SUMMARY: The American Cancer Society estimates that approximately 39,500 individuals will be diagnosed with oral cavity and oropharyngeal cancer in the United States in 2015 and about 7,500 will die of the disease. These cancers are more than twice as common in men as in women and tobacco and alcohol use are among the strongest risk factors. Routinely screening for oral mucosal lesions can improve survival in this patient group. The primary treatment of oral cavity squamous cell carcinoma is complete surgical resection with tumor free margins. Surgical management of the neck in patients with early stage oral cancers has remained unclear, with regards to the benefit of ipsilateral Elective Neck Dissection (END) at the time of primary surgery following diagnosis versus Therapeutic Neck Dissection (TND) after nodal relapse in the neck. To address this question, the authors conducted a prospective, randomized, controlled trial between 2004 and 2014, in which 596 treatment naïve patients with invasive squamous cell carcinoma of the oral cavity (tongue-85%, buccal mucosa-14%, floor of the mouth-1%) were enrolled and randomized to 1:1 to Elective Neck Dissection (END) or Therapeutic Neck Dissection (TND) following primary oral surgery. Patients had T1 (2 cm or less) or T2 (more than 2 cm and less than 4 cm) tumors that was lateralized to one side of the midline and were amenable to oral excision with adequate margins. Elective Neck Dissection (END) consisted of removal of submandibular (level 1), upper jugular (level 2)and midjugular (level 3) lymph nodes, with lower jugular (level 4) and posterior triangle (level 5) lymph nodes removed only if any of the lymph nodes in the first three levels showed intraoperative metastatic disease. Therapeutic Neck Dissection (TND) consisted of modified neck dissection (level 1-5) at the time of nodal relapse. All patients with high risk disease received adjuvant radiotherapy. The Primary end point was Overall Survival and Secondary end point was Disease Free Survival.
This publication summarizes the outcomes for the first 500 patients (245 in the END group and 255 in the TND group), following a median follow-up of 39 months. The 3 year Overall Survival was significantly higher in the Elective Neck Dissection group compared with the Therapeutic Neck Dissection group (80.0% vs. 67.5%, HR=0.63; P=0.01). The three year Disease Free Survival was also significantly higher in the END arm compared with TND (69.5% vs 45.9%, HR=0.45; P<0.001). The authors concluded that Elective Neck Dissection in patients with early stage oral squamous cell carcinoma resulted in 37% reduction in mortality risk as well as significantly high Disease Free Survival rates with a 55% reduction in the risk of disease recurrence. END should therefore be considered a standard treatment option. Elective versus Therapeutic Neck Dissection in Node-Negative Oral Cancer. D’Cruz AK, Vaish R, Kapre N, et al. N Engl J Med 2015; 373:521-529
Bisphosphonates can also reduce bone pain and may improve Quality of life. Intravenous bisphosphonates, Pamidronate (AREDIA®) and Zoledronic acid (ZOMETA®) have been approved in the US for the treatment of bone metastases. Amino-bisphosphonate, ZOMETA® has however largely replaced AREDIA®, because of its superior efficacy. Both AREDIA® and ZOMETA® are administered IV every 3 to 4 weeks during the first year, following diagnoses of bone metastases. However, the optimal treatment schedule following this initial phase of treatment has remained unclear. Further, renal toxicity, long bone fractures and OsteoNecrosis of the Jaw (ONJ) have been identified as potential problems with bisphosphonate use.
The primary endpoint was incidence of any Skeletal Related Event (SRE) and secondary endpoints included skeletal morbidity rates, performance status, pain using the Brief Pain Inventory and incidences of ONJ and renal dysfunction. Both treatment groups were well matched. Patients in this trial were stratified by disease and analyses by disease was pre-planned. It was noted that for the primary endpoint, there was no significant difference between the two treatment groups with 29% of patients in both treatment groups experiencing at least one SRE (P=0.79). With regards to secondary endpoints, there were still no significant differences between the two treatment groups, including renal dysfunction and ONJ. The authors pointed out that toxicities such as ONJ and renal dysfunction are more likely to occur after 2 years of treatment.
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 therefore play a very important role in modulating the immune system. Under normal circumstances, inhibition of an intense immune response and switching off the T cells of the immune system, is an evolutionary mechanism and is accomplished by Immune checkpoints or gate keepers. With the recognition of Immune checkpoint proteins and their role in suppressing antitumor immunity, antibodies are being developed that target the membrane bound inhibitory Immune checkpoint proteins/receptors such as CTLA-4 (Cytotoxic T-Lymphocyte Antigen 4), also known as CD152, PD-1(Programmed cell Death-1), etc. By doing so, one would expect to unleash the T cells, resulting in T cell proliferation, activation and a therapeutic respons
Non Small Cell Lung Cancer patients with squamous cell histology have been a traditionally hard- to-treat patient group, with less than 5% of patients with advanced SCC, surviving for five years or longer. Some of the advanced NSCLC tumors are dependent on the Epidermal Growth Factor Receptor (EGFR) for cell proliferation and survival, regardless of EGFR mutation status. TARCEVA® (Erlotinib) is a reversible EGFR Tyrosine Kinase Inhibitor and is presently approved by the FDA for the treatment of locally advanced or metastatic NSCLC, after failure of at least one prior chemotherapy regimen. GILOTRIF® (Afatinib) is an oral, irreversible blocker of the ErbB family which includes EGFR (ErbB1), HER2 (ErbB2), ErbB3 and ErbB4. This kinase inhibitor is indicated for the first line treatment of patients with metastatic NSCLC, whose tumors have Epidermal Growth Factor Receptor (EGFR) exon 19 deletions or exon 21 (L858R) substitution mutations.
Approximately 80% of breast tumors express Estrogen Receptors and/or Progesterone Receptors and these patients are often treated with anti-estrogen therapy as first line treatment. Cyclin Dependent Kinases (CDK) play a very important role to facilitate orderly and controlled progression of the cell cycle. Genetic alterations in these kinases and their regulatory proteins have been implicated in various malignancies. Cyclin Dependent Kinases 4 and 6 (CDK4 and CDK6) phosphorylate RetinoBlastoma protein (RB) and initiate transition from the G1 phase to the S phase of the cell cycle. CDK4 and CDK6 are activated in hormone receptor positive breast cancer, promoting breast cancer cell proliferation. Further, there is evidence to suggest that endocrine resistant breast cancer cell lines depend on CDK4 for cell proliferation. IBRANCE® (Palbociclib) is a reversible, oral, selective, small molecule inhibitor of Cyclin Dependent Kinases, CDK4 and CDK6, and prevent RB1 phosphorylation. IBRANCE® is the first CDK inhibitor approved by the FDA. It exhibits synergy when combined with endocrine therapies. In an open-label, randomized, phase II study, which included treatment naïve postmenopausal women with ER-positive, HER2-negative, advanced breast cancer, IBRANCE® given along with Aromatase Inhibitor FEMARA® (Letrozole) significantly prolonged Progression Free Survival, Overall Response rate and median duration of response, compared to FEMARA® alone. Based on this data, the U. S. Food and Drug Administration on February 3, 2015 granted accelerated approval to IBRANCE® (Palbociclib), for use in combination with FEMARA® (Letrozole) in this patient population. FASLODEX® (Fulvestrant) is a selective estrogen receptor down-regulator presently indicated for the treatment of hormone receptor positive metastatic breast cancer patients, with disease progression following antiestrogen therapy.
Immune checkpoints are cell surface inhibitory proteins/receptors that are expressed on activated T cells. They harness the immune system and prevent uncontrolled immune reactions. 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 therefore play a very important role in modulating the immune system. Under normal circumstances, inhibition of an intense immune response and switching off the T cells of the immune system, is an evolutionary mechanism and is accomplished by Immune checkpoints or gate keepers. With the recognition of Immune checkpoint proteins and their role in suppressing antitumor immunity, antibodies are being developed that target the membrane bound inhibitory Immune checkpoint proteins/receptors such as CTLA-4 (Cytotoxic T-Lymphocyte Antigen 4), also known as CD152, PD-1(Programmed cell Death-1), etc. By doing so, one would expect to unleash the 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, has been shown to prolong overall survival in patients with previously treated, unresectable or metastatic melanoma. KEYTRUDA® (Pembrolizumab) is a fully humanized, Immunoglobulin G4, monoclonal antibody, that binds to the PD-1 receptor and blocks its interaction with ligands PD-L1 and PD-L2, thereby undoing PD-1 pathway-mediated inhibition of the immune response and unleashing the tumor-specific effector T cells. The FDA granted accelerated approval to KEYTRUDA® in September 2014, for the treatment of patients with unresectable or metastatic melanoma and disease progression following YERVOY® and, if BRAF V600 mutation positive, a BRAF inhibitor. The activity of KEYTRUDA® as a single agent in advanced SCCHN patients, was previously published and was noted in PD-L1 positive tumors, regardless of the Human PapillomaVirus (HPV) status. The Overall Response Rate in this patient group was 20% and 29% of patients had stable disease. The authors in this study reported the efficacy of once every three week dose of KEYTRUDA®, in a larger expansion cohort of KEYNOTE 012 study. In this study, 132 patients with recurrent/metastatic SCCHN were enrolled, regardless of their PD-L1 expression or HPV status. These patients received a fixed dose of KEYTRUDA® 200 mg IV, every 3 weeks and patients were evaluated every 8 weeks with radiographic imaging. The mean age was 59 years and 57% of the patients had 2 or more lines of therapy for recurrent disease. Treatment was continued until disease progression. The primary end point was Overall Response Rate (ORR) and secondary endpoints included Progression Free Survival (PFS) and Overall Survival (OS). The Overall Response Rate was 25% and stable disease was noted in an additional 25% of the patients. This amounted to a disease control rate of 50%. Patients with HPV-positive disease had a response rate of 20.6% and patients with HPV-negative disease had a response rate of 27.2%, suggesting that KEYTRUDA® was active in both subgroups of patients. Serious toxicities were reported in fewer than 10% of patients and the most common adverse event was fatigue (15.2%). The authors concluded that KEYTRUDA® given every 3 weeks was well tolerated and demonstrated a meaningful response rate in a heavily pretreated population of patients, with recurrent/metastatic SCCHN. Evaluation of PD-L1 status for this patient group is ongoing. Antitumor activity and safety of pembrolizumab in patients (pts) with advanced squamous cell carcinoma of the head and neck (SCCHN): Preliminary results from KEYNOTE-012 expansion cohort. Seiwert TY, Haddad RI, Gupta S, et al. J Clin Oncol 33, 2015 (suppl; abstr LBA6008)</s
SIRFLOX is an International, multi-center, open-label, randomized phase III study, which evaluated the efficacy and safety of combining modified FOLFOX6 (Oxaliplatin, 5-FU and Leucovorin) chemotherapy regimen with or without AVASTIN® (Bevacizumab) with SIRT, using Y-90 resin microspheres, as first line treatment in patients with unresectable liver only or liver dominant metastatic ColoRectal Cancer (mCRC). The randomization included 530 patients of whom 263 patients received mFOLFOX6 with or without AVASTIN® (Group A) and 267 patients received mFOLFOX6 + SIRT administered once with cycle 1, with or without AVASTIN® (Group B), with the treatment given until disease progression. Patients were stratified based on the extent of liver involvement (25% or less versus more than 25%), presence of extra hepatic disease (liver only versus liver dominant disease) and treatment with AVASTIN®, which was at the discretion of the attending physician. Forty percent of the patients had extra hepatic disease. The primary endpoint was Progression Free Survival (PFS). With a median follow up of 36.1 months, the median PFS in the liver was 12.6 months versus 20.5 months in Group A versus Group B respectively (HR=0.69; P=0.002). The hepatic Response Rate was 68.8% versus 78.7% (P=0.042), with a Complete Response Rate of 1.9% versus 6.0% (P=0.02) in Groups A and B respectively. Even though hematologic and gastrointestinal adverse events were higher in the SIRT group, the toxicity levels were acceptable. The authors concluded that the addition of SIRT to chemotherapy resulted in a 7.9 month improvement in Progression Free Survival in the liver, for patients with unresectable metastatic ColoRectal cancer (mCRC), with a 31% reduction in the risk of tumor progression in the liver. With the liver being the most common site of spread in patients with metastatic CRC, this study provides Level One evidence to support the use of SIRT in combination with chemotherapy in this patient group. SIRFLOX: Randomized phase III trial comparing first-line mFOLFOX6 ± bevacizumab (bev) versus mFOLFOX6 + selective internal radiation therapy (SIRT) ± bev in patients (pts) with metastatic colorectal cancer (mCRC). Gibbs P, Heinemann V, Sharma NK, et al. J Clin Oncol 33, 2015 (suppl; abstr 3502)</s