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.

Advance 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 (respectable 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 carboplatinbased 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.

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 (New Engl J Med 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 (P = 0.03).

A second trial, NCIC JBR 10 (Winton TL, et al. N Engl J Med 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 (P = 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
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, (P < 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 (BMJ 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 platinumcontaining 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.

Emerging Treatments
One 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, P = 0.007), oneyear 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—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.”

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 Aktdependent 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.”

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:

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

In addition to the above options, a ortezomib/thalidomide/dexamethasone combination regimen has been added to the updated list of primary induction regimens 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

Advances in Breast Cancer

Guideline 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)—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).

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.

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 (P = 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— 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
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 in situ) (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 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.

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 in situ.