		Maryclaire Moroney and her beloved dog and “healer” George.

	Maryclaire Moroney was just a teenager when she came across a half-starved, mostly frozen tiny dog huddled outside the public library in her North Virginia town. She scooped the terrified dog into her arms and headed for home, all the while plotting her strategy for convincing her mother to let her keep the little orphan. Fortunately for Maryclaire—and especially for the foundling she named Dinah&mdash;her mother took very little convincing once she saw the pathetic dog with matted fur, and Dinah became the latest in a long line of pampered canine family members.

	Dinah wasn’t the first animal to find a hero in Maryclaire and would be far from the last. But of all the pets in her life, it’s that tiny abandoned poodle whose memory brings tears to her eyes. “When I think of Dinah I think of my mom,” she said. “That dog was so devoted to her.”

	That devotion was never as apparent as when, 8 years later, Maryclaire was called home from her graduate studies at Harvard when her mother was diagnosed with acute myelogenous leukemia. She died only 9 weeks later, never returning home from the hospital. Dinah spent each day camped out at the back door, waiting in vain for her favorite person to come home. At night, she burrowed into a pile of unwashed laundry to surround herself with the scent and feel of the person she loved most. “It’s funny,” said Maryclaire, “but the thought of someone loving you so completely is both comforting and heartbreaking.”

	Though Maryclaire’s mother wasn’t there to witness her beloved dog’s vigil, to Maryclaire, Dinah’s unwavering devotion was a comforting reminder of just how much her mother was loved. “Holding Dinah in my arms gave me a sense of connection to my mom,” she said.

	Fast-forward 23 years, and Maryclaire would experience that kind of extraordinary love firsthand, and under similar circumstances. This time, the diagnosis was Hodgkin lymphoma and the purveyor of unconditional devotion was a shepherd-mix named George.

	It was the fall of 2008 when an enlarged lymph node sent Maryclaire to her primary care physician. After a failed course of antibiotics she was referred to a head and neck surgeon for an excisional biopsy. Maryclaire was still groggy from the anesthesia when she heard a surgical resident comment that it “looks like Hodgkin lymphoma,” but it would be 9 long days before that diagnosis would be confirmed.

	The then-48-year-old single mother of 2 made a deliberate decision not to tell her children—at least, not yet. “I knew there was a chance that I could die,” she said. “My kids weren’t ready to hear that and I certainly wasn’t ready to tell them.” Indeed, Maryclaire’s adopted children, who were then 14 and 16 years old, had already experienced more than their share of pain and loss. “It had been only 7 years since they’d come to me, and we were only just beginning to work through all that had happened to them. I was terrified that I’d be taken from them before I’d had the chance to finish the task at hand.”

	Like so many women, Maryclaire was the consummate caregiver. She had a solid support system of family, friends, and colleagues, but didn’t want to worry them prematurely. And she was far from ready to open the floodgates to well-intended expressions of sympathy and concern. Even so, Maryclaire needed to talk to someone, and she found a willing volunteer in George.

	Maryclaire had adopted George in the summer of 2005 when he was just 7 weeks old. The puppy had been abandoned as a newborn and had just recovered from the highly contagious, often-fatal parvovirus. With her children at her side, Maryclaire cared for the frail pup, and George grew into a big, silly, loving family companion. Three short years later, George would return the favor a thousandfold—and would do so over and over again.

	“I was walking on eggshells around my family and friends,” Maryclaire recalled. “For their sake, I felt the need to be strong and cheerful.” For her own sake, however, Maryclaire needed someone to give her permission to fall apart, and to do so without worrying about anyone else’s feelings. Not surprisingly, George was the perfect candidate for the job. For the first of what would be many times, she buried her face in George’s fur and let the tears come. “He had no fears or expectations. He just let me feel what I was feeling. It was exactly what I needed and it was something I couldn’t have gotten from anyone else.”

	Over the next 6 months, from January to June 2009, Maryclaire went into survival mode. All that was routine and normal about her life as a mother and professor of English literature at Cleveland’s John Carroll University took a backseat to a rigorous chemotherapy regimen of adriamycin-bleomycin-vinblastine-dacarbazine (ABVD). She recalled that her usual thirst for knowledge temporarily gave way to a strong desire to take in information on a strictly need-to-know basis, noting that information overload did little more than feed her anxiety. “My oncologist explained that the ABVD turned off the mechanism for lymphoma reproduction and did so with a 90% success rate. At that point, that was all I needed to know.” When it came to her children, Maryclaire gave them the information they asked for, which, she said, was relatively little. “I was all they had and dying simply wasn’t an option,” she noted. She was told there was a “Plan B” in the event of a relapse, but decided she would deal with the specifics only when and if that eventuality occurred.

	What she couldn’t push to the background were the adverse effects of the ABVD regimen; every 2 weeks Maryclaire did her best to gear up for the relentless nausea and fatigue. She recalled a time in the spring, about halfway through her chemotherapy, when she was especially ill. “George was my ‘go-to guy’ when things got really tough,” she said. “When everyone else was out of the house, I could snuggle up with him and cry in peace. He didn’t care about my bald head, and no matter how hard I cried he never judged me or looked at me differently. George was just George. I felt free when I was alone with him.”

	Healing as they were, Maryclaire’s respites with George were only sporadic and, as any cancer patient knows, life must go on even when coping seems nearly impossible.

	As family, friends, and colleagues rallied to care for Maryclaire before and during each treatment, the care of her children, as well as that of George and Maryclaire’s 2 elderly cats, became part of her treatment plan. One friend would care for the cats, giving the older, diabetic Nina her insulin and scooping the litter, the one thing Maryclaire was advised against doing herself during treatment. Some coworkers organized meals and carpooling for the children, while others scheduled George’s walks and took him to DogTopia Daycare for Dogs, where he was accustomed to spending several days each week playing with his daycare dog-buddies. “George was active and playful and demanded an investment of positive energy. He needed to do what he’d always done,” said Maryclaire. “And while some people might have put doggie daycare in the ‘unnecessary column,’ to me it was a reminder of the few things that remained normal in my life. George was still George and that was one of the few realities that hadn’t changed.”

	In fact, Maryclaire explained, the more these plans were incorporated into her routine, the less stress she experienced—a sentiment that seemed to be shared by her children, who pitched in to help care for George and the cats. “Caring for the animals gave my kids a sense of control and pride,” said Maryclaire, who noted that they were reassured when they realized that some things didn’t change, even in a time of crisis. “They didn’t want to lose their mother and they didn’t want to lose their pets, and helping out was their way of keeping loss at bay.”

	In fact, Maryclaire is grateful that none of her physicians even hinted at the need to give up her animals, even temporarily—something she says would have been like asking her to give up her children. “That would have required a fight, and I needed all my energy to fight the cancer.”

	A sense of normalcy began to return to Maryclaire’s life with the news of her remission in July 2009. As she began to feel better, George served as her “recovery barometer.” She said, “I would measure my progress by how long I could walk George without feeling tired or ill.” Today, with 27 months of remission under her belt, Maryclaire faces the next 3 years of follow-up with a sense of optimism, knowing that the greatest risk of relapse is behind her.

	While she attributes her survival to her oncologists and the care they provided, Maryclaire is quick to stress the difference between surviving and living, noting that it was her friends and family who gave her what she needed to truly recover. And, to a large extent, it was George who gave her what she needed to heal and reclaim the joy and normalcy in her life.

	“The humans who love us are a fragile bunch. In times of crisis they struggle with what to say and do,” said Maryclaire. “But our animals know us right down to the bare soul. They’re completely present with us; they know exactly how we feel and give us precisely what we need without expecting anything in return. They make us laugh and they let us cry.”

	Today, as she looks back on where she’s been and how far she’s come, Maryclaire noted that her bond with George is stronger than ever. “People tell you that a rescued dog will always find a way to thank the person who gives him a loving home,” she noted. “There’s no doubt in my mind that George was waiting for his chance to do just that.”

	Laura Bruck is a freelance writer based in Cleveland, Ohio. She has specialized in healthcare reporting since 1987.

Articles

While she attributes her survival to her oncologists and the care they provided, Maryclaire is quick to stress the difference between surviving and living, noting that it was her friends and family who gave her what she needed to truly recover.

A Dog Named George: Rx for Recovery

	There has been a lack of meta-analyses and systematic reviews conducted in chronic lymphocytic leukemia (CLL). Structured searches were conducted in publication and conference databases to identify randomized controlled trials (RCTs) that are reporting efficacy data for treatment-naïve CLL and both RCTs and non-RCTs for relapsed/refractory CLL. Eight RCTs met prespecified inclusion criteria to permit a meta-analysis of fludarabine/cyclophosphamide/rituximab (FCR) with alemtuzumab, bendamustine, chlorambucil, fludarabine, and fludarabine/cyclophosphamide (FC). A mixed treatment comparison demonstrated that FCR significantly prolonged progression-free survival (PFS) compared with all other treatments (hazard ratios, 0.24-0.56) and significantly increased overall response rate (ORR) compared with all other treatments. FCR significantly increased the complete response (CR) rate compared with chlorambucil, fludarabine, and FC (odds ratios of 30.3, 10.1, and 2.7, respectively). For relapsed and refractory CLL, 9 RCTs and 86 non-RCTs were identified that reported efficacy data. A meta-analysis was deemed inappropriate due to trial heterogeneity. Overall, overall survival (OS) and PFS ranged from 24 to 33.8 months and from 6 to 30.6 months, respectively, depending on the therapy. Across all trials, FCR showed the greatest improvement in PFS, with robust ORR and CR rates. The identified studies indicated that FCR is highly efficacious for the treatment of both untreated and relapsed/refractory patients with CLL. These studies and the benefit of FCR are largely applicable to young and fit patients with CLL, and the best treatment for older patients could not be extracted from this analysis. Going forward, this evidence-based review should be updated with longer follow-up from trials to better determine OS benefit.

	Chronic lymphocytic leukemia (CLL) is the most common adult leukemia in the Western world, with an incidence rate of approximately 3.9 per 100,000 persons per year.

 Approximately 14,570 patients will be diagnosed with CLL in the United States in 2011.

 Primarily a malignancy of the elderly, the median age at diagnosis is 72 years in the United States, and approximately 70% of patients are aged >65 years.

 The disease is largely characterized by a slow, often asymptomatic progression over several years as malignant cells gradually accumulate in the blood, bone marrow, and lymph nodes.

 Anemia, thrombocytopenia, and immunosuppression can accompany painless lymph node enlargement and organomegaly. Systemic symptoms, such as fever, sweating, and weight loss, may be rare. Patients with early disease are usually left untreated; however, most patients will eventually require treatment.

	The treatment of CLL has advanced rapidly over the past 2 decades due to the use of chlorambucil as standard first-line treatment and subsequent clinical determination that the purine-based analog fludarabine showed superior clinical benefit over alkylator- and anthracycline- based regimens.

 Initial treatment with fludarabine is associated with response rates of 63% to 80%, and when combined with cyclophosphamide (FC) showed increased response rates of 74% to 94%.

 Adding the anti-CD20 monoclonal antibody rituximab to FC (FCR) chemotherapy resulted in further improvements in the overall response rates (ORRs) and complete response (CR) rates.

 Additional biologic and chemical agents, including alemtuzumab, ofatumumab, and bendamustine, have been added to the CLL treatment armamentarium, and a number of investigational agents are undergoing study in the clinic. Treatment options for patients with relapsed or refractory CLL remain limited, and the prognosis for these patients is still poor.

 The management of CLL depends on a number of factors, and in the first-line setting it has been proposed that 3 overriding considerations dictate treatment: tumor load with or without symptomatic or progressive disease (ie, determined by Rai or Binet stage or by lymphocyte doubling time); the physical condition of the patient (ie, fitness and comorbidity); and the prognostic risk of the leukemia (ie, due to genetic and other molecular factors).

 For relapsed disease, these factors, in addition to the choice of prior therapy and the length of remission duration from first treatment, will influence treatment decisions. Despite treatment, the vast majority of patients relapse and CLL remains an incurable disease.

 Randomized controlled trials (RCTs) are needed to determine optimal treatment for appropriate patient types, depending on stage of disease, cytogenetics, performance status, and treatment status.

	Published data from RCTs and systematic reviews have provided more definitive evidence for the role of treatment. A meta-analysis performed by the CLL Trialists’ Collaborative Group and a systematic review reported by the Swedish Council on Health Technology Assessment have provided substantial evidence that early treatment with chlorambucil with or without corticosteroids is not associated with a better outcome compared with deferred treatment.

 A systematic 2006 Cochrane Review in patients with previously untreated CLL

 on 5 randomized trials involving 1300 patients confirmed the greater response rates achievable by using purine antagonists, but provided inconclusive evidence for improvement in survival.

	Here we report on an updated systematic review and meta-analysis of first-line RCTs and a systematic review of trials and observational studies conducted in the relapsed and refractory settings.

 Where appropriate, results were combined using a Bayesian mixed treatment comparison (MTC). MTC is an extension of traditional meta-analyses; trials of direct (eg, A vs B and B vs C) comparison are used to yield indirect (eg, A vs C) estimates across multiple different pairwise comparisons and across a number of different interventions in the absence of head-to-head trials.

		Table 1. Inclusion Criteria for Systematic Reviews

		CAP indicates cyclophosphamide/adriamycin/prednisone; CHOP, cyclophosphamide/hydroxydaunorubicin/vincristine/ prednisone; CLL, chronic lymphocytic leukemia; CVP, cyclophosphamide/vincristine/prednisone; FC, fludarabine/cyclophosphamide; FCR, fludarabine/cyclophosphamide/rituximab; y, years.

	Systematic literature reviews of untreated and previously treated patients were undertaken separately, according to prespecified protocols. Search terms used both free text and medical subject headings (MeSH) and were conducted in MEDLINE, EMBASE, BIOSIS, the Cochrane Library, and conference abstract databases (ie, ASCO, ASH, EHA, and ESMO). Conference abstracts were excluded for first-line treatments because the reports rarely provided sufficient information or were not of acceptable quality to be included in meta-analyses. Articles were assessed on the basis of title and abstract according to prespecified patient population, intervention, comparison, and outcome (PICO) criteria; the full text was reviewed, where necessary. Inclusion criteria specified open or blinded RCTs of treatment-naïve adult patients aged >18 years with good performance status (ECOG 0 to 2) (

). Treatment- naïve patients were administered alemtuzumab, bendamustine, chlorambucil, fludarabine, fludarabine/cyclophosphamide (FC), and fludarabine/cyclo-phosphamide/rituximab (FCR). For treatment- ex-perienced patients, a larger number of treat- ments and treatment combinations were included (

). Studies that enrolled mixed populations (eg, both treatment-naïve and relapsed patients) were included where data for the relevant population were reported separately. Observational (non-RCT) studies in relapsed or refractory patients were also included but were not eligible for meta-analyses and were reviewed separately.

	The primary outcome was progression-free survival (PFS), defined as the time between randomization and disease progression, relapse, or death by any cause. Other outcomes of interest included ORR, partial response (PR), CR, overall survival (OS), disease-free survival, duration of remission, and mortality. Study quality was assessed using either the Oxford scale or Cochrane Handbook assessment tool.

	Meta-analyses were prespecified where studies evaluated the same treatment in a comparable patient population with few other indicators of clinical or methodological heterogeneity. Where permissible, results were combined using a Bayesian MTC.

 The Bayesian framework also permitted the derivation of relative treatment rankings and best treatment likelihoods. Information from both continuous (time-to-event) and binary outcomes were of interest for meta-analysis. Analysis of binary outcomes (such as response rates) was based on the log odds ratio. A Cox regression model was assumed for time-to-event outcomes, and the log hazards were summarized across RCTs. Analyses were performed using WinBUGS 1.4 statistical software. A noninformative prior distribution was used (ie, the mean [μ] was set to 0 and the variance [δ] was set to 1000). Credibility intervals were calculated in order to indicate uncertainty around the point estimate. The appropriateness of a fixed or random effects model was investigated using overlap of credibility intervals for residual deviance (ie, the goodness of fit).

		Table 2. RCTs in Treatment-Naïve Patients With CLL

The PFS results reported by Knauf and colleagues are from a later analysis of this trial and were not included in the MTC analysis reported in Table 3. They are reported here for completeness.

		A indicates alemtuzumab; B, bendamustine; C, cyclophosphamide; Chl, chlorambucil; CR, complete response; FC, fludarabine/ cyclophosphamide; FCR, fludarabine/cyclophosphamide/rituximab; mo, months; NA, not available; NR, not yet reached; ORR, overall response rate; OS, overall survival; PFS, progression-free survival; y, years.

	The systematic review identified 683 abstracts, of which 7 trials met the inclusion criteria (

 The CLL8 trial from the FCR clinical development program was also available for inclusion.12 Neither the age (approximately 60 y) nor gender (approximately 70% male) varied significantly across trials. The LRF CLL4 trial included a notably greater proportion of patients with Binet stage A disease and higher chlorambucil dose.27 All 8 RCTs were considered sufficiently similar in design, patient-inclusion criteria and characteristics, and outcomes to conduct an MTC. Data were available to compare PFS, CR, and ORR for FCR with alemtuzumab, bendamustine, chlorambucil, fludarabine, and FC, although only small patient numbers were reported for some treatments and outcomes.

	The MTC showed that FCR significantly prolonged PFS compared with each of the other treatments (

). Hazard ratios (HRs) ranged between 0.24 (0.17 to 0.34) compared with chlorambucil and 0.56 (0.43 to 0.72) compared with FC. The median PFS was prolonged with FCR by 20 and 8 months when compared with chlorambucil and FC, respectively. FCR had a 100% probability of being the best treatment option when PFS is used to assess efficacy.

	The MTC suggested that FCR would be the best therapy for treatment-naïve CLL for achieving response (

). The ORR was highest for FCR and superior to all comparators. The odds ratio for FCR with respect to the ORR endpoint ranged between 2.3 (1.6 to 3.4) with fludarabine to 14.2 (8.3 to 24.7) with chlorambucil. The probability of FCR being the best treatment option was greater than 99% when comparing ORR as the clinical endpoint.

	FCR increased the probability of a CR in comparison with chlorambucil, fludarabine, and FC, and was shown to be the best treatment in 58% of cases (

). When assessing CR, the lower probability of being the best treatment option when compared with PFS or ORR is due to the relative lack of data, with fewer than 5 patients achieving a CR in either treatment arm.

		Table 3. Mixed Treatment Comparison Results Describing the Relative Effect of FCR and the Probability of Being the Best Treatment

		CI indicates confidence interval; FC, fludarabine/cyclophosphamide; FCR, fludarabine/cyclophosphamide/rituximab; NR, not recorded.

	The LRF CLL4 Trial reported a greater proportion of patients with Binet stage A disease and used a higher chlorambucil dose; however, sensitivity analyses demonstrated no significant effect of excluding this study (PFS HR = 0.54; 0.42-0.68).27 All outcomes were analyzed using a fixed effects model, but results from a random effects model were also considered; the credibility intervals overlapped for all outcomes and the overall results remained the same.

	Relapsed and Refractory Patients With CLL

	The systematic review in relapsed or refractory patients identified 2318 abstracts, of which 9 articles relating to 8 RCTs (

) and 1 publication reporting additional follow-up data, were eligible for inclusion.

 The most frequent reasons for exclusion were inappropriate disease (N = 708) and insufficient reporting of either relevant outcomes (N = 385) or interventions (N = 314) (

). Assessment of trial methodology, treatment comparisons, and reported outcomes revealed significant heterogeneity across trials. As such, a meta-analysis was not deemed appropriate due to the risk of introducing bias and generating misleading results. Where 2 similar trials were available, further analyses were constrained by poor study quality, limited reporting quality, patient-inclusion criteria and length of follow-up, treatment duration, outcomes, and frequency of outcomes assessment. Given the heterogeneity across RCTs in relapsed and refractory patients with CLL, the systematic review was extended to non-RCTs to provide a comprehensive assessment of the wider evidence base. This search identified 90 publications reporting data from 86 non-RCTs.

		Table 4. RCTs in Relapsed/Refractory Patients With CLL

Randomized controlled trial that reported data only for patients who were treated with FC GM-CSF.

		C indicates cyclophosphamide; CAP, cyclophosphamide/adriamycin/prednisone; Chl, chlorambucil; CLL, chronic lymphocytic leukemia; COP/CVP, cyclophosphamide/vincristine/prednisone; CLR P, chlorambucil and prednisone; ECOG, Eastern Cooperative Oncology Group; FC, fludarabine/cyclophosphamide; FCR, fludarabine/cyclophosphamide/rituximab; FCM, fludarabine/cyclophosphamide/mitoxantrone; FCM-R, fludarabine/cyclophosphamide/mitoxantrone/rituximab; FCO, fludarabine/cyclophosphamide/oblimersen; FCR, fludarabine/cyclophosphamide/rituximab; GM-CSF, granulocyte macrophage colony-stimulating factor; mo, months; NA, not available; NCI, National Cancer Institute; NHL, non-Hodgkin lymphoma; NR, not yet reached; ORR, overall response rate; OS, overall survival; PFS, progression-free survival; P, prednisone; R, rituximab; WHO, World Health Organization; y, years.

	Overall, fludarabine with or without cyclophosphamide was the most frequently used intervention in clinical studies. Of the monoclonal antibody therapies, the largest body of evidence was identified for rituximab with 2 RCTs and 25 publications relating to 22 non-RCTs.

 To date, the phase III REACH RCT is the largest available study in this setting.

 Only non-RCTs were identified for alemtuzumab or ofatumumab.

Although not the focus of this study, it was noted that adverse event data were infrequently reported and were often incomplete, selective, or combined across treatment groups and/or study populations.

	All RCTs were parallel-group design and size, and the duration of study follow-up ranged from 16 to 552 patients and from 6 to 60 months, respectively (

); 6 out of 9 were full publications and 3 were abstracts.

 No 2 studies compared similar treatments except for 2 related publications comparing FC with FC/oblimersen (FCO).

 In REACH, the largest randomized trial conducted to date in this setting, the median OS was 52 months with FC; but the median OS has not yet been reached for the FCR comparator.

 One study did not present evaluable data (to be considered “evaluable,” data were required to be reported separately for all treatment arms).

 This trial compared FC plus granulocyte macrophage colony-stimulating factor with FC plus supportive care but reported only composite results for both treatment arms. OS data were unavailable or not reported for 2 studies.

 Results from REACH showed a substantial and significant improvement; intent-to-treat analyses showed a median PFS of 31 months with FCR compared with 21 months with FC (

 showed a benefit of fludarabine (11 mo) over CAP (6 mo). Sawitsky and colleagues

 reported an improvement in PFS with monthly chlorambucil and prednisone (16 mo) over daily chlorambucil and prednisone (7 mo) and prednisone alone (7 mo). Three studies reported CR and PR; 2 studies each reported on stable disease and progressive disease.

 The most robust data were available for ORR, with 7 studies reporting for a number of different treatment regimens.

 Across all the treatments, the ORR ranged from 11% with prednisone treatment to 70% with FCR.

	The non-RCTs ranged similarly in size (N = 5-724) and duration of follow-up (3-60 mo) to RCTs in this setting but reported on a wider range of treatment comparisons. Ninety publications relating to 86 studies were included, with 66 studies published in full and 24 available only as abstracts. Fludarabine was the most commonly evaluated treatment as monotherapy or in combination with other agents (N = 44).

		Figure. The Proportion of Patients Reporting Overall Response

	Disease response was the most frequently reported outcome. CR was reported by 77 publications, PR by 81 publications, stable disease by 33 publications, and progressive disease by 23 publications. ORR was reported by 59 publications (

 Twenty-one studies reported median survival, and across all treatments the median OS ranged from 5.9 months with alemtuzumab to 48 months with fludarabine and epirubicin.

 Direct comparisons of median OS across non-RCTs were complicated by a lack of consistency around the timepoint at which median OS was reported, ranging from 12.6 to 48 months.

 Fludarabine was the most frequently reported intervention, either administered alone (median OS values from 3 studies of 13, 18, and 20 mo) or as combination FC (24.5 mo).

 Across all treatments the reported survival rates ranged from 29% to 100% (years 2002-2004).

 Two publications were associated through long- term follow-up of patients after the initial report of results.

 Four studies reported the proportion of patients with PFS, and 8 of the 10 studies reported median PFS. The median PFS ranged from 6.5 months with rituximab and etanercept to 24.5 months with FC.

 The proportion of patients with progression-free disease ranged from 29.4% with rituximab to 75% with FCR (years 2005-2009).

	The systematic reviews and meta-analysis presented here outline the evidence base of RCT or non-RCT studies in patients with treatment-naïve CLL or with relapsed or refractory CLL. Good systematic reviews are important in that they can identify clinically relevant studies, classify them by quality, combine the data, and, where appropriate, draw reasonable conclusions. Their conclusions may have implications for clinical practice but also, importantly, implications for clinical research itself. This systematic review showed that clinical trials in the relapsed setting were heterogeneous in design (and in many cases lacked a comparator arm) and were not sufficiently powered to draw definitive conclusions about treatment. These results highlight the need to improve the quality of individual trials with patients with relapsed or refractory CLL.

	Treatment-Naïve Patients With CLL: Meta-Analysis

	The results of the MTC, including data from the 8 identified RCTs in treatment-naïve patients with CLL, confirmed the superior clinical benefits of FCR. Based on the calculated HRs, FCR significantly prolonged PFS compared with all other treatments, with the risk of progression reduced by between 44% and 76%, compared with FC and chlorambucil, respectively. ORRs were shown to significantly increase compared with all other treatments, with the likelihood of achieving response when treated with FCR ranging from more than double compared with FC, and up to 14 times compared with chlorambucil. When comparing CR rates, FCR showed significant benefits compared with chlorambucil, fludarabine, and FC, with the likelihood of achieving CR more than doubling compared with FC and increasing to >30 times compared with chlorambucil. Although FCR did show a benefit in CR compared with both bendamustine and alemtuzumab, these findings were nonsignificant as the credibility intervals overlapped. The direction of the effect is similar to that observed when comparing CR rates for FCR to FC, fludarabine, or chloram-bucil; the lack of statistical significance may be attributed to the small number of patients achieving CR in the trials.

	The findings of the MTC should be treated with some caution due to the relatively small number of trials available on which to conduct the analysis, and the possibility that heterogeneity may have confounded the analysis. Efforts were made to assess the heterogeneity across comparisons prior to conducting the MTC. However, in order to assess the potential impact of heterogeneity due to unknown effect modifiers, additional comparable trials would be needed. Finally, it should be noted that there are likely systematic differences among the patients enrolled in the first-line trials because physicians are often less likely to treat an elderly, debilitated patient with FCR, or a young healthy one with chlorambucil. These unmeasured effects may contribute to the heterogeneity.

	The MTC was conducted using the first-reported FCR data from the CLL8 trial. Subsequent to this analysis, updated results from a longer follow-up (median, 37.7 mo) of the patients in CLL8 have been reported; it was demonstrated that patients treated with FCR benefited from a significantly more prolonged PFS benefit than first observed.102 The median PFS for FCR from this longer follow-up was reported to be 51.8 months compared with 32.8 months with FC alone (HR = 0.56; 

 <.0001). Most importantly, for the first time in the treatment of CLL disease, a significant survival advantage was demonstrated with FCR therapy in the first-line setting (3-y OS rate: 87.2% vs 82.5% for FC; HR = 0.664; 

 = .012). The median survival has not yet been reached in either treatment arm. These improved PFS and OS benefits with FCR were observed across the majority of patient subgroups analyzed, with the exception of patients with Binet stage C disease. These data confirm FCR as the standard of care for young and fit patients with untreated CLL. Health-related quality-of-life analyses from CLL8 showed that the addition of rituximab to chemotherapy had little or no impact.

 The clinical benefits are provided with a reasonable incremental cost per quality-adjusted life year (QALY) gained.

 Of note, the median ages of patients in all trials in the meta-analysis was <65 years, with the exception of the study by Eichhorst and colleagues (median age, 70 y) (

), which is below the median age of 72 at diagnosis. The median age of patients in CLL8 was 61 years; exploratory analysis in CLL8 patients aged >70 years has suggested that the benefit to patients is questionable when treated with FCR.

	Review of Relapsed or Refractory Patients With CLL

	Of the 8 RCTs reporting treatment of relapsed or refractory CLL, all were parallel-group RCTs. The quality indicators essential to the assessment of clinical and methodological biases were infrequently reported or too variable in these trials to justify meta-analysis. Similarly, 90 non-RCT publications met the inclusion criteria relating to 86 studies for this review and reported approximately 30 different treatment regimens. Where similarities were found, the results were typically variable, making overall conclusions difficult. OS was the most frequently reported survival outcome.

	RCTs represent the methodological gold standard for demonstrating the efficacy and safety of treatments. Further, based on the results of CALGB-9011, longer follow-up in such studies will better determine clinically significant survival benefits. The follow-up time of trials conducted in relapsed and refractory patients ranged from 5 to 60 months, and ORR was the most frequently reported endpoint. This systematic review demonstrates the lack of robust, high-quality comparator RCT data, despite the numerous non-RCTs that have reported on a wide variety of treatment regimens. Only 2 RCTs (CLL8 and REACH) were identified; both evaluated rituximab. REACH was the largest RCT retrieved, with almost twice the number of enrolled patients of any other trial included in the systematic review. Regardless of the disease setting, it is imperative as the development of treatments for CLL evolves that both investigational and approved therapies be compared in RCTs to optimize survival outcomes for patients. Such studies continue for rituximab.

	The significant clinical benefits achieved with FCR highlight the need for more tolerable and efficacious treatments for patients with CLL who are elderly and/or have comorbidities and who cannot tolerate such immunochemotherapeutic combinations. Clinical trials in elderly patients with therapies such as chlorambucil, lenalidomide, and bendamustine in combination with monoclonal antibodies are underway. Until the results of such large studies become available and heterogeneity is reassessed, this analysis provides the most current evidence-based review and serves to facilitate the development of consensus on the use of rituximab alongside other therapies in the treatment of CLL.

	Ann Janssens, MD, is a hematologist at the University Hospitals Leuven in Belgium; Robin Foà, MD, is a professor of Hematology at Sapienza University of Rome in Italy; Michael J. Keating, MB, BS, is a professor of Medicine in Hematology at the University of Texas MD Anderson Cancer Center in Houston; Iain Tatt, PhD, and Emma S. C. Carr, BSc, MSC, PhD, are employees of F. Hoffman-La Roche in Basel, Switzerland.

	Support for third-party writing assistance for this manuscript was provided by F. Hoffman-La Roche. Dr Foa reports having served on advisory boards for Roche and lecturing upon the company’s invitation. Drs Tatt and Carr are employees of F. Hoffman-La Roche. The other authors report no financial interest with any entity that would pose a conflict of interest with the subject matter of this article.

	Ann Janssens, MD, Department of Hematology, University Hospitals Leuven, Leuven 3000, Belgium. E-mail: 

		Ries LAG, Harkins D, Krapcho M. SEER Cancer Statistics Review, 1975-2004, Bethesda, MD: 

		American Cancer Society. Cancer Facts and Figures 2011. www.cancer.org/acs/groups/content/@epidemiologysurveillance/documents/ document/acspc-029771.pdf. Accessed September 12, 2011.

		Horner MJ, Ries LAG, Krapcho M, et al. SEER cancer statistics review, 1975-2006, National Cancer Institute. Bethesda, MD. 

		Rozman C, Montserrat E. Chronic lymphocytic leukemia. 

		Byrd JC, Peterson B, Piro L, et al. A phase II study of cladribine treatment for fludarabine refractory B cell chronic lymphocytic leukemia: results from CALGB Study 9211. 

		Rai KR, Peterson BL, Appelbaum FR, et al. Fludarabine compared with chlorambucil as primary therapy for chronic lymphocytic leukemia. 

		Leporrier M, Chevret S, Cazin B, et al. Randomized comparison of fludarabine, CAP, and CHOP in 938 previously untreated stage B and C chronic lymphocytic leukemia patients. 

		Johnson S, Smith AG, Loffler H, et al. Multicentre prospective randomised trial of fludarabine versus cyclophosphamide, doxorubicin, and prednisone (CAP) for treatment of advanced-stage chronic lymphocytic leukaemia. The French Cooperative Group on CLL. 

		Keating MJ, O’Brien S, Lerner S, et al. Long-term follow-up of patients with chronic lymphocytic leukemia (CLL) receiving fludarabine regimens as initial therapy. 

		O’Brien SM, Kantarjian H, Cortes J, et al. Results of fludarabine and cyclophosphamide combination regimen in chronic lymphocytic leukemia. 

		Tam CS, O’Brien SM, Wierda W, et al. Long-term results of the fludarabine, cyclophosphamide, and rituximab regimen as initial therapy for chronic lymphocytic leukemia. 

		Hallek M, Fingerle-Rowson G, Fink A-M, et al. Immunochemotherapy with fludarabine (F), cyclophosphamide (C), and rituximab (R) (FCR) versus fludarabine and cyclophosphamide (FC) improves response rates and progression-free survival (PFS) of previously untreated patients (pts) with advanced chronic lymphocytic leukemia (CLL) [ASH Annual Meeting Abstract 325]. 

		Tsimberidou AM, Keating MJ. Treatment of fludarabine-refractory chronic lymphocytic leukemia. 

		Hallek M. State-of-the-art treatment of chronic lymphocytic leukemia. 

		Dighiero G, Hamblin TJ. Chronic lymphocytic leukaemia. 

		CLL Trialists’ Collaborative Group. Chemotherapeutic options in chronic lymphocytic leukemia: a meta-analysis of the randomized trials. 

		Kimby E, Brandt L, Nygren P, et al. A systematic overview of chemotherapy effects in B-cell chronic lymphocytic leukaemia. 

		Steurer M, Pall G, Richards S, et al. Single-agent purine analogues for the treatment of chronic lymphocytic leukaemia: a systematic review and meta-analysis. 

A mixed treatment comparison demonstrated that FCR significantly prolonged PFS compared with all other treatments and significantly increased ORR compared with all other treatments.

Rituximab for Chronic Lymphocytic Leukemia in Treatment-Naïve and Treatment-Experienced Patients

	Colorectal cancer is the third most common type of cancer diagnosed in the United States and is the third most common cause of cancer-related death. The majority of cases are sporadic, with hereditary colon cancer contributing up to 15% of all colon cancer diagnoses. Treatment consists of surgery for early-stage disease and the combination of surgery and adjuvant chemotherapy for advanced-stage disease. Management of metastatic disease has evolved from primary chemotherapeutic treatment to include resection of single liver and lung metastases in addition to resection of the primary disease and chemotherapy.

	In the United States, colorectal cancer (CRC) is the third most common type of cancer diagnosed and the third most common cause of cancer-related death in men and women. In 2010, an estimated 102,900 new cases of colon cancer were diagnosed (49,470 male, 53,430 female) and 51,370 patients (26,580 male, 24,790 female) died from CRC.

 The death rate from colon cancer decreased over the preceding decade, from 30.77 per 100,000 people to 20.51 per 100,000 people.

 The lifetime risk of developing colon cancer in industrialized nations is 5% and is stable or decreasing.

 In contrast, the incidence in developing countries continues to rise, hypothesized to be due to increased exposure to risk factors.

 It has been estimated that 1.5 million people in the United States will be living with CRC by 2020.

 The financial burden of caring for this population is significant: $4.5 to $9.6 billion per year.

 Disparities among different racial and ethnic groups are well known and attributed to a variety of factors, including environmental exposures, tumor biology, lack of access to preventive health services, and inequities in treatment.

 Both incidence and mortality rates are higher in black patients than in white patients.

						Table 1. Risk Factors for Sporadic Colorectal Cancer

					Hormonal factors: nulliparity, early menopause

	The majority of CRC cases are sporadic, with hereditary syndromes contributing approximately 5% to 15% of the incidence. There are many known risk factors for sporadic CRC, including nonmodifiable and modifiable variables (

). Preventive measures should be targeted at tobacco use, dietary habits, and weight control.

 The inflammatory bowel disease (IBD) population is the second major category of patients at increased risk of CRC.

	The 2 main syndromes accounting for 5% of the inherited cases are hereditary nonpolyposis colon cancer (HNPCC) and familial adenomatous polyposis (FAP)

 The remaining 15% to 20% of inherited CRC cases do not have a clearly defined mechanism and likely result from a combination of gene polymorphisms, alterations in multiple susceptibility loci, and environmental influences.

 These cases are grouped into familial X CRC syndrome.

	The prevalence of HNPCC, also known as Lynch syndrome, is estimated to be 2% to 5%. The syndrome is caused by a germline mutation in 1 of 6 currently identified DNA mismatch repair (MMR) genes: 

. Inactivation of these genes leads to the development of short repeats of DNA, known as microsatellites; 90% of the mutations in the MMR genes are found specifically in 

 Patients with HNPCC have an 80% lifetime risk of developing CRC.

 HNPCC is differentiated from sporadic colon cancer by a distinctive clinical picture. The average age of cancer diagnosis is much earlier (ie, 47 y vs 63 y), and there is a pattern of both metachronous and synchronous colon cancers, in addition to a high association with other primary tumors (eg, endometrial, ovarian, gastric, small bowel).

	FAP was first identified in 1861 and is the best characterized of the hereditary CRC syndromes, although it contributes only 1% to the inherited CRC syndromes.

 The disease is the result of a mutation of the 

 gene (tumor suppressor gene), which is located on the long arm of chromosome 5q21. Classic FAP is characterized by autosomal dominant inheritance and an aggressive clinical course. Penetration is nearly 100%, although there are several variants with different clinical syndromes.

 Patients develop numerous adenomas throughout the colon and rectum at an early age, typically in their teens. Early polyps are classically located in the distal colon, so it is recommended that the onset of screening with flexible sigmoidoscopy begin at age 10 to 12 years.

	Once the colon can no longer be adequately surveyed due to the degree of polyposis, prophylactic colectomy is advised. In classic FAP, the most common age of cancer diagnosis is 39, with malignant degeneration occurring by age 40 to 50.

 The clinical features of FAP include duodenal, small bowel, and gastric adenomas, requiring annual endoscopy for the surveillance of FAP patients. Approximately 95% of FAP patients will have duodenal polyps identified on upper endoscopy; however, only 5% to 10% of patients go on to develop periampullary cancers.

 Currently, duodenal and desmoid tumors represent the most common causes of death in the FAP population.

 Attenuated FAP has a less aggressive clinical course compared to classic FAP; 90% of patients do not have an identifiable APC mutation and develop fewer than 100 polyps.

	CRC has long been associated with ulcerative colitis (UC), and more recently also associated with Crohn’s disease. It is estimated that 1% of the CRC cases seen in the general population occur in UC patients.

 Duration of disease has long been considered to be a factor in the development of CRC in IBD. In 2001, a meta-analysis combining data from 116 studies found cumulative probabilities of developing CRC in UC patients of 2% by age 10, 8% by age 20, and 18% by age 30.

 Comparison of the CRC risk in Crohn’s disease and UC populations has demonstrated similar risk profiles, with a similar incidence rate and similar rate ratios.

						Table 2: Current Recommendations for Colon Cancer Screening in Average-Risk Asymptomatic Patients

					Flexible sigmoidoscopy every 5 y with FOBT every 3 y or

					Alternative: flexible sigmoidoscopy every 5 y

					Alternative: CT colonography every 5 y

					Double-contrast barium enema every 5 y or

Colorectal cancer is the third most common type of cancer diagnosed in the United States and is the third most common cause of cancer-related death.

Colorectal Cancer: A Review

	Advances in the detection, diagnosis, and treatment of cancer are developing at an increasingly rapid pace. Although evidence-based medicine has led to significant progress in our knowledge, skills, and approaches to treating patients with breast cancer, the implementation of these improvements into clinical practice requires continued learning.

	Staying abreast of the clinical research may be a good way to keep informed on novel agents and new treatments, but journal articles provide a one-dimensional interpretation of the findings and rarely discuss the practicalities of implementing these treatments into daily clinical practice. Scientific meetings, on the other hand, provide opportunity for interaction and an exchange of ideas. It is this kind of clinical debate where practical experiences are shared and where the discussions can ultimately facilitate the practical application of clinical data.

	For this reason, Contemporary Oncology is introducing a series of discussions that highlight challenging cases presented at medical education conferences hosted by our affiliate company, Physicians’ Education Resources (PER).

	The following cases were discussed at the 10th International Congress on the Future of Breast Cancer, which was held in Coronado, California, from August 4-7, 2011.

	The case discussions were moderated by Joyce A. O’Shaughnessy, MD, a medical oncologist with Texas Oncology-Baylor Charles A. Sammons Cancer Center in Dallas. Other panelists included Hope S. Rugo, MD, director of Breast Oncology and Clinical Trials Education at the University of California, San Francisco Helen Diller Family Comprehensive Cancer Center; and Frankie Ann Holmes, MD, medical/hematology oncologist at Texas Oncology in Houston.

	How should a patient with triple-negative metastatic breast cancer be treated if she received adriamycin and cyclophosphamide with Taxol (ACT) in the adjuvant setting a year ago?

	The panel noted that patients like this one are often difficult to treat because patients with triple-negative breast cancer who recur quickly like this are often refractory to ACT (doxorubicin/cyclophosphamide/paclitaxel), which means that they are likely to be refractory to several other chemotherapy agents.

	However, the panelists were quick to note that this does not mean that all chemotherapy agents will be ineffective in treating this patient. The panel referred to a study in which gemcitabine/carboplatin with iniparib was used to treat patients with triple-negative breast cancer. Patients who were given gemcitabine/carboplatin had approximately a 30% response rate with about 6 months of progression-free survival and approximately 1 year overall survival.

	Based on the experience of the panel, patients with triple-negative breast cancer tend not to benefit from platinum-based regimens. In this particular case, the panelists felt that eribulin would be another reasonable treatment option. However, the data on how patients respond to eribulin is not very robust because many of the patients in the studies have been heavily pretreated by the time they are enrolled in the trials.

	Bevacizumab might also be an option for this patient, but the panel noted that this would depend on whether a triple-negative breast cancer patient has an amplification of vascular endothelial growth factor A (VEGF-A), which tends to be overexpressed in many triple-negative cases.

	The panel pointed to promising developments on the horizon that might benefit this particular patient. For example, by the end of 2011, the Human Genome Atlas Project is expected to be completed, and it will give oncologists a better understanding of the key mutations and amplicons indicated in breast cancer. In addition, future studies of novel clinical trials might be exactly what this patient and others like her need.

	The panel concluded that somebody who is fairly refractory to ACT is highly unlikely to get a very durable benefit from more cytotoxic therapy.

	A 37-year-old woman has stage III invasive ductal breast cancer. She is estrogen receptor—positive (ER ) and human epidermal growth factor receptor–positive (HER ), but her progesterone receptor status is unknown. She’s had a bilateral mastectomy performed. She has received ACT for chemotherapy and is continuing on trastuzumab. She has not yet started to take tamoxifen because she is hoping to get pregnant. She has declined a luteinizing hormone-releasing hormone (LHRH) agonist due to her concerns about the side effects. She wants a natural pregnancy and wants to time it appropriately and inline with her treatment. She has 3 embryos available, but no surrogate to carry the embryos. She is a BRCA wild- type, she is not a mutation carrier, and she has resumed menstruation.

	As her oncologist, would you encourage gonadotropin-releasing hormone (GnRH) agonist or oophorectomy with tamoxifen? Would you discourage her from trying to achieve a natural pregnancy or carrying the embryo? Is there enough time for an ideal pregnancy? If this patient delays tamoxifen for the sake of the pregnancy, is there a role for tamoxifen after she has given birth?

	The panel acknowledged that a patient wanting to become pregnant during a course of treatment for breast cancer is not uncommon among younger women. However, in this particular case there is also the issue of whether the patient is triple-positive, since her progesterone receptor (PR) status is unknown. If she is triple-positive, it is important to know which mutation is dominant because it may end up guiding her treatment options.

	The panel discussed its experience with a similar case of a 29-year-old patient who had locally advanced triple-positive disease and who also wanted to become pregnant. The patient was treated with FEC 75 (5-fluorouracil, epirubicin, and cyclophosphamide) with trastuzumab.

	The patient’s cancer was highly proliferative. After 2 cycles of adjuvant chemotherapy, the patient’s cancer was not growing, but it was not responding either. A decision was made to add endocrine therapy via an LHRH agonist starting with cycle 3. By the time the patient came in for cycle 4, the palpable axillary adenopathy was gone and the tumor had shrunk by 50%. Based on past experience that demonstrated the value of endocrine therapy in patients with triple-positive breast cancer, the panel expressed concern as to why this young woman is declining adjuvant endocrine therapy at this time.

	The panel did not see a problem with starting tamoxifen therapy to see if the patient responded, and then taking her off the therapy while she attempts to get pregnant, assuming that the patient would resume the tamoxifen therapy soon after the birth of the child.

	“When patients have serious breast cancer like this young woman with stage III disease, I think that a few years of tamoxifen LHRH agonist is an appropriate treatment,” said O’Shaughnessy. “We know that 5 years of tamoxifen is better than 2 from the Oxford Overview. We don’t know that 3 is better than 2, but since 5 is better than 2, if I get patients on the therapy for 2 to 3 years, I’m usually pretty happy with that.”

	In the end, the panel stressed the importance of having a close relationship with the patient so that decisions are made together.

	“If you partner with the patient to make decisions about treatment, the patient will feel more empowered and focused on the big picture, which will put her in a better position to deal with the side effects of the LHRH-agonist therapy,” said O’Shaughnessy.

	A 43-year-old black woman has a 6.5 cm ductal carcinoma in situ (DCIS) and multifocal, microinvasive disease. A total mastectomy and sentinel lymph node dissection are performed. One of the sentinel lymph nodes is immunohistochemistry (IHC) cytokeratin—positive. The IHC analysis revealed the following results: I , NOI , ER is 18% positive, PR is 17% positive, and Ki-67 is 45% positive.

	Should the patient receive adjuvant treatment?

	The panel began its discussion of this case by pointing out that there was no right or wrong answer to this challenging case.

	Based on data discussed in previous sessions of the conference, studies have shown that patients with cytokeratin-positive cells in lymph nodes did have a slightly worse prognosis than patients who were node-negative. The DCIS diagnosis is also a concern because of the large area affecting the breast, increasing the chance that something could be missed.

	“[Even] if you weren’t missing something, multifocal microinvasive disease has a much more aggressive biology,” said O’Shaughnessy.

	Despite the higher probability of a poorer diagnosis, the panel said it would treat the patient with adjuvant therapy, and start her on ACT therapy.

The following cases were discussed at the 10th International Congress on the Future of Breast Cancer, which was held in Coronado, California, from August 4-7, 2011.

Fall 2011 | Contemporary Oncology®

A Dog Named George: Rx for Recovery

Rituximab for Chronic Lymphocytic Leukemia in Treatment-Naïve and Treatment-Experienced Patients

Colorectal Cancer: A Review

Advances in Breast Cancer Treatment: Expert Panel Discussion of Challenging Cases

Progress Made, but More Work Lies Ahead in CLL and CRC Treatment