National Comprehensive Cancer Network

An estimated 68,810 new cases of urinary bladder cancer will be diagnosed in the United States in 2008. Because the median age at diagnosis is 65 years, medical comorbidities are a frequent consideration in patient management. The clinical spectrum of bladder cancer can be divided into 3 categories that differ in prognosis, management, and therapeutic aims. The first category consists of noninvasive tumors, for which treatment is directed at reducing recurrences and preventing progression to a more advanced stage. The second group encompasses invasive lesions, and the goal of therapy is to determine if the bladder should be removed or preserved without compromising survival, and if the primary lesion can be managed independently or if patients are at high risk for distant spread requiring systemic approaches to improve the likelihood of cure. The critical concern of therapy for the third group, consisting of metastatic lesions, is how to prolong life. Numerous agents with different mechanisms of action have antitumor effects in this disease, and the issue has become how to use these agents to achieve the best possible outcome. Important new changes to the NCCN guidelines on bladder cancer for 2009 include updates to first- and second-line therapies and a new principle of radiation therapy management of invasive disease.

Myeloid Growth Factors

Neutropenia and resulting febrile neutropenia (FN) can be induced by myelosuppressive chemotherapy. Although the prophylactic use of colony-stimulating factors (CSFs) can reduce the risk, severity, and duration of FN, these agents are not administered to all patients undergoing myelosuppressive chemotherapy because of the associated costs. Selective use of CSFs in patients at increased risk for neutropenic complications may, however, enhance cost-effectiveness by directing treatment toward patients most likely to benefit. Filgrastim and pegfilgrastim, both granulocyte colony-stimulating factors (G-CSF), are currently approved by the FDA for preventing chemotherapy-induced neutropenia. In contrast, the labeled indication for sargramostim, a granulocyte-macrophage colony-stimulating factor (GM-CSF), is limited to use after induction therapy for acute myeloid leukemia and in various stem cell transplantation settings. Recommendations are based on evidence derived mainly from studies on G-CSFs; head-to-head studies comparing the clinical benefits of G-CSFs and GM-CSFs are lacking.
These guidelines focus on the use of CSFs in the cancer setting; specifically addressing adult patients with solid tumors and nonmyeloid malignancies. Important updates to the NCCN guidelines on myeloid growth factors include new pages addressing toxicity risks and patient risk factors for poor clinical outcomes.

Featured Articles

Integrating Perioperative Chemotherapy into the Treatment of Muscle-Invasive Bladder Cancer: Strategy Versus Reality
S. Machele Donat, MD

Since the initial Intergroup-0080 trial report confirming the benefit of combined neoadjuvant M-VAC (methotrexate, vinblastine, adriablastine, and cisplatin) chemotherapy and cystectomy in treating muscle-invasive bladder cancer, debate has continued as to the relative risks and benefits of integrating perioperative chemotherapy into the care of patients, especially those with organ-confined, muscle-invasive, node-negative disease who may experience less benefit. Because of the inaccuracies of clinical staging, potential morbidity related to M-VAC chemotherapy, a 70% cure rate in pT2No disease with surgery alone, and only a modest (5%) improvement in absolute overall survival with combined therapy, many favor limiting chemotherapy to patients with a pathologic stage of pT3 or greater or node-positive disease, a recommendation also reflected in the 2008 NCCN Clinical Practice Guidelines in Oncology: Bladder Cancer. Additionally, a recent study examining the perioperative integration of chemotherapy for stage III bladder cancer showed that only 11.6% of patients underwent any perioperative chemotherapy, with most in the adjuvant setting. These findings indicate that despite randomized trial data showing survival benefit associated with perioperative chemotherapy, and the current guidelines for therapy supporting those findings, chemotherapy is not being well integrated into the care of patients with muscle-invasive bladder cancer, even in those who have the most potential for benefit.

Carcinoma in situ of the Urinary Bladder: Review of Clinicopathologic Characteristics with an Emphasis on Aspects Related to Molecular Diagnostic Techniques and Prognosis
Nalan Nese, MD; Ruta Gupta, MD; Matthew H. T. Bui, MD, PhD; and Mahul B. Amin, MD

Carcinoma in situ (CIS) of the urinary bladder is defined as a flat lesion comprising of cytologically malignant cells which may involve either full or partial thickness of the urothelium. De novo CIS constitutes less than 3% of all urothelial neoplasms; however, CIS detected concurrently or secondarily during follow-up of urothelial carcinoma constitutes 45% and 90%, respectively, of bladder cancer. Cellular anaplasia, loss of polarity, discohesion, nuclear enlargement, hyperchromasia, pleomorphism, and atypical mitoses are the histopathologic hallmarks of CIS. Extensive denudation of the urothelium, monomorphic appearance of the neoplastic cells, inflammatory atypia, radiation induced nuclear smudging, multinucleation, and pagetoid spread of CIS may cause diagnostic difficulties. Intravesical BCG instillation is considered preferred treatment, with radical cystectomy being offered to refractory cases. Chemotherapy, α-interferon, and photodynamic therapy can also be considered in BCG-refractory cases. Patient outcome varies based on whether CIS is de novo development or diagnosed secondary to, prior to, or concomitant with papillary bladder cancer. Clinically, the principal determinants of outcome are extent of disease, involvement of prostatic urethra, response to therapy, and time to recurrence.

Limitations of Lymph Node Counts as a Measure of Therapy
Scott M. Gilbert, MD, MS, and Brent K. Hollenbeck, MD, MS

For several cancers, the number of lymph nodes removed during surgery is associated with survival. Observational studies supporting this association have prompted considerable debate regarding the extent of lymphadenectomy and, in some dieases, absolute lymph node counts have been suggested as a measure of the quality of cancer care. However, for most cancers, lymph node counts may not directly influence survival in a causal manner. In fact, several randomized clinical trials addressing the question in lung, gastric, and pancreatic cancers have not shown more extensive lymph node dissections to be linked with improved survival. Despite this negative evidence, however, lymph node counts have remained a target process in quality initiatives. Misinterpretation of the evidence may be driving some of the pressure to broadly implement more extended lymph node dissections. As a process for more accurate disease staging and as a potential marker of the completeness of surgery, lymph node counts are likely linked to quality. However, a causal association between lymph node counts (and extented lymphadenectomy) and survival is tenuous and has not been supported by high-level evidence.

The Role of Myeloid Growth Factors in Acute Leukemia
Martha Wadleigh, MD, and Richard M. Stone, MD

The myeloid growth factors granulocyte-colony stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF) have been extensively studied in acute leukemias. Whether administered before, during, or after chemotherapy for acute myeloid and acute lymphoblastic leukemias, these agents reduce the duration of neutropenia and appear to be safe and well tolerated. Despite consistently demonstrating a shorter duration of neutropenia, multiple, prospective, randomized trials have documented only modest benefits in terms of reduction in the incidence and severity of infections, without substantial gains or impact in complete remission, overall survival, and disease-free survival rates. Growth factors have also been used to recruit quiescent leukemia cells into the S phase of the cell cycle to increase their susceptibility to chemotherapy with the goal to reduce relapse and resistance. Randomized trials to evaluate this priming strategy have consistently demonstrated an improvement in terms of disease-free or event free survival in the intermediate risk group of patients with acute myeloid leukemia, but no overall survival benefit. This review will focus on the clinical experience with these agents as adjuncts to the treatment of acute leukemias.

Neutrophil Biology and the Next Generation of Myeloid Growth Factors
David C. Dale, MD

Neutrophils are the body’s critical phagocytic cells for defense against bacterial and fungal infections. Production of neutrophils depend on myeloid grow factors, particularly granulocyte colony-stimulating factor (G-CSF). After the original phase of development, researchers modified these growth factors to increase their size, delay their renal clearance, increase their biologic potency, and create unique molecules for business purposes. Pegylated G-CSF is a successful product of these efforts. In 2006, the European Medicines Agency established guidelines for the introduction of new biologic medicinal products claimed to be similar to reference products that had previously been granted marketing authorization in the European community, called bio-similars. Throughout the world, new and copied versions of G-CSF and other myeloid growth factors are now appearing. Some properties of myeloid growth factors are similar to other agents, offering opportunities for the development of alternative drugs and treatments. Advances in neutrophil biology coupled with better understanding and development of myeloid growth factors offer great promise for improving care of patients with cancer and many other disorders.

Impact of Chemotherapy Dose Intensity on Cancer Patient Outcomes
Gary H. Lyman, MD, MPH, FRCP (Edin)

Chemotherapy dose intensity represents unit dose of chemotherapy administered per unit time. Dose intensity can be increased or decreased through altering the dose administered, time interval of administration, or both. Evidence supporting the importance of delivered chemotherapy dose intensity in patients with potentially curable malignancies comes from in vitro studies of cancer cell lines and in vivo preclinical studies, in addition to retrospective and prospective clinical trials in both advanced and early-stage disease settings. Several retrospective and prospective randomized trials have shown that chemotherapy dose–intensity reductions established in efficacy studies may compromise long-term disease control and survival. Despite compelling data, surveys have reported that dose reductions and delays frequently occur in clinical practice even in the potentially curative setting. Alternatively, an increase in dose intensity above standard may be achieved through either dose escalation or dose-dense schedules. In early studies, dose-dense schedules showed an increase in survival, whereas the benefit of dose escalation studies has been less consistent and may be accompanied by other dose-limiting toxicities. This article focuses on the rationale for delivering full chemotherapy dose intensity, the apparent reasons for failing to deliver optimal treatment, and available strategies for sustaining full chemotherapy dose intensity when indicated. The delivery of full chemotherapy dose intensity in patients with potentially curable malignancies should be considered a quality of care indicator in clinical oncology.

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National Comprehensive Cancer Network

NCCN Guidelines® & Clinical Resources

JNCCN – The Journal of the National Comprehensive Cancer Network

Table of Contents - Volume 7 Number 1: January 2009

NCCN Clinical Practice Guidelines in Oncology™

Featured Articles

NCCN Guidelines^® & Clinical Resources