The National Comprehensive Cancer Network Conference: Clinical Practice Guidelines and Quality Cancer Care

Click here to view as PDF.

The National Comprehensive Cancer Network Conference

Clinical Practice Guidelines and Quality Cancer Care

The National Comprehensive Cancer Network (NCCN) 13th Annual Conference: Clinical Practice Guidelines and Quality Cancer Care, was held in Hollywood, Florida, from March 5—9, 2008. The conference provided attendees with updates to the NCCN’s Clinical Practice Guidelines in Oncology, protocols that, according to the organization (a not-for-profit alliance of 21 of the world’s leading cancer centers), currently cover the management of more than 97% of all cancer patients. Updated treatment guidelines were presented for an array of disease states, including breast cancer, leukemia, colon and rectal cancer, kidney cancer, multiple myeloma, and lung cancer.

The conference also featured cutting-edge data from recent academic research and clinical trials and discussions of and presentations on new therapies. Other sessions focused on quality issues and initiatives related to cancer care and emerging economic challenges related to fiscal issues and oncology business management. In addition, expert faculty presented newly released NCCN task force reports, and participated in roundtable discussions. Numerous satellite symposia, networking events, and a major exhibition of various and varied oncology vendors (including pharmaceutical manufacturers, medical device concerns, biotechnology companies, health care publishers, patient advocacy organizations, and managed care companies) were also featured.

The meeting was attended by roughly 1,300 practicing oncologists, oncology fellows, scientists, researchers, academicians, key opinion leaders and other cancer care professionals (i.e., nurses, physician assistants, pharmacists, administrators) as well as patient group, physician group, employer group, and government agency representatives from around the globe. The following sections provide a general overview of breaking news and session highlights from the conference.

â–º Advances in Lung Cancer

Updates to NSCLC Guidelines

David S. Ettinger, MD, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland, and Mark G. Kris, MD, Memorial Sloan Kettering Cancer Center, New York City, provided an update” to NCCN’s Non-Small Cell Lung Cancer (NSCLC) Guidelines, which were released in October 2007.

Dr. Ettinger began the presentation with a summary review of the changes that have occurred in the NCCN’s NSCLC Guidelines as a result of the recent update. Several changes took place in the realm of postoperative adjuvant treatment (NSCL-3) for early-stage NSCLC. In stage IA, margins negative, “the recommendation for chemotherapy for high-risk patients was changed to a category three,” reported Dr. Ettinger. In stage IA, margins positive, Dr. Ettinger related that “the recommendation for chemotherapy after re-resection was changed to a category three.” For stage IIIA, margins negative, “the recommendation for chemoradiation followed by chemotherapy was removed. Mediastinal radiation therapy (RT) was added to chemotherapy.”

Some of the other guideline changes Dr. Ettinger highlighted included the following: “For stage IIIB (resectable other than satellite), the recommendation for chemotherapy followed by chemoradiation was added for R1, R2 disease after initial treatment with surgery (NSCL-8).” Under the ‘Therapy for Recurrence and Metastasis (NSCL-13)’ section of the guidelines, “PS2 patients were removed from the grouping with PSO and 1 patients and their recommended treatment is chemotherapy.” Also, a clarification was added (as footnote ‘w’) that bevacizumab (Avastin) should not be used as a single agent, “unless as maintenance, if initially used with chemotherapy.”

The updated version of the NCCN guidelines also contained several therapy-specific alterations. These revisions included:

• The designation of cisplatin/etoposide (Etopophos) and cisplatin/vinblastine (Velban) as preferred (in adjuvant therapy) and the addition of a category 2B designation for paclitaxel (Taxol)/carboplatin;
• The addition of a category three designation for cisplatin/etoposide in concurrent chemotherapy/ RT followed by chemotherapy;
• A recommendation to consider the use of erlotinib (Tarceva) with or without chemotherapy in advanced or metastatic NSCLC patients, “with known active epidermal growth factor receptor (EGFR) mutation and gene amplification,” who were never smokers.

“The regimens have been expanded and clarified by providing additional cisplatin-based regimens and chemotherapy regimens to use for patients with comorbidities or patients not able to tolerate cisplatin. These alternatives are mainly carboplatin-based regimens,” summarized Dr. Ettinger.

The latter update to the guidelines (recommending erlotinib utilization) is particularly notable because it “involves the use of molecular markers to individualize therapy for patients,” reported Dr. Ettinger. Commenting on the update, Dr. Ettinger stated, “the era of personalized medicine has come to lung cancer.”

The Expanded Role of Chemotherapy

Dr. Ettinger and Dr. Kris then moved into a review of some of the evidence supporting the expanded role of chemotherapy called for in the updated guidelines.

New Engl J Med

P

Presenting data on cisplatin-based adjuvant chemotherapy in patients with completely resected NSCLC, Dr. Kris reported on the results of the International Adjuvant Lung Cancer Trial, conducted by the International Adjuvant Lung Cancer Trial Collaborative Group ( 2004;350:351-360). The study of 1,867 patients with stage I-III NSCLC (who had undergone complete surgical resection within 60 days of the study period) randomized subjects into four groups: three of the groups received different regimens of cisplatin-based chemotherapy following surgery and one group underwent no chemotherapy following surgery. Findings demonstrated that compared with the cohort that received no chemotherapy following surgery, the groups who underwent cisplatin-based chemotherapy benefited from a 4% higher rate of overall survival (OS) after five years ( = 0.03).

N Engl J Med

P

A second trial, NCIC JBR 10 (Winton TL, et al. 2005;352:2589-2597), randomized T2NO (IB) and T1-2N1 (II) NSCLC patients who had undergone complete resection into two groups: one cohort underwent a combination regimen of cisplatin (50mg/m² d1,8) and vinorelbine (Navelbine) (25mg/m²) four cycles, while the other cohort was kept under observation. Results were encouraging. They included, for the cisplatin/vinorelbine group, when compared with the group who underwent observation only, an increase in terms of OS (94 months versus 73 months), a 15% improvement in 5-year survival (69% versus 54%), and a 30% reduction in risk of death ( = 0.012).

Commenting on these data, Dr. Kris pointed out that “consistent reduction in the risk of death has been observed in recent adjuvant platinum-based trials (stage II-III).” Consequently, “adjuvant platinum-based chemotherapy should be recommended to completely resected NSCLC patients with good performance status (stage II-III). Adjuvant cisplatin-based chemotherapy reduces the risk of death for resected patients with stage II and stage III.” Dr. Kris advised that adjuvant cisplatin-based chemotherapy be considered for stage IB patients as well.

After reviewing further data linking increased survival rates with adjuvant chemotherapy, Dr. Kris concluded that “adjuvant chemotherapy is the standard of care for early-stage NSCLC.”

Treatments for Severe and Advanced NSCLC

P

BMJ

Next, the presentation shifted its focus toward a discussion of optimal treatment in cases of more severe and advanced NSCLC. Several studies were reviewed, including research on patient response and survival following preoperative chemotherapy, research examining concurrent chemoradiotherapy with consolidation docetaxel (Taxotere) in stage III NSCLC, an analysis of multimodality therapy in stage IIIA NSCLC that compared the advantages and drawbacks of induction versus adjuvant chemotherapy and a survival comparison between sequential and concurrent chemoradiation therapy (in which concurrent chemoradiation was associated with a statistically significant survival benefit, ( < 00.5) - in stage III patients). One of the more clear-cut benefits shown was in a meta-analysis of phase IV patients who underwent combination chemotherapy regimens ( 1995; 311:899-909).

Compared with a cohort of patients who received best supportive care, the combination chemotherapy group attained a six-to- eight week improvement in median survival and a 10% increase in one-year survival (from 15% to 25%). It is important to note, counseled Dr. Kris, that this survival benefit was confined to various platinum-containing chemotherapy regimens (not alkylators). Commenting on the data, Dr. Kris asserted that the meta-analysis demonstrated that “platinum (based-chemotherapy regimens are) better than nothing,” and that “two drugs are better than one drug.”

The positive data from the meta-analysis underscores the point that NSCLC is not a hopeless diagnosis. Even in very severe, very advanced, latestage cases, NSCLC should be treated aggressively and medical professionals should not ‘give up’ on NSCLC patients. As Dr. Kris stated, “survivorship is an issue in NSCLC. Too many patients are leaving their doctor’s office with little more than a ‘goodbye’ and a ‘good luck,’ when what they need is a plan of care. The (medical) literature is devoid (of content) when it comes to addressing severe, advanced lung cancer. The eventual goal of therapy should be a cure.”

Specific chemotherapeutic combination choices should be customized, based upon individual patient characteristics and levels of response. Although standard NSCLC chemotherapy combinations (i.e., cisplatin and paclitaxel, cisplatin and gemcitabine (Gemzar), cisplatin and docetaxel, and carboplatin (Paraplatin) and paclitaxel) have demonstrated similar outcomes in recent studies, the efficacy and tolerability of a given chemotherapy combination can vary widely from one patient to another. Thus, it is important that the right regimen be tailored to fit the right patient. The same principle should be followed when standard chemotherapy regimens are combined with new chemotherapeutic agents and/or with other treatment modalities.

“Multimodality therapy is the standard of care for stage IIIA (and higher) NSCLC,” reported Dr. Kris, who asserted that the addition of RT should be considered as a therapeutic component in patients being treated for stage IIIA NSCLC. “Very aggressive care should always be on the table,” continued Dr. Kris, adding that if a given agent demonstrates evidence of efficacy, it should be considered as a treatment option. “Clinical trials trump everything,” asserted Dr. Kris.

P

Emerging TreatmentsOne agent mentioned as potentially having value as an additional component to a combination chemotherapy regimen was bevacizumab. Dr. Kris presented data from ECOG 4599, a phase III trial of bevacizumab in patients with stage IIIB, stage IV or recurrent NSCLC (Sandler et al. ASCO, 2005. Abstract LBA4 and oral presentation). In the study, one group (PC) was given a combination of paclitaxel 200 mg/m² plus carboplatin AUC = 6 (q 3 weeks) X six cycles. The second group (PCB) underwent the same regimen, but with the addition of bevacizumab (15 mg/kg q 3 wks) to progressive disease (PD). Outcomes for the PCB group were superior to the PC group in terms of complete response (CR) (1.4% versus 0%), partial response (PR) (25.8% versus 10%), progression-free survival (PFS) (6.4 months versus 4.5 months), overall survival (OS) (12.5 months versus 10.2 months, = 0.007), one-year survival (51.9% versus 43.7%) and two-year survival (22.1% versus 16.9%).

“Bevacizumab improves survival, response rates (RR) (RR = CR + PR), and PFS when added to carboplatin chemotherapy in patients with nonsquamous cell NSCLC. Bevacizumab plus PC is now the ECOG reference regimen for the firstline treatment of advanced nonsquamous cell NSCLC,” concluded Dr. Kris (research such as the AVAIL trial has shown improved outcomes similar to ECOG—including a statistically significant increase in PFS, a higher response rate, and a longer median response duration&mdash;when bevacizumab is added to a regimen of gemcitabine and cisplatin). He warned, however, that bevacizumab is associated with an increase in serious bleeding and counseled caution if bevacizumab is utilized in conjunction with other (non-PC) chemotherapy regimens particularly if the estimated risk of grade four thrombocytopenia is high.

Dr. Kris also discussed second-line therapeutic options in cases of progressive disease. The NCCN guidelines currently suggest three agents: docetaxel, pemetrexed (Alimta), and erlotinib (the latter agent is indicated in NCCN guidelines as a third-line treatment as well). All three agents have demonstrated improved survival in recent clinical trials.

Dr. Kris concluded his talk by expressing the hope that in the interim period between the present and when curative lung cancer treatments become available, therapeutic advances, such as those reflected in the updated NCCN NSCLC Guidelines, “can make (even) stage IV NSCLC a chronic disease,” rather than a death sentence.

Although many unanswered questions remain with regard to NSCLC and NCCN is still seeking consensus on a number of issues (i.e., “the jury is still out on whether computed tomography (CT) screening decreases lung cancer mortality”), there is one sure-fire means, according to Dr. Kris, to prevent NSCLC incidence and decrease mortality: “Stop cigarette smoking…stop lung cancer.”

â–º Advances in Lung Cancer

Innovative Mechanisms of Action in Combination Therapy for the Treatment of Lung Cancer

In a separate session, entitled, “Innovative Mechanisms of Action in Combination Therapy for the Treatment of Lung Cancer,” Wallace Akerley, MD, Huntsman Cancer Institute at the University of Utah, Salt Lake City, Utah, spoke on the subject of advances in lung cancer treatment, elaborating upon and drilling down into the combination therapy strategies addressed by Dr. Ettinger and Dr. Kris.

Although lung cancer mortality rates have improved over the past several years (decreasing among men and leveling off in women after several years of sharp increases), it remains one of the most devastating and challenging diseases facing the oncology sector. More women perish from lung cancer than breast cancer and more men die of lung cancer than prostate, colon, pancreatic, and liver cancer combined. While the overall cure rate for all cancers is roughly 41%, less than 25% of patients survive a diagnosis of lung cancer.

In order to improve the prospects of patients with lung cancer, asserted Dr. Akerley, “We need better therapies.” One means of improving therapy, according to Dr. Akerley, is to more fully explore the available range of existing therapeutic combinations, more aggressively utilize novel agents as they become available (especially those that specifically target NSCLC), and experiment with a variety of innovative regimens that employ multiple new agents, both in tandem with one another and in conjunction with established therapeutic combinations. Two drug classes that warrant particular attention, as single-agent therapies and as components of intraand inter-class combinations, stated Dr. Akerley, are EGFR (epidermal growth factor receptor) and VEGF (vascular endothelial growth factor) inhibitors.

Dr. Akerley stressed the importance of targeted therapies that can distinguish between tumor and host. Targeted therapies, however, are not a silver bullet, because of the challenging nature of malignant disease. A given chemotherapy, for example, can effectively target proliferation by focusing on the molecular driver of a tumor-specific pathway. The flaw in this treatment strategy is that solid tumors, just like their hosts, are essentially “mini-biosystems” that contain built-in redundancies and may be able to utilize multiple alternate pathways to proliferate. “It may be a good thing (for a therapy) to be promiscuous (and target multiple pathways),” speculated Dr. Akerley. The use of therapeutic combinations also provides clinicians with a means of targeting multiple pathways and attacking tumor adaptations.

J Clin Onco

After discussing the mechanisms of action employed by drugs in the EGFR inhibitor class, Dr. Akerley focused on data detailing the performance of individual EGFR inhibitor agents in lung cancer therapy. Among the data presented was a study that analyzed the impact of adding erlotinib to a regimen of paclitaxel and carboplatin (Herbst, et al. l 2005;23:5892-5899). Results indicated that the addition of erlotinib yielded only a slight improvement in median survival (10.6 months versus 10.5 months) and one year survival rates (46.9% versus 43.8%).

P

Results of a study (BR.21) examining erlotinib as monotherapy in a population of locally advanced or metastatic NSCLC patients who had failed one or two prior chemotherapy regimens, however, were markedly more robust (Shepherd F, et al. N Engl J Med 2005;353:123-132). In the study, 731 patients were randomized (the ratio of the randomization was two to one, with 488 patients enrolled in the erlotinib arm and 243 on placebo) to receive erlotinib 150 mg/d plus best supportive care or placebo and best supportive care. The erlotinib group experienced superior median overall survival (6.7 months versus 4.7 months, = <0.001) and one-year survival rates (31.2% vs. 21.5%). “(The) erlotinib benefit (was) seen across all groups including race, histology, performance status, gender, and smoking,” commented Dr. Akerley.

in situ

P

< 0.001), and expression of EGFR (P = 0.03) were associated with objective response. “Survival after treatment with erlotinib was not influenced by the status of EGFR expression, the number of EGFR copies, or EGFR mutation,” noted Dr. Akerley.

Dr. Akerley summarized the mechanism of action of agents targeting the VEGF pathway. When presenting data on individual VEGF inhibitors, Dr. Akerley focused on two recent bevacizumab studies (ECOG 4599 and AVAIL), which yielded positive data on the agent’s role as an added component of a combination regimen (due to spatial considerations and because ECOG 4599 and AVAIL were already highlighted in the previous presentation by Dr. Ettinger and Dr. Kris, they will not be revisited in detail herein).

Other bevacizumab data presented by Dr. Akerley included a randomized phase II study (Herbst, et al. J Clin Oncol 2007;25:4743-4750), comparing the following three combination therapy regimens in the treatment of second-line NSCLC:

• Docetaxel plus pemetrexed
• Chemotherapy plus bevacizumab
• Bevacizumab plus erlotinib.

Key results from the study appear in Figure 1. Dr. Akerley concluded his presentation by reporting on ongoing studies of agents currently being considered for use in novel combinations to treat NSCLC. For example, a phase II study of bevacizumab plus erlotinib as a first-line NSCLC treatment has recently been initiated.

An interesting avenue of ongoing research that has the potential to lead to an unprecedented level of ‘personalized medicine—while enhancing the speed and targeting of developing therapies&mdash;is the utilization of molecular and clinical predictors (immunohistochemical analysis, fluorescence hybridization, and mutational analysis) to forecast outcomes (i.e., response to therapy, survival). A multivariate analysis conducted on the erlotinib cohort concluded that adenocarcinoma ( = 0.01), never having smoked (P

RR

MS (in months

1YS

Ch

12%

8.6

33%

Ch-B

13%

12.6

54%

BE

18%

13.7

57%

Figure 1. Selected Results From a Phase II StudyComparing Docetaxel/Pemetrexed (Ch), Chemotherapy/Bevacizumab (Ch-B), and Bevacizumab/Erlotinib (BE)Combination Therapies in the Second-Line Treatmentof NSCLC

RR = Response Rate (Complete Response (CR) Plus PartialResponse (PR))MS = Median Survival (in months)1YS = One-year survival

“Bevacizumab,” asserted Dr. Akerley, “improves response and survival in first-line treatment.” Patient age, however, may be a factor in the ultimate viability of bevacizumab, especially from a tolerability perspective. Also, more research is needed to determine optimum dosing of the drug.

In addition, the utility of multitargeted agents such as sorafenib (Nexavar) or sunitinib (Sutent) (as well as a potential ZD6474 [Zactima] plus gefitinib [Iressa] combination) are in the process of being evaluated as potential lung cancer therapies.

â–º Advances in Solid Tumors

mTOR Pathway in Cancer Therapy

In a presentation entitled, “The mTOR Pathway as a Target for Cancer Therapy,” Robert A. Figlin, MD, City of Hope National Medical Center, Duarte, California, presented an NCCN task force report on the emerging role of the mTOR pathway in recent solid tumor research.

According to Dr. Figlin, mTOR, a kinase in the PI3-K/Akt signaling pathway, controls cell growth and angiogenesis. The mTOR kinase integrates multiple signals, including growth factor receptor activity, cellular energy, nutrients, and oxygen levels; signals from other cellular signaling pathways; and estrogen receptor signaling. In addition, mTOR, in response to the aforementioned signals, controls the production of proteins regulating cell growth, angiogenesis, and nutrient uptake in the cell.

“In cancer cells,” explained Dr. Figlin, “mTOR is often activated by excessive EGFR, IGF-1R, and VEGFR signaling; gain of function mutations in upstream kinases including PIK3CA, Ras/Raf, Erb receptors, and Abl; and loss of function of negative regulators such as PTEN and TSC 1/2.” The inhibition of mTOR, according to Dr. Figlin, “counters many common defects in cancer cells.”

Indeed, the mTOR pathway is activated in many cancers. Cancers of the brain, thyroid, breast, lung, blood, pancreas, kidney, ovary, prostate, colon, uterus, and skin were among the malignancies cited by Dr. Figlin in which the mTOR pathway is activated.

Although mTOR inhibition offers promise as a treatment modality for a number of cancers, the case for its use in some cancers is stronger than it is in others. “I’m not a big believer in throwing (an mTOR inhibition) agent at all cancers,” reported Dr. Figlin. “Most diseases will not benefit from mTOR monotherapy,” he said, adding that mTOR inhibitors “often must be combined with other therapies” for optimal treatment. “One of the problems,” explained Dr. Figlin, “with mTOR (or any single pathway) inhibition is that tumors have built-in redundancies. Inhibiting a single pathway tends to activate a feedback loop” that adapts to and circumvents mTOR inhibition, bypassing it downstream and finding another pathway.

The next generation of the therapies, predicted Dr. Figlin, will still target the PI3 kinase pathway — but will do so upstream of mTOR inhibition.

One area in which mTOR is causing excitement, as well as showing a great deal of potential, is kidney cancer. Citing a successful proof of concept study and several evolving clinical trials, Dr. Figlin asserted that mTOR inhibitor prospects are “best in kidney cancer…obviously.”

Illustrating how mTOR inhibitors target renal cell carcinoma (RCC) cancer cells, Dr. Figlin explained the rationale for mTOR inhibition in RCC: mTOR is a positive regulator of HIF-1 and HIF-2 response to hypoxic stress. HIF-1a and HIF-2a are targeted for degradation by VHL. Loss of VHL sensitizes RCC to growth inhibition by mTOR inhibitors. VHL mutations (57%) and LOH (98%) occur in clear-cell RCC (Horiguchi. J Urol 2003;169:710). HIF’s turn on genes responsible for tumor cell growth and angiogenesis. Thus, according to Dr. Figlin, “blocking mTOR inhibits RCC growth and tumor-induced angiogenesis.”

Although other data were cited, Dr. Figlin focused on one study in particular to demonstrate the evolving body of evidence supporting the safety and efficacy of the mTOR inhibitor class in RCC.

N Engl J Med

The study, a global phase III trial of temsirolimus (Torisel) and IFN-a (Interferon alpha) for the first line treatment of metastatic renal cell carcinoma (mRCC), randomized 626 patients into three cohorts (Hudes, et al. 2007;356:2271-2281). The first group (N = 207) received IFN-a monotherapy, escalating to 18 MU SC three times per week. Group two (N = 209) was treated with temsirolimus 25 mg IV once weekly. The third group (N = 210) was given a combination of temsirolimus 15 mg IV once weekly plus IFN-a 6 MU SC three times a week.

The temsirolimus monotherapy cohort demonstrated improved overall survival (the primary endpoint), progressionfree survival, and objective response rates, when compared with the two groups treated with IFN-a monotherapy and temsirolimus plus IFN-a combination therapy, respectively (Figure 2). According to Dr. Figlin, this trial is the first in which an mTOR inhibitor was shown to have a survival benefit.

Figure 2. Phase III Study of Temsirolimus and IFN-a forFirst-Line Treatment of mRCC: Key Findings

Median OS (in months)

Median PFS (in months)

ORR (%)

IFN

12%

8.6

33%

Temsirolimus

13%

12.6

54%

Temsirolimus plus IFN

18%

13.7

57%

While concluding the portion of his talk dealing with mTOR inhibitor use in RCC, Dr. Figlin stated, “mTOR is an important therapeutic target. mTOR inhibitors provide a platform for the treatment of angiogenesis and refractory kidney cancer. Phase III trials both in patients with poor prognosis and in patients progressing on prior VEGF therapy show a survival benefit (as a result of mTOR inhibitor therapy).” Further clinical trials are needed, advised Dr. Figlin, in order to explore tumor characteristics and molecular context so that information may be gained regarding resistance mechanisms likely to develop against mTOR inhibition and what patient groups are most likely to benefit from mTOR inhibitor therapy.

Currently, reported Dr. Figlin, the latest NCCN guidelines indicate mTOR inhibitors as first-line therapy in poor risk patients (with both clear and non-clear cell mRCC, as second-line therapy after cytokine failure (and following sorafenib or sunitinib failure), and as second-line therapy after two tyrosine kinase inhibitor (TKI) failures.

Other malignancies in which mTOR inhibitor therapy may prove a viable and formidable therapeutic weapon include neuroendocrine tumors and gastrointestinal (GI), breast, lung, prostate, endometrial, and ovarian cancers.

â–º Advances in Solid Tumors

mTOR Inhibition: Future Directions

Breast cancer research is also progressing steadily. The mTOR inhibitor drug candidate RAD-001 is currently the subject of six ongoing clinical trials, in combination with various chemotherapeutic regimens, testing the safety and efficacy of the agent in various forms of breast cancer.

There is a strong rationale for targeting the mTOR pathway in lung cancer, asserted Dr. Figlin. Among the reasons cited by Dr. Figlin: “the PI3K/AKT pathway is frequently activated in human NSCLC. mTOR inhibition can sensitize cancer cells to chemotherapy and radiation…(and) mTOR inhibition plays a role in overcoming chemoresistance in lung cancer.”

Although, according to Dr. Figlin, “mTOR inhibition as monotherapy in lung cancer has minimal activity…chemotherapy and mTOR inhibition has a rationale for combined therapy…( and) radiation therapy and mTOR inhibition warrants further investigation.” Data suggest a role for mTOR as a component in a number of other combinations as well. For example, reported Dr. Figlin, “mTOR inhibition may improve EGFR TKI efficacy in all lung cancer populations,” and “mTOR inhibition may augment tumor responses with irreversible, dual EGFR/ErbB2 inhibitors.”

Prostate cancer represents another active area of mTOR inhibitor therapy study. Conclusions from preclinical studies have found that rapalogs have growth inhibitory and antiangiogenic activity in prostate cancer models and that mTOR inhibition can reverse an Akt-dependent PIN phenotype, glycosis, survival, and hypoxic response.

A number of mTOR inhibitor agents are currently being studied in prostate cancer, including temsirolimus (phase I in combination with short-term combined androgen blockade (CAB) therapy in patients with a rising PSA—often the first sign of prostate cancer recurrence), RAD001 (phase II as monotherapy and phase II in combination with docetaxel), rapamycin (several phase I studies), and AP23573 (phase II as monotherapy in taxaneresistant HRPC).

Combination approaches being explored include utilizing an mTOR inhibitor with an HDAC inhibitor (for enhanced HIF1 modulation, PTEN restoration, and antiangiogenic effects), antiangiogenic agents, chemotherapy, radiation, and several drug classes (i.e., EFGR) that affect inhibition of signal transduction pathways implicated in castration refractory prostate cancer (CRPC) progression and mTOR feedback.

Finally, endometrial cancer and ovarian cancer researchers have reported encouraging data. A phase II trial of temsirolimus (CCI-779) resulted in the following outcomes: PR 26%, stable disease 63%, and preventable disease 11% (Oza et al. ASCO Abstract 3003, 2006). A phase II trial of AP23573 (deforolimus) in recurrent endometrial cancer demonstrated a 33% clinical benefit (Columbo, et al. ASCO Abstract 5516, 2007). Ovarian cancer researchers have demonstrated mTOR inhibition activity in several phase II trials. Outcomes have been most robust when mTOR inhibitors are utilized in conjunction with various chemotherapeutic regimens and antiangiogenesis agents.”

Dr. Figlin concluded that “in the next decade of research, (the mTOR pathway) will be integral. The mTOR pathway is activated in a large number of cancers…thyroid, lung, kidney, melanoma…all have mTOR pathway activation. It is ubiquitous across cancers."

â–º Advances in Multiple Myeloma

Guideline Updates

An update on NCCN’s “Multiple Myeloma Guidelines” (released in October, 2007), was presented by Kenneth C. Anderson, MD, Dana-Farber, Brigham and Women’s Cancer Center, Boston, and William Bensinger, MD, Fred Hutchinson Cancer Research Center/Seattle Cancer Care Alliance, Seattle.

Perhaps the most significant development affecting the NCCN’s multiple myeloma (MM) guidelines has been the frenetic pace of the myriad clinical advances that have taken place over the past few years. Guideline designers have had to scramble to keep abreast of a radically changing treatment landscape, in which rapidly evolving research efforts have yielded four new FDA approved drugs in the last three years: (1) (bortezomib (Velcade), (2) lenalidomide (Revlimid), (3) thalidomide (Thalomid), and (4) pegylated liposomal doxorubicin (Doxil). Indeed, one of the key challenges presented by the latest edition of the NCCN guidelines, according to Dr. Anderson, has been the “integration of novel therapy into myeloma management.”

The recent drug approvals have affected all phases of guidelines development, altering treatment protocols for both single agent and combination treatment regimens across the continuum of care (i.e., induction/first-line therapy, post-transplant maintenance therapy, and treatment of relapsed/ refractory MM). Currently, NCCN guidelines for initial therapy include the following options:

OS = Overall Survival; PFS = Progression-Free Survival;ORR = Overall Response Rate

• Cyclophosphamide (Cytoxan)
• Melphalan (Alkeran) and prednisone - With or without thalidomide - With or without bortezomib - With or without lenalidomide
• Thalidomide plus dexamethasone
• Bortezomib plus dexamethasone
• Bortezomib (in various combinations
• Bortezomib plus pegylated liposomal doxorubicin
• Lenalidomide plus dexamethasone.

In addition to the above options, a bortezomib/thalidomide/desamethasone combination regimen has been added to the updated list of primary induction regiments for transplant candidates.

Following initial therapy, transplant candidates are advised to undergo a stem cell harvest and subsequent autologous stem-cell transplantation (SCT) (single versus double) with or without thalidomide, bortezomib or lenalidomide maintenance therapy. Investigational therapy (i.e.- allogeneic SCT) is another NCCN-sanctioned option for transplant candidates. For nontransplant candidates, the guidelines indicate one of the following salvage therapies:

• Repeat primary therapy (if relapse occurs in less than six months)
• Cyclophosphamide
• Etoposide, dexamethasone, cytarabine (Cytosar), cisplatin
• Etoposide, dexamethasone, cyclophosphamide, cisplatin (newly added to the updated guidelines)
• Thalidomide with or without dexamethasone
• Lenalidomide with or without dexamethasone
• Bortezomib with or without dexamethasone
• Bortezomib (in various combinations)
• Other novel therapies (clinical trials).

Also, the updated guidelines now include bortezomib in combination with pegylated liposomal doxorubicin as a category 1 recommendation for patients with relapsed/refractory multiple myeloma in several specific clinical situations. These include:

• Patients with progressive disease following allogeneic or autologous SCT
• Patients with primary progressive disease following initial autologous or allogeneic SCT
• Non transplant candidates with progressive or relapsing disease after initial induction therapy.

â–º Advances in Multiple Myeloma

Overview of the Clinical Evidence

After reviewing therapeutic modifications in the updated guidelines, Dr. Anderson engaged in a lengthy review of the clinical evidence supporting the incorporation of the new therapeutic agents into the guidelines. Highlights of presented data included:

• ECOG, a trial in which 445 patients were randomized to receive four cycles of either lenalidomide plus low-dose dexamethasone (arm A) or lenalidomide plus high-dose dexamethasone (arm B) (Rajkumar, et al. ASH 2007). Both the low-dose and high-dose arms boasted impressive rates of complete or partial response (82% in Arm A versus 70% in Arm B). The low dose cohort demonstrated a slight edge in 12 month (.96 versus .88, P = 0.003) and 24 month (.87 versus .75, P = 0.009) survival probability. However, the most significant point of differentiation was toxicity. The high-dose dexamethasone arm (B) was associated with a higher incidence of serious (grade three or higher) adverse events, especially deep vein thrombosis (DVT)/pulmonary embolism (PE) (9% versus 25% in arm B, P < 0.001) and infection/pneumonia (7% versus 14% in arm B, P,/i> = 0.030).
• VISTA (Velcade as Initial Standard Therapy in multiple myeloma), a randomized, international phase III trial assessing bortezomib, melphalan, and prednisone (BMP) versus melphalan and prednisone (MP) in previously untreated with multiple myeloma (MM) patients who were not candidates for high-dose therapy (HDT) autologous stem cell transplant SCT (San Miguel, et al. ASH 2007). Results indicated that BMP was significantly superior for all efficacy endpoints (Figure 3).
• A phase I/II evaluation of bortezomib, lenalidomide, dexamethasone combination therapy in newly diagnosed MM patients, which demonstrated a 98% overall response rate (ORR) in 42 evaluable patients (Harousseau, et al. ASH 2007). The maximum planned dosages of all agents were reached and toxicities were found to be manageable (no Grade 4 peripheral neuropathy [PNY] and only 2 DVTs). In fact, Dr. Anderson commented that the “active and well tolerated” combination therapy was associated with “a significant absence of toxicities.”
• APEX trial, an international, randomized, open-label phase III trial in relapsed or refractory MM (N = 669) comparing bortezomib monotherapy with HD dexamethasone, in which bortezomib was associated with a 78% improvement in median time-to-progression (TTP) (P < 0.001), the primary endpoint of the study (Richardson, et al. NEJM 2005). Bortezomib also yielded more than double the ORR of HD dexamethasone (43% vs. 18%). Dr. Anderson noted that “approximately 20% of patients responding to bortezomib achieved maximal M-protein reduction in cycle eight or later. (Thus,) the best response (was) achieved after longer duration of bortezomib therapy.” According to subgroup analysis (i.e., refractory patients, elderly patients), “bortezomib is effective in high-risk disease.”

In addition to posting strong efficacy data, many of the recently approved agents offer enhanced treatment flexibility. The lenalidomide/dexamethasone combination, for example, “is effective in patients regardless of response to prior thalidomide (according to data drawn from a prospective subgroup analysis of relapsed/refractory MM patients enrolled in MM-009 and MM-010, two recent phase II trials evaluating lenalidomide/dexamethasone in relapsed refractory MM),” reported Dr. Anderson. In addition, asserted Dr. Anderson, “lenalidomide/ dexamethasone is more effective than dexamethasone at first relapse and beyond” and “may overcome poor prognosis conferred by cytogenic abnormalities.” Furthermore, data were presented demonstrating that both bortezomib and lenalidomide offer increased tolerability in patients with renal impairment.

According to Dr. Anderson, synergies yielded by new combinations of novel agents have the potential to overcome a diversity of treatment challenges. For example, “phase I and II trials show that the majority of patients refractory to either lenalidomide or bortezomib alone respond to the combination.” In a separate combination, “low-dose bortezomib enhances and restores sensitivity to DNA damaging chemotherapy (i.e., doxorubicin).” To underline the latter assertion, Dr. Anderson presented data from two separate studies affirming the enhanced efficacy (in terms of TTP, response rates, and overall survival) of the pegylated liposomal doxorubicin/bortezomib combination compared with bortezomib monotherapy.

Looking forward, Dr. Anderson forecasted that “future molecular-based, rationally designed combination therapies will achieve durable complete response (CR) in the majority of patients.” Commenting on the present state of MM therapy, Dr. Anderson stated, “ongoing oncogenomic and proteomic studies are informing clinical protocol design and identifying novel therapeutic targets. A new treatment paradigm targeting both the tumor cell and its microenvironment has already markedly improved overall response, CR, event-free survival (EFS), and overall survival (OS). Autologous SCTs remain as a standard of care, (but) maintenance (utilizing drug therapy) may be beneficial. New drug combinations for front-line therapy are under evaluation. These include various combinations of) thalidomide, bortezomib, and lenalidomide. More data are needed, however, to determine the effect of these agents on OS, with and without transplant.”

Figure 3. Phase III VISTA Trial Results: Assessment of

Primary and Secondary Endpoints

Bortezomib, melphalan, and prednisone (BMP) (N = 336)

Versus Melphalan and prednisone (MP) (N = 331)

(In previously untreated MM patients who were not candidates for

high-dose therapy [HDT] autologous SCT)

Primary Endpoint

Time-to-Progression

BMP

24.0 months, (83 events), P < 0.000001

MP

16.6 months, (146 events)

Reduced Risk of

Progression on VMP

Roughly 52%

Selected Secondary Endpoints

Overall Survival

Median follow-up

16.3 months

BMP

Not reached (45 deaths), P = 0.0078

MP

Not reached (76 deaths)

Overall Survival Rates at Two Years

BMP

82.6%

MP

69.5%

Progression-Free Survival

BMP

(BMP Showed Statistically

Significant

Superiority)

P = 0.00001

Hazard Ratio

0.609

95% Cl

0.486—0.763

Response to Treatment

(As measured by M-protein in serum or urine by a centralized laboratory)

PR

BMP

46%

MP

45%

CR

BMP

35%, P < 0.000001

MP

5%

ORR (CR+PR)

BMP

82%, P < 0.000001

MP

50%

MM = Multiple Myeloma; SCT = stem cell transplantation;

VMP = combination of Velcade, melphalan, and prednisone;

CI = confidence interval; PR = partial response; CR = complete response;

ORR = overall response rate.

â–º Advances in Breast CancerGuideline Updates

Robert W. Carlson, MD, Stanford Comprehensive Cancer Center, Stanford, California, and Stephen B. Edge, MD, Roswell Park Cancer Institute, Buffalo, New York, provided an update on (NCCN’s 2008) “Breast Cancer Guidelines” (which were released earlier this year in January).

Alterations in the updated guidelines were primary driven by new data and therapeutic advances. For example, recently approved ixabepilone (Ixempra)—as monotherapy and in combination with capecitabine (Xeloda) (category 2B)&mdash;has been added to the list of ‘other active options’ in the section of the guidelines detailing `preferred chemotherapy regimens for recurrent or metastatic breast cancer’ (Figure 4).

Figure 4. National Chemotherapy Regimens for Recurrentor Metastatic Breast Cancer

Preferred Chemotherapy Regimens for Recurrent or Metastatic Breast Cancer

Preferred Single Agents

Doxorubicin

Epirubicin

Pegylated liposomal doxorubicin

Paclitaxel

Docetaxel

Capecitabine

Vinorelbine

Gemcitabine

Albumin-bound paclitaxel

Preferred Agents with Bevacizumab

Paclitaxel

Preferred Combinations

CAF/FAC (cyclophosphamide/doxorubicin/fluorouracil

FEC (fluorouracil/epirubicin/cyclophosphamide)

AC (doxorubicin/cyclophosphamide)

EC (epirubicin/cyclophosphamide)

AT (doxorubicin/docetaxel; doxorubicin/paclitaxel)

CMF (cyclophosphamide/methotrexate/fluorouracil)

Docetaxel/capecitabine

GT (gemcitabine/paclitaxel)

Other Active Options

Cisplatin

Carboplatin

Etoposide (po)

Vinblastine

Fluorouracil continuous infusion

Ixabepilone

Ixabepilone plus capecitabine (category 2B)

Capecitabine has also been included as a preferred chemotherapy agent in combination with lapatinib (Tykerb) for patients with human epidermal growth factor receptor-2 (HER2)—positive recurrent or metastatic disease. For adjuvant chemotherapy, docetaxel with cyclophosphamide represents a new addition to the recommendations.

“Ixabepilone,” explained Dr. Carlson, “is an epothilone analog (that has been shown to) stabilize microtubules. (The agent, currently) active in (several) phase II breast cancer trials, (has demonstrated a) preclinical synergy with capecitabine (and was) not susceptible to multiple resistance mechanisms in preclinical models.”

In one of the phase II trials presented by Dr. Carlson, 42% of patients who had undergone prior anthracycline, taxane, and capecitabine therapy, and were dosed with 40 mg/m2 of ixabepilone over three hours every three weeks, experienced at least a partial response after only six weeks.

Another study presented by Dr. Carlson illustrated the synergistic effect of ixabepilone/ capecitabine combination therapy. Researchers randomized anthracycline- and taxane-resistant patients with metastatic or locally advanced breast cancer into one group that received ixabepilone (40 mg/m² IV over three hours d 1) plus capecitabine (2,000 mg/m² PO in two divided doses days 1—14) and another group that underwent capecitabine monotherapy (2,500 mg/m² PO in two divided doses days 1—14). Both cohorts received therapy in 21 day cycles.

P

According to the results of the research, the group of patients who underwent ixabepilone/ capecitabine combination therapy demonstrated a statistically significant advantage in terms of progression-free survival (PFS) (as assessed by an independent radiologic review), the primary endpoint of the study. Median PFS for the combination therapy cohort was 5.8 months, compared with 4.2 months for the capecitabine monotherapy cohort ( = 0.0003).

Caution should be exercised with this particular combination treatment, however, warned Dr. Carlson, in patients with impaired liver function. “Roughly 31% of patients with Grade 2 or higher liver function test dysfunction (aspartate transaminase or alanine transaminase greater than or equal to 2.5 x upper limit of normal [ULN] or bilirubin greater than or equal to 1.5 x ULN) in the combination ixabepilone plus capecitabine (group) died of neutropenia,” reported Dr. Carlson.

Dr. Carlson reported that a new section focusing on the treatment of patients with inflammatory breast cancer (IBC), a rare, aggressive form of breast cancer estimated to account for 1% to 6% of breast cancer cases in the United States has been added to the updated guidelines. Recommendations from the NCCN Guideline Panel for treatment of IBC (without evidence of metastases), a condition characterized by redness and swelling of the skin of the breast caused by blockage of lymph vessels by cancer cells, involves a combined modality approach including preoperative chemotherapy with an anthracycline with or without a taxane followed by total mastectomy and radiation therapy for patients responding to preoperative chemotherapy.

Previous editions of the NCCN breast cancer practice guidelines had been criticized for folding inflammatory breast cancer recommendations into a larger section on locally advanced treatment. The updated guidelines now differentiate inflammatory breast cancer— considered a distinct pathologic entity&mdash; and furnish a separate treatment algorithm. “This had been a consistent criticism of previous breast cancer guidelines. We have now responded and given inflammatory breast cancer its own guideline,” stated Dr. Carlson.

Updates in Local Regional Therapy

in situ

Dr. Edge discussed the updates in local regional therapy that have been incorporated into the 2008 edition of the NCCN breast cancer guidelines. “A major change to the DCIS (ductal carcinoma ) (treatment) guideline (has occurred),” reported Dr. Edge.

In the 2007 version, the guideline for DCIS treatment called for lumpectomy without lymph node dissection plus radiation therapy or total mastectomy without lymph node dissection with or without reconstruction. In cases of small (less than 0.5 cm) unicentric, lowgrade DCIS, treatment options consisted of lumpectomy plus radiation therapy or total mastectomy without lymph node dissection with or without reconstruction or lumpectomy alone (category 2B).

The 2008 guidelines have been modified to eliminate the separate protocol for small, unicentric, low-grade DCIS. The guideline for treatment of DCIS now reads as follows: lumpectomy without lymph node surgery plus whole breast radiation therapy (category 1) or total mastectomy with or without sentinel node biopsy with or without reconstruction or lumpectomy without lymph node surgery without radiation therapy (category 2B).

Despite the variety of recommended treatment options provided, Dr. Edge pointed out that “no controlled data show any survival difference by type of treatment.” The guidelines suggest that some patients may be treated by excision alone if the patient and clinician view the individual risks as low. “This puts the onus back on the physician to have an appropriate conversation with the patient,” stated Dr. Edge.

Although DCIS cancer-specific survival approaches 100%, actual survival percentages are markedly lower because of comorbidity. According to recent data published in the ,i>Journal of the National Cancer Institute, five-year survival rates for DCIS patients between the ages of 65 and 70, with two or more comorbidities, is lower than 80%. Patients with DCIS plus multiple comorbidities in their 70s have survival rates below 70% and patients who are 80 years of age and older (with DCIS plus two or more comorbidities have survival rates ranging from below 60% (age 80—84) to less than 45% (85 and older).

A new section of the guideline explores the principles of breast reconstruction after a mastectomy. It defines the options and sequencing of reconstruction and discusses the importance of multidisciplinary evaluation, coordination, patient involvement, and counseling.

in situ

Another new section addresses the principles of radiation therapy. Dr. Edge pointed out that at NCCN centers between the year 2003 and 2006, a total of 81% of patients received radiation therapy for ductal carcinoma .