on these data, k-ras status should be assayed in patients who are candidates for cetuximab or panitumumab therapy, as it appears that only those with WT k-ras will benefit. This will spare k-ras mutant patients unnecessary toxicity. It is also important to tell patients with k-ras mutation that traditional chemotherapies remain effective. Further development of an easily accessible, reliable assay to determine k-ras status is still necessary to implement these findings on a wide-spread basis.
* The median is the "middle of the pack", where half of the patients have had more years since treatment and half have less. For instance, if the patients were 2, 4, 6, 10.8, 12, 12 and 14 years since treatment, 10.8 is the mid point, or the median. It is different from the mean, which would be the average time since treatment.
A phase II randomized, placebo-controlled, double blind trial of a eugeroic agent in 642 cancer patients reporting fatigue during chemotherapy: A URCC CCOP study
Cancer-related fatigue (CRF) is one of the most common side effects of cancer and its treatment, and has been shown to affect nearly 70-100% of cancer patients in previous studies. This study evaluated the effect of modafanil, an agent used in the treatment of narcolepsy, on cancer related fatigue.
642 participants were randomly assigned to receive modafanil or placebo from the second cycle of chemotherapy through the fourth. The drug had a positive effect on fatigue, but only for those patients who rated their fatigue as severe. The group receiving modafanil also reported less sleepiness.
Unfortunately, the researchers did not report on the side effects of the drug, so it is difficult to know how well tolerated it was among the participants. The scale used to measure fatigue may not have been the best choice. More data may have been gained from evaluating functional status or time spent sleeping during the day. Although some questions remained unanswered, this data may help to further study this or other drugs in the treatment of fatigue.
A phase III randomized study comparing the effects of oxandrolone (Ox) and megestrol acetate (Meg) on lean body mass (LBM), weight (wt) and quality of life (QOL) in patients with solid tumors and weight loss receiving chemotherapy
A study by DeWys, et. al. in 1980 showed that unintentional weight loss in cancer patients is a significant problem and is a poor prognostic factor. It is associated with decreased survival and QOL, and increased toxicity to cancer treatment. The weight loss in cancer patients is disproportionately seen as a loss of muscle mass rather than fat, which may be a reason for the negative effects mentioned above. Common drugs such as megestrol acetate (or Megace) and corticosteroids (such as dexamethasone and prednisone) have been standardly used to reduce unintentional weight loss, and can actually help patients gain weight. Oxandrolone (Oxandrin, Ox) is an oral anabolic steroid, which has a high anabolic-to-androgenic ratio. For this reason, it is proposed that this drug promotes weight gain by promoting muscle regrowth and increasing LBM. Ox has been used for a variety of medical disorders causing involuntary weight loss, and has often been used by body builders to build muscle. The purpose of this phase III study was to compare the effects of Ox to Meg (a current standard) on LBM and weight of patients.
155 cancer patients who had experienced a 3% or greater loss of body weight were randomly assigned to receive Ox twice a day or Megace daily while undergoing chemotherapy. 60% of those enrolled had advanced disease. There was a significant improvement in weight and change in fat mass in the Megace group. The Ox group actually lost weight and fat mass. There was a 50% study dropout rate, which was much higher in the Ox arm (69%) versus 39% in the Megace arm.
It is unclear whether the advanced stage of disease played a role in the patients on Ox losing weight. The authors neglected to discuss why the drop out rate was so high, which could be related to toxicity. The researchers are now looking to perform a trial comparing megace to Ox given with megace and it will be useful to see if the combination improves weight outcomes.
A Phase III trial comparing FULV to FULV + oxaliplatin in stage II or III carcinoma of the colon: Survival results of NSABP Protocol C-07
Previous studies have shown a benefit to adding oxaliplatin to the standard 5-FU and leucovorin in adjuvant therapy for stage II or III colon cancer. This report is an update of the results of a phase III study comparing 5-FU/LV (FULV) with 5-FU/LV and oxaliplatin (FLOX) in stage II and III colon tumors.
The study had 2,409 participants randomized to the two regimens. 29% of the participants had stage II disease. At the 3-year update, the difference in disease-free survival was reported as 4.6% (superior in FLOX arm). At this 5-year update, the disease-free survival advantage had increased to a 5.2% advantage in the FLOX arm. However, these differences were not statistically significant. Nonetheless, the authors feel that longer follow up may result in a statistically significant difference. Interestingly, when stage II (node negative) patients were teased out, no benefit was seen for them.
This study could result in a change in the standard of care for adjuvant therapy, but longer follow up is necessary to determine if the benefits seen are significant. The addition of oxaliplatin is not without consequence, as it can cause significant neurotoxicity, affecting quality of life.
Prophylaxis of recurrent chemotherapy-induced oral mucositis: A phase II multicenter, randomized, placebo-controlled trial of recombinant human intestinal trefoil factor (rhITF)
Oral mucositis is a common, debilitating symptom affecting many patients on high-dose chemotherapy. It is an inflammation of the mucous membranes of the mouth, and can often range from erythema and sores to severe ulcerations. It can be quite painful, and often prevents patients from eating, drinking, or talking for long periods of time.
Intestinal Trefoil Factor (ITF), is a protein found mostly on mucosal surfaces throughout the gastrointestinal tract. ITF has been shown to promote mucosal protection, repair, and restitution. Therefore, it is hypothesized that therapy with recombinant human ITF (rhITF) can alleviate damage to the mucosa of the oral cavity and lessen the effects of oral mucositis. This study randomly assigned 99 patients receiving 5-FU chemotherapy, who had mucositis with their first cycle of chemotherapy, to receive placebo, low dose ITF, or high dose ITF (in the form of an oral spray).
# of patients with grade 2 or greater mucositis
No serious side effects were reported. These results are quite promising, but this is a very small study and further study must be done on larger groups. It will also be interesting to study this drug in other patient populations, particularly stem cell transplants, where oral mucositis is quite severe.
RAD001 versus placebo in patients with metastatic renal cell carcinoma (RCC) after progression on VEGFr-TKI therapy: Results from a randomized, double-blind, multicenter phase III study
RAD001 (Everolimus) is an oral targeted therapy medication that inhibits mTOR, which regulates cell proliferation (growth) and angiogenesis (development of blood vessels). This phase III study compares RAD001 to placebo in patients with metastatic renal cell cancer that has progressed with either sorafenib or sutent.
Many studies perform "interim analyses", where they stop the study partway through, evaluate the results, and stop the study if one arm appears to be superior. This study was stopped after a second analysis found the RAD001 arm to be superior. This allows those patients receiving placebo to receive the therapy as well.
The median progression-free survival was 4.0 months in the RAD001 arm versus 1.9 months in the placebo arm. Benefit was seen in patients classified as favorable risk, intermediate risk, and poor risk. 60% of those receiving RAD001 achieved stable disease, versus 30% on placebo.
Toxicities reported include stomatitis, anemia, and aesthesia. Rarely, pneumonitis, hypercholesterolemia and hyperglycemia were seen in the RAD001 arm.
The benefit of everolimus over placebo is clear from this study, and the authors’ conclusion that everolimus should be a standard of care in this setting seems valid, particularly given the fact that no other agent has been demonstrated to be as efficacious to date. Having said this, with the recent advent of targeted agents available to treat metastatic RCC, the timing and sequence with which they will be ultimately used to achieve the best outcomes is undetermined as of yet. Further studies may look at combining therapies or comparing sorafenib/sutent to everolimus to better clarify how to best utilize these therapies.
Radiotherapy versus carboplatin for Stage I seminoma: Updated analysis of the MRC/EORTC randomized trial (ISRCTN27163214)
Seminoma (the most common type of testicular cancer) has traditionally been treated with orchiectomy followed by radiation therapy. Follow-up of these patients found that the radiation therapy resulted in higher risk of mortality, secondary cancers and cardiac issues. Seminomas are known to be quite sensitive to platinum chemotherapy agents. Therefore, this study compared 1 cycle of carboplatin to radiation therapy in stage I seminomas following orchiectomy.
1477 patients were randomly assigned to receive radiation or carboplatin after surgery. This report is based on 6.5 years follow up. There was no significant difference in recurrence-free survival between the groups. There was, however, a significant difference in the rate of 2 nd primary germ cell tumors (GCT). There were 2 (0.3%) cases in the carboplatin group (C) and 15 (1.7%) in the radiation therapy (RT) group.
As for side effects, patients were scored based on percentage of patients able to work at 4 weeks and 12 weeks. There was a significant difference at week 4 between C and RT, with 19% of carboplatin patients unable to do normal work vs. 38% unable to in the radiation group. However, this difference was not present at 12 weeks, at which time the majority of patients in both arms were able to function normally. There was increased grade 2 and 3 thrombocytopenia in the C group compared to the RT group. These results tell us that carboplatin is an effective alternative to radiation therapy for stage I seminomas and should be considered in this population. Longer follow up will look further at secondary cancers and cardiac problems, which may be possible in either group.
Randomised, double-blind, placebo controlled, phase III study of bevacizumab (BV) with docetaxel (D) or docetaxel with placebo (PL) as first line therapy for patients with locally recurrent or metastatic breast cancer (mBC): AVADO
Bevacizumab is a monoclonal antibody that targets VEGF, which allows it to inhibit angiogenesis (growth of blood vessels). A previous study demonstrated that combining bevacizumab with paclitaxel resulted in improved response rate and progression-free survival in metastatic breast cancer. This study was conducted in Europe, where docetaxel is used more frequently than paclitaxel, and looked to combine bevacizumab with docetaxel.
736 participants with metastatic breast cancer were randomized to receive docetaxel + placebo (P), docetaxel + low dose bevacizumab (LD) or docetaxel + high dose bevacizumab (HD). Statistically significant advantages in progression-free survival (PFS) were seen in both bevacizumab arms. Median* PFS in the P arm was 8 months, 8.7 months for the LD arm, and 8.8 months for the HD arm. The percentage of patients who achieved at least a partial response were 44% (P), 55% (LD) and 63% (HD). Survival was not reported, as the median follow up is only 10 months, and more mature data is needed to evaluate survival. Limited toxicity was seen, according to the authors.
The PFS benefit was small in this trial, compared with the trial of paclitaxel and bevacizumab, which saw a greater benefit (5.9 versus 11.8 months). In that trial, paclitaxel was given weekly, which may account for the improvement in PFS. Ongoing studies (RIBBON trial) will further investigate adding antiangiogenesis agents to the treatment options in metastatic breast cancer.
* The median is the "middle of the pack", where half of the patients have had more years since treatment and half have less. For instance, if the patients were 2, 4, 6, 10.8, 12, 12 and 14 years since treatment, 10.8 is the mid point, or the median. It is different from the mean, which would be the average time since treatment.
Randomized Phase III Study of Capecitabine, Oxaliplatin, and Bevacizumab with or without Cetuximab in Advanced Colorectal Cancer (ACC), the CAIRO2 Study of the Dutch Colorectal Cancer Group (DCCG)
This study compared patients with advanced colorectal cancers treated with capcitabine, oxaliplatin and bevacizumab (COB) versus COB + cetuximab. Bevacizumab inhibits the vascular endothelial growth factor (VEGF) receptor, and cetuximab inhibits EGFR. Researchers theorized that combining the two targeted therapies might result in better outcomes.
This unfortunately did not prove to be true. The addition of cetuximab had no effect on overall survival, and actually resulted in worse progression-free survival. The rates of toxicities were higher with the addition of cetuximab. There is some suggestion that there could be a benefit for carefully selected patients. This study highlights the fact that newer targeted therapies are not without toxicities, and combining them may not always be possible.
A Randomized Phase III Study of Gemcitabine in Combination with Radiation Therapy Versus Gemcitabine Alone in Patients with Localized, Unresectable Pancreatic Cancer: E4201
Prior studies of gemcitabine with radiation therapy in pancreatic cancer have concluded that the drug adds toxicity, with little, if any benefit. But, gemcitabine if known to make tissues more sensitive to radiation (called radiosensitization). This study was designed to further study the role of radiation with gemcitabine in unresectable pancreatic cancer.
The study was stopped early due to poor accrual. 71 patients (out of a planned 316) were randomly assigned to receive gemcitabine (G) or G + radiation therapy (GRT). As previously reported, patients with grade 4 (out of 0-4, 4 being most severe) toxicity was much greater in the GRT arm (41.2%), compared to the G arm (5.7%). Overall toxicity was similar, however. There was a small difference in overall survival, 9.2 months for G and 11 months for GRT.
Overall, it appears that radiation prolonged survival, but ultimately most patients still die, based on the overall survival over time that was presented by the authors. Weight loss, QOL, and toxicity were recorded but not reported at this time. Aggressive supportive care is essential, and we await reports of toxicity. With aggressive supportive care, it may be possible to escalate the dose of chemotherapy or radiation used in order to improve outcomes. Unfortunately, after nearly three decades of research, the role of radiation in pancreatic cancer is still not clear at present. These results do appear to affirm that radiation therapy and gemcitabine are more effective than gemcitabine alone, but due to the poor accrual, a larger study is still needed.
A randomized phase III trial of four cisplatin (CIS)- containing doublet combinations in stage IVB, recurrent, or persistent cervical carcinoma: A Gynecologic Oncology Group (GOG) study
Several studies have demonstrated varying degrees of benefit to adding a second chemotherapy to cisplatin when treating advanced cervical cancer. This GOG sponsored study compared 4 potential regimens looking to identify the optimal regimen. Participants were randomized to receive cisplatin given in combination with paclitaxel (P) (which is standard therapy), vinorelbine (V), gemcitabine (G) or topotecan (T). Many studies will perform a data analysis at pre-specified time points during the study and close early if one arm appears superior. In this study, interim analysis found that no arm was superior to the already standard P arm.
Tumor response rates were not significantly different across the four arms. Rates of complete response were 29.1%, 25.9%, 22.3%, and 23.4% for PC, VC, GC, and TC, respectively. No significant overall survival benefit was seen in any arm, nor was there any significant difference in quality of life scores. Toxicities were also similar.
The authors conclude paclitaxel/ cisplatin should remain the doublet of choice in the treatment of advanced or recurrent cervical cancer. An upcoming trial plans to add bevacizumab (an antiangiogenic agent) to the regimen, which will hopefully provide additional benefit as this disease remains very difficult to treat with current therapies.
Randomized Trial of Standard Versus Higher Dose Prophylactic Cranial Irradiation (PCI) in Limited Stage Small Cell Lung Cancer (SCLC) Complete Responders (CR): Primary End Point Analysis (PCI99-01, EORTC 22003-08004, RTOG 0212)
The use of prophylactic cranial irradiation (PCI) in patients with limited stage small cell lung cancer (SCLC) has been shown to provide an overall survival benefit (3-year overall survival of 20.7% with PCI versus 15.3% without) in a large meta-analysis (a study combining the results of several studies) by decreasing the risk of developing brain metastasis. There were a variety of doses and fractionation schemes used in the above mentioned meta-analysis. When the total dose was examined, it appeared that there was a trend towards decreased brain metastasis with higher doses of PCI. This study looked to compare the standard PCI dose to a higher dose.
Participants (n=720) had limited stage small cell lung cancer and were randomly assigned to receive standard dose PCI (SD) or a higher dose, twice-a-day regimen (HD). Toxicities were similar in the two arms. There was no statistically significant difference in the rates of brain metastases between the groups. For unknown reasons, there were lower rates of chest recurrence in the HD group and a decrease in survival in the HD group. For now, standard dose PCI should remain the standard of care.
Relation between perceived cognitive function and neuropsychological performance in survivors of breast and colorectal cancer
"Chemobrain" or "chemofog" was originally described by the female breast cancer population, and refers to symptoms of decreased cognitive acuity described by patients. Often, these symptoms include problems with linear thought and multi-tasking. Studies have found that these symptoms can persist for years after therapy. Other studies have found that patients’ self-reported cognitive problems do not match up with how they score on formal cognitive testing. Researchers have suggested that patients may experience a "disorder of insight", or an inability to see how well they actually do function. This study looked to evaluate perceived cognitive function with function based on formal cognitive testing in patients with colorectal and breast cancer.
428 patients were assessed in the study. Overall, 15% of patients reported major perceived cognitive impairment (12% of colorectal patients, and 33% of breast cancer patients). Over the four assessments performed for colorectal cancer patients, perceived cognitive impairment was approximately constant at baseline, 6 months, and 12 months, but appeared to decrease somewhat at 24 months. Formal testing deficit was identified in 22% of patients (22% of colorectal patients, and 14% of breast cancer patients). Interestingly, 31% of colorectal patients had deficits on formal testing at baseline. This improved to 10% at 24 months after treatment.
Perceived poor cognitive function was more closely associated with fatigue, quality of life, and depression than with deficits on formal testing. Patients who received chemotherapy perceived greater impairment, worse quality of life, and worse fatigue, but demonstrated no significant difference on formal testing from those who did not receive chemotherapy.
Correlation between perceived cognitive function and actual NP varied according to diagnosis and gender:
- Among colorectal cancer patients, 71% reported normal perceived function and performed normally on formal testing. This was the case for 51% of breast cancer patients.
- Among colorectal cancer patients, 7% reported impaired function, but performed normally on formal testing. This was the case for 35% of breast cancer patients.
Overall, female patients were more likely to report impairment in the setting of normal formal testing, while male patients were more likely to report normal function in the setting of deficits on formal testing.
While these results appear interesting, there are a few concerns. The formal testing used was not designed for this population and is known to be a poor test for multi-tasking", which is a common complaint in this population. The study evaluated colorectal cancer patients over a period of time, but breast cancer patients only once. The presence of anxiety early on in the diagnosis and treatment process may have a significant affect, but was not tested.
This study demonstrates significant cognitive impairment reported by a high percentage of patients undergoing cancer treatment. The authors demonstrate that this impairment is often not detectable on classical or computer based formal testing. This finding does not decrease the importance or validity of perceived cognitive impairment, however. As the authors point out, both perceived cognitive deficit and objective deficit on formal testing are extremely important, and should be considered as separate but equally important contributions to a patient’s quality of life after cancer.
SO124: A Randomized Phase III Trial Comparing Irinotecan/Cisplatin (IP) with Etoposide/Cisplatin (EP) in Patients (pts) with Previously Untreated Extensive Stage Small Cell Lung Cancer (E-SCLC)
The combination of etoposide and cisplatin (EP) is the most widely used chemotherapy regimen for small cell lung cancer. Two large studies looked at using irinotecan and cisplatin (IP), but had conflicting results. The first trial was conducted in Japan and found a significant improvement in overall survival with IP. The follow-up study was conducted in North America and Australia and failed to show a benefit to the newer regimen. It is not clear if the different outcomes were due to ethnic differences in the metabolism of irinotecan. The current study looked at the comparison of EP to IP again to try to determine the best regimen.
645 patients with extensive stage small cell lung cancer participated in the study. The EP arm experienced more neutropenia and thrombocytopenia, while the IP arm experienced more diarrhea. There were no differences seen in overall survival, progression free survival or response rates between the two groups.
This is now the second clinical trial that has failed to demonstrate a survival benefit with IP therapy versus EP therapy in patients with extensive stage SCLC. The authors point out that genetic variability may be responsible for the discrepancy between the two studies. Another potential confounder is cigarette smoking. There have been some data to suggest that smoking affects the metabolism of irinotecan. Unfortunately, smoking status was not recorded in the present study. However, it is also certainly possible, as the authors point out, that the results from the JP511 study were incorrect because it had been stopped early due to toxicities. Nonetheless, from the combined results of the two American trials, it is clear that EP remains the standard of care for extensive stage SCLC.