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Atraumatic splenic rupture as an initial presentation of chronic myelogenous leukemia

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Chronic myelogenous leukemia (CML) is a myeloproliferative neoplasm associated with the fusion of the BCR gene located on chromosome 22 and the ABL1 gene on chromosome 9. The fusion results in a reciprocal translocation between chromosomes 9 and 22, leading to the formation of the Philadelphia (Ph) chromosome found in 90%-95% of patients with CML. The incidence of CML is 1.5 per 100,000 people per year, with a male predominance and an average age at diagnosis of 64.¹

About 85%-90% of newly diagnosed patients present in the chronic phase and therefore many of them are asymptomatic at the time of diagnosis. If symptoms are present, they often include fatigue, malaise, unintentional weight loss, early satiety, or left upper quadrant pain. Progression of the disease is associated with worsening symptoms such as unexplained fever, significant weight loss, bone or joint pain, bleeding, thrombosis, and infections suggestive of transformation to the accelerated phase or blast crisis. Physical exam findings most commonly include splenomegaly and occasionally mild hepatomegaly.

Atraumatic splenic rupture is a rare complication of this hematologic malignancy, and there are almost no reported cases of CML as the underlying cause.^2-4 Here we present the case of a man with sudden-onset generalized abdominal pain and leukocytosis. A computed-tomography scan showed splenic rupture, and the patient was taken for emergency splenectomy. The patient was subsequently positive for t(9,22)(q34;q11.2).

Case presentation and summary

A 59-year-old white man with a history of hypertension and kidney stones presented to a community emergency department with a chief complaint of abdominal pain. About 30 minutes before his arrival, the patient had woken up from sleep with generalized, nonradiating, abdominal pain, which he described as “like my previous kidney stones.” He also reported worsening dyspnea, nausea without vomiting, and lightheadedness without loss of consciousness. The remainder of the review of systems was negative. A physical exam revealed that he was in moderate distress with clear lung fields and had tachycardia without murmur, no CVA tenderness, and a diffusely tender abdomen.

Complete blood count with differential showed leukocytosis (109.1 x 10³/uL), normocytic anemia (8.1 g/dL), thrombocytopenia (100,000 cells/uL), neutrophils (71.06 cells/uL), bands (27.13 cells/uL), and monocytes (11.63 cells/uL). A CT scan of the abdomen and pelvis showed a grade 4 splenic laceration with significant free abdominal fluid (Figure 1).

Figure 1 Coronal and axial views of a CT scan of the abdomen and pelvis showed a grade 4 splenic laceration with significant free abdominal fluid

The patient was taken to the operating room where he underwent a splenectomy which was complicated by partial gastrectomy and partial omentectomy. He remained intubated on mechanical ventilation in the intensive care for 7 days. His progress was complicated by profound hypotension that required significant fluid administration and ultimately multiple pressors for blood pressure support. Hypotensive shock was beginning to improve on day 3 and was completely resolved by day 5. The patient underwent continuous positive airway pressure (CPAP) trials on day 6 and was successfully extubated on day 7.

After extubation a more thorough history could be obtained from the patient. He denied any history of weight loss, night sweats, or fatigue. Patient denied any known family history of hematologic malignancies. His peripheral smear showed basophilia and granulocytosis with neutrophils and immature granulocytes (Figure 2). The patient was evaluated by the hematology service and was started on allopurinol and hydroxyurea for presumed hematologic malignancy. He was given the meningococcus and streptococcus pneumoniae vaccine and was discharged home in stable condition on day eleven. Patient was subsequently positive for t(9,22)(q34;q11.2) and was started on imatinib. He has continued to follow in the clinic and is currently in remission.

Figure 2 The results of a peripheral smear showed basophilia and granulocytosis with neutrophils and immature granulocytes

Discussion

CML has a triphasic clinical course and treatment is based on the specific disease phase. The 3 phases of the disease include the chronic (more indolent) phase, accelerated (more aggressive) phase, and blast crisis. If the disease is left untreated, it will inevitably transition from a chronic to an accelerated phase and finally to blast crisis within a median time of 4 years.

The chronic phase is the most common, representing 85% of diagnoses. Patients can be asymptomatic and many in this phase will be diagnosed by routine lab testing.⁵According to the World Health Organization, the accelerated phase is defined as CML patients with one of the following: 10%-19% blasts, basophils ≥20%, platelets <100,000/microL or >1,000,000/microL, unresponsive to therapy, splenomegaly unresponsive to therapy, an increasing white cell count unresponsive to therapy, or cytogenetic evolution.⁶ Blast crisis is the most aggressive phase and is usually defined by ≥20% blasts, large foci or clusters of blasts on the bone marrow biopsy, or the presence of extramedullary blastic infiltrates.^7,8

The diagnosis of CML should be suspected in the presence of distinct lab abnormalities in the peripheral blood. These include elevated white blood cell counts with a median count of 100,000 cells/microL, elevated platelet counts, and a mild normocytic normochromic anemia. Platelet counts of 600,000 or greater have been seen in 15%-30% of patients at the time of diagnosis. The white count differential can show a variety of cells but there will be a notably greater percentage of myelocytes than metamyelocytes. Bone marrow biopsy will reveal increased cellularity, normal to slightly elevated percentage of blasts, and reticulin fibrosis. The diagnosis should be confirmed by the presence of the Philadelphia chromosome either by cytogenetics, fluorescence in situ hybridization, or reverse-transcription polymerase chain reaction (RT-PCR). The Philadelphia chromosome is found in 90%-95% of patients with CML. Most of the remaining patients will have other translocations, but a small minority will have no detectable genetic abnormalities and those patients are known as Ph-negative.⁹

Treatment options for CML include potential cure with allogeneic hematopoietic stem-cell transplant (HSCT) or disease control using tyrosine kinase inhibitors (TKIs). TKIs are the initial treatment of choice for newly diagnosed patients and are able to produce long-term remission in most patients. The drugs in this category include imatinib, dasatinib, and nilotinib. They work by inhibiting the Bcr-Abl tyrosine kinase, thereby blocking proliferation and inducing apoptosis in Bcr-Abl-positive cells. The majority of patients with chronic-phase CML will have an excellent response to initial treatment with a TKI. It is critical to follow these patients on a regular basis and monitor their disease status. Although the gold standard for assessing cytogenetic response is cytogenetic analysis of a bone marrow biopsy, more sensitive methods such as quantitative PCR using peripheral blood are now available, thereby minimizing the need for bone marrow biopsy. Patients in the accelerated phase are more difficult to manage because they are resistant to most forms of treatment and have short-lived responses to TKI therapy. These patients should strongly be considered for transplantation. Patients in blast crisis have aggressive disease that is more complex and requires more extensive testing. These patients should ideally be treated at tertiary care centers and treatment often involves chemotherapy in addition to TKI therapy usually followed by HSCT.

Atraumatic splenic rupture (ASR) presents similarly to traumatic splenic rupture with typical symptoms being acute onset of upper abdominal, left chest wall, or left shoulder pain (Kehr’s sign) but without a known history of trauma. Quick recognition and surgical intervention represent the best means of definitive care.¹⁰ Renzulli and colleagues conducted a literature review for all ASR cases from 1980-2008, examining 632 publications representing 845 cases. They examined the cases using logistic regression analysis to better define the clinicopathology behind ASR. The reported causes of ASR are neoplastic processes (30.3%), infectious (27.3%), inflammatory noninfectious (20.0%), drug- and treatment-related (9.2%), mechanical (6.8%), and normal spleen (6.4%). Treatment included total splenectomy in 84.1% of cases, organ-preserving surgery in 1.2%, and conservative measures in 14.7%. They reported an ASR-related mortality of 12.2%, with being older than 40 and neoplastic disorders associated with increased mortality – although male sex and splenomegaly have also been reported.^11-13Thomas and colleagues have reported on 48 cases of ASR related to hematologic malignancy showing acute myeloid leukemia being the most common cause (21%), followed by acute lymphoblastic leukemia (19%).²

Hematologic malignancies commonly cause splenic engorgement and pain although splenic rupture is an extremely rare event. Recent literature review has shown fewer than a thousand reported cases since 1980.⁴ There far fewer reported cases of ASR being related to CML, with most being reported as a complication.^3,14 Based on our review, we could identify only a handful cases of CML with ASR being the initial symptom. These include a patient with Ph-negative CML and ASR following blast crisis, a patient with Phil-negative BCR-ABL-positive essential thrombocythemia, several cases in which the patient ultimately died, and 1 in which the patient survived into remission.^4,14-16 Our case is different because the patient was ultimately positive for t(9,22)(q34;q11.2) and although he experienced multiple complications, he is currently functioning at his baseline and in remission. We hope this case will remind others that CML should be considered in the differential diagnosis of patients ASR.

References

1. American Cancer Society. Cancer Facts & Figures 2015. Atlanta, Ga: American Cancer Society; 2015.

2. Bauer TW, Haskins GE, Armitage JO. Splenic rupture in patients with hematologic malignancies. Cancer. 1981;48:2729-2733.

3. Giagounidis AA, Burk M, Meckenstock G, Koch AJ, Schneider W. Pathologic rupture of the spleen in hematologic malignancies: two additional cases. Ann Hematol. 1996;73(6):297-302.

4. Goodard SL, Chesney AE, Reis MD, et al. Pathologic splenic rupture: a rare complication of chronic myelomonocytic leukemia. Am J Hematology. 2007;82:405-408.

5. Faderl S, Talpaz M, Estrov Z, et al. The biology of chronic myeloid leukemia. N Engl J Med. 1999;341:164-172.

6. Cortes JE, Talpaz M, O’Brien S, et al. Staging of chronic myeloid leukemia in the imatinib era: an evaluation of the World Health Organization proposal. Cancer. 2006;106:1306-1315.

7. Vardiman JW, Harris NL, Brunning RD. The World Health Organization (WHO) classification of the myeloid neoplasms. Blood. 2002;100:2292-2302.

8. Kantarjian HM, O’Brien S, Cortes J, et al. Results of decitabine (5-aza-2’deoxycytidine) therapy in 130 patients with chronic myelogenous leukemia. Cancer.2003; 98:522-528.

9. Swerdlow SH, Campo E, Harris NL, et al, editors. WHO classification of tumours of haematopoietic and lymphoid tissues. Lyon, France: IARC Press; 2008.

10. Maung A, KaplanL. Management of splenic injury in the adult trauma patient. In: UpToDate, Basow DS (ed), Waltham, MA, 2013.

11. Renzulli P, Hostettler A, Schoepfer AM, Gloor B, Candinas D. Systematic review of atraumatic splenic rupture. Br J Surg. 2009;8(10):1114-1121.

12. Hehlmann R, Heimpel H, Hasford J, et al. Randomized comparison of interferon-alpha with busulfan and hydroxyurea in chronic myelogenous leukemia. The German CML Study Group. Blood. 1994;84:4064-4077.

13. Cortes J, Kantarjian H. How I treat newly diagnosed chronic phase CML. Blood. 2012;120:1390-1397.

14. Nestok BR, Goldstein JD, Lipkovic P. Splenic rupture as a cause of sudden death in undiagnosed chronic myelogenous leukemia. Am J Forensic Med Pathol. 1988;9:241-245.

15. Sachithanandan A, Gleadhil I, Alexander HD, Morris TC. Spontaneous splenic rupture in atypical (Philadelphia chromosome negative) chronic myeloid leukemia following blastic crisis. Ir Med J. 2003;96(6):181-182.

16. Chim CS, Kwong YL, Shek TW, Ma SK, Ooi GC. Splenic rupture as the presenting symptom of blastic crisis in a patient with Philadelphia-negative, BCR-ABL-positive ET. Am J Hematology. 2001;66:70-71.

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Erik Frost, DO,^a Azmina Patel, DO,^b and April Brill, DO, FACOEP^a

^aEmergency Medicine, Midwestern University, Downers Grove, Illinois; and ^bHematology Oncology Franciscan St James Hospital, Olympia Fields, Illinois

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Hospitalizations for fracture in patients with metastatic disease: primary source lesions in the United States

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Nikkel et al

It has been well established that metastatic disease to bone has major significance in the morbidity associated with the diagnosis of cancer.¹ More than 75% of patients with metastatic cancer will have bone involvement at the time of death.^2-4 Moreover, there is a reported 8% incidence of a pathologic fracture in patients who carry the diagnosis of cancer.⁵ Common sites of involvement include the spine, ribs, pelvis, and long bones such as humerus and femur.⁶ Pathologic fracture is fracture caused by disease rather than injury or trauma (referred to here as nonpathologic). In any bone, pathologic fracture will be associated with increased morbidity for the patient, but it is the spine and long bones that frequently require surgical intervention and are associated with high mortality and morbidity. Advanced cancer can also increase fracture risk through increasing falls; in one prospective study of patients with advanced cancer, more than half the patients experienced a fall.⁷

Based on historical studies of patients who have died from common cancers,^4,6 it is commonly believed that breast, lung, thyroid, kidney, and prostate cancers are the most common sources of metastasis to bone, and that other common cancers, such as colorectal carcinoma (CRC), have lower rates of metastasis to bone.^6,8,9 It has been inferred from this data that cancers such as CRC thereby have lower rates of pathologic fracture.

Presence of bone metastasis at time of death may be less clinically relevant than occurrence of pathologic fracture and, especially, pathologic fracture requiring hospitalization. The authors are aware of no studies that have determined the number of patients hospitalized as a result of pathologic fracture from common tumors. Despite cadaveric findings, clinical experience dictates that colorectal carcinoma is not an uncommon primary tumor in patients presenting with metastatic disease and pathologic fracture, whereas thyroid carcinoma is more rare.

Despite lower rates of metastasis to bone from CRC, progression to advanced disease is common, with projected 50,000 deaths in the United States in 2014, and tumor progression is associated with metastasis to bone.¹⁰ Patterns of health care use and costs associated with skeletal-related events in more common metastatic prostate and breast cancer are well documented.^11-13 The authors are aware of no population-based studies examining the burden from metastatic fractures or hospitalization incidence attributed to CRC.

Methods

This is a retrospective study of patients hospitalized in the United States with metastatic disease. Data for this study were obtained from the 2003-2010 National (Nationwide) Inpatient Sample (NIS), the Healthcare Cost and Utilization Project (HCUP), and the Agency for Healthcare Research and Quality.¹⁴ The NIS is a stratified sample of approximately 20% of inpatient hospitalization discharges in the United States with more than 7 million hospital stays each year. The dataset contains basic patient demographics, dates of admission, discharge, and procedures, as well as diagnosis and procedure codes for unique hospitalizations. The numbers of new cases of each type of cancer diagnosed in the United States during 2003-2010 were determined from fact sheets published by the American Cancer Society.¹⁵

In all, 1,008,641 patients with metastatic disease in the NIS database, were identified by the presence of International Classification of Diseases, 9th revision, Clinical Modification (ICD-9-CM) diagnosis codes 196.0-199.1. Patients were then classified by primary cancer type based on the presence of additional ICD-9-CM codes for a specific cancer type (140.x-189.x) or for a history of a specific cancer type (V10.00 – V10.91). The analysis was limited to the 10 most common types of cancer. Multiple myeloma, leukemia, lymphoma, and primary cancers of bone also cause pathologic fractures, but they were purposefully excluded from the analysis because they do not represent truly metastatic disease. Patients were excluded if they were younger than 18 years (n = 9,425), had been admitted with major significant trauma (Major Diagnostic Category 24; n = 287), or if the cancer type was either not listed in discharge billing data or not one of the 10 most common types (n = 324,249). Therefore, the final study sample consisted of 674,680 hospitalizations.

The primary outcome assessed was pathologic fracture, identified with ICD-9-CM codes 733.10-733,19. Fractures not due to bone metastasis can occur in patients with metastatic disease owing to falls and general debility; therefore, the secondary outcome was nonpathologic fracture, identified with ICD-9-CM codes for fracture (805.0-829.0) in the absence of a code for pathologic fracture. Fractures classified as a “stress fracture” (ICD-9-CM code 733.9x) or where there was a concomitant diagnosis of osteoporosis (ICD-9-CM cod 733.0x) were also considered nonpathologic for the purpose of this study. Thus there were 3 groups of hospitalized patients identified: metastatic disease without fracture (No Fracture); Pathologic Fracture; and Nonpathologic Fracture. The study was limited to the 10 types of cancer with the highest numbers of pathologic fracture, leaving 647,680 hospitalizations for analysis.

Univariate analyses comparing the Pathologic, Nonpathologic, and No Fracture groups were performed with the Student t test for continuous characteristics and chi-square test for categorical characteristics. All analyses were performed with use of Stata 13.1 (StataCorp, College Station, TX).

This study protocol (RSRB00055625) was reviewed by the Office for Human Subject Protection Research Subjects Review Board at the University of Rochester and was determined to meet exemption criteria.

Results

From 2003-2010 there were 674,680 hospitalizations in patients with metastatic cancer that met the inclusion criteria. Hospitalization was most frequent for lung cancer (187,059 admissions), colorectal cancer (172,039), and breast cancer (124,303; Table 1).

There were 17,303 hospitalizations with pathologic fracture and 12,770 hospitalizations with nonpathologic fracture (Figure 1).

$Figure. Pathologic and nonpathologic fractures by tumor type in patients hospitalized with metastatic cancer.$

Among the most commonly occurring primary cancers in hospitalizations with pathologic fracture were lung, breast, prostate, kidney, and colorectal cancers (Table 1).

$Table 1. Hospitalizations and fractures in patients with metastatic disease.$

Relative to the annual incidence,¹⁵ kidney, lung, and breast cancer had the highest rates of hospital admission for pathologic fracture during the study period. Hospital admission with pathologic fracture was more common than nonpathologic fracture for every type of metastatic disease except colorectal and uterine cancer. Pathologic fracture in patients with metastatic disease was most likely to occur in the spine, hip, and femur (Table 2), and ratio of anatomic sites fractured was relatively consistent across each of the 10 primary malignancies (Table 3).

$Table 2. Number and costs of pathologic fractures by site.$

$Table 3. Percentage of fractures at each site by primary malignancy.$

Demographic characteristics of patients in the 3 study groups are shown in Table 4. Patients with pathologic fracture were more likely than those in the no-fracture group to be white (63.0% vs 60.3%, respectively; P < .001) and female (55.5% vs 49.8%; P < .001), but were similar in age (66.4 years; P = 0.7). In-hospital mortality was lower in the pathologic fracture group compared with the no-fracture group (6.4% vs 8.8%; P < .001). People in the pathologic fracture group were more likely than others to be treated at a teaching hospital (P < .001) with ≥450 beds (P < .001), and reside in a zip code with higher income (P < .01).

Pathologic fracture hospitalizations, on average, had higher billed costs and longer length of stay ($62,974, 9.1 days; Table 4), compared with the no-fracture group ($39,576, 6.9 days; both P < .001) and the nonpathologic fracture group ($42,029, 7.2 days; both P < .001). Pathologic fracture in patients with thyroid, liver, and kidney cancer was associated with the highest costs of hospitalization.

In patients with metastatic disease, differences were found between those with pathologic and nonpathologic fractures: those with pathologic fracture were younger (66.4 vs 74.3 years; P < .001), less likely to be white (63.0% vs 69.0%; P < .001), and more commonly treated at a large hospital (68.4% vs 62.1%; P < .001) or a teaching hospital (53.5% vs 41.0%; P < .001).

Discussion

Other investigators have looked at risk factors for pathologic fracture, such as degree of bone involvement, location, and the presence of lytic versus blastic disease, as well as the optimal management of such patients.^16-20 In those analyses, there is an emphasis on large, lytic lesions with cortical destruction in weight-bearing long bones, and on functional pain as a key determinant of fracture risk. Although the guidelines outlined by Mirel and others are helpful in predicting fractures, they are not widely applied by practicing oncologists.¹⁸ Oncologists and surgeons lack foolproof criteria to predict impending pathologic fracture despite evidence that the pathologic fracture event greatly increases mortality and morbidity.^1,4,21,22 As far as we know, this is the first study to determine which types of primary carcinomas were most associated with pathologic fracture requiring hospitalization. This finding will hopefully raise awareness among doctors who care for these patients to be particularly conscientious with patients who present with symptoms of bone pain with activity (functional bone pain) or with lytic disease in the long bones. The results of the present study are similar to those from cadaveric studies, which emphasize the importance of lung, breast, prostate, and kidney cancers as primary tumors that metastasize to bone and lead to pathologic fracture. A novel finding is the nearly 4-fold greater number of pathologic fractures from colorectal carcinoma than thyroid carcinoma.

The importance of detecting patients at risk for pathologic fracture is now more relevant than ever because there are treatment modalities that are readily available to patients with metastatic bone involvement. Two classes of medications, the RANK-ligand inhibitors and bisphosphonates, reduce the number of skeletal events, such as pathologic fracture, in patients with metastatic disease to bone.^23-26 However, most of those studies focused on the 3 most common carcinomas (breast, lung, and prostate) to metastasize to bone and cause pathologic fracture. There is greater variability in the prophylactic treatment of other forms of cancer that have metastasized to bone amongst oncologists.

Despite a lower proportion of hospitalizations for fracture in patients with CRC than for thyroid carcinoma (0.5% vs 1.6%, respectively), there were more pathologic fractures from CRC than from thyroid carcinoma because there are far more cases of CRC. SEER data estimate that in 2014 there were 62,000 cases of thyroid cancer and 1,890 deaths, compared with 136,000 cases of CRC and 50,000 deaths.¹⁰ Previous findings have shown that bone metastasis from CRC is more common than originally thought, based on autopsies of CRC patients.³ However, the lower rate of bone metastasis in CRC compared with other malignancies has led to a decreased focus on skeletal-related events in CRC. Our results suggest vigilance to bone health is warranted in patients with metastatic CRC. A novel finding is that patients with metastatic CRC also have a high number of hospital admissions for nonpathologic fracture. In establishing that patients with metastatic CRC with bone involvement have a real and significant risk of developing both pathologic and nonpathologic fractures, it may alter the treatment practice for these patients going forward, with greater consideration for an antiresorptive therapy, fall prevention education, or other preventive modalities, such as external-beam radiation therapy after it has been established that patients have metastatic bone disease.

There were some demographic differences between patients with metastatic disease who sustain pathologic fractures and those who do not fracture or sustain nonpathologic fractures. Patients with pathologic fracture were younger than those with nonpathologic fractures, and patients who sustained any fracture were more likely to be white than were patients in the no-fracture group. Known osteoporosis risk factors including older, female, and white with Northern European descent.²⁷ Those findings emphasize the importance of osteoporosis screening and fracture prevention in patients with metastatic disease in general, regardless of the presence of bony metastasis. The present study found that patients who reside in zip codes areas with higher incomes were at slightly increased risk of hospitalization for pathologic fracture. Economic disparities in access to health care and cancer care are well documented,²⁸ and the basis for this finding is a direction for future research.

Both mean billed costs and length of stay were greatest in the pathologic fracture group. The large number of admissions for no-fractured patients may be a final opportunity for intervention and preventative measures in this fragile population. Improved surveillance for bony lesions and attention to pain, especially at night, or unexplained hypercalcemia may help with early diagnosis and prevent some pathologic fractures. Patients with pathologic fracture often undergo additional treatments such as radiation therapy or chemotherapy. These additional treatments may partially explain the higher billed costs associated with inpatient hospitalization; future studies may be able to elucidate treatment differences or other reasons for the increased costs associated with pathologic fractures and identify targets to reduce expenditures.

Limitations

This study is subject to the limitations of a retrospective analysis based on hospital administrative discharge data. It evaluates only billed charges and does not account for costs associated with rehabilitation stays. However, it represents a stratified cross-sample of hospitalizations in the United States, in both teaching and nonteaching hospitals, and is the largest study to date that the authors are aware of looking at the burden of pathologic fractures in patients with metastatic disease.

This study specifically included only patients with metastatic disease, which therefore limits comparisons with the rate of hospitalization for nonpathologic fracture in patients without metastatic disease. Patients with metastatic disease who were not hospitalized during the study period are nevertheless at risk for fracture but would not have been captured in this study. It is also likely that some patients with metastatic disease had multiple hospitalizations, including some that were not for fracture; therefore, this study likely underestimates the percentage of patients with metastatic disease who sustain pathologic and nonpathologic fracture.

Some patients were excluded because we were not able to identify a primary cancer from hospital discharge records. The lack of an included diagnosis may be a result of indeterminate primary during the fracture admission or may represent a failure to accurately code a primary, known cancer. Although the NIS does not permit identification of these patients to determine if a primary cancer was subsequently identified, future studies using other databases may target patients presenting with pathologic fracture and an unknown primary tumor to evaluate subsequent cancer diagnosis.

Summary

The significance of bone metastasis in causing pathologic fractures in lung, breast, prostate, and kidney cancers was confirmed. Colorectal carcinoma has been established as the fifth most common primary cancer in patients with metastatic disease who are hospitalized with pathologic fracture, and a large number of patients with metastatic CRC sustain nonpathologic fractures requiring hospitalization. In patients with metastatic CRC or new skeletal pain, education on fall prevention and increased vigilance should be considered. Further studies are needed to determine the best method for prevention of pathologic fractures in all highly prevalent cancers, with previous hospitalizations without fracture as an appropriate target. Previous paradigms about which cancers metastasize to bone should be reconsidered in the context of which lead to clinically important fractures and hospitalization.

References

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2. Clain A. Secondary malignant disease of bone. Br J Cancer. 1965;19:15-29.

3. Coleman RE. Clinical features of metastatic bone disease and risk of skeletal morbidity. Clin Cancer Res. 2006;12(20 Pt 2):6243s-6249s.

4. Coleman RE. Skeletal complications of malignancy. Cancer. 1997;80(8 Suppl):1588-1594.

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6. Hess KR, Varadhachary GR, Taylor SH, et al. Metastatic patterns in adenocarcinoma. Cancer. 2006;106(7):1624-1633.

7. Stone CA, Lawlor PG, Savva GM, Bennett K, Kenny RA. Prospective study of falls and risk factors for falls in adults with advanced cancer. J Clin Oncol. 2012;30(17):2128-2133.

8. Coleman RE. Metastatic bone disease: clinical features, pathophysiology and treatment strategies. Cancer Treat Rev. 2001;27(3):165-176.

9. Katoh M, Unakami M, Hara M, Fukuchi S. Bone metastasis from colorectal cancer in autopsy cases. J Gastroenterol. 1995;30(5):615-618.

10. Howlader N NA, Krapcho M, Garshell J, Miller D, Altekruse SF, Kosary CL, Yu M, Ruhl J, Tatalovich Z,Mariotto A, Lewis DR, Chen HS, Feuer EJ, Cronin KA (eds). SEER Cancer Statistics Review, 1975-2011, National Cancer Institute. Bethesda, MD, http://seer.cancer.gov/csr/1975_2011/, based on November 2013 SEER data submission. Posted April 2014. Accessed January 19, 2018.

11. Hagiwara M, Delea TE, Saville MW, Chung K. Healthcare utilization and costs associated with skeletal-related events in prostate cancer patients with bone metastases. Prostate Cancer Prostatic Dis. 2013;16(1):23-27.

12. Hagiwara M, Delea TE, Chung K. Healthcare costs associated with skeletal-related events in breast cancer patients with bone metastases. J Med Econ. 2014;17(3):223-230.

13. Yong C, Onukwugha E, Mullins CD. Clinical and economic burden of bone metastasis and skeletal-related events in prostate cancer. Curr Opin Oncol. 2014;26(3):274-283.

14. HCUP Nationwide Inpatient Sample (NIS). Healthcare Cost and Utilization Project (HCUP). 2011. Agency for Healthcare Research and Quality R, MD. http://www.hcup-us.ahrq.gov/nisoverview.jsp. Last modified January 17, 2018. Accessed January 18, 2018.

15. American Cancer Society. Cancer Facts & Figures. Atlanta: American Cancer Society; 2003-2010. https://www.cancer.org/research/cancer-facts-statistics/all-cancer-facts-figures/cancer-facts-figures-2010.html Published January 2010. Accessed January 17, 2018.

16. Harrington KD. Orthopedic surgical management of skeletal complications of malignancy. Cancer. 1997;80(8 Suppl):1614-1627.

17. Harrington KD. Impending pathologic fractures from metastatic malignancy: evaluation and management. Instr Course Lect. 1986;35:357-381.

18. Mirels H. Metastatic disease in long bones. A proposed scoring system for diagnosing impending pathologic fractures. Clin Orthop Relat Res. 1989;249:256-264.

19. Weber KL. Evaluation of the adult patient (aged >40 years) with a destructive bone lesion. J Am Acad Orthop Surg. 2010;18(3):169-179.

20. Rougraff BT. Evaluation of the patient with carcinoma of unknown origin metastatic to bone. Clin Orthop Relat Res. 2003(415 Suppl):S105-109.

21. Coleman RE, Rubens RD. The clinical course of bone metastases from breast cancer. Br J Cancer. 1987;55(1):61-66.

22. Dijstra S, Wiggers T, van Geel BN, Boxma H. Impending and actual pathological fractures in patients with bone metastases of the long bones. A retrospective study of 233 surgically treated fractures. Eur J Surg. 1994;160(10):535-542.

23. Henry D, Vadhan-Raj S, Hirsh V, et al. Delaying skeletal-related events in a randomized phase 3 study of denosumab versus zoledronic acid in patients with advanced cancer: an analysis of data from patients with solid tumors. Support Care Cancer. 2014;22(3):679-687.

24. Lorusso V, Duran I, Garzon-Rodriguez C, et al. Health resource utilisation associated with skeletal-related events in European patients with lung cancer: Alpha subgroup analysis from a prospective multinational study. Mol Clin Oncol. 2014;2(5):701-708.

25. Lothgren M, Ribnicsek E, Schmidt L, et al. Cost per patient and potential budget implications of denosumab compared with zoledronic acid in adults with bone metastases from solid tumours who are at risk of skeletal-related events: an analysis for Austria, Sweden and Switzerland. Eu J Hosp Pharm Sci Pract. 2013;20(4):227-231.

26. Luftner D, Lorusso V, Duran I, et al. Health resource utilization associated with skeletal-related events in patients with advanced breast cancer: results from a prospective, multinational observational study. SpringerPlus. 2014;3:328.

27. Cauley JA. Defining ethnic and racial differences in osteoporosis and fragility fractures. Clin Orthop Relat Res. 2011;469(7):1891-1899.

28. VanEenwyk J, Campo JS, Ossiander EM. Socioeconomic and demographic disparities in treatment for carcinomas of the colon and rectum. Cancer. 2002;95(1):39-46.

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^aDepartment of Orthopaedic Surgery, Duke University Medical Center, Durham, North Carolina; ^bHospital for Special Surgery, New York; ^cDepartment of Orthopaedic Surgery, University of Rochester Medical Center, Rochester, New York; ^dDepartment of Orthopaedic Surgery, Emory University, Atlanta, Georgia; ^e Department of Orthopaedic Surgery, Columbia University Medical Center, New York; and ^fDepartment of Orthopaedic Surgery and Rehabilitation and Center for Orthopaedic Research and Translational Science, The Pennsylvania State University College of Medicine and Milton S Hershey Medical Center, Hershey, Pennsylvania

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Methods

Results

There were 17,303 hospitalizations with pathologic fracture and 12,770 hospitalizations with nonpathologic fracture (Figure 1).

$Figure. Pathologic and nonpathologic fractures by tumor type in patients hospitalized with metastatic cancer.$

Among the most commonly occurring primary cancers in hospitalizations with pathologic fracture were lung, breast, prostate, kidney, and colorectal cancers (Table 1).

$Table 1. Hospitalizations and fractures in patients with metastatic disease.$

$Table 2. Number and costs of pathologic fractures by site.$

$Table 3. Percentage of fractures at each site by primary malignancy.$

Discussion

Limitations

Summary

Methods

Results

There were 17,303 hospitalizations with pathologic fracture and 12,770 hospitalizations with nonpathologic fracture (Figure 1).

$Figure. Pathologic and nonpathologic fractures by tumor type in patients hospitalized with metastatic cancer.$

Among the most commonly occurring primary cancers in hospitalizations with pathologic fracture were lung, breast, prostate, kidney, and colorectal cancers (Table 1).

$Table 1. Hospitalizations and fractures in patients with metastatic disease.$

$Table 2. Number and costs of pathologic fractures by site.$

$Table 3. Percentage of fractures at each site by primary malignancy.$

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$Figure. Pathologic and nonpathologic fractures by tumor type in patients hospitalized with metastatic cancer.$

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Measurement of physical activity and sedentary behavior in breast cancer survivors

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Welch et al

Physical activity has numerous physical, mental, and psychosocial benefits for cancer survivors, such as a reduction in the risk of mobility disability, depression, and anxiety, and improved patient quality of life.^1,2 In addition, higher levels of physical activity are associated with reduced cancer-specific and all-causes mortality as well as cancer-specific outcomes including reduced risk of cancer progression and recurrence and new primary cancers.^3-5 However, fewer than one-third of cancer survivors are meeting government and cancer-specific recommendations of 150 minutes a week of moderate to vigorous physical activity (MPVA; ≥3 metabolic equivalents [METs]).^6,7 Growing evidence also demonstrates a significant association between higher levels of sedentary behavior and many deleterious health effects after cancer, including an increased risk for decreased physical functioning and development of other chronic diseases such as cardiovascular disease or diabetes.⁸ Distinct from physical activity, sedentary behavior is defined as any waking activity resulting in low levels of energy expenditure (≤1.5 METs) while in a seated or reclined position.⁹ Increased sedentary behavior, even when controlling for moderate and vigorous physical activity (MVPA), is associated with poor quality of life and increased all-cause mortality in cancer survivors.^10,11 Given the associations observed between higher levels of physical activity, lower levels of sedentary behavior, and improved health and disease outcomes among the large and increasing number of cancer survivors in the United States, it is important to identify low-cost methods that can be used in a in a variety of settings (ie, research, clinical, community) to accurately and efficiently measure survivors’ lifestyle behaviors to identify high-risk survivors for early intervention, better understand the effects of these behaviors on survivors’ health outcomes and disease trajectories, and ultimately, improve survivors’ health and quality of life.^12,13

Two methods commonly used to capture physical activity and sedentary behavior across the lifespan are accelerometry (Actigraph, Pensacola, FL) and self-report questionnaires such as the Godin Leisure-Time Questionnaire (GLTEQ), International Physical Activity Questionnaire (IPAQ), and Sitting Time Questionnaire (STQ).^14-17 Each method has unique strengths and weaknesses. Sending accelerometers to multiple individuals at a single time point can be costly, particularly in large-scale epidemiological studies, and the accelerometer’s waist-worn, nonwaterproof design may prevent researchers from capturing certain activities such as swimming and resistance training. However, the accelerometer provides objective, precise assessments of most physical activities and may help remove response bias.¹⁸ Conversely, self-report questionnaires rely solely on individuals’ memories and often result in recall bias, inaccurate reporting, and under- or overestimation of physical activity engagement.^19,20 Nevertheless, these questionnaires can be widely disseminated at low cost in a variety of settings (eg, clinical, research, community) and are less of a burden to participants.

Recent studies comparing objective (eg, accelerometer) with subjective (eg, self-report) methods of measuring physical activity and sedentary behavior in healthy middle-aged adults and older adults have demonstrated mixed findings with no distinct trends in the degree to which these methods differ.^19,21,22 To date, little consideration has been given to the measurement of these lifestyle behaviors in cancer survivors. Boyle and colleagues recently investigated the concurrent validity of an accelerometer to the GLTEQ in colon cancer survivors, finding significant differences in estimated MVPA (~11 minutes). However, no studies, to our knowledge, have compared accelerometer and self-report measures in breast cancer survivors, so it remains unclear how these different measurement tools relate to each another in this population.

It is particularly important to compare these measurement tools among breast cancer survivors because evidence indicates this population’s behavioral habits, self-perceived activity, and sitting time and movement patterns may differ significantly from the general population and other survivor groups across the lifespan.^23,24 Further, previous studies examining these behaviors in cancer survivors focused primarily on sitting time and MVPA.^15,25,26 Examining other lower-intensity intensities (eg, light activity or lifestyle) in cancer survivors may also be important given that increased levels of activity are associated with health benefits, ranging from reduced disability and fatigue to improved cardiovascular health and quality of life, and that breast cancer survivors engage in fewer of these activities compared with noncancer controls.²³ These lower levels of physical activity may be more prevalent among cancer survivors of their high levels of fatigue and propensity toward increased sitting time during the first year of treatment,¹¹ so it is important to be able to accurately assess these activities in this population. The purpose of the present study was to compare estimates of time spent in light physical activity (LPA), MVPA, and sitting time (ST) obtained from an accelerometer and 3 self-report measurement tools (GLTEQ, IPAQ, STQ) in a large, US-based sample of breast cancer survivors. A secondary purpose was to determine whether estimate comparisons among measurements changed by participant characteristics.

Methods

Participants and procedures

This study consisted of a subsample of women who participated in a larger study whose findings have been reported elsewhere by Phillips and McAuley.²⁷ In that study, breast cancer survivors (n = 1,631) were recruited nationally to participate in a 6-month prospective study on quality of life. Eligibility criteria included being aged 18 years or older, having had a diagnosis of breast cancer, being English speaking, and having access to the internet. Once consented to participate in the study, 500 women were randomly selected to wear the accelerometer.

Participants in this group were mailed an accelerometer, an activity log, instructions for use, and a self-addressed stamped envelope to return the monitor. They were asked to wear the accelerometer during all waking hours for 7 consecutive days of usual activity. They were also sent a secure link to complete 3 activity questionnaires online. The questionnaires were to be completed by the end of the 7-day monitoring period. Only women with 3 or more valid days of accelerometer data and complete data on variables of interest (n = 414) were included in the present analyses. All of the participants consented to the study procedures approved by the University of Illinois Institutional Review Board.

Measures

Demographics. The participants self-reported their age, level of education, height, and weight. Their body mass index (BMI; kg/m²) was estimated using the standard equation. They also self-reported their health and cancer history, detailing breast cancer disease stage, time since diagnosis, treatment type, and whether they had had a cancer recurrence. They were also asked to report whether they had ever been diagnosed (Yes/No) with 18 chronic conditions (eg, diabetes, arthritis).

Godin Leisure-Time Exercise Questionnaire.¹⁶ The GLTEQ assessed participants’ weekly frequency and mean amount of time performing MVPA (moderate exercise, such as fast walking, combined with vigorous exercise, such as jogging), and LPA (light/mild exercise, eg, easy walking) during the previous 7 days. The mean daily duration (in minutes) for each intensity category (MVPA, LPA) was calculated using activity frequencies and the amount of time spent in each activity presented as minutes/day.

The International Physical Activity Questionnaire.¹⁴ The IPAQ evaluated participants’ physical activity of at least moderate intensity in 4 domains of everyday life: job-related physical activity, transportation, housework/caring for family, and leisure-time activity. Within each domain, participants were asked the number of days per week and time per day (hours and minutes) spent performing MVPA. To estimate sitting time, the questionnaire asks participants to report the total amount of time spent sitting per day in 2 conditions, during weekdays and during weekends. The present analysis averaged sitting time for a typical 7-day (5 week days, 2 weekend days) period. We multiplied reported minutes per day and frequency per week of each activity category (MVPA and ST) to calculate the mean number of minutes per day.^29,30

Sitting Time Questionnaire.^17,28 The STQ estimated the mean time (hours and minutes) participants spent sitting each day on weekdays and at weekends within 5 domains: while traveling to and from places, at work, watching television, using a computer at home, and at leisure, not including watching television (eg, visiting friends, movies, dining out). Mean minutes per day of ST were calculated using all sitting domains.

Actigraph accelerometer (model GT1M, Health One Technology, Fort Walton Beach, FL). The Actigraph GT1M is a reliable and objective measure of physical activity.^31-33 Participants wore the monitor on the right hip for 7 consecutive days during all waking hours, except when bathing or swimming. Activity data was analyzed in 1-minute intervals. A valid day of accelerometer wear time was defined as ≥600 minutes with no more than 60 minutes of consecutive zero-values, with allowance of 2 minutes or fewer of observations <100 counts/minute within the nonwear interval.³⁴ Each minute of wear time was classified according to intensity (counts/min) using the following cut-points:³⁴ sedentary, <100 counts/min; LPA, 100-2,019 counts/min; and MVPA, ≥2,020 count/min. Mean daily durations (min/day) spent in each behavior were estimated by dividing the number of minutes in each category by the number of valid days.

Statistical analysis

All statistical analyses were completed in SPSS Statistics 23 (IBM, Chicago, IL). Descriptive statistics were used to define participant characteristics. Rank-order correlation between the methods was assessed using Spearman’s rho (r_s) and results were interpreted as follows: r_s = 0.10, small; 0.30, moderate; and 0.50, strong.³⁵ Within each activity intensity group, we jointly modeled daily minutes of self-report and accelerometer data using a random-intercept mixed-effects regression model. Differences between measurement tools were assessed based on regression coefficients with accelerometer as the reference category. Finally, we did a post hoc analysis of leisure-time–only MVPA from the IPAQ to compare with other estimates of MVPA.

We calculated the measurement tool difference scores for each estimated intensity category (ST, LPA, MVPA), that is, accelerometer estimated ST minus STQ estimated ST, and GLTEQ estimated MVPA minus IPAQ estimated MVPA. We used these data in an exploratory analysis to examine whether there were statistically significant differences between measurement difference scores by demographic or disease characteristics using linear regression stratified analyses. For example, we were interested in whether there was a significant difference in measurement tool estimates for sitting time in older compared with younger survivors. Analyses were stratified by age (<60/≥60 years), body mass index (<25 kg/m²/≥25 kg/m²), race (white/people of color), disease stage (I and II/III and IV), years since diagnosis (≤5 years/>5 years), recurrence (Yes/No), received chemotherapy (Yes/No ), received radiation (Yes/No ), and the presence of 1 or more chronic diseases (Yes/No ).

Results

Participants

The mean age of the participants was 56.8 years [9.2], they were overweight (BMI, 26.2 kg/m² [5.4]), and predominantly white (96.7%; Table 1). Table 2 provides a summary of mean daily duration of activity estimates for ST, LPA, and MVPA and the estimate mean difference scores between measurements.

Table 2. Mean daily duration by measurement tool.

Also shown are the results of the stratified analyses to investigate whether congruence among the questionnaires and accelerometer measures were different based on participant characteristics for physical activity (Table 3) and ST (Table 4) estimates.

Table 3. Mean difference scores of physical activity minutes

Table 4. Mean difference score of sedentary time

Moderate and vigorous physical activity

Accelerometer−GLTEQ. The mean difference in MVPA estimates between the accelerometer and GLTEQ was less than 5 minutes (M_{accelerometer}= 20.2 minutes; M_GLTEQ= 23.6 minutes), even though the difference was statistically significant (P = .02). Estimates of MVPA from the accelerometer and GLTEQ (r_s = 0.564, P < .001) showed a strong relationship. Stratified analyses showed that the difference scores between the GLTEQ and accelerometer were lower for older survivors (≥60 years) compared with younger survivors such that older survivors reported significantly less time in MVPA on the GLTEQ compared with accelerometer estimates (difference score [D] = 6.8 minutes less, P = .001).

Accelerometer−IPAQ. The accelerometer estimated significantly fewer minutes of MVPA per day when compared with the IPAQ (M_diff= -67.4; 95% confidence interval [CI], -78.6, -55.8; P < .001). Estimates of MVPA from the accelerometer and IPAQ (r_s = 0.011, P = .680) were poorly related. Differences between the IPAQ and accelerometer were greater for later-stage breast cancer, compared with early-stage diagnoses such that participants with late-stage disease reported significantly less MVPA on the IPAQ compared with accelerometer estimates (D = 41.8 minutes less than early-stage disease, P = .018). Finally, participants of color reported a greater difference in MVPA between the accelerometer and the IPAQ than did their white counterparts (D = 47.5 minutes, P = .033).

GLTEQ−IPAQ. GLTEQ estimated significantly fewer minutes of MVPA per day compared with the IPAQ (M_diff= -64.6; 95% CI, -76.6, -52.5; P < .001). The estimates of MVPA from the GLTEQ had a small correlation with IPAQ estimates (r_s = 0.128, P = .011).

IPAQ estimates showed almost triple the MVPA minutes per day as were estimated by the accelerometer and GLTEQ. As the MVPA estimate for the IPAQ include nonleisure activities, we conducted a post hoc analyses that only included the leisure-time items from the IPAQ. Leisure-time only IPAQ items, estimates indicated survivors spent a mean 18.5 [SD, 14.2] min/day in MVPA. Although the magnitude of the difference between the accelerometer and GLTEQ estimates (~10 minutes) was much smaller using the leisure-time only IPAQ items, a repeated measures analysis of variance revealed there was still a significant difference between these estimates (P < .05 for both) and negligible correlation.

Light intensity physical activity

Accelerometer−GLTEQ. There was a large and significant difference between LPA estimates from the GLTEQ and accelerometer (M_diff= 224.5; 95% CI, 218.2, 230.7; P < .001) with estimates from the accelerometer being higher than those for the GLTEQ. Additionally, the measurements showed a negligible correlation (r_s = 0.004, P = .94). Difference scores for GLTEQ and accelerometer estimated LPA were significantly different by age, with survivors aged 60 years or older demonstrating a difference that was 18.3 minutes shorter (P = .005) than the difference in younger survivors (<60 years).

Sitting time

Accelerometer−IPAQ. Mean IPAQ estimates were significantly lower (M = 303.8 [63.4]) than accelerometer estimates (M = 603.9 [78.0]). Rank-order correlations between IPAQ and accelerometer estimated ST was small (r_s =0.26, P < .001). Difference scores between IPAQ and accelerometer estimates were significantly greater for survivors who were 60 years or older, compared with those younger than 60 years (D = 47.6 minutes, P = .006), indicating that older survivors tended to self-report significantly more ST than estimated by the accelerometer.

Accelerometer−STQ. There was no significant difference in estimated mean ST minutes per day between the STQ and the accelerometer, but the correlation between estimates was low (r_s = 0.30, P < .001). Stratified analyses revealed estimates for the difference scores for mean daily ST between the STQ and accelerometer were greater for participants who were diagnosed with later-stage breast cancer (D= -158.3 minutes, P < .001) and those who had received chemotherapy (D= -61.7 minutes, P = .028; Table 2) than for those who were diagnosed with early-stage breast cancer or had not received chemotherapy. Women who had later-stage disease reported significantly less ST than did women diagnosed with early-stage disease, when compared with estimates by the accelerometer.

IPAQ−STQ. The estimated mean ST was significantly lower for IPAQ (M = 303.8 minutes [163.4]) than for the STQ (M = 605.2 minutes [296.2]). There were no significant estimate differences among the stratified groups.

Discussion

The purpose of the present study was to compare 4 measurement tools, an accelerometer-based activity monitor and 3 self-report questionnaires, to estimate ST, LPA, and MVPA in breast cancer survivors. Developing and evaluating accurate and precise measurement tools to assess physical activity and ST in breast cancer survivors remains a critical step toward better understanding the role of physical activity in cancer survivorship. Our results indicate that the congruency of the measurement tools examined was highly dependent on the activity intensity of interest and participants’ demographic or disease characteristics. Overall, the accelerometer estimated a greater amount of time spent sitting and engaging in LPA and less time in MVPA than was estimated on the STQ, GLTEQ, and IPAQ. In addition, our findings suggest significant subgroup differences that will be important in future development and implementation of physical activity measurement for breast cancer survivors.

MVPA has been the most commonly measured activity intensity among cancer survivors to date.^15,25,26 The present results indicate mean daily MVPA estimates were significantly higher for the GLTEQ compared with the accelerometer (M_diff = 2.8 min/d, P = .019), although the magnitude of these differences was relatively small. This difference is lower than in another study that compared these measures in colon cancer survivors and found the GLTEQ over-estimated MVPA by 10.6 min/day compared with the accelerometer (P < .01).¹⁵ However, the correlation between the 2 tools in our study was similar to that of Boyle and colleagues (r_s = 0.56 and r_s = 0.51, respectively). A possible explanation for the equivocal findings across these studies may lie in the difference in study sample demographics; a previous study results finding breast cancer survivors may be better at recalling their physical activities because they may be more attentive to activities they perform daily.²⁶

The IPAQ significantly estimated more than an hour more of MVPA minutes per day compared with the accelerometer and GLTEQ. There are a number of limitations to the reporting of MVPA on the IPAQ. These limitations have been previously reported in the literature and include cross-cultural differences as well as overreporting of nonleisure-time MVPA (eg, occupational or household activities). However, the IPAQ has consistently been shown to be a valid and reliable tool for physical activity surveillance in different populations across the world.^29,36,37 This shows that although MVPA was overestimated in our population, we do not mean to undermine the IPAQ value in other populations in which it has shown great utility for overall physical activity surveillance. When we excluded nonleisure-time MVPA, MVPA equated to about 18 min/day, which was closer in magnitude to the GLTEQ and accelerometer. These data highlight the importance of identifying the specific activity parameters of interest when selecting a measurement tool to ensure congruency between the tool and construct of interest.

The differences in MVPA estimation from the 3 tools have significant translational consequences, notably the potential for misclassification of meeting physical activity guidelines. For example, the percentage of women in the present sample that met physical activity guidelines ranged from 0% (using the accelerometer) to 19.5% (using the IPAQ), depending on the measurement tool used. These findings have meaningful implications for future physical activity assessment because multiple measurement tools are currently being used to estimate physical activity in breast cancer survivors and would provide useful information regarding how breast cancer survivors report their physical activity time.

For example, scores from the IPAQ may result in a survivor being classified as meeting physical activity guidelines when in fact they are not, and thereby missing the opportunity for intervention; or the accelerometer may classify an active survivor as inactive, which could result in using time and resources for a behavior change intervention that is not necessary. The clinical significance of these findings is to provide providers with data-based information on the strengths and limitations of the measurement tools so that they can accurately estimate physical activity and ST and appropriately optimize resources and treatments.

The degree of measurement tool congruence is likely influenced by a number of factors. First, survivors’ perceptions of the intensity of their activity are relative and subjective to their state of feeling during the activity. For example, breast cancer survivors with lower functional capacity may perceive activities with lower absolute intensity as having a higher relative intensity (ie, they think they are working at a moderate intensity so record an activity as such, but the activity is classified as light by the accelerometer). Second, although our self-report measures asked survivors to record the time they had spent active over the previous 7 days, survivors might report on what they consider a “usual” week, which may reflect the ideal rather than the reality. Third, the accelerometer cut-points used were derived from young, healthy adults on a treadmill. Thus, generalization to an older, sick, less active population that could be experiencing treatment-related side effects could lead to underestimation of time spent in MVPA. To better understand measurement congruency in breast cancer survivors, future research should investigate how functional capacity and activity intensity perceptions are influenced by a breast cancer diagnosis and how those factors may influence subjective and objective physical activity measurement. If those factors were found to have significant influence on activity in breast cancer survivors, it would warrant future development of breast-cancer–specific accelerometer reduction techniques.

The comparison of LPA presented another interesting significant contrast between self-report (GLTEQ) and accelerometry. Results indicated the GLTEQ underestimated LPA by 224.5 [3.2] min/day compared with the accelerometer. This equates to over 3.5 h/day of active time (or about 280 kcal/day) that was potentially unaccounted for by the GLTEQ. The difference between these estimates could be due to the fact that the GLTEQ was designed to measure exercise time and therefore may not be as sensitive as the accelerometer to nonexercise-related LPA. Light intensity activities typically span a large range of domains (ie, occupational, leisure time, household) and tend to occur in higher volumes than MVPA, which may lead to some challenges with recall. Expanding existing LPA questionnaires to encompass these domains would likely provide increased congruency between self-reported and accelerometer-derived estimates for LPA, as it may provide a better trigger for recalling these high volume activities. With increasing literature advocating the important role of LPA in adults’ health in concert with data suggesting survivors may engage in lower levels of LPA than healthy controls,²³, accurately accounting for these lower intensity activities to provide a “whole picture” of a survivor’s active day remains an important future research direction. Combining accelerometer and self-report data using ecological momentary assessment to capture these behaviors in real-time in the real world could provide a better understanding of the context in which LPA occurs as well as survivors’ perceptions of intensity to build more accurate and scalable measurement tools for LPA.

Our ST results indicate nonsignificant difference estimates from the accelerometer and the STQ (M_diff = 1.3 [15.3] min/day) with slightly higher estimates for the STQ versus accelerometer. This finding is consistent with the one other study that has examined these relationships in cancer survivors.¹⁵ However, our findings also indicate the IPAQ significantly underestimated ST compared with the accelerometer and the STQ by about half (Table 1). These differences may be because both the STQ and Marshall questionnaire used in the previous study measure multiple domains of sitting (ie, computer, television, travel) on both weekdays and weekends whereas the IPAQ uses only two recall items of overall sitting time (for weekday and weekend separately). The domain-specific, structured approach has been shown to improve recall and may help to prevent underestimation and general underreporting of the high volume, ubiquitous behavior of sitting.^17,38 Finally, we would be remiss to not acknowledge the known limitations to estimating ST using the count-based approach on the waist-worn accelerometer. Due to the monitor’s orientation at the hip, the accelerometer may misrepresent total ST by misclassifying standing still as sitting. However, Kozey-Keadle and colleagues have previously examined estimation of ST using waist-worn accelerometers and have shown the 100 count per minute cut off yields ST estimates within 5% range of accuracy for a seated position compared with direct observation.³⁹

Of further interest are our exploratory results indicating that age and disease stage may modify the congruency between activity and ST measures. Specifically, older survivors and those with more advanced disease stage generally reported more PA and less ST than were measured by the accelerometer. These differences raise the question of whether these subgroups are systematically reporting more time physically active, overestimating their intensity, or the accelerometer is misclassifying their activity intensity. These misclassifications could be due to their age, disease stage, fatigue status, functional status, cognitive function, occupational status, etc. and would be important next steps for exploration of measurement of physical activity in breast cancer survivors. Finally, the difference score for MVPA was greater for survivors of color than for white survivors, with survivors of color overreporting MVPA compared with accelerometer-derived estimates. This may be due in part to cultural differences between white survivors and survivors of color. Previous research has suggested that people of color may accumulate a majority of their activity in occupational or household-related domains, thus explaining lower levels of leisure-time MVPA but high levels of reported total MVPA from other nonleisure domains.²⁰ However, given the small number of survivors of color in the present study, these results should be interpreted with caution.

With the multitude of physical activity and ST measurement tools available, many factors including cost, sample size, primary outcome of interest, and activity characteristics of interest (eg, duration, intensity, energy expenditure) need to be considered⁴⁰ when choosing a tool. Our findings may help inform these decisions for breast cancer survivors. For example, if LPA is of interest, an accelerometer may provide a more comprehensive assessment of these activities than the GLTEQ. In contrast, if MVPA is the activity of interest, our results suggest the GLTEQ and accelerometer were more congruent than the IPAQ was with either measure, therefore, if budgetary constraints are a concern, the more cost-efficient GLTEQ could provide similar results to an accelerometer. In addition to considering measurement congruency, it is also critically important to carefully consider the population (breast cancer survivors) and subsequent burden that accompanies the measurement tool of choice. Overall, our results indicate, when choosing a questionnaire for ST or LPA for breast cancer survivors, the more comprehensive the questions, to encompass multiple domains or time of day, the greater amount of time that will be captured within that activity category. Conversely, since the majority of MVPA is completed in leisure-time, dependent on the age and race of the population, a shorter questionnaire may be sufficient. Additionally, dependent on time since diagnosis and treatment received, activity recall or body movement patterns may be affected which could influence measurement tool selection.^23,24 Finally, it is also important to consider the setting in which measurement is taking place. In busy clinical settings, shorter, self-report measures may have a greater chance of being implemented than accelerometers or longer self-report measures and would still provide useful information regarding an overall snapshot of survivors’ MVPA or ST that could be used to initiate a conversation or referral for a program to help survivors positively change one or both of these behaviors.

Limitations

There were a few limitations within the current study that should be taken into account. First, the accelerometer cut-points used were developed with healthy, young adults; therefore using different cut-points may have yielded different results.³⁴ Given the large age range in our participants (23-84 years), we believe the use of these cut-points was justified, in lieu of population-specific (ie, older adults) cut-points. In addition, limitations to estimating activity from an accelerometer include the inability to capture certain activities such as swimming and cycling and the aforementioned inability to distinguish between body postures (ie, sitting vs standing).⁴¹ The participants were predominantly white, highly educated, and high earners (85.2% earned ≥$40,000 per year), therefore, the present results may not be generalizable to survivors from more diverse backgrounds. However, as far as we know, this is the first study to report the congruency of estimated ST, LPA, and MVPA across multiple measurement tools in a nationwide sample of breast cancer survivors who were heterogeneous in terms of disease characteristics (ie, stage, treatment, time since diagnosis).

Conclusions

Our findings suggest that physical activity and ST estimates in breast cancer survivors may be dependent on the measurement tool used. In addition, congruency of measurement tools was dependent on activity intensity of interest, and participant age, race, and disease history may also influence these factors. Therefore, researchers should consider the intended outcomes of interest, the context in which the tool is being used (ie, clinical versus research), the available resources, and the participant population before they select a measurement tool for estimating physical activity and sitting time in breast cancer survivors.

Acknowledgment
This work was supported by grant #F31AG034025 from the National Institute on Aging (Dr Phillips); Shahid and Ann Carlson Khan endowed professorship and grant #AG020118 from the National Institute on Aging (Dr McAuley). Dr Phillips is supported by the National Cancer Institute #K07CA196840, and Dr Welch is supported by National Institute of Health/National Cancer Institute training grant CA193193. All data for this study were collected at the University of Illinois Urbana Champaign.

References

1. Speck RM, Courneya KS, Masse LC, Duval S, Schmitz KH. An update of controlled physical activity trials in cancer survivors: a systematic review and meta-analysis. J Cancer Surviv. 2010;4(2):87-100.

2. Brenner DR. Cancer incidence due to excess body weight and leisure-time physical inactivity in Canada: implications for prevention. Prev Med. 2014;66:131-139.

3. Courneya KS, Friedenreich CM. Relationship between exercise pattern across the cancer experience and current quality of life in colorectal cancer survivors. J Altern Complement Med. 1997;3(3):215-226.

4. Ibrahim EM, Al-Homaidh A. Physical activity and survival after breast cancer diagnosis: meta-analysis of published studies. Med Oncol. 2011;28(3):753-765.

5. Lahart IM, Metsios GS, Nevill AM, Carmichael AR. Physical activity, risk of death and recurrence in breast cancer survivors: a systematic review and meta-analysis of epidemiological studies. Acta Oncol. 2015;54(5):635-654.

6. Irwin ML, McTiernan A, Bernstein L, et al. Physical activity levels among breast cancer survivors. Med Sci Sports Exerc. 2004;36(9):1484-1491.

7. Schmitz KH, Courneya KS, Matthews C, et al. American College of Sports Medicine roundtable on exercise guidelines for cancer survivors. Med Sci Sports Exerc. 2010;42(7):1409-1426.

8. Lynch BM. Sedentary behavior and cancer: a systematic review of the literature and proposed biological mechanisms. Cancer Epidemiol Biomarkers Prev. 2010;19(11):2691-2709.

9. Owen N, Healy GN, Matthews CE, Dunstan DW. Too much sitting: the population health science of sedentary behavior. Exerc Sport Sci Rev. 2010;38(3):105-113.

10. Campbell PT, Patel AV, Newton CC, Jacobs EJ, Gapstur SM. Associations of recreational physical activity and leisure time spent sitting with colorectal cancer survival. J Clin Oncol. 2013;31(7):876-885.

11. Lynch BM, Dunstan DW, Vallance JK, Owen N. Don’t take cancer sitting down: a new survivorship research agenda. Cancer. 2013;119(11):1928-1935.

12. Bluethmann SM, Mariotto AB, Rowland JH. Anticipating the ‘silver tsunami:’ prevalence trajectories and comorbidity burden among older cancer survivors in the United States. Cancer Epidemiol Biomarkers Prev. 2016;25(7):1029-1036.

13. Miller KD, Siegel RL, Lin CC, et al. Cancer treatment and survivorship statistics, 2016. CA Cancer J Clin. 2016;66(4):271-289.

14. Booth M. Assessment of physical activity: an international perspective. Res Q Exerc Sport. 2000;71(2 suppl):S114-120.

15. Boyle T, Lynch BM, Courneya KS, Vallance JK. Agreement between accelerometer-assessed and self-reported physical activity and sedentary time in colon cancer survivors. Support Care Cancer. 2015;23(4):1121-1126.

16. Godin G, Shephard RJ. A simple method to assess exercise behavior in the community. Canadian journal of applied sport sciences. Can J Appl Sport Sci. 1985;10(3):141-146.

17. Marshall AL, Miller YD, Burton NW, Brown WJ. Measuring total and domain-specific sitting: a study of reliability and validity. Med Sci Sports Exerc. 2010;42(6):1094-1102.

18. Matthews CE, Hagstromer M, Pober DM, Bowles HR. Best practices for using physical activity monitors in population-based research. Med Sci Sports Exerc. 2012;44(1 Suppl 1):S68-76.

19. Prince SA, Adamo KB, Hamel ME, Hardt J, Connor Gorber S, Tremblay M. A comparison of direct versus self-report measures for assessing physical activity in adults: a systematic review. Int J Behav Nutr Phys Act. 2008;5:56.

20. Sallis JF, Saelens BE. Assessment of physical activity by self-report: status, limitations, and future directions. Res Q Exerc Sport. 2000;71(2 Suppl):S1-14.

21. Hart TL, Swartz AM, Cashin SE, Strath SJ. How many days of monitoring predict physical activity and sedentary behaviour in older adults? Int J Behav Nutr Phys Act. 2011;8:62.

22. Hart TL, Ainsworth BE, Tudor-Locke C. Objective and subjective measures of sedentary behavior and physical activity. Med Sci Sports Exerc. 2011;43(3):449-456.

23. Phillips SM, Dodd KW, Steeves J, McClain J, Alfano CM, McAuley E. Physical activity and sedentary behavior in breast cancer survivors: new insight into activity patterns and potential intervention targets. Gynecol Oncol. 2015;138(2):398-404.

24. Boyle T, Vallance JK, Ransom EK, Lynch BM. How sedentary and physically active are breast cancer survivors, and which population subgroups have higher or lower levels of these behaviors? Support Care Cancer. 2016;24(5):2181-2190.

25. Broderick JM, Guinan E, Kennedy MJ, et al. Feasibility and efficacy of a supervised exercise intervention in de-conditioned cancer survivors during the early survivorship phase: the PEACH trial. J Cancer Surviv. 2013;7(4):551-562.

26. Su CC, Lee KD, Yeh CH, Kao CC, Lin CC. Measurement of physical activity in cancer survivors: a validity study. J Cancer Surviv. 2014;8(2):205-212.

27. Phillips SM, McAuley E. Social cognitive influences on physical activity participation in long-term breast cancer survivors. Psychooncology. 2013;22(4):783-791.

28. Wojcicki TR, White SM, McAuley E. Assessing outcome expectations in older adults: the multidimensional outcome expectations for exercise scale. J Gerontol B Psychol Sci Soc Sci. 2009;64(1):33-40.

29. Craig CL, Marshall AL, Sjostrom M, et al. International physical activity questionnaire: 12-country reliability and validity. Med Sci Sports Exerc. 2003;35(8):1381-1395.

30. Ainsworth BE, Haskell WL, Whitt MC, et al. Compendium of physical activities: an update of activity codes and MET intensities. Med Sci Sports Exerc. 2000;32(9 Suppl):S498-504.

31. Hacker ED, Ferrans CE. Ecological momentary assessment of fatigue in patients receiving intensive cancer therapy. J Pain Symptom Manage. 2007;33(3):267-275.

32. Swartz AM, Strath SJ, Bassett DR, Jr, O’Brien WL, King GA, Ainsworth BE. Estimation of energy expenditure using CSA accelerometers at hip and wrist sites. Med Sci Sports Exerc. 2000;32(9 Suppl):S450-456.

33. Jim HS, Small B, Faul LA, Franzen J, Apte S, Jacobsen PB. Fatigue, depression, sleep, and activity during chemotherapy: daily and intraday variation and relationships among symptom changes. Ann Behav Med. 2011;42(3):321-333.

34. Troiano RP, Berrigan D, Dodd KW, Masse LC, Tilert T, McDowell M. Physical activity in the United States measured by accelerometer. Med Sci Sports Exerc. 2008;40(1):181-188.

35. Cohen J. Statistical power analysis for the behavioral sciences. 2nd ed. Hillsdale, NJ: L Erlbaum Associates; 1988.

36. Bauman A, Ainsworth BE, Bull F, et al. Progress and pitfalls in the use of the International Physical Activity Questionnaire (IPAQ) for adult physical activity surveillance. J Phys Act Health. 2009;6 Suppl 1:S5-8.

37. Hagströmer M1, Oja P, Sjöström M. The International Physical Activity Questionnaire (IPAQ): a study of concurrent and construct validity. Public Health Nutr. 2006;9(6):755-762.

38. Johnson-Kozlow M, Sallis JF, Gilpin EA, Rock CL, Pierce JP. Comparative validation of the IPAQ and the 7-Day PAR among women diagnosed with breast cancer. Int J Behav Nutr Phys Act. 2006;3:7.

39. Kozey-Keadle S, Libertine A, Lyden K, Staudenmayer J, Freedson PS. Validation of wearable monitors for assessing sedentary behavior. Med Sci Sports Exerc. 2011;43(8):1561-1567.

40. Strath SJ, Kaminsky LA, Ainsworth BE, et al. Guide to the assessment of physical activity: clinical and research applications. Circulation. 2013;128(20):2259-2279.

41. Bassett DR. Device-based monitoring in physical activity and public health research. Physiol Meas. 2012;33(11):1769-1783.

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^aDepartment of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois; and ^bDepartment of Kinesiology and Community Health, University of Illinois at Urbana-Champaign, Urbana, Illinois

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Methods

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Moderate and vigorous physical activity

Light intensity physical activity

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Abemaciclib becomes first CDK inhibitor to clinch single-agent approval for breast cancer

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The fall 2017 approval by the US Food and Drug Administration (FDA) of abemaciclib made it the third cyclin-dependent kinase (CDK) inhibitor approved for the treatment of hormone receptor (HR)-positive breast cancer, and the first to receive an approved indication as monotherapy in that setting. Abemaciclib is a small-molecule inhibitor of the CDK4 and CDK6 proteins, which are key gatekeepers of the cell cycle and frequently dysregulated in HR-positive breast cancer. On the basis of the randomized, placebo-controlled, multicenter phase 3 MONARCH-2 trial, it was approved in combination with fulvestrant for the treatment of women with HR-positive, HER2-negative advanced or metastatic breast cancer who had progressed during endocrine therapy.¹

A total of 669 women aged 18 years and older, with any menopausal status, an Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1, measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST, version 1.1) or nonmeasurable bone-only disease, were enrolled. Patients had progressed during neoadjuvant or adjuvant endocrine therapy, within 12 months of adjuvant endocrine therapy, or during frontline endocrine treatment for metastatic disease.

Those who had received more than 1 endocrine therapy or any prior chemotherapy for metastatic breast cancer or prior treatment with everolimus or CDK4/6 inhibitors, as well as those with the presence of visceral crisis or evidence or history of central nervous system (CNS) metastases, were excluded from the study.

Patients were randomized 2:1 to receive 150 mg abemaciclib or placebo, both in combination with 500 mg fulvestrant. The initial dose of abemaciclib was 200 mg, but this was amended to 150mg after enrollment of the first 178 patients to alleviate diarrhea-related toxicity concerns. Randomization was stratified according to metastatic site (visceral, bone only, or other) and endocrine therapy resistance (primary or secondary).

Tumors were measured by computed tomography (CT) and magnetic-resonance imaging (MRI) according to RECIST-1.1 within 28 days before random assignment, every 8 weeks for the first year, every 12 weeks thereafter, and then within 2 weeks of clinical progression. Bone scintigraphy was also performed at baseline and then every 6th cycle starting with cycle 7. Hematologic and blood chemistry laboratory tests were performed centrally on days 1 and 15 of the first cycle and day 1 of all remaining cycles.

The primary endpoint was progression-free survival (PFS); median PFS was 16.4 months in the abemaciclib arm, compared with 9.3 months in the placebo arm in the intent-to-treat population (hazard ratio [HR], 0.553;P < .0000001), translating to a 45% reduction in the risk of disease progression or death with the combination. Objective response rate in the 2 groups among patients with measurable disease was 48.1% and 21.3%, respectively, which included a complete response rate of 3.5% in the abemaciclib arm. The median duration of response was not yet reached in the study group, compared with 25.6 months for placebo. Overall survival data were not yet mature.

The agency also approved abemaciclib as monotherapy for women and men with HR-positive, HER2-negative advanced or metastatic breast cancer with disease progression following endocrine therapy and prior chemotherapy in the metastatic setting. That approval was based on data from the single-arm MONARCH-1 trial of 132 patients who received 200 mg abemaciclib twice daily on a continuous schedule.²

Patients had adequate organ function, measurable disease per RECIST-1.1, and an ECOG performance status of 0 or 1. Patients must have progressed on or after previous endocrine therapy and have received prior treatment with at least 2 chemotherapy regimens, at least 1 of them, but no more than 2, having been administered in the metastatic setting. Exclusion criteria included prior receipt of a CDK inhibitor, major surgery within 14 days of the start of the study, and CNS metastases.

Tumor assessments were performed by CT or MRI according to RECIST-1.1 within the 4 weeks prior to the first dose of study drug and then subsequently at every other cycle. Responses were confirmed at least 4 weeks after the initial observation. The overall response rate was 19.7%, made up completely of partial responses. Median duration of response was 8.6 months, median PFS was 6 months and median OS was 17.7 months.

Adverse events

The most common adverse events experienced with the combination of abemaciclib and fulvestrant were neutropenia (23.6%) and diarrhea (13.4%). The rate of grade 4 neutropenia was higher in the combination arm (2.9% vs 0.4%) and there were 3 deaths with the combination that were linked to treatment-related AEs. In the monotherapy trial, abemaciclib treatment most commonly caused diarrhea (90.2%), fatigue (65.2%), nausea (64.4%), decreased appetite (45.5%), and abdominal pain (38.6%). Grade 3 diarrhea and fatigue occurred in 19.7% and 12.9% of patients, respectively. Serious AEs occurred in 24.2% of patients and AEs led to treatment discontinuation in 7.6% of patients.

Warnings and precautions

Abemaciclib is marketed as Verzenio by Eli Lilly and Company. Warnings and precautions relating to diarrhea, neutropenia, hepatotoxicity, venous thromboembolism (VTE), and embryofetal toxicity are detailed in the prescribing information. In the event of diarrhea, patients should be treated with antidiarrheal therapy and should increase oral fluids and notify their health care provider. Treatment should be interrupted for grade 3 or 4 diarrhea and then resumed at a lower dose upon return to grade 1.

To guard against neutropenia, complete blood counts should be performed prior to starting therapy, every 2 weeks for the first 2 months, monthly for the subsequent 2 months, and then as clinically indicated. Treatment should be interrupted or delayed or the dose reduced for grade 3 or 4 neutropenia and patients should report episodes of fever.

Liver function tests should be performed before starting abemaciclib, every 2 weeks for the first 2 months, monthly for the next 2 months, and then as clinically indicated. For patients who develop persistent or recurrent grade 2, 3 or 4 hepatic transaminase elevation, dose interruption, reduction, discontinuation, or delay should be considered.

Patients should be monitored for signs and symptoms of VTE and pulmonary embolism, and treated appropriately. Pregnant women should be advised of the potential risk to a fetus, and those of reproductive potential should be counselled on the importance of using effective contraception during treatment and for at least 3 weeks after the last dose.³

References

1. Sledge Jr GW, Toi M, Neven P, et al. MONARCH 2: Abemaciclib in combination with fulvestrant in women with HR+/HER2- advanced breast cancer who had progressed while receiving endocrine therapy. J Clin Oncol. 2017;35(25):2875-2884.
2. Dickler MN, Tolaney SM, Rugo HS, et al. MONARCH 1, a phase 2 study of abemaciclib, a CDK4 and CDK6 inhibitor, as a single agent, in patients with refractory HR+/HER2- metastatic breast cancer. Clin Cancer Res. http://clincancerres.aacrjournals.org/content/early/2017/05/20/1078-0432.CCR-17-0754. Published online first on May 22, 2017. Accessed January 19, 2018.
3. Verzenio (abemaciclib) tablets, for oral use. Prescribing information. Eli Lilly and Co. http://uspl.lilly.com/verzenio/verzenio.html#pi. September 2017. Accessed November 20, 2017.

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Adverse events

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Checkpoint inhibitors forge new treatment paradigm for metastatic bladder cancer

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Last spring, the US Food and Drug Administration (FDA) granted accelerated approval to 3 different immune checkpoint inhibitors for the treatment of patients with metastatic urothelial carcinoma in the second-line setting, bringing the total number of approved members of this drug class for this indication to 5.

Avelumab and durvalumab, like atezolizumab, are monoclonal antibodies that target the programmed cell death protein ligand-1 (PD-L1) and prevent it from binding to and activating the programmed cell death protein-1 (PD-1) and CD80 receptors, which transmit inhibitory signals into T cells. In this way, it is hypothesized that their use reactivates the anti-tumor immune response conducted by tumor-infiltrating T cells. Both drugs were approved for the treatment of patients with locally advanced or metastatic urothelial carcinoma who are refractory to platinum-based chemotherapy, and the approvals provide additional treatment options for this group of patients who typically have poor prognosis.^1,2

Avelumab trial findings

The approval of avelumab was based on the urothelial cancer cohorts of the JAVELIN Solid Tumor trial, a phase 1, open-label, dose-escalation study.³ Patients aged 18 years and older, with an Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1 (range, 0-5; 0, fully active, and 5, dead), life expectancy of at least 3 months, and cytologically or histologically confirmed metastatic or locally advanced solid tumors were eligible.

Patients were excluded from the study if they had a history of or active central nervous system metastases, had other malignancies within the previous 5 years, had undergone organ transplant, had conditions requiring immune suppression, had active HIV or hepatitis B or C infection, or had autoimmune diseases other than type 1 diabetes, vitiligo, psoriasis, or thyroid disease that does not require immunosuppressive treatment.

Patients were also required to have adequate end organ function (white blood cell count, ≥3 x 10⁹ cells/L; absolute neutrophil count, ≥1.5 x 10⁹ cells/L; lymphocyte count, ≥0.5 x 10⁹ cells/L; platelet count, ≥100 x 10⁹ platelets/L; hemoglobin, ≥9 g/dL; total bilirubin concentration, ≤1.5 x upper limit of normal [ULN] range; aspartate- and alanine- aminotransferase (ALT/AST) concentrations, ≤2.5 x ULN); and estimated creatinine clearance, >50 mL/min.

A total of 242 patients were treated with a 10 mg/kg intravenous dose of avelumab every 2 weeks until disease progression or unacceptable toxicity. Before avelumab infusion, all patients received premedication with an antihistamine and acetaminophen.

The primary endpoint was objective response rate (ORR), which was 13.3% among 226 patients followed for at least 13 weeks, including 4% complete response (CR) rate, and 16.1% among 161 patients followed for at least 6 months, including 5.6% CR rate. The median time to response was 2 months and the median response duration had not been reached at the time of data cut-off. PD-L1 expression was evaluable in 84% of patients and there was no discernable variation in the response rates according to the levels of PD-L1 expression on the tumor.

The most common adverse events (AEs) that occurred in at least 20% of patients included fatigue, infusion-related reaction, musculoskeletal pain, nausea, decreased appetite, and urinary tract infection (UTI). Serious AEs occurred in 41% of patients and most commonly involved UTI, abdominal pain, musculoskeletal pain, creatinine increase/renal failure, dehydration, hematuria, intestinal obstruction, and pyrexia. Deaths owing to AEs occurred in 6% of patients and were related to pneumonitis, respiratory failure, sepsis/urosepsis, cerebrovascular accident, or gastrointestinal AEs.

Durvalumab approval

The agency’s approval of durvalumab rested on the results of an ongoing single-arm phase 1/2 trial (Study 1108).⁴ Eligibility criteria were the same as for the avelumab study. Patients were ineligible for the trial if they had received any immunotherapy within the previous 4 weeks, any monoclonal antibody within the previous 6 weeks, or had received concurrent chemotherapy, immunotherapy, biologic, or hormonal therapy.

Durvalumab was administered as an intravenous infusion at a dose of 10 mg/kg every 2 weeks, for up to 12 months or until disease progression or unacceptable toxicity. PD-L1 expression was evaluated by immunohistochemistry in tumor tissue obtained before treatment using the Ventana PD-L1 (SP263) assay (Ventana Medical Systems), which was approved by the FDA alongside durvalumab as a companion diagnostic. The first 20 patients were enrolled regardless of their PD-L1 expression, and the subsequent 43 patients were required to have PD-L1 expression of at least 5% of their tumor cells, but that requirement was removed at an interim analysis when objective responses occurred in patients with a PD-L1 expression of lessthan 5%.

In the most up-to-date analysis, published after FDA approval, a total of 191 patients had been treated. The ORR as assessed by blinded independent central review per RECIST-1.1, was 17.8%, including 7 CRs (3.7%). In patients with high PD-L1 expression, the ORR was 27.6%, compared with 5.1% in those with low or no PD-L1 expression. Responses were observed across all subgroups, including patients with a poor prognosis. The ORRs in patients with visceral and liver metastases were 15.3% and 7.3%, respectively. The median time to response was 1.41 months, and the median duration of response had not yet been reached.

The most common AEs experienced by patients treated with durvalumab included fatigue, musculoskeletal pain, constipation, decreased appetite, nausea, peripheral edema, and UTI. Serious treatment-related AEs occurred in 4.7% of patients, and treatment-related AEs leading to death occurred in 2 patients owing to autoimmune hepatitis and pneumonitis.

Toxicities and warnings for both therapies

Avelumab is marketed as Bavencio by EMD Serono, and durvalumab as Imfinzi by AstraZeneca. According to the prescribing information for both drugs, the recommended dose is 10 mg/kg administered as an intravenous infusion over 60 minutes every 2 weeks.^5,6

Both drugs are associated with serious or potentially life-threatening toxicities for which warnings and precautions are detailed in the prescribing information, predominantly for immune-mediated toxicities such as pneumonitis, hepatitis, colitis, nephritis, and endocrinpathy. Patients should be monitored for signs and symptoms of these toxicities and managed appropriately. Avelumab and durvalumab should both be withheld for grade 2 or higher pneumonitis, hepatitis, colitis, severe or life-threatening adrenal insufficiency, thyroid disorders or hyperglycemia, and moderate or severe nephritis or renal dysfunction.

These drugs should be permanently discontinued in the event of life-threatening or recurrent AEs. Immune-mediated pneumonitis, colitis, and hepatitis and adrenal insufficiency can be managed with corticosteroids; hypothyroidism, with hormone-replacement therapy; and hyperglycemia, with hyperglycemics or insulin.

To manage infusion-related reactions, patients should be premedicated with antihistamines and acetaminophen before the first 4 infusions and closely monitored for symptoms such as pyrexia, chills, flushing, hypotension, and dyspnea. Infusion can be interrupted or slowed for mild to moderate infusion-related reactions, but should be stopped and the drug discontinued for severe or life-threatening reactions.

Durvalumab is also associated with a risk of infection and patients should be monitored for signs and symptoms of infection and treated with anti-infectives. Durvalumab should be withheld for grade 3 infections. Patients being treated with durvalumab or avelumab should also be warned of the potential for embryofetal toxicity and advised to take appropriate precautions.

References

1. United States Food and Drug Administration. FDA grants accelerated approval to avelumab for urothelial carcinoma. US FDA Web site. https://www.fda.gov/drugs/informationondrugs/approveddrugs/ucm557162.htm. Last updated May 9, 2017. Accessed September 15, 2017.
2. United States Food and Drug Administration. Durvalumab (Imfinzi). US FDA Web site. https://www.fda.gov/drugs/informationondrugs/approveddrugs/ucm555930.htm. Last updated May 1, 2017. Accessed September 15, 2017
3. Heery CR, O’Sullivan-Coyne G, Madan RA, Cordes L, et al. Avelumab for metastatic or locally advanced previously treated solid tumors (JAVELIN Solid Tumos): a phase 1a, multicohort, dose-escalation trial. Lancet Oncol. 2017;18(5):587-598.
4. Powles T, O’Donnell PH, Massard C, Arkenau H-T, et al. Efficacy and safety of durvalumab in locally advanced or metastatic urothelial carcinoma. Updated results from a phase 1/2 open-label study. JAMA Oncol. 2017;3(8):e172411.
5. Bavencio (avelumab) injection, for intravenous use. Prescribing information. EMD Serono Inc. https://www.bavencio.com/en_US/document/Prescribing-Information.pdf. Revised October 2017. Accessed September 18th, 2017.
6. Imfinzi (durvalumab) injection, for intravenous use. Prescribing information. AstraZeneca Pharmaceuticals. https://www.azpicentral.com/imfinzi/imfinzi.pdf#page=1. Revised May 2017. Accessed September 18, 2017.

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Avelumab trial findings

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Toxicities and warnings for both therapies

Avelumab trial findings

Durvalumab approval

Toxicities and warnings for both therapies

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Concurrent ipilimumab and CMV colitis refractory to oral steroids

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Perry et al

Immune checkpoint inhibitors, including anti-cytotoxic T-lymphocyte antigen 4 (anti-CTLA4) and anti-programmed cell death protein-1 (anti-PD-1) antibodies, have demonstrated clinical and survival benefits in a variety of malignancies, which has led to an expansion in their role in oncology. In melanoma, the anti-CTLA-4 antibody, ipilimumab, has demonstrated a survival benefit in patients with advanced metastatic melanoma and in patients with resectable disease with lymph node involvement.^1,2

Ipilimumab exerts its effect by binding CTLA-4 on conventional and regulatory T cells, thus blocking inhibitory signals on T cells, which leads to an antitumor response.³ The increased immune response counteracts the immune-evading mechanisms of the tumor. With increased use of these agents, immune-related adverse events (irAEs) have become more prevalent. The most common irAEs secondary to ipilimumab are skin rash, colitis/diarrhea, hepatitis, pneumonitis, and various endocrinopathies.⁴ In a phase 3 trial of adjuvant ipilimumab in patients with resected stage III melanoma, grade 3 or 4 adverse events occurred in 54.1% of participants in the ipilimumab arm, the most common being diarrhea and colitis (9.8% and 6.8%, respectively).²Recognition and management of irAEs has led to the implementation of treatment guidelines.^4,5 Management of irAEs includes checkpoint inhibitor discontinuation and reversal of the immune response by institution of immunosuppression with corticosteroids. Here we present the case of a patient with stage IIIB, BRAF V600E-positive melanoma, who developed colitis refractory to standard therapy after treatment with ipilimumab and whose clinical course was complicated by cytomegalovirus (CMV) reactivation and bowel perforation.

Case presentation and summary

A 40-year-old white woman with stage IIIB BRAF V600E-positive melanoma presented with diarrhea refractory to high-dose prednisone (1 mg/kg BID). She had recently undergone wide local excision and sentinel node biopsy and received her inaugural dose of ipilimumab (10 mg/kg).

The patient first presented with loose, watery stools that had begun 8 days after she had received her first dose of adjuvant ipilimumab. She was admitted to the hospital, and intravenous methylprednisolone was initiated along with empiric ciprofloxacin (400 mg, IVPB Q12h) and metronidazole (500 mg, IVPB Q8h) as infectious causes were concurrently ruled out. During this initial admission, the patient’s stool was negative for Clostridium difficile toxin, ova, and parasites, as well as enteric pathogens by culture. After infectious causes were excluded, she was diagnosed with ipilimumab-induced colitis. Antibiotics were discontinued, and the patient ultimately noted improvement in her symptoms. On hospital day 7, she was experiencing only 2 bowel movements a day and was discharged on 80 mg of prednisone twice daily.

After discharge the patient noted persistence of her symptoms. At her follow-up, 9 days after discharge, the patient noted continued symptoms of low-grade diarrhea. She failed a trial of steroid tapering due to exacerbation of her abdominal pain and frequency of diarrhea. Further investigation was negative for C. diff toxin and a computed-tomography scan was consistent with continuing colitis. The patient’s symptoms continued to worsen, with recurrence of grade 3 diarrhea, and she was ultimately readmitted 17 days after her earlier discharge (36 days after her first ipilimumab dosing).

On re-admission, the patient was again given intravenous methylprednisolone and experienced interval improvement in the frequency of diarrhea. A gastroenterology expert was consulted, and the patient underwent a flexible sigmoidoscopy that demonstrated findings of diffuse and severe inflammation and biopsies were obtained (Figure 1). After several days of continued symptoms, the patient received infliximab 5 mg/kg for treatment of her adverse autoimmune reaction. After administration, the patient noted improvement in the frequency and volume of diarrhea, however, her symptoms still persisted.

Figure 1. Image from sigmoidoscopy showing severe infl<?AID 001f?>ammation by its edematous, erythematous, friable, and granulation tissue.

Biopsy results subsequently revealed findings compatible with ipilimumab-induced colitis, and immunohistochemical staining demonstrated positivity for cytomegalovirus (CMV). Specifically, histologic examination showed lymphoplasmacytic expansion of the lamina propria, some architectural distortion, and increased crypt apoptosis. Scattered cryptitis and crypt abscesses were also noted, as were rare stromal and endothelial cells with characteristic CMV inclusions (Figure 2 and Figure 3).

Figure 2. Image A, Lymphoplasmacytic expansion of the lamina propria with mild architectural disarray. Image B, Increased intraepithelial lymphocytes and prominently increased crypt apoptosis.

Figure 3. Image A, Focal crypt abscess and stromal cells with characteristic viral cytopathic effect. Image B, Immunohistochemical stain for cytomegalovirus.

Serum CMV polymerase chain reaction (PCR) was also positive at 652,000 IU/mL (lower limit of detection 100 IU/mL). Induction dosing of ganciclovir (5 mg/kg IV Q12h) was initiated. The combined treatment with intravenous methylprednisone and ganciclovir led to an improvement in diarrhea frequency and resolution of blood in the stool. She was transitioned to oral prednisone, but it resulted in redevelopment of grade 3 diarrhea. The patient was therefore resumed on and discharged on daily intravenous methylprednisolone.

After discharge, the patient was started on budesonide 9 mg daily. Her serum CMV PCR level reduced and she was transitioned to oral valgancyclovir (900 mg daily) for maintenance. Another unsuccessful attempt was made to switch her to oral prednisone.

About 14 weeks after the initial ipilimumab dosing, the patient underwent another flexible sigmoidoscopy that again demonstrated severe colitis from the rectum to sigmoid colon. Biopsies were negative for CMV. Patient was readmitted for recurrence of diarrhea the following week. Treatment with IV methylprednisone (1mg/kg BID) and infliximab (5 mg/kg) again led to an improvement of symptoms. She was again discharged on IV methylprednisone (1 mg/kg BID) with a taper.

In the 15th week after her initial ipilimumab dose, the patient presented with a perforated bowel, requiring a subtotal colectomy and end ileostomy. She continued on a slow taper of oral prednisone (50 mg daily and decrease by 10 mg every 5 days).

At her last documented follow-up, 8 months after her first ipilimumab dose, she was having normal output from her ileostomy. She developed secondary adrenal insufficiency because of the long-term steroids and continued to take prednisone 5 mg daily.

Discussion

Diarrhea and colitis are common irAEs attributable to checkpoint-inhibitor therapy used for the treatment of melanoma. This case of ipilimumab-induced colitis refractory to high-dose oral steroids demonstrates the risks associated with management of anti-CTLA-4 induced colitis. In particular, the high-dose corticosteroids required to treat the autoimmune component of this patient’s colitis increased her susceptibility to CMV reactivation.

The diagnosis of colitis secondary to ipilimumab is made primarily in the appropriate clinical setting, and typically onsets during the induction period (within 12 weeks of initial dosing) and most resolve within 6-8 weeks.⁶ Histopathologically, there is lymphoplasmacytic expansion of lamina propria, increased intraepithelial lymphocytes, and increased epithelial apoptosis of crypts. One can also see acute cryptitis and crypt abscesses. Reactive epithelial changes with mucin depletion are also often seen in epithelial cells.

Findings from immunohistochemical studies have shown the increased intraepithelial lymphocytes to be predominantly CD8-positive T cells, while the lamina propria contains an increase in the mixture of CD4- and CD8-positive T cells. In addition, small intestinal samples show villous blunting. There is an absence of significant architectural distortion and well-developed basal lymphoplasmacytic infiltrates characteristic of chronic mucosal injury, such as idiopathic inflammatory bowel disease.⁷ Granulomas are also absent in most series, though they have been reported in some cases.⁸ The features are similar to those seen in autoimmune enteropathy, but goblet and endocrine cells remain preserved. Graft-versus-host disease has similar histologic features, however, the clinical setting usually makes the distinction between these obvious.

Current treatment algorithms for ipilimumab-related diarrhea, begin with immediate treatment with intravenous methylprednisolone (125 mg once). This is followed with oral prednisone at a dose of 1-2 mg/kg tapered over 4 to 8 weeks.⁴ In patients with persistent symptoms despite adequate doses of corticosteroids, infliximab (5 mg/kg every 2 weeks) is recommended until the resolution of symptoms, and a longer taper of prednisone is often necessary.

Institution of high-dose corticosteroids to treat grade 3 or 4 irAEs can increase the risk for infection, including opportunistic infections. One retrospective review of patients administered checkpoint inhibitors at a single institution revealed that 7.3% of 740 patients developed a severe infection that lead to hospitalization or treatment with intravenous antibiotics.⁹ In that patient cohort, only 0.6% had a serious infection secondary to a viral etiology, and 1 patient developed CMV enterocolitis. Most patients who developed an infection in this cohort had received corticosteroids (46/54 patients, 85%) and/or infliximab (13/54 patients, 24%).⁹

CMV is a member of the Herpesviridae family. After a primary infection, which can often go unrecognized in an immunocompetent host, CMV can persist in a latent state.¹⁰ In a study by Bate and colleagues, the age-adjusted seropositivity of CMV was found to be 50.4%.¹¹ Based on those results, immunosuppression in a patient who has previously been infected with CMV can lead to a risk of reactivation or even reinfection. In the era of checkpoint-inhibitor therapy, reactivation of CMV has been described previously in a case of CMV hepatitis and a report of CMV colitis.^12,13 Immunosuppression, such as that caused by corticosteroids, is a risk factor for CMV infection.¹⁴ Colitis caused by CMV usually presents with abdominal pain, diarrhea, and bloody diarrhea.¹⁵ In suspected cases of CMV colitis, endoscopy should be pursued with biopsy for tissue examination. A tissue diagnosis is required for CMV colitis because serum PCR can be negative in isolated cases of gastrointestinal CMV infection.¹⁵

Conclusion

Despite appropriate treatment with ganciclovir and the noted response in the patient’s serum CMV PCR, symptom exacerbation was observed with the transition to oral prednisone. The requirement for intravenous corticosteroids in the present case demonstrates the prolonged effects exerted by irAEs secondary to checkpoint-inhibitor therapy. Those effects are attributable to the design of the antibody – ipilimumab is a fully humanized monoclonal antibody and has a plasma half-life of about 15 days.^1,4

By the identification of CMV histopathologically, this case, along with the case presented by Lankes and colleagues,¹³ illustrates the importance of considering CMV colitis in patients who are being treated with ipilimumab and who develop persistent or worsening diarrhea after initial treatment with high-dose steroids.

Early recognition of possible coexistent CMV colitis in patients with a history of treatment with ipilimumab can have important clinical consequences. It can lead to quicker implementation of proper antiviral therapy and minimization of immune suppression to levels required to maintain control of the patient’s symptoms.

References

1. Hodi FS, O’Day SJ, McDermott DF, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010;363(8):711-723.

2. Eggermont AM, Chiarion-Sileni V, Grob JJ, et al. Prolonged survival in stage III melanoma with ipilimumab adjuvant therapy. N Engl J Med. 2016;375(19):1845-1855.

3. Glassman PM, Balthasar JP. Mechanistic considerations for the use of monoclonal antibodies for cancer therapy. Cancer Biol Med. 2014;11(1):20-33.

4. Weber JS, Kahler KC, Hauschild A. Management of immune-related adverse events and kinetics of response with ipilimumab. J Clin Oncol. 2012;30(21):2691-2697.

5. Fecher LA, Agarwala SS, Hodi FS, Weber JS. Ipilimumab and its toxicities: a multidisciplinary approach. Oncologist. 2013;18(6):733-743.

6. Weber JS, Dummer R, de Pril V, Lebbe C, Hodi FS, Investigators MDX. Patterns of onset and resolution of immune-related adverse events of special interest with ipilimumab: detailed safety analysis from a phase 3 trial in patients with advanced melanoma. Cancer. 2013;119(9):1675-1682.

7. Oble DA, Mino-Kenudson M, Goldsmith J, et al. Alpha-CTLA-4 mAb-associated panenteritis: a histologic and immunohistochemical analysis. Am J Surg Pathol. 2008;32(8):1130-1137.

8. Beck KE, Blansfield JA, Tran KQ, et al. Enterocolitis in patients with cancer after antibody blockade of cytotoxic T-lymphocyte-associated antigen 4. J Clin Oncol. 2006;24(15):2283-2289.

9. Del Castillo M, Romero FA, Arguello E, Kyi C, Postow MA, Redelman-Sidi G. The spectrum of serious infections among patients receiving immune checkpoint blockade for the treatment of melanoma. Clin Infect Dis. 2016;63(11):1490-1493.

10. Pillet S, Pozzetto B, Roblin X. Cytomegalovirus and ulcerative colitis: place of antiviral therapy. World J Gastroenterol. 2016;22(6):2030-2045.

11. Bate SL, Dollard SC, Cannon MJ. Cytomegalovirus seroprevalence in the United States: the national health and nutrition examination surveys, 1988-2004. Clin Infect Dis. 2010;50(11):1439-1447.

12. Uslu U, Agaimy A, Hundorfean G, Harrer T, Schuler G, Heinzerling L. autoimmune colitis and subsequent CMV-induced hepatitis after treatment with ipilimumab. J Immunother. 2015;38(5):212-215.

13. Lankes K, Hundorfean G, Harrer T, et al. Anti-TNF-refractory colitis after checkpoint inhibitor therapy: possible role of CMV-mediated immunopathogenesis. Oncoimmunology. 2016;5(6):e1128611.

14. Ko JH, Peck KR, Lee WJ, et al. Clinical presentation and risk factors for cytomegalovirus colitis in immunocompetent adult patients. Clin Infect Dis. 2015;60(6):e20-26.

15. You DM, Johnson MD. Cytomegalovirus infection and the gastrointestinal tract. Curr Gastroenterol Rep. 2012;14(4):334-342.

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Worldwide, head and neck cancers account for more than half a million cases annually and nearly 400,000 deaths.¹ Although the exact incidence of metastatic disease of these primarily squamous cell tumors is difficult to determine, the incidence is thought to be much lower than that of other solid tumors.² When the different sites of metastatic disease of these tumors have been studied previously, the most common have been (in descending order of frequency) the lungs, bones, liver, skin, mediastinum, and bone marrow.^2,3 It is extremely rare area for head and neck squamous cell cancers to metastasize to the retroperitoneum. To our knowledge, only 2 other such cases have been reported in the literature.^4,5 In those two cases, the metastatic recurrence occurred at 6 and 13 months after definitive treatment of the primary cancer.

Case presentation and summary

The patient in this case is a 60-year-old man with a history of stage IV moderately differentiated invasive squamous cell carcinoma (p16 negative, Bcl-2 negative, EGFR positive) of the hypopharynx that had been initially diagnosed in 2012. At that time, he underwent a total laryngectomy, partial pharyngectomy, and total thyroidectomy. A 2-centimeter mediastinal mass was also identified on a computed-tomography scan of the thorax and resected during the initial curative surgery. Final surgical pathology on the primary hypopharygeal tumor revealed a 4.1-cm moderately differentiated squamous cell carcinoma with negative margins, but positive lymphovascular invasion (Figure 1). The 2-cm mediastinal mass also revealed the same squamous cell carcinoma as the hypopharyngeal primary. Final surgical margins were negative.

Figure 1. The original SCC, showing invasive hypopharyngeal squamous cell carcinoma (H&E stain, 400x).

The patient went on to receive adjuvant treatment in the form of concurrent chemoradiation with cisplatin (100 mg/m² every 21 days for 3 doses, with 70 Gy of radiation]. After his initial treatment, he was followed closely by a multidisciplinary team, including otolaryngology, radiation oncology, and medical oncology specialists. He underwent a positron-emission tomography–CT scan 1 year after the conclusion of adjuvant therapy that showed no evidence of local or distant disease. The patient underwent 12 fiberoptic pharyngoscopy procedures over the course of 4 years without any evidence of local disease recurrence. He underwent a CT scan of the neck in October of 2016 without any evidence of local disease recurrence.

In early 2017, the patient presented with fatigue, abdominal pain, and back pain during the previous month. CT imaging revealed a left retroperitoneal mass of 8.8 x 4.0 x 6.6 cm, with bony destruction of L3-L4 causing left hydronephrosis (Figure 2 and Figure 3). Other staging work-up and imaging did not reveal any other distant disease or locoregional disease recurrence in the head and neck. Lab work was significant for an acute kidney injury that was likely secondary to mass effect from the tumor.

Figure 2. A CT scan, transverse view, showing a large left retroperitoneal mass of 8.8 x 4.0 x 6.6 cm.

Figure 3. A CT scan, coronal view, shows the left retroperitoneal mass, with mass effect on adjacent structure.

The mass was biopsied, with pathology revealing squamous cell carcinoma consistent with metastatic, recurrent disease from the previously known head and neck primary, and it was also p16 negative, Bcl-2 negative, and EGFR positive (Figure 4).

Figure 4. Metastatic recurrent SCC from the retroperitoneal mass (H&E stain, 200x).

After a multidisciplinary discussion it was determined that the best front-line treatment option would be to treat with definitive concurrent chemoradiation. However, due to the size and location of the mass, it was not possible to deliver an effective therapeutic dose of radiation without unacceptable toxicity to the adjacent structures. Therefore, palliative systemic therapy was the only option. These treatment options, including systemic chemotherapy and immunotherapy, were discussed with the patient. However, he did not want to pursue any further cancer treatment and wanted instead to focus on palliation (pain control, antiemetics and nephrostomy to relieve obstruction) and hospice. He passed away 3 months later.

Discussion

Masses of the retroperitoneum have a wide differential diagnosis.⁶ Primary malignancies including lymphomas, sarcomas, neurogenic tumors, and germ cell tumors may all present primarily as retroperitoneal masses.^6,7 Nonmalignant processes such as retroperitoneal fibrosis may also present in this manner.⁷ Certain tumors are known to metastasize to the retroperitoneum, namely carcinomas of the gastrointestinal tract and ovary as well as lung cancer or melanoma.^5,8 Some primary retroperitoneal masses in women have been described in the literature as being HPV-associated squamous cell cancers of unknown primaries.⁹

When head and neck cancers metastasize they typically metastasize to the lungs, bone, liver, mediastinum, skin, and bone marrow. Most metastasis is pulmonary in origin, with the literature indicating it accounts for 52%-66% of head and neck cancer metastases, with bone metastases next in frequency at 12%-22%.^2,3,10 In general, the incidence of distant metastatic disease in head and neck cancers is not as common as its other solid tumor counterparts, and even metastasis to other lymph node groups other than locoregional cervical nodes is rare.¹¹ Furthermore, late metastasis occurring more than 2 years after definitive treatment is also an infrequent occurrence.¹²

When discussing distant metastatic disease in head and neck cancer, previous literature has described an increasing likelihood of distant metastases when there is locoregional disease recurrence.¹³ Moreover, the retroperitoneum is an exceedingly rare site of distant metastatic disease for head and neck cancer. There have been only 2 previous cases that have described this phenomenon, and in both cases the metastases occurred within or close to 1 year of definitive locoregional treatment.^4,5

Conclusion

We present our case to present an exceedingly rare case of distant metastatic, recurrent disease from head and neck cancer to the retroperitoneum (without locoregional recurrence) that occurred 4 years after definitive treatment. We believe this to be the first case of its kind to be described when taking into consideration the site of metastases, when the metastatic recurrence occurred and that it happened without loco-regional disease recurrence. This case highlights the importance of keeping a wide differential diagnosis when encountering a retroperitoneal mass in a patient with even a remote history of head and neck cancer.

Acknowledgments

The authors thank the following members of the Department of Pathology at the University of Texas Medical Branch: Asad Ahmad, MD; Eduardo Eyzaguirre, MD; Timothy C Allen, MD, JD, FACP; and Suimmin Qiu, MD, PHD.

References

1. Fitzmaurice C, Allen C, Barber RM, et al. Global, regional, and national cancer incidence, mortality, years of life lost, years lived with disability, and disability-adjusted life-years for 32 cancer groups, 1990 to 2015: a systematic analysis for the Global Burden of Disease Study. JAMA Oncol. 2017;3:524-548.

2. Ferlito A, Shaha AR, Silver CE, Rinaldo A, Mondin V. Incidence and sites of distant metastases from head and neck cancer. ORL J Otorhinolaryngol Relat Spec. 2001;63:202-207.

3. Wiegand S, Zimmermann A, Wilhelm T, Werner JA. Survival after distant metastasis in head and neck cancer. Anticancer Res. 2015;35:5499-5502.

4. Hofmann U, O’Connor JP, Biyani CS, Harnden P, Selby P, Weston PM. Retroperitoneal metastatic squamous cell carcinoma of the tonsil (with elevated beta human chorionic gonadotrophin): a misdiagnosis as extra-gonadal germ cell tumour. J Laryngol Otol. 2006;120:885-887.

5. Purkayastha A, Sharma N, Suhag V. Extremely rare and unusual case of retroperitoneal and pelvic metastasis from squamous cell carcinoma of vallecula. Int J Cancer Ther Oncol. 2016;4(2):1-4.

6. Rajiah P, Sinha R, Cuevas C, Dubinsky TJ, Bush WH, Kolokythas O. Imaging of uncommon retroperitoneal masses. Radiographics 2011;31:949-976.

7. Scali EP, Chandler TM, Heffernan EJ, Coyle J, Harris AC, Chang SD. Primary retroperitoneal masses: what is the differential diagnosis? Abdom Imaging. 2015;40:1887-1903.

8. Levy AD, Shaw JC, Sobin LH. Secondary tumors and tumorlike lesions of the peritoneal cavity: imaging features with pathologic correlation. Radiographics. 2009;29:347-373.

9. Isbell A, Fields EC. Three cases of women with HPV-related squamous cell carcinoma of unknown primary in the pelvis and retroperitoneum: a case series. Gynecol Oncol Rep. 2016;16:5-8.

10. León X, Quer M, Orús C, del Prado Venegas M, López M. Distant metastases in head and neck cancer patients who achieved loco-regional control. Head Neck. 2000;22:680-686.

11. Alavi S, Namazie A, Sercarz JA, Wang MB, Blackwell KE. Distant lymphatic metastasis from head and neck cancer. Ann Otol Rhinol Laryngol. 1999;108:860-863.

12. Krishnatry R, Gupta T, Murthy V, et al. Factors predicting ‘time to distant metastasis’ in radically treated head and neck cancer. Indian J Cancer. 2014;51:231-235.

13. Goodwin WJ. Distant metastases from oropharyngeal cancer. ORL J Otorhinolaryngol Relat Spec. 2001;63:222-223.

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Balancing quality and cost of care with patient well-being

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Welcome to the first issue of The Journal of Community and Supportive Oncology for this year. 2017 was a rollercoaster year for the oncology community, literally from day 1. January 1 saw the kick-off for participation in the MACRA [Medicare Access and CHIP Reauthorization Act] Quality Payment Program, and soon after came the growing concern and uncertainty around the future of President Barack Obama’s Affordable Health Care Act. Attempts during the year to repeal the ACA failed, but with the December passage of the tax bill came Medicare cuts and the repeal of the individual mandate, which will effectively sever crucial revenue sources for the ACA. Nevertheless, against that backdrop, there was a slew of exciting therapeutic approvals – some of them landmark, as my fellow Editor, Linda Bosserman, noted in her year-end editorial (JCSO 2017;15[6]:e283-e290). As often happens, and as noted in the editorial, such advances come with concerns about the high cost of the therapies and their related toxicities, and the combined negative impact of those on quality and cost of care and patient quality of life. (QoL).

In this issue, 2 research articles examine bone metastasis in late-stage disease and their findings underscore the aforementioned importance of care cost and quality and patient QoL. Bone metastases are a common cause of pain in patients with advanced cancer. That pain is often associated with higher rates of depression, anxiety, and fatigue, and patient QoL will diminish if the pain is not adequately treated. Although radiotherapy is effective in palliating painful bone metastases, relief may be delayed and interim analgesic management needed. Garcia and colleagues (p. e8) examined the frequency of analgesic regimen assessment and intervention during radiation oncology consultations for bone metastases and evaluated the impact on analgesic management before and after implementation of a dedicated palliative radiation oncology service. They found that pain assessment and intervention were not common in the radiation oncology setting before establishment of the service and suggest that integrating palliative care within radiation oncology could improve the quality of pain management and by extension, patient well-being.

Patients with bone metastases are also at greater risk of bone fracture, for which they often are hospitalized at great cost. Nikkel and colleagues sought to determine the primary tumors in patients hospitalized with metastatic disease and who sustained pathologic and nonpathologic fractures, and to estimate the costs and lengths of stay for those hospitalizations (p. e14). The most common primary cancers in these patients were lung, breast, prostate, kidney, and colorectal – a novel finding in this study was that there were almost 4 times as many pathologic fractures from colorectal than from thyroid carcinoma. Patients hospitalized for pathologic fracture had higher billed costs and longer length of stay. The authors emphasize the importance of identifying patients at risk for pathological fracture based on primary tumor type, age, and socio-economic group; improving surveillance; and doing timely osteoporosis screening.

Therapeutic advances and the ensuing new options and combination possibilities are the substrate for our daily engagement with our patients. On page e53, Dr David Henry, the JCSO Editor-in-Chief, talks with Dr Kenneth Anderson of Harvard Medical School about advances in multiple myeloma therapies and how numerous therapy approvals have pushed the disease closer to becoming a manageable, chronic disease. On page e47, Jane de Lartigue describes the latest developments in the therapeutic targeting of altered metabolic pathways in cancer cells.

Also in this issue are new approval updates for abemaciclib as the first CDK inhibitor for breast cancer (p. e2) and the checkpoint inhibitors avelumab and durvalumab for metastatic bladder cancer (p. e5), a brief report on whether patient navigators’ personal experience with cancer has any effect on patient experience (p. e43), a research article on physical activity and sedentary behavior in survivors of breast cancer, and Case Reports (pp. e30-e42).

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