Author: RR

Late Breaking Abstract – ASH 2019: DARZALEX®, KYPROLIS® and Dexamethasone Combination Improves PFS in Relapsed or Refractory Multiple Myeloma

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SUMMARY: Multiple Myeloma is a clonal disorder of plasma cells in the bone marrow and the American Cancer Society estimates that in the United States, 32, 270 new cases will be diagnosed in 2020 and 12,830 patients are expected to die of the disease. Multiple Myeloma (MM) in 2020 remains an incurable disease. The therapeutic goal therefore is to improve Progression Free Survival (PFS) and Overall Survival (OS). Multiple Myeloma is a disease of the elderly, with a median age at diagnosis of 69 years and characterized by intrinsic clonal heterogeneity. Almost all patients eventually will relapse, and patients with a high-risk cytogenetic profile or refractory disease have the worst outcomes. The median survival for patients with Myeloma is over 10 years.

REVLIMID® (Lenalidomide) in combination with VELCADE® (Bortezomib) and Dexamethasone is the preferred regimen according to the NCCN guidelines, for both transplant and non-transplant candidates with newly diagnosed Multiple Myeloma, and when given continuously or with maintenance therapy, has improved survival outcomes. Nonetheless, a significant number of patients progress while on these agents or discontinue therapy due to toxicities. There is therefore a need for effective and tolerable regimens for patients who are exposed or refractory to REVLIMID® or VELCADE®.Mechanism-of-Action-of-Daratumumab

KYPROLIS® (Carfilzomib) is a second generation selective, epoxyketone Proteasome Inhibitor and unlike VELCADE®, proteasome inhibition with KYPROLIS® is irreversible. DARZALEX® (Daratumumab) is a human IgG1 antibody that targets CD38, a transmembrane glycoprotein abundantly expressed on malignant plasma cells and with low levels of expression on normal lymphoid and myeloid cells. DARZALEX® exerts its cytotoxic effect on myeloma cells by multiple mechanisms, including Antibody Dependent Cellular Cytotoxicity (ADCC), Complement Dependent Cytotoxicity (CDC) and direct Apoptosis. Additionally, DARZALEX® may play a role in immunomodulation, by depleting CD38-positive regulator immune suppressor cells, and thereby expanding T cells, in patients responding to therapy. Both KYPROLIS® and DARZALEX® are approved as single agents, as well as in combination with other drugs, for the treatment of patients with Relapsed/Refractory Multiple Myeloma. In a Phase I study, KYPROLIS® in combination with Dexamethasone and DARZALEX® demonstrated safety and efficacy in patients Relapsed/Refractory Multiple Myeloma.

CANDOR is a multicenter, open-label, Phase III trial, which included Relapsed/Refractory Multiple Myeloma patients with measurable disease who had received 1-3 prior lines of therapy, with Partial Response or better to one or more lines of therapy. A total of 466 patients were randomly assigned 2:1 to receive triplet of KYPROLIS®, Dexamethasone, and DARZALEX® (KdD)- N=312 or KYPROLIS® and Dexamethasone (Kd) alone- N=154. All patients received KYPROLIS® as a 30 minute IV infusion on days 1, 2, 8, 9, 15, and 16 of each 28-day cycle (20 mg/m2 on days 1 and 2 during cycle 1 and 56 mg/m2 thereafter). DARZALEX® 8 mg/kg was administered IV on days 1 and 2 of cycle 1 and at 16 mg/kg once weekly for the remaining doses of the first 2 cycles, then every 2 weeks for 4 cycles (cycles 3-6), and every 4 weeks thereafter. All patients received Dexamethasone 40 mg oral or IV weekly (20 mg for patients over 75 years of age). The median age was 64 years, 42% and 90% received prior REVLIMID® and VELCADE® (Bortezomib) containing regimens respectively, and a third of patients were refractory to REVLIMID®. The Primary endpoint was Progression Free Survival (PFS) and Secondary endpoints including Overall Response Rate (ORR), Minimal Residual Disease (MRD)-negative status, Complete Response (CR) rate at 12 months, Overall Survival (OS), Duration of Response, and Safety.

After a median follow up of 17 months, the study met its Primary endpoint and the median PFS was not reached for the KdD arm and was 15.8 months for the Kd arm (HR=0.63; P=0014). This represented a 37% reduction in the risk of progression or death in the KdD group. The PFS benefit of KdD was maintained across prespecified subgroups, particularly among REVLIMID®-exposed and REVLIMID®-refractory patients. The ORR was 84.3% in the KdD group versus 74.7% in the Kd group (P=0.004), with a CR rate or better of 28.5% versus 10.4% respectively. The median time to first response was one month in both treatment groups. Patients treated with KdD achieved deeper responses which was nearly 10 times higher, with a MRD-negative Complete Response rate at 12 months of 12.5% for KdD versus 1.3% for Kd (P<0.0001). The median treatment duration was longer in the KdD group compared to the Kd group (70.1 versus 40.3 wks). The median OS was not reached in either groups, at a median follow up time of 17 months. Toxicities were generally manageable and the incidence of Adverse Events leading to treatment discontinuation was similar in both treatment groups.

It was concluded that a combination of KYPROLIS® along with Dexamethasone and DARZALEX® resulted in a significant PFS benefit over KYPROLIS® and Dexamethasone alone, with deeper responses, and the PFS benefit of KdD was maintained across prespecified, clinically important subgroups, particularly REVLIMID®-exposed and REVLIMID®-refractory patients. The authors added that KdD regimen should be considered as a novel, efficacious, and tolerable immunomodulatory-free treatment option for Relapsed/Refractory Multiple Myeloma patients. Carfilzomib, Dexamethasone, and Daratumumab Versus Carfilzomib and Dexamethasone for the Treatment of Patients with Relapsed or Refractory Multiple Myeloma (RRMM): Primary Analysis Results from the Randomized, Open-Label, Phase 3 Study Candor (NCT03158688). Usmani SZ, Quach H, Mateos M-V, et al. Presented at the 61st American Society of Hematology Annual Meeting and Exposition; Orlando, Florida; December 7-10, 2019; Abstract LBA-6.

MYELOID GROWTH FACTORS

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DEFINITIONS: Neutropenia is defined as an Absolute Neutrophil Count (ANC) of 500 or less per microL or ANC less than 1000/microL and a predicted decline to 500 or less per microL over the next 48 hours. Febrile Neutropenia (FN) is defined as a temperature of 38.0 degrees C orally in a Neutropenic patient.

RISK FACTORS: The risk for of Febrile Neutropenia is not only dependent on the treatment regimen and delivered dose intensity but also on the overall condition of the patient. It is important that all these risk factors be taken into consideration before considering Primary Prophylaxis with CSF (Colony Stimulating Factors given prior to first chemotherapy cycle).

Patients at a risk of developing Febrile Neutropenia include

1) Patients 65 years of age or older

2) Poor Performance Status

3) Previous chemotherapy or radiation therapy

4) Preexisting Neutropenia

5) Tumor involving the bone marrow

6) Poor Liver function with elevated bilirubin

7) Poor renal function

8) Recent surgery

9) Preexisting Infection

10) Open wounds

Based on the treatment regimen and patient related risk factors, patients can fall in one of the three risk groups to develop Febrile Neutropenia (FN)

High Risk: More than 20% risk of FN

Intermediate Risk: 10-20% risk of FN

Low Risk: Less than 10% risk

Approximately 25%-40% of patients who had no prior chemotherapy develop FN with commonly prescribed chemotherapy regimens1. A notable group falling in the high risk category are those in whom dose intensity has to be maintained, in spite of a Neutropenic complication in the immediate previous chemotherapy cycle. The risk of FN associated with various chemotherapy regimens has been extensively published2 and is beyond the scope of this review.

BENEFITS OF CSF:

1) Use of G-CSF (Granulocyte – Colony Stimulating Factor) as recommended, reduces the incidence, severity and duration of chemotherapy induced Neutropenia. Neutropenic colitis or Typhlitis can be associated with prolonged neutropenia in patients with hematologic malignancies. The decreased duration of WBC (White Blood Cell) nadir in turn can decrease the chance of infectious complications including infection related mortality and improve quality of life3

2) There can be potential cost savings, preventing patient hospitalization4

3) G-CSF can facilitate delivery of full dose intensity of chemotherapy on schedule5

RISKS ASSOCIATED WITH CSF:

1) Mild to moderate bone pain

2) Rare cases of Splenic rupture

3) Allergic reactions involving the skin, cardiovascular and respiratory system with Filgrastim

FDA APPROVED MYELOID GROWTH FACTORS:

NEUPOGEN® (Filgrastim)

NEULASTA® (Pegfilgrastim)

NEUTROVAL® (Tbo-filgrastim)

LEUKINE® (Granulocyte Macrophage-CSF, Sargramostim)

The first three are currently approved for use in preventing chemotherapy induced Neutropenia, whereas LEUKINE® is indicated for use in patients with Acute Myeloid Leukemia following induction therapy and in Stem Cell Transplantation

PREVENTION OF NEUTROPENIC COMPLICATIONS:

1) Primary prophylaxis (Prior to start of the first cycle of chemotherapy) with CSF’s is recommended for all patients who are considered to be at high risk for FN6, regardless of whether the treatment intent is palliative or curative

2) CSF’s should be considered on an individualized basis for patients who fall in the Intermediate risk category.

3) CSF’s are not usually recommended for patients considered to be at low risk for FN. The exception however will be for those patients who are being treated with a curative intent or receiving adjuvant therapy who cannot risk FN as this could lead to fatal complications.

4) Research in the area of pharmacogenomics may help us better understand how Neutropenic complications could be prevented

NEUTROPENIA AFTER FIRST CYCLE OF CHEMOTHERAPY:

1) FN or dose limiting Neutropenia (Unable to give treatment on schedule) following first cycle of chemotherapy warrants use of CSF

2) If a patient experiences dose limiting Neutropenia or FN inspite of primary prophylaxis with CSF’s, dose reductions or change in treatment regimen has to be considered

3) For a patient hospitalized with FN, CSF’s may be considered if the patient is deemed to be at high risk, provided the patient did not receive prophylactic NEULASTA® following chemotherapy. NEULASTA® is only indicated for the prevention of chemotherapy induced Neutropenia but not for therapy, when a patient presents with Neutropenia.

ADMINISTRATION OF CSF:

1) Start NEUPOGEN® within 24-72 hours after completion of chemotherapy and continue until post nadir ANC is normal or close to normal

2) NEULASTA® is administered 24 hours after completion of chemotherapy and is not recommended for administration on a schedule less than 2 weeks.

3) NEULASTA® is not recommended following weekly chemotherapy2.

MANAGEMENT of Febrile Neutropenia – OTHER ASPECTS:

1) Hospitalization is recommended

2) Patients should be started on broad spectrum antibiotics, following appropriate cultures

3) Start CSF if appropriate

4) Good hand hygiene

5) If prolonged Neutropenia is anticipated, minimize exposure to pets and live plants

Reference List

1. Dale DC. Colony-stimulating factors for the management of neutropenia in cancer patients. Drugs 2002;62 Suppl 1:1-15.

2. Crawford J, Allen J, Armitage J et al. Myeloid growth factors. J Natl Compr Canc Netw 2011;9(8):914-932.

3. Fortner BV, Schwartzberg L, Tauer K, Houts AC, Hackett J, Stolshek BS. Impact of chemotherapy-induced neutropenia on quality of life: a prospective pilot investigation. Support Care Cancer 2005;13(7):522-528.

4. Lyman GH, Kuderer NM. The economics of the colony-stimulating factors in the prevention and treatment of febrile neutropenia. Crit Rev Oncol Hematol 2004;50(2):129-146.

5. Citron ML, Berry DA, Cirrincione C et al. Randomized trial of dose-dense versus conventionally scheduled and sequential versus concurrent combination chemotherapy as postoperative adjuvant treatment of node-positive primary breast cancer: first report of Intergroup Trial C9741/Cancer and Leukemia Group B Trial 9741. J Clin Oncol 2003;21(8):1431-1439.

6. Smith TJ, Khatcheressian J, Lyman GH et al. 2006 update of recommendations for the use of white blood cell growth factors: an evidence-based clinical practice guideline. J Clin Oncol 2006;24(19):3187-3205.

CHEMOTHERAPY INDUCED NAUSEA AND VOMITING (CINV)

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Chemotherapy Induced Nausea and Vomiting (CINV) is quite common and occurs in about 80% of patients receiving chemotherapy1,2. It is important to differentiate nausea from vomiting, as more patients experience nausea rather than vomiting3. There are 6 different categories of CINV

1. Acute CINV

2. Delayed CINV

3. Breakthrough CINV

4. Refractory CINV

5. Anticipatory CINV

6. Radiation Induced Nausea and Vomiting

ACUTE CINV: Acute CINV by definition begins within the first 24 hours following chemotherapy administration, with most patients experiencing symptoms within the first four hours of treatment.

DELAYED CINV: This is defined as nausea and vomiting occurring more than 24 hours after chemotherapy administration and can persist for several days4. This is often underestimated, as a third of the patients receiving chemotherapy may experience delayed nausea and vomiting with out prior acute nausea or vomiting.

BREAKTHROUGH CINV: This is defined as nausea and/or vomiting experienced by patients despite prophylactic treatment with antiemetics. These patients require additional intervention with antiemetics to treat their symptoms.

REFRACTORY CINV: Patients on chemotherapy may experience nausea and vomiting following subsequent cycles of chemotherapy administration when prophylaxis/rescue for nausea and vomiting have failed in earlier cycles.

ANTICIPATORY CINV: This is a “learned conditioned response” with psychologic undertones as a result of prior experience of nausea and vomiting with chemotherapy. It usually occurs about 12 hours leading up to chemotherapy administration5,6. The incidence varies from 20%-50%. It is more often seen in younger patients and nausea is more common than vomiting. This entity is difficult to treat and may require psychologic counseling.

RADIATION INDUCED NAUSEA AND VOMITING: This is often experienced by patients undergoing Total Body Irradiation (TBI), a technique that is used prior to bone marrow transplantation7. Patients undergoing radiation to the upper abdomen will also experience nausea and vomiting8.

Pathophysiology of Nausea and Vomiting

The brain controls the multistep pathway that results in vomiting. There are two separate units in the medulla that play a vital role in the causation of nausea and vomiting.

• Chemoreceptor trigger zone (CTZ) also called Area Postrema, present on the floor of the fourth ventricle. This area is very sensitive to chemical stimuli and is easily accessible to emetogenic substances in the general circulation.

• Vomiting Center (Emetic Center) located in the reticular formation of the medulla. This center integrates the emetic response and coordinates the act of vomiting.

The neuroreceptors involved in mediating vomiting include Serotonin (5HT), Dopamine (D2), Neurokinin-1(NK-1), Cannabinoid(CB1), Opiate, Histamine(H1), Corticosteroid and Acetylcholine or Muscarinic(M) receptors. These receptors are located in the vomiting and vestibular centers of the brain9. The most important receptors involved in the emetic response however are Serotonin and Dopamine receptors10. Vomiting is triggered by the Vomiting Center after it receives impulses from CTZ, GI tract, and cerebral cortex and vestibular apparatus in the inner ear. Chemotherapeutic agents and radiation therapy generally induce vomiting by producing free radicals, which in turn act on the enterochromaffin cells, resulting in the release of Serotonin(5-hydroxytryptamine-5HT3). Serotonin activates the serotonin receptors. Activation of the receptors then activates the vagal afferent pathway, which in turn activates the vomiting center and causes an emetic response. Chemotherapeutic agents along with its metabolites also directly stimulate the CTZ by way of general circulation, triggering vomiting through the Vomiting Center.

Classification of Chemotherapeutic agents based on Emetogenicity11

High Risk: More than 90% of the patients experience acute emesis

Moderate Risk: 30-90% of the patients experience acute emesis

Low Risk: 10-30% of the patients experience acute emesis

Minimal Risk: Less than 10% of the patients experience acute emesis

Risk Factors for Nausea and Vomiting

• Emetogenic potential of the chemotherapy agent used

• Younger age

• Female gender

• History of motion sickness

• Alcohol consumption

Classification of Antiemetics

Serotonin (5-HT3) Receptor Antagonists

ZOFRAN ® (Ondansetron): This agent is the first in its class approved by the FDA in 1991 for the treatment of CINV. This first generation 5-HT3 receptor antagonist is available as an IV preparation, sublingual/chewable tablet, oral tablet and oral solution. This agent has a shorter half life than KYTRIL® and ALOXI®.

KYTRIL® (Granisetron): This first generation 5-HT3 receptor antagonist provides 24-hour protection against chemotherapy induced nausea and vomiting. It is available as a single dose Injection as well as tablets or oral solution

ALOXI ® (Palonosetron): This second generation 5-HT3 antagonist has a 100 fold higher binding affinity to 5-HT3 receptor than other 5-HT3 receptor antagonists12. This agent is effective in preventing both acute and delayed onset nausea and vomiting. This agent has to be given IV and oral administration is not feasible due to poor bioavailability, unlike the first generation 5-HT3 antagonists.

Neurokinin-1 (NK-1) Receptor Antagonist

EMEND® (Aprepitant): This agent selectively blocks the binding of substance P to the NK-1 receptor in the central nervous system and thereby complements the antiemetic activity of 5-HT3 receptor antagonists by virtue of its different mechanism of action. It is available as tablets as well as parenteral preparation. This agent can interact with several other drugs more, so when given orally because of first-pass metabolism13. It is therefore important to check the package insert for drug interactions.

Dopamine Receptor Antagonists

These agents antagonize dopamine (D2)-receptors which are involved in the emetic signaling through the chemoreceptor trigger zone. Dopamine receptor antagonists also counteract dopamine receptors in the stomach, implicated in decreasing stomach motility during nausea and vomiting. The three main classes of dopamine receptor antagonists are phenothiazines, butyrophenones, and benzamides.

Phenothiazines – PHENERGAN® (promethazine) belongs to this class. Low doses of phenothiazines antagonize interaction of dopamine with D2-receptors and thus exert an antiemetic effect.

Benzamides – Are strong central and peripheral D2-antagonists. They exert antiemetic effects by increasing lower esophageal sphincter tone and decreasing transit time through the upper gastrointestinal tract. REGLAN® (metoclopramide) belongs to this class.

Butyrophenones

HALDOL® (Haloperidol) belongs to this group of agents.

H1 Receptor Antagonists

Antihistamines antagonize the H1 receptors and inhibit the action of histamine. They also affect the vestibular system, decreasing stimulation of the vomiting center. Further, they also exhibit activity by inhibiting the muscarinic receptor. However, second generation antihistamines such as CLARITIN® (Loratidine), ALLEGRA® (Fexofenadine) and ZYRTEC® (Cetirizine) do not cross the blood brain barrier, and as such do not cause drowsiness and cannot be used as antiemetics. Some examples of H1 receptor antagonists include

• DRAMAMINE® (Dimenhydrinate)

• ANTIVERT® (Meclizine)

• BENADRYL® (Diphenhydramine)

Muscarinic Receptor Antagonists

These agents are good for motion sickness. They antagonize the acetylcholine receptors in the brain. Scopolamine transdermal belongs to this class

Cannabinoids Receptor Antagonists

These agents antagonize the CB1 receptors in the brain. The two drugs in this class

• MARINOL® (Dronabinol)

• CESAMET® (Nabilone)

Corticosteroids

The mechanism of action not clear. It may be related to the inhibition of arachidonic acid release. The agents in this class include

• DECADRON® (Dexamethasone)

• SOLUMEDROL® (Methylprednisolone)

Benzodiazepines

These agents are sometimes effective for anticipatory nausea and vomiting associated with cancer therapy. It may also be useful for vestibular disorders.

• VALIUM® (Diazepam)

• ATIVAN® (Lorazepam)

• XANAX®: (Alprazolam) Miscellaneous

• TIGAN® (Trimethobenzamide)

General Principles of treating Nausea and Vomiting

1) Prevention is better than cure. Aggressively preventing nausea and vomiting will not only improve patients quality of life but will also decrease the incidence of anticipatory nausea and vomiting.

2) The addition of DECADRON® to 5-HT3 and NK-1 receptor antagonists improves the efficacy of the antiemetic regimen.

3) The choice of an antiemetic regimen should be based on patient risk factors as well as emetogenic potential of a given chemotherapy regimen.

4) The toxicity of a given antiemetic agent and potential drug interactions should be taken into consideration before prescribing.

5) Breakthrough emesis should be aggressively managed with round the clock dosing rather than PRN dosing and a drug from a different class should be considered for treatment of this entity. Also consider rectal or IV route of administration rather than PO route.

6) Ensure patients are well hydrated and electrolyte imbalances are promptly addressed.

7) Think “outside the box” when addressing nausea and vomiting in cancer patients. Do not overlook bowel obstruction, brain metastases, uremia, nausea from pain meds such as opiates, chemo or tumor related gastroparesis and anticipatory nausea and vomiting.

8) Anticipatory nausea and vomiting can be difficult to treat and benzodiazepines (ATIVAN®, XANAX®) along with behavioral therapy may be beneficial.

Reference List

1. Morran C, Smith DC, Anderson DA, McArdle CS. Incidence of nausea and vomiting with cytotoxic chemotherapy: a prospective randomised trial of antiemetics. Br Med J 1979; 1(6174):1323-1324.

2. Jenns K. Importance of nausea. Cancer Nurs 1994; 17(6):488-493.

3. Hickok JT, Roscoe JA, Morrow GR et al. 5-Hydroxytryptamine-receptor antagonists versus prochlorperazine for control of delayed nausea caused by doxorubicin: a URCC CCOP randomised controlled trial. Lancet Oncol 2005; 6(10):765-772.

4. Kris MG, Gralla RJ, Clark RA et al. Incidence, course, and severity of delayed nausea and vomiting following the administration of high-dose cisplatin. J Clin Oncol 1985; 3(10):1379-1384.

5. Moher D, Arthur AZ, Pater JL. Anticipatory nausea and/or vomiting. Cancer Treat Rev 1984; 11(3):257-264.

6. Jacobsen PB, Redd WH. The development and management of chemotherapy-related anticipatory nausea and vomiting. Cancer Invest 1988; 6(3):329-336.

7. Kris MG, Hesketh PJ, Somerfield MR et al. American Society of Clinical Oncology guideline for antiemetics in oncology: update 2006. J Clin Oncol 2006; 24(18):2932-2947.

8. Harding RK. Prodromal effects of radiation: pathways, models, and protection by antiemetics. Pharmacol Ther 1988; 39(1-3):335-345.

9. Dodds LJ. The control of cancer chemotherapy-induced nausea and vomiting. J Clin Hosp Pharm 1985; 10(2):143-166.

10. BORISON HL, WANG SC. Physiology and pharmacology of vomiting. Pharmacol Rev 1953; 5(2):193-230.

11. Grunberg SM, Osoba D, Hesketh PJ et al. Evaluation of new antiemetic agents and definition of antineoplastic agent emetogenicity–an update. Support Care Cancer 2005; 13(2):80-84.

12. Grunberg SM, Koeller JM. Palonosetron: a unique 5-HT3-receptor antagonist for the prevention of chemotherapy-induced emesis. Expert Opin Pharmacother 2003; 4(12):2297-2303.

13. Shadle CR, Lee Y, Majumdar AK et al. Evaluation of potential inductive effects of aprepitant on cytochrome P450 3A4 and 2C9 activity. J Clin Pharmacol 2004; 44(3):215-223.

PROSE: Randomized proteomic stratified phase III study of second line erlotinib versus chemotherapy in patients with inoperable non–small cell lung cancer (NSCLC)

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SUMMARY: VeriStrat ® is a clinically validated serum/plasma-based assay, for patients with advanced Non Small Cell Lung Cancer (NSCLC). VeriStrat® is a serum test of prognostic and predictive value that classifies patients as VeriStrat-Good (VS-G) or VeriStrat-Poor (VS-P) based on eight mass spectral peaks or proteomic patterns of the patients serum. Proteomics is the large-scale study of protein structure and functions. VeriStrat® testing is protein based and therefore has no correlation with known genomic biomarkers. It is well established that EGFR-TKIs (Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitors) are more effective in NSCLC patients with EGFR activating mutations. PROSE is a multicenter, double blind, randomized, VeriStrat® stratified, phase III study. In this trial, over 90% of the patients had no EGFR mutations (EGFR-Wild Type). Two hundred and eighty five (285) patients with advanced NSCLC who had first line treatment regimen with platinum-based therapy were randomly assigned to receive second line chemotherapy (CT) with single agent ALIMTA® (Pemetrexed) or TAXOTERE® (Docetaxel), at standard doses (N=129) or TARCEVA® (Erlotinib) 150 mg po qd (N=134). Patients and study investigators were blinded to the patients VeriStrat® status. Patients were classified as VeriStrat-Good or VeriStrat-Poor based on the VeriStrat® results. Patients in the treatment groups were stratified by age, gender, tumor histology, ECOG-PS and smoking history. Crossover was permitted upon disease progression. The primary objective of the study was to demonstrate differential treatment benefit between TARCEVA® and CT with regards to Overall Survival (OS). Median overall survival (OS) was 9 months for the patients in the CT group and 7.7 months for TARCEVA® group and this was not statistically significant (P=0.3). However when evaluated by VeriStrat® status, CT was beneficial for the VeriStrat-Poor patients compared to TARCEVA®, with significantly better median OS (6.3 vs 3 months, P=0.02). Age, gender, histology (squamous vs non-squamous) and smoking history had no impact on the overall survival. The authors concluded that patients classified as VeriStrat-Poor have better survival with CT than TARCEVA®, whereas patients classified as VeriStrat-Good have similar survival with TARCEVA® and CT. VeriStrat® testing therefore, can help physicians choose between TARCEVA® and CT, for their patients with advanced NSCLC. This test helps physicians identify patients who are likely to have good or poor outcomes after treatment with EGFR inhibitors and thereby can provide valuable insight into whether CT or targeted therapy with TARCEVA®, a EGFR-TKI, is appropriate for their patients with advanced NSCLC, in the second line setting. This information is especially important for patients without an EGFR mutation or for those, whose EGFR mutation status is unknown. Sorlini C, Barni S, Petrelli F, et al. J Clin Oncol 29: 2011 (suppl; abstr TPS214)

 

TTP, HUS and aHUS: Different diseases – Different treatments

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SUMMARY: Thrombotic Thrombocytopenic Purpura (TTP), Hemolytic Uremic Syndrome (HUS) and Atypical Hemolytic Uremic Syndrome (aHUS) are Thrombotic Microangiopathies (TMA’s) associated with MicroAngiopathic Hemolytic Anemia and thrombocytopenia. Even though their clinical presentation has some similarities, they are distinct entities with different pathophysiology and hence managed differently. With the identification of von Willebrand Factor (vWF) cleaving protease ADAMTS13 (A disintegrin and metalloprotease with thrombospondin type 1 repeats, member 13) in 1996, we are now able to better understand and appropriately manage these TMA’s. Patients with TTP are deficient in ADAMTS13 and therefore develop platelet microthrombin in small blood vessels due to uninhibited propagation of platelet aggregates bound to ultra high molecular weight VWF multimers. Approximately 10% or less of Shiga-Toxin producing Escherichia Coli (STEC) infections may be associated with HUS. aHUS is caused by a genetic deficiency of one or more complement regulatory proteins which results in uncontrolled activity of the alternate complement pathway. Plasma Exchange in TTP restores the protease activity of ADAMTS13 whereas aHUS is treated with SOLIRIS® (Eculizumab) to inhibit complement mediated TMA. Once a diagnosis of STEC-HUS is confirmed, hospitalization and intensive care with transfusions and kidney dialysis may become necessary. George JN. Blood 2010:116; 4060-4069

MUCOSITIS

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Mucositis or inflammation of the mucous membranes is one of the most common complications of cancer treatment. This condition is often underestimated and involves the entire gastrointestinal tract. Oral mucositis can result in significant morbidity and for this reason properly managing oral mucositis can have a significant impact on the patient’s quality of life. With the breakdown in the mucosal barrier, patients with severe myelosuppression and mucositis can potentially contract serious infections, requiring hospitalization1. Further, appropriate management of oral mucositis will allow optimal treatment of the patient’s cancer without treatment interruptions.

Pathogenesis of Mucositis

It involves the production of reactive oxygen species (ROS) which damages the mucosal cells and its vasculature, followed by active inflammation, ulceration, and subsequent healing2,3. Genetics may also play a role in increasing the incidence and duration of mucositis in certain individuals4,5.

WHO (World Health Organization) Mucositis Scale

Grade 1 – Oral Soreness,Erythema

Grade 2 – Ulcers but able to eat solids

Grade 3 – Oral ulcers and able to take liquids only

Grade 4 – Oral alimentation impossible

The risk to develop mucositis can be Treatment Related or Patient Related

Risk Factors-Treatment Related

1. Multiple cycles of chemotherapy with agents such as 5-FU, Methotrexate, Cisplatin and Cyclophosphamide.

2. Concurrent chemotherapy and radiation

3. Myeloablative therapy and Transplantation

Risk Factors-Patient Related

1. Women are at a greater risk6

2. African Americans tend to have a lower incidence of mucositis with Fluorouracil than Caucasians7

3. Oral mucosa dryness

4. Irritation and trauma caused by ill fitting dentures

5. Dental hygiene

Prevention of Oral Mucositis

• Oral hygiene should be rigorously maintained by flossing every day, brushing teeth with a soft toothbrush twice a day and rinsing the mouth with bland rinses such as normal saline, baking soda or water.

• Cryotherapy (Ice chips) for 30 minutes before and for 4 to 6 hours after therapy. Cryotherapy causes vasoconstriction resulting in decreased drug delivery to the oral mucosa8.

• KEPIVANCE® (Palifermin), a keratinocyte growth factor, given IV, only for patient’s undergoing myeloablative therapy and transplantation9. This agent increases the thickness of the mucosa.

• ETHYOL® (Amifostine), an organic, thiophosphate given IV, which scavenges reactive oxygen species (ROS), thereby reducing toxicity to the normal mucosa. It is recommended for prevention of xerostomia associated with head and neck radiation, as well as mucositis associated with high-dose melphalan. It is also approved for the prevention of renal toxicity associated with platinum compounds10.

Treatment of Oral Mucositis

• Bland rinses as mentioned above

• Topical anesthetics such as lidocaine viscous or gel

• Magic mouthwash, which is a combination of viscous lidocaine, nystatin, diphenhydramine, and dyclonine magnesium hydroxide. When using topical anesthetics, patients should be instructed not to swallow or gargle, as this can impair the gag reflex and put the patient at a risk for aspiration pneumonia. No more than 25 ml of topical anesthetic is recommended over a 24 hr period, as there is a chance for systemic absorption.

• Other agents that may benefit include GELCLAIR®, MUGARD®, CAPHOSOL®, and MUCOTROL®.

• Myelosuppressed patients with severe mucositis can be at an increased risk of contracting viral and fungal infections. Prophylactic antiviral and antifungal agents must be considered along with prophylactic antibiotics and hematopoietic growth factors.

• Severe mucositis can be associated with pain. If narcotics are indicated, transdermal or liquid preparations should be considered. Managing constipation while on narcotics should not be overlooked.

• Some patients receiving radiation treatment for head and neck cancer may benefit from a prophylactic percutaneous endoscopy gastrostomy (PEG) tube.

• Patient’s with excess oral secretions secondary to mucositis may benefit from antihistamines and scopolamine patches.

• Chlorhexidine and alcohol-containing mouthwashes should be avoided.

• It is important that these patients are adequately hydrated and nourished, avoiding any food products that could traumatize the mucosa.

Reference List

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Medication-Related Osteonecrosis of the Jaw: MASCC/ISOO/ASCO Clinical Practice Guideline Summary

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SUMMARY: Medication-Related OsteoNecrosis of the Jaw (MRONJ) is defined as progressive bone destruction in the maxillofacial region resulting in exposed bone, or bone that can be probed through an intraoral or extraoral fistula (or fistulae) in the maxillofacial region and that does not heal within 8 weeks, occurring in a patient who has received a Bone-Modifying Agent (BMA) or an angiogenic inhibitor agent and with no history of head and neck radiation. The condition may involve the mandible or the maxilla and can be challenging to treat and can cause significant pain, impacting patients quality of life.
BMAs that have been linked with MRONJ principally include bisphosphonates such as Zoledronic acid and Pamidronate and Rank Ligand inhibitor, Denosumab. BMAs are an integral part of cancer management and have essential roles in supportive oncology for the treatment of hypercalcemia of malignancy and bone metastases, and prevention of skeletal-related events such as pathologic fractures and reduce the need for radiation or surgical intervention. BMAs disrupt the bone remodeling cycle by reducing osteoclast survival and function.
The incidence of MRONJ in the osteoporosis patient population is very low and majority of the MRONJ cases occur in the oncology patient population receiving high doses of BMAs and prevalence has been estimated to be as high as 18.6%. The incidence in cancer patients appears to be related to dose and duration of exposure to BMAs. Bisphosphonates-related ONJ occurs after a mean IV administration of 33 months in cancer patients, whereas Denosumab-related ONJ occurs early after treatment, independent of the number of previous administrations. Risk factors for ONJ while on BMAs include smoking, poor oral hygiene, ill-fitting dentures, invasive dental procedures, and uncontrolled diabetes. Chemotherapeutic agents such as angiogenesis inhibitors, Tyrosine Kinase Inhibitors, mTOR inhibitors and immunotherapeutic agents have also been implicated.
The expert panel including representatives from ASCO, the Multinational Association of Supportive Care in Cancer, and the International Society of Oral Oncology outlined best practice recommendations for the prevention and management of MRONJ in patients with cancer who receive BMAs for oncologic indications, following a systematic review of the medical literature. Given the paucity of high-quality evidence, a majority of the recommendations are based on consensus using ASCO’s formal consensus process. The guideline does not address BMAs used for osteoporosis, which are administered at a lower dose and carry a lower risk for MRONJ.
Medication-Related Osteonecrosis of the Jaw: MASCC/ISOO/ASCO Clinical Practice Guideline Summary
Guideline Question: What are the recommended best practices for preventing and managing medication-related osteonecrosis of the jaw (MRONJ) in patients with cancer?
Target Population: Adult patients with cancer who are receiving Bone-Modifying Agents (BMAs) for any oncologic indication.
Target Audience: Oncologists and other physicians, dentists, dental specialists, oncology nurses, clinical researchers, oncology pharmacists, advanced practitioners, and patients with cancer.
Recommendations:
Clinical Question 1. What is the preferred terminology and definition for OsteoNecrosis of the Jaw (maxilla and mandible) associated with pharmacologic therapies in oncology patients?
Recommendation 1.1. It is recommended that the term Medication-Related OsteoNecrosis of the Jaw (MRONJ) be used when referring to bone necrosis associated with pharmacologic therapies.
Recommendation 1.2. Clinicians should confirm the presence of all three of the following criteria to establish a diagnosis of MRONJ – a) Current or previous treatment with a BMA or angiogenic inhibitor b) Exposed bone or bone that can be probed through an intraoral or extraoral fistula in the maxillofacial region and that has persisted for longer than 8 weeks c) No history of radiation therapy to the jaws or metastatic disease to the jaws
Clinical Question 2. What steps should be taken to reduce the risk of MRONJ?
Recommendation 2.1. (Coordination of care.) For patients with cancer who are scheduled to receive a BMA in a non-urgent setting, oral care assessment (including a comprehensive dental, periodontal, and oral radiographic exam when feasible to do so) should be undertaken before initiating therapy. On the basis of the assessment, a dental care plan should be developed and implemented. The care plan should be coordinated between the dentist and the oncologist to ensure that medically necessary dental procedures are undertaken before initiation of the BMA. Follow-up by the dentist should then be performed on a routine schedule (eg, every 6 months) once therapy with a BMA has commenced.
Recommendation 2.2. (Modifiable risk factors.) Members of the multidisciplinary team should address modifiable risk factors for MRONJ with the patient as early as possible. These risk factors include poor oral health, invasive dental procedures, ill-fitting dentures, uncontrolled diabetes mellitus, and tobacco use.
Recommendation 2.3. (Elective dentoalveolar surgery.) Elective dentoalveolar surgical procedures (eg, non–medically necessary extractions, alveoloplasties, and implants) should not be performed during active therapy with a BMA at an oncologic dose. Exceptions may be considered when a dental specialist with expertise in prevention and treatment of MRONJ has reviewed the benefits and risks of the proposed invasive procedure with the patient and the oncology team.
Recommendation 2.4. (Dentoalveolar surgery follow-up.) If dentoalveolar surgery is performed, patients should be evaluated by the dental specialist on a systematic and frequently scheduled basis (eg, every 6 to 8 weeks) until full mucosal coverage of the surgical site has occurred. Communication with the oncologist regarding status of healing is encouraged, particularly when considering future use of BMA.
Recommendation 2.5. (Temporary discontinuation of BMAs before dentoalveolar surgery.) For patients with cancer who are receiving a BMA at an oncologic dose, there is insufficient evidence to support or refute the need for discontinuation of the BMA before dentoalveolar surgery. Administration of the BMA may be deferred at the discretion of the treating physician, in conjunction with discussion with the patient and the oral health provider.
Clinical Question 3. How should MRONJ be staged?
Recommendation 3.1. A well-established staging system should be used to quantify the severity and extent of MRONJ and to guide management decisions. Options include the 2014 American Association of Oral and Maxillofacial Surgeons staging system, the Common Terminology Criteria for Adverse Events version 5.0, and the 2017 International Task Force on Osteonecrosis of the Jaw staging system for MRONJ. The same system should be used throughout the patient’s MRONJ course of care. Diagnostic imaging may be used as an adjunct to these staging systems.
Recommendation 3.2. Optimally, staging should be performed by a clinician experienced with the management of MRONJ
Clinical Question 4. How should MRONJ be managed?
Recommendation 4.1. (Initial treatment of MRONJ.) Conservative measures compose the initial approach to treatment of MRONJ. Conservative measures may include antimicrobial mouth rinses, antibiotics if clinically indicated, effective oral hygiene, and conservative surgical interventions (eg, removal of a superficial bone spicule).
Recommendation 4.2. (Treatment of refractory MRONJ.) Aggressive surgical interventions (eg, mucosal flap elevation, block resection of necrotic bone, soft tissue closure) may be used if MRONJ results in persistent symptoms or affects function despite initial conservative treatment. Aggressive surgical intervention is not recommended for asymptomatic bone exposure. In advance of the aggressive surgical intervention, the multidisciplinary care team and the patient should thoroughly discuss the risks and benefits of the proposed intervention.
Clinical Question 5. Should BMAs be temporarily discontinued after a diagnosis of MRONJ has been established?
Recommendation 5. For patients diagnosed with MRONJ while being treated with BMAs, there is insufficient evidence to support or refute the discontinuation of the BMAs. Administration of the BMA may be deferred at the discretion of the treating physician, in conjunction with discussion with the patient and the oral health provider.
Clinical Question 6. What outcome measures should be used in clinical practice to describe the response of the MRONJ lesion to treatment?
Recommendation 6. During the course of MRONJ treatment, the dentist or dental specialist should communicate with the medical oncologist the objective and subjective status of the lesion (ie, resolved, improving, stable, or progressive). The clinical course of MRONJ may impact local and/or systemic treatment decisions with respect to cessation or recommencement of BMAs.
The Multinational Association of Supportive Care in Cancer, International Society of Oral Oncology, and ASCO believe that cancer clinical trials are vital to inform medical decisions and improve cancer care, and that all patients should have the opportunity to participate.
Medication-Related Osteonecrosis of the Jaw: MASCC/ISOO/ASCO Clinical Practice Guideline Summary. Shapiro CL, Yarom N, Peterson DE, et al. J Oncol Practice 2019;15: 603-606.