Tag: General Medical Oncology & Hematology

SUMMARY: Immune checkpoints are cell surface inhibitory proteins/receptors that harness the immune system and prevent uncontrolled immune reactions. Immune checkpoints are an area of increasing interest as they utilize the patient’s immune system to reject cancer cells. Survival of cancer cells in the human body may be to a significant extent, related to their ability to escape immune surveillance, by inhibiting T lymphocyte Activation . The T cells of the immune system play a very important role in modulating the immune system. EFFECTOR T cells include Cytotoxic T cells, Helper T cells, and Natural Killer (NK) cells, that enable the immune system to destroy cancer cells and pathogens. The REGULATORY T cells however, suppress immune response. Under normal circumstances, inhibition of an intense immune response and switching off the EFFECTOR T cells of the immune system, is an evolutionary mechanism and is accomplished by Immune checkpoints or gate keepers. The mechanism can be compared to a lock and key where the appropriate Ligand (KEY) binds to the Immune checkpoint protein/receptor (LOCK) and activates or inhibits a T lymphocyte. With the ongoing understanding of tumor immunology and the recognition of Immune checkpoint proteins, researchers have focused on the development of antibodies that either target the membrane bound inhibitory Immune checkpoint proteins/receptors such as CTLA-4, PD-1, IDO, etc. (LOCK) or target the inhibitory soluble Ligands or antigens that are located on the surface of certain cancer cells (KEY) that bind to these Immune check point proteins/receptors. By doing so, one would expect to unleash the EFFECTOR T cells resulting in T cell proliferation, activation and a therapeutic response. The first immune checkpoint protein to be clinically targeted was CTLA-4. YERVOY® (Ipilimumab), an antibody that blocks Immune checkpoint protein/receptor CTLA-4, was approved by the FDA in March 2011 and has been shown to prolong overall survival in patients with previously treated unresectable or metastatic melanoma. The next immune check point protein/receptor studied for targeted therapy was PD-1. Lambrolizumab (MK-3475) is a humanized anti–PD-1 monoclonal antibody that demonstrated a 38% rapid and durable response rate and a more than 7 month median progression-free survival in patients with advanced melanoma, regardless of their prior therapy with YERVOY®. Nivolumab, another PD-1 targeted antibody demonstrated remarkable efficacy in a Phase I study with an overall response rate of 30%, median survival of 16.8 months and a 2 year survival of 44%. Based on this provocative data, a combination of Nivolumab and YERVOY® were studied in patients with advanced Stage III or IV melanoma who had received up to three prior therapies.. The idea was to block both the Immune checkpoints, PD-1 and CTLA-4, for improved efficacy. Fifty three (N=53) patients were treated with a combination of these two agents and 33 patients received these agents sequentially. Indeed, the highest response rate was over 50% in the combination group with 30% of these patients experienced a more than 80% response rate at 12 weeks of treatment whereas the response rate in the sequential treatment group was 20%. This preliminary study confirmed that blocking multiple Immune checkpoint proteins/receptors may result in rapid and durable responses in patients with advanced malignant melanoma. Phase III studies are underway to confirm this efficacy data and this concept is also being studied in other tumor types. Targeting/inhibiting the ligands (KEY) and preventing their binding to the Immune checkpoint protein/receptor, is another approach to stimulate antitumor immune response. PD-L1 protein (Ligand) which is often elevated in melanoma tumor cells, bind to PD-1 check point protein/receptor and can inhibit T cells and escape immune surveillance. An investigational PD-L1 targeted (Ligand targeted) engineered antibody (MPDL3280A) demonstrated a rapid response in 26% of the 45 patients with metastatic melanoma and the benefit was more so in those tumors expressing PD-L1. Promising activity has also been seen in advanced renal cell carcinoma. Antibodies targeting the Immune checkpoint receptor/protein or the Ligands binding to these receptors, are being developed, to carry payloads that are lethal to the checkpoint protein/receptor or Ligand. In conclusion, identifying as well as inhibiting certain Immune checkpoint proteins/receptors and/or Ligands that bind to these receptors, may give us new insights in the field of tumor immunology, resulting in better outcome for our cancer patients. Patel JD, Krilov L, Adams S, et al. J Clin Oncol 2013;32:129-160

SUMMARY: The 2013 Top five list in Oncology was published to optimize the use of diagnostic and therapeutic modalities and enhance patient care, by following evidence-based guidelines, thereby providing cost-effective medical care.

1) Do not give patients starting a chemotherapy regimen that has a low or moderate risk of causing nausea or vomiting antiemetic drugs intended for use with a regimen that has a high risk of causing nausea or vomiting.

Highly emetogenic chemotherapy: The recommendations are a three drug combination of an NK1 receptor antagonist given on days 1-3 for oral Aprepitant (EMEND®) or IV EMEND® given on Day 1 only, a 5-HT3 receptor antagonist given on day 1 only and Dexamethasone (DECADRON®) given on days 1-3 or 4.

Moderately emetogenic chemotherapy: A two drug combination of Palonosetron (ALOXI®) given on day 1 only and DECADRON® given on days 1-3 is recommended. Even though ALOXI® is the preferred agent, a first-generation 5-HT3 serotonin receptor antagonist such as Granisetron (KYTRIL®) or Ondansetron (ZOFRAN®) may be substituted if it is not feasible to give ALOXI®.

Low emetogenic chemotherapy: A 5-HT3 serotonin receptor antagonist is recommended. Patients experiencing nausea and vomiting while on Radiation therapy may need prophylaxis with these agents throughout the course of their therapy.

2) Do not use combination chemotherapy (multiple drugs) instead of chemotherapy with one drug when treating an individual for metastatic breast cancer unless the patient needs a rapid response to relieve tumor-related symptoms.

Combination chemotherapy for metastatic Breast Cancer is only recommended when a patient has significant symptoms related to tumor burden and a rapid tumor response is needed for symptom palliation. Because combination chemotherapy can be associated with significant toxicity without improvement in overall survival (OS), it is recommended that single agent therapy given sequentially reduces the risk of toxicity besides allowing optimal drug delivery and could improve quality of life, without compromising OS. It should be noted however that in tumors overexpressing a specific biomarker such as HER 2, anti–HER 2 therapy in combination with cytotoxic chemotherapy can improve survival compared with chemotherapy alone. Patients with hormone receptor–positive tumors should receive sequential endocrine therapies before cytotoxic chemotherapy, in the absence of life threatening organ dysfunction. Combining cytotoxic chemotherapy with an anti-hormonal agent is not beneficial. Rapid symptom palliation using Radiation treatment, insertion of a stent, surgical intervention, etc., if more efficacious, has to be considered under appropriate circumstances, before initiating chemotherapy.

3) Avoid using positron emission tomography or positron emission tomography–computed tomography scanning as part of routine follow-up care to monitor for cancer recurrence in asymptomatic patients who have finished initial treatment to eliminate the cancer unless there is high-level evidence that such imaging will change the outcome.

Once staging and restaging is complete, routine surveillance using PET or PET-CT scanning for solid tumors and lymphomas remains unproven and is not recommended. This has been validated in multiple studies and has been endorsed by cancer organizations both in the U.S. and abroad.

4) Do not perform prostate-specific antigen testing for prostate cancer screening in men with no symptoms of the disease when they are expected to live fewer than 10 years.

Elevated levels of PSA can be associated with conditions other than Prostate Cancer such as Benign Prostate Hyperplasia. Even though men who undergo PSA testing are less likely to die specifically as a result of prostate cancer, when all cause mortality is taken into consideration, men undergoing PSA screening do not live any longer than those who do not undergo screening. If the life expectancy of an individual is less than 10 years based on medical conditions, PSA screening is unlikely to benefit this individual, as there is a greater probability of dying as a result of the underlying medical problems rather than asymptomatic prostate cancer. The US Preventive Services Task Force, American College of Physicians, American Urological Association, have all changed their recommendations in accordance to these findings.

5) Do not use a targeted therapy intended for use against a specific genetic aberration unless a patient’s tumor cells have a specific biomarker that predicts an effective response to the targeted therapy.

Targeted therapy is expensive and can be associated with toxicities, but can benefit patients significantly if their tumor cells demonstrate the specific gene alteration that makes the tumor cells susceptible to the targeted therapy. Usually, a specific biomarker is present in the tumor cells that may in turn predict effectiveness of the targeted therapy. Exceptions include high level evidence supporting the use of a targeted agent despite absence of the biomarker. It is recommended that targeted agents be used only as intended.

Schnipper LE, Lyman GH, Blayney DW, et al. J Clin Oncol 2013;31:4362-4370

OncoPrescribe LLC published their first newsletter on metastatic lung cancer. The title of the article is “Improving Survival for Patients with Advanced Non−Small-Cell Lung Cancer”.  This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of A. Webb Roberts Center for CME of Baylor Health Care System and Oncoprescribe, LLC. A. Webb Roberts Center for CME of Baylor Health Care System is accredited by the ACCME to provide continuing medical education for physicians.

Oncoprescribe is a comprehensive Web-Based Resource for Oncologists, Nurses, Nurse Practitioners, Physician Assistants and Pharmacists. OncoPrescribe is regularly updated by our Oncology professionals who scour the published literature – and constantly attend conferences at which the latest research findings are presented.

With OncoPrescribe, you’ll probably see regimens available for specific diagnoses and stages that you didn’t even know about, and you’ll be able to prescribe that regimen with confidence because you’ll know there’s a corresponding reference, too.

So, what are you waiting for? Check it out. You will love it