Clinical Insights: May 2014

Thursday, June 05, 2014

STATEMENT OF NEED

The overall goal is to update the healthcare professional’s knowledge of cancer detection and prevention and to understand current and new research regarding state-of-the-art care for those with or at risk for cancer.

TARGET AUDIENCE

Intended for advanced practice nurses, registered nurses, and other healthcare professionals who care for cancer patients.

OVERALL EDUCATIONAL OBJECTIVES

Upon completion, participants should be able to:

  • Describe new preventive options and treatments for cancer patients
  • Identify options for individualizing the treatment for cancer patients
  • Review new evidence to facilitate survivorship and supportive care for cancer patients

ACCREDITATION STATEMENT

Dannemiller is approved by the California Board of Registered Nursing, Provider Number 4229, for 1.0 contact hour. CBRN credit is not accepted by the Michigan and Utah State licensing boards.

DISCLOSURES

The planners and authors of this CE activity have disclosed no relevant financial relationships with any commercial companies pertaining to this activity.

METHOD OF PARTICIPATION

  1. Read the articles in this section in its entirety.
  2. Go to www.dannemiller.com/onn-may-2014.
  3. Complete and submit the CE posttest and activity evaluation.
  4. Print your Certificate of Credit.

This activity is provided free of charge to participants.

Ovarian Cancer

Irregular Menstruation Can Increase Risk of Death From Ovarian Cancer

Women with irregular menstrual cycles have a 2.4-fold increased risk of death from ovarian cancer, according to a large, prospective study presented at the 2014 American Association of Cancer Research (AACR) Annual Meeting held April 5-9.

“This information may help earlier diagnosis and perhaps lead to a strategy to prevent ovarian cancer by pointing toward how the cancer develops and spreads,” said Barbara A. Cohn, PhD, MPH, director of the Child Health and Development Studies at the Public Health Institute in Berkeley, California.

The Child Health and Development Studies enrolled more than 15,000 pregnant women between 1959 and 1967, following them for more than 50 years to study factors impacting health during pregnancy. Medical reports and self-reported data were collected from these women on their menstrual irregularity, including those whose cycles were longer than 35 days, and those who experienced anovulation.

Of the 13% of women who said they had menstrual irregularities when they were 26 years old, 64 of them died from ovarian cancer. “It is notable that the 2.4-fold increase in risk of ovarian cancer death we observed for women with irregular/infrequent cycles in this study is close to the threefold increase in risk observed for women with a family history of ovarian cancer in a first-degree relative,” explained Cohn.

The authors of the study said that the association between menstrual irregularities and ovarian cancer death was independent of age, race, parity, and weight. The association between menstrual irregularities and ovarian cancer death was stronger after the women reached their mid-60s.

Menstrual irregularities also increased the risk for serous- and endometrioid-type cancers by nearly threefold and fourfold, respectively. In addition, the incidence of late-stage ovarian cancer was found to be twofold higher for women with irregular or infrequent menstrual cycles.

These findings are contrary to the expectation that polycystic ovarian syndrome (PCOS), which is characterized by less frequent ovulation and irregular or long menstrual cycles, would protect the ovary. However, in addition to infrequent ovulation, there are a number of anatomical, hormonal, and metabolic abnormalities associated with PCOS that might account for the study findings, noted Cohn.

“Among reproductive cancers, ovarian cancer is the most common cause of death, because it is usually diagnosed late in the disease process after it has spread,” said Cohn. “Unfortunately, there is no reliable method for early diagnosis or screening, and symptoms like abdominal pain and bloating often do not come to a woman’s attention until the cancer has spread.”

 

Colorectal Cancer

High BMI Before Diagnosis a Risk Factor in Colorectal Cancer Mortality

Patients who had a high Body Mass Index (BMI) before being diagnosed with colorectal cancer had an increased risk of death after diagnosis, even if their tumor harbored the microsatellite instability (MSI) marker, which is normally associated with a better prognosis, according to results of a large prospective study presented at the 2014 Annual AACR Meeting held April 5-9.

The study identified 6763 patients with invasive colorectal cancer among participants who enrolled in the Colon Cancer Family Registry from 1997 to 2008. Researchers calculated the patients’ Body mass index (BMI) 2 years prior to diagnosis based on self-reports of height and weight. MSI tumor status was available for 4987 patients and median follow-up was 5.3 years.

After a maximum follow-up of 13.7 years from enrollment to the end of the study, it was found that 2335 patients had died. For colorectal cancer-specific mortality, every 5 kg per m2 increase in BMI increased mortality by 7%.

In patients with tumors high in MSI, every 5 kg per m2 increase in BMI increased the risk of all-cause mortality by 19%, whereas patients with stable-MSI tumors/low-MSI tumors saw an increase of 8%.

Results showed that a higher BMI 2 years before a general cancer diagnosis (per 5-kg/m2) was associated with higher risk of all-cause mortality overall. For every 5 kg per m2 increase in BMI, researchers saw an increased risk of all-cause mortality by10%.

 

Head and Neck Cancer

Doxepin Rinse Relieves Pain in Patients With Radiation-Related Oral Mucositis

Doxepin rinse may prove to be a viable option for the relief of pain associated with oral mucositis in patients with head and neck cancers, according to findings of a phase III trial published online ahead of print April 14 in the Journal of Clinical Oncology.

Painful oral mucositis (OM) occurs in the majority of head and neck cancer patients treated with radiation, regardless of whether they receive chemotherapy. OM-triggered pain can lead to malnutrition and dehydration; when severe, it can result in an increased risk of infection, as well as dose limitations and treatment interruptions.

This randomized, double-blind, placebo-controlled trial, conducted under the auspices of the Alliance for Clinical Trials in Oncology cooperative group, enrolled 155 patients who were being treated at 26 cancer centers across the country between December 2010 and May 2012. To be eligible, patients were undergoing radiotherapy to a minimum planned dose of 50 Gy and experiencing OM-related pain ≥4 on a 0 to 10 scale.

Participants were randomized 1:1 to receive either doxepin (25 mg diluted to 5 mL with 2.5 mL of sterile or distilled water) on day 1, then crossing over to a placebo of a sugar-free flavored syrup on a subsequent day (arm A), or placebo on the first day followed by the doxepin preparation (arm B). Patients in both arms were instructed to swish the solution in their mouth for 1 minute, gargle, and expectorate.

The study’s primary endpoint was a reduction in pain as measured by the pain scale’s area under the curve (AUC), using assessments based on the Oral Mucositis Daily and Weekly Questionnaires– Head and Neck Cancer, administered at baseline and at 5, 15, 30, 60, 120, and 240 minutes for each treatment arm. Patients were allowed to leave after the first hour, instructed to complete the questionnaires at 2- and 4-hour intervals, and received telephone reminders.

Researchers reported that the AUC for the mean reduction in mouth and throat pain was significantly greater with doxepin than placebo, —9.1 and —4.7, respectively; P <.001. Intrapatient changes of +4.1 for arm A and —2.8 for arm B were determined through crossover analyses, equivalent to a treatment difference of —3.5 (95% CI, —5.1 to —1.8; P <.001), for doxepin versus placebo.

As secondary outcomes, researchers also assessed any stinging or burning, unpleasant taste, and/or drowsiness resulting from the rinse, as well as whether additional analgesia was required 2 and 4 hours after administration.

Adverse effects of doxepin were typically mild and consistent with those identified in previous phase I/II studies. The AUC for stinging and burning was significantly higher with doxepin, being highest 5 minutes after rinsing. The sensations were reduced, but remained statistically significant, over the 4-hour postrinse assessment.

Taste also was ranked using AUC on a 0 (acceptable) to 10 (terrible) scale; patients preferred the placebo rinse (5.5) to the doxepin rinse (7.7). After 5 minutes, however, both were deemed acceptable: doxepin rinse (2.9), placebo rinse (1.6)

No significant differences were reported in the use of additional analgesics following use of the rinse versus placebo. Drowsiness was associated more with doxepin, a known adverse effect of the agent; however, differences with placebo did not reach statistical significance until assessment at 2 hours (3.9 for doxepin vs 2.8 for placebo; P = .02), based on a scale of 0 (no drowsiness) to 10 (extreme drowsiness resulting in sleep). The researchers noted that some patients deemed the rinse’s sedative effect beneficial as a sleep aid.

Notably, the researchers reported that 63% of patients (n = 81) chose to continue using the doxepin rinse at the conclusion of the trial, with more patients in arm A indicating a desire to continue treatment than those in arm B. Of those who continued the treatment, 14 (17%) subsequently stopped, citing burning discomfort and drowsiness most often.

Numerous studies over the years have examined the efficacy of other rinse agents such as chlorhexidine, “magic mouthwash,” and phenytoin to relieve OM. The study reported here, noted corresponding author Robert C. Miller, MD, et al, represents “the largest placebo-controlled trial to date specifically testing the efficacy of a rinse agent in controlling established mucositis pain and the only such trial with positive results.” The authors recommended further study to fully evaluate the rinse’s efficacy in treating OM pain in this setting.

Nurse Perspective

 
Colleen M. O’Leary Colleen M. O’Leary, RN, MSN, AOCNS
Clinical Nurse Specialist
The James Cancer Hospital
The Ohio State University Comprehensive Cancer Center
Columbus, OH
 

The incidence of oral mucositis (OM) in patients with head and neck cancer receiving radiotherapy is between 80% and 100%. If the patients are receiving concomitant chemotherapy, it is virtually guaranteed they will experience OM. As the authors point out, this can lead to several untoward results, including a change in the amount, duration, or frequency of treatment. In addition, patients with head and neck cancer are usually already at risk for malnutrition due to their disease, surgical interventions, or lifestyle prior to starting radiotherapy. The development of severe OM increases this risk exponentially.

Although several agents and treatments have shown promise with the management of OM, very few have truly made a consistent dent in this problem for patients. The use of doxepin may be something that can be used to finally get a handle on this for patients. However, as the authors note, more research is needed.

It is important to focus on the unpleasant side effects of this rinse and work to eliminate them. As with several other agents that have been studied, the taste of this rinse was not as pleasant as the placebo. Where a patient might use this product during the study, in the long run, if it is not pleasant tasting, they are more inclined to stop using it and return to other agents or therapies such as opioids for pain control.

In addition, the study indicated that this rinse caused stinging, burning, and taste changes. As with the unpleasant taste, if a patient has to endure increased pain temporarily in order to get some relief, they may use it, but it would serve our patients better if we could find something to decrease pain that doesn’t cause pain itself. And, if this agent causes changes in taste, then perhaps the taste of the few foods that our patients can eat and enjoy will be altered.

RFinally, doxepin was shown to cause more drowsiness than placebo, which again works against known therapies for side effects, such as pain and fatigue—namely moderate aerobic exercise. We know it is better for our patients to be at least moderately active for a variety of reasons, and if we now are giving them something that decreases their ability to be active, the efforts basically work against each other

An interesting finding was that, even given the side effects of doxepin, more people in the study said they would want to continue with the rinse than with placebo. This perhaps warrants further study looking at the reasons behind this, and if the desire to continue the treatment will be long lasting.

OM continues to be a devastating toxicity of both chemotherapy and radiotherapy for patients with head and neck cancer. It is imperative that research continue to find effective long-lasting treatment. Rinses such as doxepin are promising. Low-level laser therapy is another treatment that is being used with very good results and few side effects, but it is not generally available in all areas due to the cost of the equipment and need for specially trained clinicians. However, this is a treatment where nurses can step up and take the reins.

It is clear that the area of prevention and management of OM is vital to improving the quality of life of patients with head and neck cancer as well as other cancers. Continued efforts to develop and refine treatments can only benefit our patients.

 

Bladder Cancer

Chemotherapy Underutilized in High-Risk Bladder Cancer

Despite evidence supporting its efficacy, chemotherapy is not routinely administered to patients with muscle-invasive bladder cancer (MIBC), according to a population-based outcomes study from Canadian researchers.

“Patients having surgery for bladder cancer should have chemotherapy, either before or after surgery. Efforts are needed to improve uptake of this treatment, which appears to be vastly underutilized,” lead author Christopher Booth, MD, Division of Cancer Care and Epidemiology, Queen’s University Cancer Research Institute, Ontario, Canada, said in a statement.

Research supports the use of neoadjuvant chemotherapy (NACT) in MIBC, including a meta-analysis of randomized controlled trials that found a significant 5% overall survival benefit with NACT (Eur Urol. 2005;48[2]:202-205). Although the efficacy of adjuvant chemotherapy (ACT) is not as firmly established in the literature, the authors wrote, “the clinical community appears to have accepted the efficacy of ACT.”

Booth et al sought to determine the use and efficacy of perioperative chemotherapy among the general population of Ontario. They evaluated records of 2944 patients with MIBC from the Ontario Cancer Registry who received a cystectomy between 1994 and 2008. The majority of patients had locally advanced (T3/T4) tumors (71%), were male (75%), and were aged >70 years (60%). Positive lymph nodes were reported in one-fourth of cases.

Overall, NACT was administered to 4% of patients (n = 129), 19% received ACT (n = 572), and 1% (n = 30) were treated with both. To examine usage trends, the researchers segmented patients into three groups: 1994-1998 (n = 705), 1999-2003 (n = 964), and 2004-2008 (n = 1275). NACT use remained static across the three intervals at 5%, 3%, and 6%, respectively, while use of chemotherapy after cystectomy increased from 16%, to 18%, to 22%.

The researchers were able to identify the specific regimen for 46% (n = 308) of the patients who received perioperative chemotherapy. Among this group, treatment included cisplatin in 82% of patients and carboplatin in 14%. Adjusted analyses linked younger age to increased use of chemotherapy in general and poor pathology with higher ACT use.

The 5-year overall survival (OS) rate for the study population as a whole was 29% (95% CI, 28-31), with a cancer-specific survival (CSS) rate of 33% (95% CI, 31-35). Patients receiving chemotherapy before surgery had a 5-year OS of 25% (95% CI, 17-34) and a 5-year CSS of 28% (95% CI, 18-39). The corresponding rates for the adjuvant group were 29% (95% CI, 25-33) and 28% (95% CI, 24-33), respectively.

Adjusted analyses of ACT use in the general population showed a hazard ratio of 0.71 for OS (95% CI, 0.62-0.81) and 0.73 for CSS (95% CI, 0.64-0.84). “Results from our study demonstrate that chemotherapy given after surgery improves patient survival—probably on the same order of magnitude as chemotherapy before surgery,” Booth said.

The authors noted that the 5-year OS rates of 25% and 29% for NACT and ACT, respectively, were “substantially” lower than rates reported in previous studies. With NACT, a 5-year OS rate of 57% was reported in a phase III randomized trial (N Engl J Med. 2003;349:859-866).

Likewise, an updated meta-analysis showed a 5-year OS with ACT of about 50% (Eur Urol. 2005;48[2]:189-199). Possible explanations for these OS discrepancies, according to the authors, are varying surgical strategies, biases in patient selection/referral, and the “known association between greater cystectomy volumes and improved outcomes.”

In their conclusion, Booth et al wrote, “Given the potential for perioperative chemotherapy to improve patient outcomes, further efforts are needed to understand reasons for underutilization.”


Reference
Booth CM, Siemens DR, Li G, et al. Perioperative chemotherapy for muscle-invasive bladder cancer: a population-based outcomes study [published online April 14, 2014]. Cancer. doi:10.1002/cncr.28510.

 

Supportive Care

Patients With Advanced Cancer Benefit When Palliative Care Starts Earlier

Patients with advanced cancer who received early specialized palliative care reported better quality of life and satisfaction, according to results from a randomized trial comparing such services with usual care published in The Lancet.

The findings demonstrate the benefits of cancer centers that provide early palliative care in outpatient clinics, noted Camilla Zimmermann, MD, PhD, FRCPC, the study’s principal investigator and associate professor and Rose Family Chair in Supportive Care at the University of Toronto in Canada.

“Oncologists should be referring the patient earlier to outpatient palliative care teams to provide collaborative care, because typically palliative care is provided much later in the disease process,” said Zimmermann. “However, a lot of cancer centers and hospitals don’t provide outpatient palliative care teams, so the palliative care team has to make themselves relevant in the outpatient setting.” And even where palliative care is available, she added, “oncologists still tend to refer quite late because of biases and stigmas associated with palliative care.”

Carried out over 4 years at 24 medical oncology clinics under the auspices of the Princess Margaret Cancer Centre, University Health Network, the study enrolled 461 patients (228 intervention, 233 control) with advanced lung, gastrointestinal, genitourinary, breast, or gynecologic cancer. Patients were assessed via completion of questionnaires at baseline and then monthly over 4 months.

The specialized palliative care intervention differed from standard cancer care in several respects. Within 1 month of enrollment, patients receiving the intervention had a 60- to 90- minute consultation with a palliative care physician and nurse to assess symptoms, psychosocial distress, social support, and home services; this was followed by monthly 20– to 50-minute follow-up palliative care consultations. Patients in the intervention group also received telephone calls from a palliative care nurse 1 week after the initial consultation, followed by additional calls as needed. The intervention group had access to a 24-hour telephone service for urgent concerns.

Participants in clinics assigned to the control had no formal intervention. Standard care included treatment by oncologists and oncology nurses rather than a palliative care physician and nurse, with no routine assessment of psychosocial issues or structured assessment of symptoms.

A change in score on the Functional Assessment of Chronic Illness Therapy—Spiritual Well- Being (FACIT-Sp) at 3 months was the study’s primary endpoint. Secondary outcomes included a change in the FACIT-Sp score at 4 months and change scores on other measures, such as the Quality of Life at the End of Life (QUAL-E) and the Edmonton Symptom Assessment System (ESAS), which measures the intensity of nine common symptoms experienced by patients with cancer.

Scores on the FACIT-Sp at 3 months did not differ significantly between the intervention (mean change score +1.60) and the control group (-2.00; P = .07). For the QUAL-E measure, however, a significant difference between the intervention and control was reported at 3 months (+2.33 vs +0.06, respectively; P = .05). FACIT-Sp scores were significantly different for the intervention and control at 4 months (+2.46 vs -3.95, respectively; P = .006). Four-month score differences for intervention versus control were also significant for the QUAL-E (+3.04 vs -0.51, respectively; P = .003) and the ESAS (-1.34 vs +3.23; P = .05).

Zimmermann said that an important outcome of the study is that patients reported improved satisfaction with care. “We found that patients appreciated having a team of professionals available to provide additional support navigating the cancer system and coping with multiple medical and social issues.”

Additional studies are planned to assess the impact of providing early palliative care on the family caregivers of patients with advanced cancers and are under way to assess the model’s economic impact.

 

Nurse Perspective

 
Mari Damhof Mari Damhof RN, BSN, OCN, ONN
Nurse Navigator
Willmar Regional Cancer Center
Willmar, MN
 

Palliative care in the last 20 years has evolved in part because cancer research and treatments have improved and people with cancer are living longer. Cancer is one of the most feared of all illnesses, largely due to the stigma that it means suffering and an early death. This is where palliative care is initiating a change and improving quality of life.

Palliative care, when it was first introduced, became coupled more closely with hospice, which as stated by Camilla Zimmermann, MD, PhD, FRCPC, “gave a view that palliative care is end-of-life measures.” In several studies of palliative care including this one, it is evidence-based that palliative care is most effective when established early on with an illness.

Zimmermann points out that an important outcome of this 4-year study was that patients reported improved satisfaction with the care that they received from the palliative care team. The key words here are improved care and team. Despite the fact that there is not a cure for every individual who is diagnosed with cancer, this doesn’t mean that there isn’t a cure for someone’s suffering, which may be emotional or physical. The palliative care team may include a social worker, a chaplain, a pharmacist, a nutritionist, physicians, nurses, and a physical therapist.

As additional studies are being planned, we will learn more about the barriers to palliative care and also the benefits that palliative care can bring—not only to the patient, but also to the family. Patient care is being brought back to the home with the goal of keeping patients out of care facilities such as hospitals, nursing homes, and swing beds. I anticipate that palliative care will have a significant role in these types of situations.

 

Melanoma

Long-Term Outcomes Support Sentinel-Node Biopsy for Staging Melanoma

A 10-year follow-up study of regional melanoma staging strategies found that patients who underwent sentinelnode biopsies had significantly greater disease-free survival rates (DFSRs) compared with patients monitored through nodal observation.

The final results of the Multicenter Selective Lymphadenectomy Trial (MSLT-1), which began in 1994 and enrolled patients through 2002, also showed that biopsy-based staging provides important prognostic information (N Engl J Med. 2014;370(7):599-609).

During the phase III trial, 2001 patients with primary cutaneous melanomas were randomly assigned to undergo wide excision and nodal observation, with lymphadenectomy for nodal relapse (40%) or wide excision and sentinel-node biopsy (SNB) with intermediate lymphadenectomy for nodal metastases detected on biopsy (60%).

In the MSLT-1 trial, researchers sought to determine whether the minimally invasive SNB could be used after primary surgery to identify patients with clinically occult nodal metastases, instead of waiting for nodal recurrence. Of the 2001 patients initially involved in the study, 1661 underwent randomization and 1638 were included in the 10-year follow-up. Of the initial patient population, 1347 had intermediate-thickness (1.20 to 3.50 mm) primary melanomas and 314 had thick primary melanomas (>3.50 mm).

Mean (± standard error) 10-year DFSRs, the primary endpoint of the study, were significantly improved in the biopsy group, compared with the observation group, among patients with intermediate- thickness melanomas (71.3 ± 1.8% with SNB vs 64.7 ± 2.3% in the observation group), and among those with thick melanomas (50.7 ± 4.0% vs 40.5 ± 4.7%, respectively).

Although sentinel-node biopsies resulted in better DFSRs, there was no significant treatmentrelated difference in the 10-year melanomaspecific survival rates among those in the biopsy group (81.4 ± 1.5%) and those in the observation group (78.3 ± 2.0%) among patients with intermediate- thickness melanomas.

Similarly, there was no difference among patients with thick melanomas (58.9 ± 4.1 with SNB vs 64.4 ± 4.6 with observation). Researchers said the lack of a survival advantage for patients with intermediate-thickness melanomas was not surprising because the overall event rates were lower than expected. In addition, they said the false-negative rates were higher in the earlier years of the study, possibly clouding therapeutic benefits, because staff members had not yet gained experience with the procedures.

Christopher Puleo, PA-C, a coauthor of the study from Moffitt Cancer Center who worked with the patients throughout the course of the trial, said that there are long-term side effects associated with removing the lymph nodes prematurely.

“The one main long-term side effect associated with a node dissection is lymphedema,” Puleo said. “This phenomenon occurs approximately as often as 5% of the time in the axilla and up to 15% to 20% of the time in the groin with rare effects in neck dissections. Depending upon whose statistics you review, the overall chances of patients developing spread of the melanoma to their lymph nodes was 16% to 25% on average.

If you were to take 100% of your patients and electively remove their lymph nodes, only 16% to 25% of them would be getting a benefit from that procedure, but 100% of your patients would have the potential for developing any and all of the side effects associated with the surgery.”

To test sentinel melanoma lymph nodes, a radioactive tracer and a blue-colored dye are injected at or near the melanoma site on the skin and tracked to the sentinel nodes. “It has made it much easier without doing surgeries that are potentially debilitating,” said Puleo.

 

Nurse Perspective

 
Rajni Kannan Rajni Kannan, BS, MS, RN, ANP-BC
Nurse Practitioner
Perlmutter Cancer Center
NYU Langone Medical Center
New York, NY
 

Sentinel lymph node biopsies in melanoma patients are based on the location of the primary melanoma. The skin is the largest organ in the body, and lymphatic circulation encompasses the entire surface area of the skin. The primary melanoma may have multiple lymphatic drainage sites that flow to many nodal basins. A patient may, therefore, have multiple sentinel lymph node biopsies in various sites based on the drainage of the melanoma.

A lymph node drainage mapping, known as lymphoscintigraphy, is generally obtained as part of presurgical testing to determine the flow of lymphatic drainage from the primary melanoma. This helps surgeons to identify where and which areas require a sentinel lymph node biopsy. A sentinel node biopsy of the various basins must be completed to properly assess the patient’s melanoma.

Sentinel lymph node biopsies are important in predicting a patient’s risk for recurrence and/or metastatic disease. The size of the metastases in the lymph node also is important, for a micrometastases versus a macrometastases determine staging, prognosis, and possible adjuvant therapy recommendations.

By assessing the patient’s sentinel lymph node, it prevents unnecessary removal of additional lymph nodes. Complete lymph node dissections can lead to lymphedema that may impact the patient’s quality of life without necessarily changing overall survival. Sentinel lymph node biopsy prevents erroneous surgeries and unnecessary side effects or complications.

Although overall survival may not be affected with a sentinel lymph node biopsy versus observation, we are able to have predictive information that helps manage the patient’s risk for recurrence.

As new therapies emerge in melanoma, prognostic factors—including sentinel lymph node biopsies—will become more important in deciding a patient’s course of treatment and surveillance.

 


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