The frontline treatment of patients with Philadelphia chromosome—positive (Ph+) chronic myelogenous leukemia (CML) continues to be debated as imatinib (Gleevec) rapidly approaches the end of its patent protection and next-generation agents continue to show efficacy in clinical trials.

Enhancing this debate is the fact that there are currently three highly effective tyrosine kinase inhibitors (TKIs) approved for the frontline treatment of patients with Ph+ chronic CML, including imatinib, and three unique therapies approved in secondary settings. Due to the depth of this armamentarium, several factors go into the decision of which therapy to utilize, including efficacy, costs, and toxicities.

 Peer Exchange roundtable entitled “Recent Advances in MDS and CML,” moderator Harry P. Erba, MD, PhD, led a discussion on the optimal use of approved therapies across the treatment paradigm for patients with CML. The patent for the active ingredient in Gleevec expires in the United States in 2015, although other patents on certain features and processes remain in effect from 2018 to 2023, according to documents that Novartis, the drug’s manufacturer, posted on its website. Generic versions already have been launched in at least six other countries, including Canada, said Novartis.

The second-generation BCR-ABL inhibitors dasatinib (Sprycel) and nilotinib (Tasigna) demonstrated better efficacy than imatinib in the ENESTnd (

) for the first-line treatment of patients with Ph+ CML. At 24 months, the complete cytogenetic response (CCyR) rate for patients receiving dasatinib in the DASISION trial was 86%, compared with 82% with imatinib.

 Similarly, in the ENESTnd study, the 24-month CCyR rate with nilotinib was 87% at 300 mg twice daily dosing versus 77% with imatinib at 400 mg daily.

		Table 1. Four-Year Efficacy Findings From ENESTnd

		BID indicates twice daily; MMR, major molecular response; MR4.5, molecular response grade 4.5; OS, overall survival; PFS, progression-free survival; QD, daily. Saglio et al. Blood. 2013;122(21; abstr 92).

Given the similar efficacy at a lower cost, imatinib remains an attractive option in the frontline setting. However, the second-generation agents are usually recommended across all settings, as a result of their increased efficacy and lesser toxicity. “I’d say that the main drivers of not using a secondgeneration TKI upfront are really economic, and I think it’s a fair discussion that’s based on limitations and things of that nature,” suggests Ruben A. Mesa, MD. “For the individual patient in the room with me, I typically advise a second-gen TKI as frontline [therapy].”

Although there is an economic advantage with imatinib, treatment with the drug is not as well tolerated as therapy with the newer agents. Moreover, as the toxicity profile becomes more severe, patients are less likely to be compliant.

“Noncompliance leads to disease progression. And it is perfectly well established that a patient taking imatinib may not be compliant due to side effects,” explained Mark J. Levis, MD, PhD. “I can’t think of a greater reason for a patient to be noncompliant than what we would regard as, ‘Oh, it’s not that bad.’ ” To confront these conundrums, researchers have developed several strategies that involve utilizing these drugs in various patient populations or in distinct sequences. In the patient characteristic strategy, patients with high-risk disease receive treatment with the second-generation agents while imatinib is utilized primarily in the low-risk setting. In the sequencing strategy, imatinib is administered for 3 to 6 months followed by a switch to dasatinib or nilotinib; or, in a reverse approach, the second-generation agents are used as an induction therapy with imatinib as maintenance.

“I’m coming at it from the point of view of arguing that the difference in progression is the key because we might be curing patients, but what we really know is we’re preventing progression and we should use the drug that does that the best and the quickest,” said Erba. “And so that’s why I would use a second-generation [therapy upfront], everything else being equal.”

		Table 2. Four-Year Efficacy Findings From DASISION

		MMR indicates major molecular response; MR4.5, molecular response grade 4.5; OS, overall survival; PFS, progression-free survival; QD, daily. Cortes et al. Blood. 2013;122(21; abstr 653).

While limited data are available regarding sequencing strategies, Sokal score data are accessible for newly diagnosed patients with CML (

). These findings suggest that patients with intermediate- to high-risk scores should receive second-generation agents first, while patients at lower risk are better served by treatment with imatinib.

“In the lower risk, sometimes I’m still willing to offer them imatinib but with the exact point that you should look earlier than 6 months. Maybe at 3 months is a better option,” suggests Rami S. Komrokji, MD. “Then the choice between the other new agent is probably also going to depend on some of the toxicity profile for those two agents, whether to select nilotinib or dasatinib.” 

If costs were not a concern, the second-generation TKIs would undeniably be used in the first-line setting, panelists agreed. However, since costs are a concern, better tools are needed to determine the optimal patients for each therapy. In order to be effective, these tools would need to look at features intrinsic to each patient, such as metabolites, polymorphisms, or immune response data. This level of individualization could make research difficult.

Adding to this difficulty is the fact that outside of BCR-ABL mutations, there are not genetic alterations that facilitate the selection of frontline therapies in CML. As a result, genetic sequencing is often reserved for the detection of a possible resistance mutation, such as BCR-ABL T315I. The presence of these alterations could help determine an optimal therapy in the second-line or salvage setting.

In reference to genetic analyses, Rafael Bejar, MD, PhD, noted that he “saves that type of analysis for when patients are actually showing resistance to treatment. That’s the right time to look for these resistance mutations, and really, no other genes have been informative.”

Unfortunately, as imatinib becomes available generically, payers may not provide physicians with much of a choice when it comes to first-line therapies based on reimbursement models. If this is the case, concerns over determining the correct treatment based on patient characteristics could be an exercise in futility, Levis believes.

“I think this is going to be completely turned on its head if imatinib goes generic, and we’re going to be under tremendous pressure to not prescribe those second-generation [therapies],” Levis believes. “So everything we’re doing carefully—thinking that you really need nilotinib versus imatinib&mdash;is potentially going to go right out the window.”

The effective frontline treatment of patients with CML has dramatically changed the natural history of the disease, with the approval of TKIs that target the BCR-ABL fusion gene. However, the long-term administration of TKIs to control CML can result in a range of adverse events and financial burdens, begging the question of whether or not their administration should ever be stopped.

“For hypertension, we prescribe beta blockers forever and nobody complains of that. In CML, we need to stop therapy,” explains Elias J. Jabbour, MD. “So we’re pressured by the patient, by the society, by the financial world to stop therapy.”

		Table 3. Four-Year OS by Sokal Risk in ENESTnd

Articles

The frontline treatment of patients with Philadelphia chromosomeâ€“positive (Ph+) chronic myelogenous leukemia (CML) continues to be debated as imatinib (Gleevec) rapidly approaches the end of its patent protection and next-generation agents continue to show efficacy in clinical trials.


Frontline Treatment Questions Abound as Generic Imatinib Approaches

At the recent National Comprehensive Cancer Network (NCCN) 19th Annual Conference, experts discussed this year’s updates to the NCCN Clinical Practice Guidelines in Oncology. The meeting also included reviews of NCCN Task Force reports on issues in supportive care. We asked eleven NCCN panel members to select the most significant updates and insights presented at the conference.

“The most significant changes are the addition of two newly approved agents for chronic lymphocytic leukemia, obinutuzumab and ibrutinib. That’s quite a lot in a single year. These drugs have the potential to make major changes in how we treat patients, particularly as we have more important non-chemotherapy options. Additionally, the brand-new guidelines for several rare lymphomas are important educational tools. Because they are for rarer diseases, they will hopefully provide useful guidance for clinicians who infrequently encounter these illnesses.”

				Obinutuzumab (Gazyva) plus chlorambucil was added as an option for previously untreated patients with chronic lymphocytic leukemia (CLL). The combination therapy is an option for those patients without an 11q or 17p deletion who are frail with significant comorbidities, and both older and younger patients either with or without comorbidities. The combination is also an option for CLL patients with either an 11q or 17p deletion.

				Ibrutinib (Imbruvica) was added as a treatment option for CLL patients with or without an 11q or 17p deletion who have received at least one prior therapy.

				For patients with diffuse large B-cell lymphoma, recommended follow-up imaging posttreatment was changed from CT scans every “6 months to 2 years” to “only as clinically needed.”

				PET-CT scan should now be considered to evaluate at presentation and following initial response to therapy in follicular lymphoma.

				Rituximab (Rituxan) plus low-dose CHOP chemotherapy (R-mini-CHOP) was added under a separate heading for patients with comorbidities aged ≥80 years with aggressive B-cell lymphoma.

				Two additional guidelines for two rare lymphomas added:				

						Primary Cutaneous CD30+ T-Cell Lymphoproliferative Disorders

						T-cell Large Granular Lymphocyte Leukemia

						“These guidelines are largely educational to define these diseases and help clinicians accurately recognize and distinguish these disorders from other types of lymphomas or even benign, reactive processes. There are also some basic therapy recommendations. Because there is little data on these disorders, these recommendations are largely based on expert experience and retrospective studies.”

		Waldenström’s Macroglobulinemia, Multiple Myeloma

		Dana-Farber/Brigham and Women’s Cancer Center

“The updates for Waldenström’s incorporate major progress in our ability to identify a common mutation that helps determine proper treatment. As for multiple myeloma, none of the updates will radically change clinical practice, but we did add a new footnote that may indicate major changes to come. A small study has shown benefit to treating smoldering multiple myeloma rather than observing it. Further studies—which could make such treatment a standard of care&mdash;are starting up and we’re urging doctors to enroll eligible patients.”

				Ibrutinib (Imbruvica) now appears as a non—stem cell toxic, salvage therapy option.

				MYD88 L265P AS-PCR testing of bone marrow has proven itself useful in working up certain patients.

				The intent of therapy should be based on palliation of symptoms and not necessarily levels of IgM, unless the patient is exhibiting evidence of symptomatic hyperviscosity.

				Bortezomib (Velcade) plus prednisone now appears, under category 2B, as an option for maintenance therapy.

				Bortezomib plus thalidomide (Thalomid) now appears, under category 2B, as an option for maintenance therapy.

				Recent studies on smoldering myeloma show that patients with certain characteristics including IgG levels >3 g/dL, IgA >2 g/dL, urinary Bence Jones protein >1 g/24 hours, or abnormal free light chain ratios, have an increased risk of progression to active myeloma.

				There is a growing consensus that the classical definition of smoldering myeloma using certain tests such as plain x-rays is outdated. Efforts to modify these criteria and reclassify some patients previously classified as “asymptomatic” to having “active disease” are under way.

				Retrospective studies suggest a 2- to 3-year minimum length of remission before caregivers consider a second autologous stem cell transplant for salvage therapy (category 2B).

		Robert H. Lurie Comprehensive Cancer Center of Northwestern University

“Substantial findings in two research areas have produced widespread changes in the recent guidelines. First, trials of pertuzumab demonstrated value in a number of situations. Second, research showed that axillary lymph node dissection, while still indicated in some situations, provides no survival benefit in others.”

				A pertuzumab (Perjeta)—containing regimen may be administered preoperatively to patients with ≥T2 or ≥N1, HER2+, early-stage breast cancer.

				Patients who qualify for a neoadjuvant pertuzumab-containing regimen but do not receive it can be considered for pertuzumab after surgery on the same schedule and dosage as presurgical regimens.

				Paclitaxel + trastuzumab (Herceptin) was added to the list of therapies for patients with low-risk, stage l, HER2+ disease, particularly those not eligible for other standard adjuvant regimens due to comorbidities.

				Clinically negative axillary lymph node(s) should have axillary ultrasound; suspicious nodes should be sampled by FNA or core biopsy and clipped with image-detectable marker.

				Clinically positive axillary lymph node(s) should be sampled by FNA or core biopsy and clipped with image-detectable marker.

				Positive clipped lymph nodes must be removed if FNA or core biopsy was positive prior to neoadjuvant therapy.

				Concurrent use of trastuzumab and pertuzumab with an anthracycline should be avoided because of cardiac toxicity risks.

				For patients who have particularly favorable tumors, patients whose adjuvant systemic therapy is unlikely to be affected, the elderly, or patients with serious comorbid conditions, the performance of axillary lymph node dissection may be considered optional—except where definitive data supports it.

				In patients with HER2+ and axillary node—positive breast cancer, trastuzumab should be incorporated into adjuvant therapy (category 1).

				Trastuzumab should also be considered for patients with HER2+, node-negative tumors ≥1 cm (category 1).

				Trastuzumab should optimally be given concurrently with paclitaxel as part of the AC followed by paclitaxel regimen, and should be given for 1-year total duration.

“In this year’s NCCN prostate cancer guideline update, three definitions and clarifications have been added that more accurately assess risk and will allow patients and physicians to make better treatment decisions. Still, more data are necessary on active surveillance monitoring strategies to provide clarity on this issue. The Early Detection Panel, led by Peter Carroll, MD, and our Treatment Panel have re-emphasized strongly our interdependence and the need for patients and physicians to consider carefully the recommendations of the two guidelines to minimize the risks posed by overdetection and overtreatment of lowrisk prostate cancer. Additionally, the panel tried to place the new FDA-approved therapies for men with advanced prostate cancer in the approximate order in which they should be considered in the pre- and postchemotherapy settings. The guidelines may assist with proper choice and sequence of treatments in advanced disease, which has become more challenging due to the FDA approval of five new agents since 2010.”

				Radium Ra 223 dichloride (Xofigo) is now a category 1 option for patients who have symptomatic bone metastases after androgen deprivation therapy and a docetaxel-based chemotherapy have failed.

				A distinct clarification between active surveillance (actively monitoring the course of disease with the expectation to intervene with potentially curative therapy) and observation (monitoring the course of disease with the expectation to deliver palliative therapy for the development of symptoms or a change in exam or a PSA level that suggests symptoms are imminent) was added to the current guidelines.

				For patients with stage IIA or IIB disease who have a less than 10-year life expectancy, active surveillance was replaced with observation.

				“Recurrence group” was replaced with “risk group” to help clarify treatment discussions for different stages of prostate cancer.

				Hypofractionated intensity-modulated radiation therapy (IMRT) should now be considered carefully for localized prostate cancer, since studies have shown similar efficacy and toxicity compared with conventional fractionated IMRT.

“This year’s updates contain small but significant changes on several fronts—everything from the use of chemotherapy regimens to the consistency of guideline wording&mdash;but the most substantial change, by far, is the call for additional testing of tumor genetics and the increased contraindication of two targeted therapies.”

				All patients with metastatic colorectal cancer should have tumor tissue genotyped for KRAS and NRAS mutations. Whenever possible, non-exon 2 KRAS and NRAS mutation status should also be determined. Patients with any KRAS mutation (exon 2 or non-exon 2) or any NRAS mutation (exon 2 or non-exon 2) should not be treated with either cetuximab (Erbitux) or panitumumab (Vectibix).

				Lynch syndrome tumor screening such as IHC or MSI should be considered for all colorectal cancer patients diagnosed when they are aged ≤70 years or, for patients who are diagnosed later in life, when they meet the Bethesda Guidelines.

				Bevacizumab (Avastin) has been added as an option, in combination with FOLFOXIRI, as an initial therapy for advanced or metastatic disease or for unresectable synchronous liver and/or lung metastases.

				Regorafenib (Stivarga), which had been recommended only for KRAS mutant tumors, is now a treatment option for all patients who have progressed through all available regimens (eg, KRAS mutant or KRAS wild-type with previous exposure to an anti-EGFR inhibitor).

				For untreated, resectable metachronous metastases, the preferred adjuvant and neoadjuvant chemotherapy regimens are FOLFOX or CapeOx. Other indicated—though less preferred&mdash;regimens are FLOX or capecitabine or 5-FU/leucovorin.

				The indication for laparoscopic-assisted colectomy has been expanded to cases where there is some indication of disease in the rectum or significant abdominal adhesions.

				Recommendations for serial CEA evaluation no longer include that physicians consider a PET scan or CT scan when performing their work-ups on patients.

At the recent National Comprehensive Cancer Network (NCCN) 19th Annual Conference, experts discussed this year's updates to the NCCN Clinical Practice Guidelines in Oncology. The meeting also included reviews of NCCN Task Force reports on issues in supportive care. We asked eleven NCCN panel members to select the most significant updates and insights presented at the conference.

2014 NCCN Guideline Updates: Experts Highlight New Recommendations for Clinical Practice

		Lymphoma Division Chief John Theurer Cancer Center at HackensackUMC

		Chief Science Officer and Director of Research and Innovation Regional Cancer Care Associates

The National Comprehensive Cancer Network (NCCN) guidelines have been a very valuable resource for practicing oncologists for 15 years. These guidelines are based on recommendations of expert faculty panels for each subspecialty, and are being updated regularly based on newly published practice-changing data. They are intended primarily to summarize scientific evidence, formulate best practice recommendations, and reduce variations in care.

Public and private health insurers commonly use these guidelines and compendia to support reimbursement decisions. What is unclear, however, is the actual proportion of physicians who follow these evidence-based cancer treatment algorithms.

The decision for a particular patient is indeed complex and multifactorial—from comorbidities, to convenience factors (eg, travel distance, oral vs infusion), to insurance issues. Looking at the NCCN database or other longitudinal studies, such as the National LymphoCare study, it appears striking how patterns of care remain heterogeneous across the board. This has implications for population studies, finding historical controls for comparison, and potentially affects the ability to enroll patients on clinical trials. Though the NCCN guidelines represent a great effort to streamline patterns of care in oncology, they typically offer a range of options that are considered acceptable for each cancer and episode of care. On the other hand, they do not incorporate nonclinical factors, such as treatment cost, expected patient out-of-pocket financial burden, or cost effectiveness, into the guidelines development process. The rapidly rising cost of cancer care is not sustainable, with an estimated price tag of $128 billion in 2014 and current projections of a 46% increase in cancer incidence over the next 20 years. In addition, a huge portion of the money spent in cancer is in the form of empiric palliative care during the last few months of a patient’s life.

Unfortunately, patients and physicians often have very little advanced knowledge about copayments for chemotherapeutics or supportive medications, which might vary among states and carriers. Further, many US oncologists are unaware of the varying total costs associated with one chemotherapy regimen versus another.

For each tumor type and phase of care, there are several options available within the NCCN guidelines deemed acceptable, as they provide similar clinical benefit. However, the treatment options can vary widely in terms of cost. Some analyses have shown a cost variation for 6 months of therapy ranging from under $1,000.00 to more than $57,000.00 for the same reported median overall survival! Moving forward, the incorporation of cost information into guideline development will help increase awareness of the economic implications of routine clinical decision making and reduce the financial burden of cancer treatment on patients and society. Choosing the best option for a patient with cost in mind will definitely become part of the responsibility of caregivers.

On the other hand, we need to make sure that by factoring in cost, we do not compromise patient outcomes. Measuring the outcome for every episode of care is the answer and outcomes should be monitored collectively for optimum results. This would also help categorize—based on priority and success&mdash;the many options that have accumulated over time as part of the NCCN guidelines. Finally, the NCCN guidelines do not address in detail the prognostic stratification of patients. Integrating methods to stratify patients based on the ultimate&mdash; and evolving&mdash;clinical and molecular relevant prognostic markers would certainly help refine oncology treatment algorithms into reliable evidence-based medicine recommendations.

The development of more rationale therapeutics will translate into clinical benefit and improve drug development by focusing on more homogeneous subsets of patients. Oncology is undergoing unprecedented changes with more than 3800 new drugs in the pipeline (mostly targeted therapies) and a growing understanding of and access to the molecular diversity of cancer (the expanding role of molecular diagnostics).

The NCCN guidelines were a first step toward reasoning care in oncology. We now need to embrace the rapid ongoing changes as we evolve toward rationalizing care instead of rationed care. We owe this to our field, our patients, and our society.

The National Comprehensive Cancer Network (NCCN) guidelines have been a very valuable resource for practicing oncologists for 15 years. 

NCCN Guidelines Are Effective, but Must Address Cost and Prognostic Stratification

Two recently published clinical studies demonstrated a strong association between higher levels of vitamin D and improved outcomes among patients with various cancers.

In one study, researchers from the Institute for Nutritional Sciences at the Shanghai Institutes for Biological Sciences in China examined circulating 25-hydroxyvitamin D [25(OH)D] levels among 17,332 patients with different tumor types across 25 studies. Vitamin levels were measured at or near diagnosis.

Overall, the meta-analysis showed that a 10-nmol/L increase in circulating 25(OH)D levels was linked to a 4% improvement in overall survival (OS; HR = 0.96; 95% CI, 0.95-0.97).

The strongest association between vitamin D levels and improved OS was observed in patients with colorectal cancer, breast cancer, and lymphoma. In these groups, the pooled HR for OS for the highest versus the lowest quartile of circulating 25(OH)D levels was 0.55, 0.63, and 0.48, respectively. A positive correlation was also observed in patients with lung cancer, gastric cancer, prostate cancer, leukemia, melanoma, and Merkel cell carcinoma; however, the connection was not as strong.

“Considering that vitamin D deficiency is a widespread issue all over the world, it is important to ensure that everyone has sufficient levels of this important nutrient,” one of the study authors, Hui Wang, MD, PhD, a professor at the Institute for Nutritional Sciences, said in statement. “Physicians need to pay close attention to vitamin D levels in people who have been diagnosed with cancer.”

In a second study, researchers found that men at high risk of prostate cancer who had a vitamin D deficiency are more likely to have aggressive disease at diagnosis.

The researchers examined serum 25(OH)D levels in 667 high-risk men who were screened for vitamin D deficiency prior to receiving their first prostate biopsy. The men, aged 40 to 79 years, had elevated PSA levels and other prostate cancer risk factors.

“This is the first study to look at vitamin D deficiency and biopsy outcomes in men at high risk of prostate cancer,” said senior author Rick Kittles, associate professor in the Department of Medicine at the University of Illinois at Chicago. “Previous studies focused on vitamin D levels in men either with or without prostate cancer.”

Among the study population, African-American men with 25(OH)D <20 ng/mL had 2.43-fold increased odds of receiving a prostate cancer diagnosis of any stage (

 = .01). Additionally, African-American men with 25(OH)D <12 ng/mL were 4.89 times more likely to have a Gleason score ≥4+4 (

= .006) and 4.22 times more likely to have a tumor stage ≥cT2b (

European-American men with 25(OH)D <12 ng/mL were 3.66 times more likely to have a Gleason score ≥4+4 (

 = .008) and 2.42 times more likely to have a tumor stage ≥cT2b (P = .008).

The increased odds for aggressive disease among patients with vitamin D deficiency were established after adjusting for potential confounding factors, including obesity, smoking, family history, diet, and calcium intake.

“Vitamin D deficiency could be a biomar ker of advanced prostate tumor progression in large segments of the general population,” said leader author Adam B. Murphy, MD, assistant professor in Urology at Northwestern University Feinberg School of Medicine, in a statement. “More research is needed, but it would be wise for men to be screened for vitamin D deficiency and treated.”

			Li M, Chen P, Li J, Chu R, et al. Review: the impacts of Circulating 25-hydroxyvitamin D levels on cancer patient outcomes: a systematic review and meta-analysis [published online April 29, 2014]. 

			Murphy AB, Nyame Y, Martin IK, et al. Vitamin D deficiency predicts prostate biopsy outcomes. 

Studies Link Higher Vitamin D Levels With Improved Cancer Prognosis

Despite evidence supporting its efficacy, chemotherapy is not routinely administered to patients with muscle-invasive bladder cancer (MIBC), according to a population-based outcomes study from Canadian researchers.

“Patients having surgery for bladder cancer should have chemotherapy, either before or after surgery. Efforts are needed to improve uptake of this treatment, which appears to be vastly underutilized,” lead author Christopher Booth, MD, Division of Cancer Care and Epidemiology, Queen’s University Cancer Research Institute, Ontario, Canada, said in a statement.

Research supports the use of neoadjuvant chemotherapy (NACT) in MIBC, including a metaanalysis of randomized controlled trials that found a significant 5% overall survival benefit with NACT (

. 2005;48[2]:202-205). Although the efficacy of adjuvant chemotherapy (ACT) is not as firmly established in the literature, the authors wrote, “the clinical community appears to have accepted the efficacy of ACT.”

Booth et al sought to determine the use and efficacy of perioperative chemotherapy among the general population of Ontario. They evaluated records of 2944 patients with MIBC from the Ontario Cancer Registry who received a cystectomy between 1994 and 2008. The majority of patients had locally advanced (T3/T4) tumors (71%), were male (75%), and were aged >70 years (60%). Positive lymph nodes were reported in one-fourth of cases.

Overall, NACT was administered to 4% of patients (n = 129), 19% received ACT (n = 572), and 1% (n = 30) were treated with both. To examine usage trends, the researchers segmented patients into three groups: 1994- 1998 (n = 705), 1999-2003 (n = 964), and 2004-2008 (n = 1275). NACT use remained static across the three intervals at 5%, 3%, and 6%, respectively, while use of chemotherapy after cystectomy increased from 16%, to 18%, to 22%.

The researchers were able to identify the specific regimen for 46% (n = 308) of the patients who received perioperative chemotherapy. Among this group, treatment included cisplatin in 82% of patients and carboplatin in 14%. Adjusted analyses linked younger age to increased use of chemotherapy in general and poor pathology with higher ACT use.

The 5-year overall survival (OS) rate for the study population as a whole was 29% (95% CI, 28-31), with a cancer-specific survival (CSS) rate of 33% (95% CI, 31-35). Patients receiving chemotherapy before surgery had a 5-year OS of 25% (95% CI, 17-34) and a 5-year CSS of 28% (95% CI, 18-39). The corresponding rates for the adjuvant group were 29% (95% CI, 25-33) and 28% (95% CI, 24-33), respectively.

Adjusted analyses of ACT use in the general population showed a hazard ratio of 0.71 for OS (95% CI, 0.62-0.81) and 0.73 for CSS (95% CI, 0.64-0.84). “Results from our study demonstrate that chemotherapy given after surgery improves patient survival—probably on the same order of magnitude as chemotherapy before surgery,” Booth said.

The authors noted that the 5-year OS rates of 25% and 29% for NACT and ACT, respectively, were “substantially” lower than rates reported in previous studies. With NACT, a 5-year OS rate of 57% was reported in a phase III randomized trial (

. 2003;349:859-866). Likewise, an updated meta-analysis showed a 5-year OS with ACT of about 50% (

 2005;48[2]:189- 199). Possible explanations for these OS discrepancies, according to the authors, are varying surgical strategies, biases in patient selection/referral, and the “known association between greater cystectomy volumes and improved outcomes.”

In their conclusion, Booth et al wrote, “Given the potential for perioperative chemotherapy to improve patient outcomes, further efforts are needed to understand reasons for underutilization.”

	Booth CM, Siemens DR, Li G, et al. Perioperative chemotherapy for muscle-invasive bladder cancer: a population-based outcomes study [published online April 14, 2014]. 

Despite evidence supporting its efficacy, chemotherapy is not routinely administered to patients with muscle-invasive bladder cancer.

Chemotherapy Underutilized in High-Risk Bladder Cancer

Doxepin rinse may prove to be a viable option for the relief of pain associated with oral mucositis (OM) in patients with head and neck cancers, according to findings of a phase III trial.

This randomized, double-blind, placebo-controlled trial, conducted under the auspices of the Alliance for Clinical Trials in Oncology cooperative group, enrolled 155 patients who were being treated at 26 cancer centers across the country between December 2010 and May 2012. To be eligible, patients were undergoing radiotherapy to a minimum planned dose of 50 Gy and experiencing OM-related pain ≥4 on a 0 to 10 scale.

Participants were randomized 1:1 to receive either doxepin (25 mg diluted to 5 mL with 2.5 mL of sterile or distilled water) on day 1, then crossing over to a placebo on a subsequent day (arm A), or placebo on the first day followed by the doxepin preparation (arm B). Patients in both arms were instructed to swish the solution in their mouth for 1 minute, gargle, and expectorate.

The study’s primary endpoint was a reduction in pain as measured by the pain scale’s area under the curve (AUC), using assessments based on the Oral Mucositis Daily and Weekly Questionnaires—Head and Neck Cancer, administered at baseline and at 5, 15, 30, 60, 120, and 240 minutes for each treatment arm. Patients were allowed to leave after the first hour, instructed to complete the questionnaires at 2- and 4-hour intervals, and received telephone reminders.

Researchers reported that the AUC for the mean reduction in mouth and throat pain was significantly greater with doxepin than placebo, -9.1 and -4.7, respectively (

 <.001). Intrapatient changes of +4.1 for arm A and -2.8 for arm B were determined through crossover analyses, equivalent to a treatment difference of -3.5 (95% CI, -5.1 to -1.8; 

As secondary outcomes, researchers also assessed any stinging or burning, unpleasant taste, and/or drowsiness resulting from the rinse, as well as whether additional analgesia was required 2 and 4 hours after administration.

Adverse effects of doxepin were typically mild and consistent with those identified in previous phase I/II studies. The AUC for stinging and burning was significantly higher with doxepin, being highest 5 minutes after rinsing. The sensations were reduced, but remained statistically significant over the 4-hour postrinse assessment.

Taste also was ranked using AUC on a 0 (acceptable) to 10 (terrible) scale; patients preferred the placebo (5.5) to the doxepin (7.7). After 5 minutes, however, both were deemed acceptable: doxepin (2.9), placebo (1.6).

No significant differences were reported in the use of additional analgesics following use of the rinse versus placebo. Drowsiness was associated more with doxepin, a known adverse effect of the agent; however, differences with placebo did not reach statistical significance until assessment at 2 hours (3.9 for doxepin vs 2.8 for placebo; 

 = .02), based on a scale of 0 (no drowsiness) to 10 (extreme drowsiness resulting in sleep). The researchers noted that some patients deemed the rinse’s sedative effect beneficial as a sleep aid.

Notably, the researchers reported that 63% of patients (n = 81) chose to continue using the doxepin rinse at the conclusion of the trial, with more patients in arm A indicating a desire to continue treatment than those in arm B. Of those who continued the treatment, 14 (17%) subsequently stopped, most often citing burning discomfort and increased drowsiness.

The authors noted that their research represents “the largest placebo-controlled trial to date specifically testing the efficacy of a rinse agent in controlling established mucositis pain and the only such trial with positive results.”

Leenstra JL, Miller RC, Martenson JA, et al. Doxepin rinse versus placebo in the treatment of acute oral mucositis pain in patients receiving head and neck radiotherapy with our without chemotherapy: a phase III, randomized, double-blind trial (NCCTGN09C6 [Alliance])[published online April 14, 2014].

May 2014 | Oncology & Biotech News

Frontline Treatment Questions Abound as Generic Imatinib Approaches

2014 NCCN Guideline Updates: Experts Highlight New Recommendations for Clinical Practice

NCCN Guidelines Are Effective, but Must Address Cost and Prognostic Stratification

Studies Link Higher Vitamin D Levels With Improved Cancer Prognosis

Chemotherapy Underutilized in High-Risk Bladder Cancer

Doxepin Rinse Relieves Pain in Patients With Radiation-Related Oral Mucositis