ORIGINAL ARTICLE
Stereotactic Body Radiotherapy for Elderly Patients With Medically Inoperable Pancreatic Cancer Raphael L. Yechieli, MD,* Jared R. Robbins, MD,w Meredith Mahan, MS,z Farzan Siddiqui, MD, PhD,* and Munther Ajlouni, MD*
Objectives: People over the age of 75 years account for approximately 40% of patients diagnosed with pancreatic cancer, many with comorbidities that may limit their treatment options. This study reports on the use of stereotactic body radiation therapy (SBRT) in this population. Materials and Methods: Twenty consecutively treated patients over the age of 75 with pathologically proven localized pancreatic cancer were included in this retrospective review. All had been evaluated by a multidisciplinary team as unable to tolerate surgery or combined chemoradiation therapy. Patient outcomes were analyzed to determine the safety and efficacy of SBRT in this elderly cohort. Results: The median age was 83.2 years (minimum 77 y, maximum 90 y). Eighteen patients were treated at time of initial diagnosis, and 2 for recurrence after surgery. Eleven (55%) of the patients had an Adult Comorbidity Evaluation-27 comorbidity index score of 3 (severe) and 6 (30%) had a score of 2 (moderate). Fourteen patients were treated with 35 Gy in 5 fractions, 5 with 30 Gy in 5 fractions, and 1 patient with 36 Gy in 3 fractions. Seven (35%) patients had common terminology criteria for adverse events (CTCAE) V4.0 toxicity grade of 1-2, and 3 patients had a CTCAE V4.0 toxicity grade of 3-4, 2 with dehydration, and 1 had episodes of gastrointestinal bleeding. Three patients recurred locally, 10 had distant metastases, 4 of whom were found on the first posttreatment scan. Median overall survival was 6.4 months (95% confidence interval, 3.5-10.8 mo). Median recurrencefree survival was 6.8 months (95% confidence interval, 1.3-23.5 mo). Two patients survived >23 months. Conclusion: SBRT for pancreatic cancer appears to be a safe and effective method for treatment of elderly patients, even in the setting of severe comorbidities. Key Words: pancreatic cancer, radiation, SBRT, elderly
(Am J Clin Oncol 2014;00:000–000)
I
t was estimated that in 2013, approximately 45,220 people will be diagnosed with pancreatic cancer in the United States, and 38,460 will die from the disease.1 It was also estimated that of those diagnosed, >40% will be 75 years or older.2 This number was projected to increase significantly as the overall population continues to age.3 Surgical resection remains the standard for curative therapy. Unfortunately, only 10% to 20% of patients of any age present with surgically resectable disease.4 In elderly patients with pancreatic cancer, combined radiation and chemotherapy From the Departments of *Radiation Oncology; zBiostatistics, Henry Ford Health System, Detroit, MI; and wDepartment of Radiation Oncology, Medical College of Wisconsin, Milwaukee, WI. The authors declare no conflicts of interest. Reprints: Raphael L. Yechieli, MD, Department of Radiation Oncology, Henry Ford Health System, 2799W. Grand Blvd, Detroit, MI 48202. Email: [email protected]. Copyright r 2014 by Lippincott Williams & Wilkins ISSN: 0277-3732/14/000-000 DOI: 10.1097/COC.0000000000000090
American Journal of Clinical Oncology
has been used both as adjuvant therapy following surgery and as primary therapy. However, in a Surveillance Epidemiology and End Results analysis, only 44% of patients over the age of 65, with locally advanced pancreatic cancer were reported to have received any treatment.5 Without any tumor-directed therapy for pancreatic cancer, the median survival is only 2.5 months and quality-adjusted survival of only 1 month.6 The associated increase in comorbidities in this population may preclude the use of chemotherapy, or even a prolonged course of radiation therapy. Stereotactic body radiation therapy (SBRT) as a primary therapy for unresectable pancreatic cancer has been reported to have good local control and acceptable side effect profile. The majority of patients in previously reported series were also treated with adjuvant chemotherapy.7–9 There is a paucity of data regarding treatment of elderly patients with pancreatic adenocarcinoma. This is especially evident among those who are unable to tolerate an invasive surgical procedure or systemic chemotherapy. This study reports on the use of SBRT as the sole modality of treatment, in an elderly population with pancreatic carcinoma who are medically unable to undergo resection or systemic therapy.
MATERIALS AND METHODS Twenty patients, over the age of 75, with nonmetastatic pathologically proven pancreatic adenocarcinoma, were identified in this institutional review board–approved retrospective study. The patients were treated at a single institution from April 2008 through September 2012. All patients had been evaluated by a multidisciplinary tumor board, and considered unable to tolerate surgery, systemic chemotherapy, or combined chemoradiation therapy due to medical comorbidities. During treatment, patients were clinically evaluated after every second fraction. Regular follow-up after treatment with clinical examination, dedicated pancreatic computed tomography (CT) imaging, and appropriate blood-work, such as tumor-markers, was performed at 6 weeks after treatment, every 3 months for the first year, and every 6 months for the following year. For treatment planning, patients were immobilized using a custom foam mold with vacuum support (KGF Enterprise, Columbus, MI) or Vac-Loc full-body cushion with vacuum support (Civco Medical Solutions, Kalona, IA) and simulation CT (Phillips, Cleveland, OH) with oral and IV contrast was obtained. Initially patients were simulated using a freebreathing technique. Since 2010, a 4-D simulation CT technique was used. The gross tumor volume was defined based on the contrast-enhanced simulation scan, and aided by endoscopic reports. Pretreatment diagnostic imaging was coregistered to the simulation CT in cases where the patient was unable to tolerate IV contrast. With use of 4-D simulation
Volume 00, Number 00, ’’ 2014
www.amjclinicaloncology.com |
1
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
American Journal of Clinical Oncology
Yechieli et al
techniques, an integrated tumor volume was defined. A 6-mm expansion was added for the planning treatment volume (PTV), with no expansion into the duodenum. The duodenum, stomach, kidneys, and the liver were contoured as organs-at-risk. Dose constraints followed the American Association of Physicists in Medicine guidelines in TG-101.10 For treatment in the head of the pancreas, the duodenum was constrained to not receive 50% of the prescribed dose to its complete circumference. For lesions in the body of the pancreas, care was taken for the stomach to not receive more than 30% of the prescribed dose. Treatments were delivered using 7-9 stereotactic intensity-modulated radiation therapy beams. For patients treated with the Novalis BrainLab (Brainlab AG, Feldkirchen, Germany) system, a frameless stereotactic system and a stereoscopic image guidance system were used for patient repositioning. The initial patient setup was assisted by the infrared camera and stereotactic localizer. Two stereoscopic x-ray images were taken to adjust the position of the patient in 6 degrees of freedom. Before delivery of radiation treatment, final position verification was obtained using orthogonal portal films. For patients treated on the Varian Trilogy and TrueBeam (Varian Medical Systems, Palo Alto, CA) linear accelerators, patient setup was assisted by daily cone-beam CT imaging to match planned imaging, and final position verification with KV imaging was obtained before each fraction. In patients with a previous stent placement, this was used to help verify positioning. No patient had fiducial markers placed. Pretreatment factors including stage, size of the lesion, Eastern Cooperative Oncology Group (ECOG) performance status, and comorbidity scores were evaluated. The comorbidity score was obtained from the medical record and calculated using the Adult Comorbidity Evaluation-27 (ACE-27) instrument. Adverse events during treatment were collected and scored using the Radiation Therapy Oncology Group acute toxicity score, and late toxicities were scored using the common terminology criteria for adverse events (CTCAE) V4.0 toxicity grade. The primary aim of this analysis was to determine the overall survival time and recurrence-free survival time after pancreatic SBRT. Time-to-event data were calculated using the SBRT end-date to the date of death, date of recurrence, or date of last follow-up. Product-limit survival curves were used to estimate survival and time to recurrence. The data analysis for this paper was generated using SAS/STAT software, Version 9.4 of the SAS System for Windows. (SAS Institute Inc., Cary, NC).
RESULTS Twenty patients, older than 75 years of age, were identified. Detailed patient and tumor characteristics are listed in Table 1. The median age for the cohort at the time of SBRT was 83.2 (minimum 77, maximum 90) years. The ECOG performance status was 2-3 in 12 (60%) of the patients. The majority of patients had an ACE-27 comorbidity index of moderate-severe, with an ACE-27 score of 2 in 6 (30%) patients and 3 (severe) in 11 (55%) patients. The most common presenting symptoms were weight loss and other abdominal symptoms. The tumors were located in the head of the pancreas in 14 (70%) patients, in the body or tail of the pancreas in 6 (30%) patients. The median pretreatment CA 19-9 was 92.2 (minimum 23 months (Fig. 1).
DISCUSSION The optimal treatment of elderly patients with pancreatic cancer has yet to be elucidated. Pancreatic cancer is a disease of the elderly, with >40% of those diagnosed over the age of 75 years, and population data show that many do not receive any treatment. It is likely that the comorbidities found in this population preclude the use of curative surgery, prolonged courses of radiotherapy or systemic chemotherapy. Although systemic disease is the primary cause of mortality in these patients, local control is clinically important, as 30% of patients are found to have locally destructive disease at the time of autopsy.10 Tumordirected therapy appears to provide a survival benefit because as noted above with best supportive care, the median survival is only 2.5 months, and quality-adjusted survival of only 1 month.6 The use of SBRT for treatment of unresectable locally advanced pancreatic cancer has been described. Chang and colleagues reported on 77 patients treated with SBRT for unresectable pancreatic cancer. All patients were treated with a single fraction of 25 Gy. The median age of the cohort was 64 years, and 96% of the patients had received systemic TABLE 2. Toxicities
Acute toxicity (RTOG) Subacute toxicity (CTCAE V4.0)
GI bleed
Grade
N = 20 (n [%])
0
16 (80)
1
4 (20)
0
10 (50)
1 2
3 (15) 4 (20)
3 4 No Yes
2 1 18 2
(10) (5) (90) (10)
Description
Fatigue, nausea (2), decreased appetite Diarrhea, fatigue (2) Nausea, pain (2), GI bleed Dehydration (2) GI bleed Stent erosion (source unknown)
CTCAE indicates common terminology criteria for adverse events; GI, gastrointestinal; RTOG, radiation therapy oncology group.
r
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Pancreatic SBRT for Elderly Patients
gemcitabine-based chemotherapy as part of their treatment regimen. Progression-free survival at 6 months was 26%, and 13% experienced local failure. Median survival from time of SBRT was 6.4 months.7 Another cohort reported by Rwigema and colleagues showed similar findings. Seventy-one patients were treated with a median dose of 24 Gy in single-fraction SBRT. The median age of the entire cohort was 71 years, and 90% received chemotherapy as part of their treatment regimen. Of this cohort, 36% experienced local failure. A total of 56% of the patients had locally advanced unresectable disease, and the freedom from local failure at 1 year was reported to be 38%. Median survival in the locally advanced unresectable group was 6.2 months.8 Outcomes of elderly patients treated for pancreatic cancer has also been reported. Horowitz and colleagues described the experience of patients over the age of 75 treated surgically with and without postoperative adjuvant chemoradiation therapy. Median survival was 22.6 months for patients treated with adjuvant chemoradiation therapy and 14.3 months for those treated with surgery alone. This was similar to results for the patients under the age of 75 treated at the same institution although performance status and comorbidity information was not reported in this study.11 Miyamato and colleagues reported on outcomes for patients over the age of 75 treated with chemoradiation therapy. Median age of the cohort was 78 years. Forty-two patients were treated, 24 with CRT alone, and 18 with adjuvant CRT after surgery. Median OS was 8.6 months in those treated with CRT alone, and 20.6 months when treated with adjuvant CRT. The median ECOG was 1, with 75% of patients with ECOG 0-1. ACE-27 comorbidity index scores were 0-1 for 57% of the population.12 These studies support the use of aggressive therapy for pancreatic cancer as tolerated, regardless of age. The question remains in how to best manage those patients who cannot tolerate aggressive curative therapy. Our cohort included patients who were deemed unable to safely undergo surgery or complete systemic therapy or prolonged radiation therapy. More than half of our patients had an ACE27 score of 3, signifying severe comorbidities. The performance status at time of treatment was ECOG 2-3 in 60%. The median survival of 6.4 months in this report is comparable with the previously reported patients with unresectable disease treated with SBRT and chemotherapy.7,8 Similarly, local control with SBRT was very good, comparable with previously reported experiences, with 3 patients experiencing local failure. Ten other patients (50%) developed distant metastases. Four of these patients developed evidence of systemic disease at the time of the first posttreatment CT scan. This is similar to the median time to distant recurrence or progression of approximately 3 months in the experience reported by Rwigema et al.8 A distinct advantage of SBRT over conventional radiation therapy is its short course of therapy. For patients facing a median survival of 6 months, being able to complete treatment in 2 weeks, and not spending up to a fourth of their expected lifespan under treatment, is a major quality-of-life consideration. SBRT in this elderly population was well tolerated, with minimal reported acute side effects. The toxicities experienced by our group of patients is comparable with previously reported studies, with minimal acute toxicity, and late grade 34 toxicity reported in 0% to 22% of the treated patients.7–9,13 The grade 3-4 toxicities seen in this population were considered unlikely to have been directly caused by SBRT, although as they were temporally related to the treatment, it was felt appropriate to attribute them to the SBRT. www.amjclinicaloncology.com |
3
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Yechieli et al
American Journal of Clinical Oncology
Volume 00, Number 00, ’’ 2014
FIGURE 1. A, Kaplan-Meier survival curve for overall survival. Median survival of 6.4 months (95% confidence interval [CI], 3.510.8 mo). B, Kaplan-Meier survival curve for recurrence-free survival (RFS). Thirteen patients had a recurrence. Median RFS is 6.8 months (95% CI, 1.3-23.5 mo).
This study is limited by the small size of the cohort and its retrospective nature. Although these patients were unable to tolerate systemic or aggressive surgical therapy, they were able to tolerate the immobilization and time required to treat with SBRT. Further study, including collection of patient-reported outcomes, are necessary to evaluate the impact of this treatment on quality-of-life. In conclusion, the use of SBRT in elderly patients with unresectable pancreatic cancer appears to be a safe and effective treatment. It is an excellent option for patients who otherwise would not have any other option for treatment, with median survival of 6.4 months comparable with other experiences where
4 | www.amjclinicaloncology.com
patients were treated even more aggressively, and providing a vast improvement from the 2.5-month median survival reported in those without tumor-directed therapy.6 Continued study with prospective evaluation of patient-reported quality-of-life outcomes, are an important next step to determine its value even in the most fragile patients. REFERENCES 1. Siegel R, Naishadham D, Jemal A. Cancer statistics, 2013. CA: Cancer J Clin. 2013;63:11–30. 2. Howlader NNA, Krapcho M, Neyman N, et al. SEER Cancer Statistics Review, 1975-2009 (Vintage 2009 Populations). r
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American Journal of Clinical Oncology
3. 4. 5. 6. 7.
r
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Bethesda, MD: National Cancer Institute; 2013. Available at: http://seer.cancer.gov/csr/1975_2009_pops09/, based on November 2011 SEER data submission, posted to the SEER web site, April 2012. 2012; seer.cancer.gov/statfacts/html/pancreas.html Accessed April 18, 2013. Smith BD, Smith GL, Hurria A, et al. Future of cancer incidence in the United States: burdens upon an aging, changing nation. J Clin Oncol. 2009;27:2758–2765. Palta Manisha CGW, Brian GC. Perez and Brady’s Principles and Practice of Radiation Oncology. 6th ed. Wolters Kluwer: Lippincott Williams & Wilkins; 2013. Krzyzanowska MK, Weeks JC, Earle CC. Treatment of locally advanced pancreatic cancer in the real world: population-based practices and effectiveness. J Clin Oncol. 2003;21:3409–3414. Glimelius B, Hoffman K, Sjo¨de´n P-O, et al. Chemotherapy improves survival and quality of life in advanced pancreatic and biliary cancer. Ann Oncol. 1996;7:593–600. Chang DT, Schellenberg D, Shen J, et al. Stereotactic radiotherapy for unresectable adenocarcinoma of the pancreas. Cancer. 2009;115:665–672.
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Pancreatic SBRT for Elderly Patients
8. Rwigema J-CM, Parikh SD, Heron DE, et al. Stereotactic body radiotherapy in the treatment of advanced adenocarcinoma of the pancreas. Am J Clin Oncol. 2011;34:63–69. 9. Chuong MD, Springett GM, Freilich JM, et al. Stereotactic body radiation therapy for locally advanced and borderline resectable pancreatic cancer is effective and well tolerated. Int J Radiat Oncol Biol Phys. 2013;86:516–522. 10. Iacobuzio-Donahue CA, Fu B, Yachida S, et al. DPC4 gene status of the primary carcinoma correlates with patterns of failure in patients with pancreatic cancer. J Clin Oncol. 2009;27:1806–1813. 11. Horowitz DP, Hsu CC, Wang J, et al. Adjuvant chemoradiation therapy after pancreaticoduodenectomy in elderly patients with pancreatic adenocarcinoma. Int J Radiat Onco Biol Phys. 2011;80:1391–1397. 12. Miyamoto DT, Mamon HJ, Ryan DP, et al. Outcomes and tolerability of chemoradiation therapy for pancreatic cancer patients aged 75 years or older. Int J Radiat Onco Biol Phys. 2010;77:1171–1177. 13. Didolkar M, Coleman C, Brenner M, et al. Image-guided stereotactic radiosurgery for locally advanced pancreatic adenocarcinoma results of first 85 patients. J Gastrointest Surg. 2010;14:1547–1559.
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Stereotactic Body Radiotherapy for Elderly Patients With Medically Inoperable Pancreatic Cancer Raphael L. Yechieli, MD,* Jared R. Robbins, MD,w Meredith Mahan, MS,z Farzan Siddiqui, MD, PhD,* and Munther Ajlouni, MD*
Objectives: People over the age of 75 years account for approximately 40% of patients diagnosed with pancreatic cancer, many with comorbidities that may limit their treatment options. This study reports on the use of stereotactic body radiation therapy (SBRT) in this population. Materials and Methods: Twenty consecutively treated patients over the age of 75 with pathologically proven localized pancreatic cancer were included in this retrospective review. All had been evaluated by a multidisciplinary team as unable to tolerate surgery or combined chemoradiation therapy. Patient outcomes were analyzed to determine the safety and efficacy of SBRT in this elderly cohort. Results: The median age was 83.2 years (minimum 77 y, maximum 90 y). Eighteen patients were treated at time of initial diagnosis, and 2 for recurrence after surgery. Eleven (55%) of the patients had an Adult Comorbidity Evaluation-27 comorbidity index score of 3 (severe) and 6 (30%) had a score of 2 (moderate). Fourteen patients were treated with 35 Gy in 5 fractions, 5 with 30 Gy in 5 fractions, and 1 patient with 36 Gy in 3 fractions. Seven (35%) patients had common terminology criteria for adverse events (CTCAE) V4.0 toxicity grade of 1-2, and 3 patients had a CTCAE V4.0 toxicity grade of 3-4, 2 with dehydration, and 1 had episodes of gastrointestinal bleeding. Three patients recurred locally, 10 had distant metastases, 4 of whom were found on the first posttreatment scan. Median overall survival was 6.4 months (95% confidence interval, 3.5-10.8 mo). Median recurrencefree survival was 6.8 months (95% confidence interval, 1.3-23.5 mo). Two patients survived >23 months. Conclusion: SBRT for pancreatic cancer appears to be a safe and effective method for treatment of elderly patients, even in the setting of severe comorbidities. Key Words: pancreatic cancer, radiation, SBRT, elderly
(Am J Clin Oncol 2014;00:000–000)
I
t was estimated that in 2013, approximately 45,220 people will be diagnosed with pancreatic cancer in the United States, and 38,460 will die from the disease.1 It was also estimated that of those diagnosed, >40% will be 75 years or older.2 This number was projected to increase significantly as the overall population continues to age.3 Surgical resection remains the standard for curative therapy. Unfortunately, only 10% to 20% of patients of any age present with surgically resectable disease.4 In elderly patients with pancreatic cancer, combined radiation and chemotherapy From the Departments of *Radiation Oncology; zBiostatistics, Henry Ford Health System, Detroit, MI; and wDepartment of Radiation Oncology, Medical College of Wisconsin, Milwaukee, WI. The authors declare no conflicts of interest. Reprints: Raphael L. Yechieli, MD, Department of Radiation Oncology, Henry Ford Health System, 2799W. Grand Blvd, Detroit, MI 48202. Email: [email protected]. Copyright r 2014 by Lippincott Williams & Wilkins ISSN: 0277-3732/14/000-000 DOI: 10.1097/COC.0000000000000090
American Journal of Clinical Oncology
has been used both as adjuvant therapy following surgery and as primary therapy. However, in a Surveillance Epidemiology and End Results analysis, only 44% of patients over the age of 65, with locally advanced pancreatic cancer were reported to have received any treatment.5 Without any tumor-directed therapy for pancreatic cancer, the median survival is only 2.5 months and quality-adjusted survival of only 1 month.6 The associated increase in comorbidities in this population may preclude the use of chemotherapy, or even a prolonged course of radiation therapy. Stereotactic body radiation therapy (SBRT) as a primary therapy for unresectable pancreatic cancer has been reported to have good local control and acceptable side effect profile. The majority of patients in previously reported series were also treated with adjuvant chemotherapy.7–9 There is a paucity of data regarding treatment of elderly patients with pancreatic adenocarcinoma. This is especially evident among those who are unable to tolerate an invasive surgical procedure or systemic chemotherapy. This study reports on the use of SBRT as the sole modality of treatment, in an elderly population with pancreatic carcinoma who are medically unable to undergo resection or systemic therapy.
MATERIALS AND METHODS Twenty patients, over the age of 75, with nonmetastatic pathologically proven pancreatic adenocarcinoma, were identified in this institutional review board–approved retrospective study. The patients were treated at a single institution from April 2008 through September 2012. All patients had been evaluated by a multidisciplinary tumor board, and considered unable to tolerate surgery, systemic chemotherapy, or combined chemoradiation therapy due to medical comorbidities. During treatment, patients were clinically evaluated after every second fraction. Regular follow-up after treatment with clinical examination, dedicated pancreatic computed tomography (CT) imaging, and appropriate blood-work, such as tumor-markers, was performed at 6 weeks after treatment, every 3 months for the first year, and every 6 months for the following year. For treatment planning, patients were immobilized using a custom foam mold with vacuum support (KGF Enterprise, Columbus, MI) or Vac-Loc full-body cushion with vacuum support (Civco Medical Solutions, Kalona, IA) and simulation CT (Phillips, Cleveland, OH) with oral and IV contrast was obtained. Initially patients were simulated using a freebreathing technique. Since 2010, a 4-D simulation CT technique was used. The gross tumor volume was defined based on the contrast-enhanced simulation scan, and aided by endoscopic reports. Pretreatment diagnostic imaging was coregistered to the simulation CT in cases where the patient was unable to tolerate IV contrast. With use of 4-D simulation
Volume 00, Number 00, ’’ 2014
www.amjclinicaloncology.com |
1
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
American Journal of Clinical Oncology
Yechieli et al
techniques, an integrated tumor volume was defined. A 6-mm expansion was added for the planning treatment volume (PTV), with no expansion into the duodenum. The duodenum, stomach, kidneys, and the liver were contoured as organs-at-risk. Dose constraints followed the American Association of Physicists in Medicine guidelines in TG-101.10 For treatment in the head of the pancreas, the duodenum was constrained to not receive 50% of the prescribed dose to its complete circumference. For lesions in the body of the pancreas, care was taken for the stomach to not receive more than 30% of the prescribed dose. Treatments were delivered using 7-9 stereotactic intensity-modulated radiation therapy beams. For patients treated with the Novalis BrainLab (Brainlab AG, Feldkirchen, Germany) system, a frameless stereotactic system and a stereoscopic image guidance system were used for patient repositioning. The initial patient setup was assisted by the infrared camera and stereotactic localizer. Two stereoscopic x-ray images were taken to adjust the position of the patient in 6 degrees of freedom. Before delivery of radiation treatment, final position verification was obtained using orthogonal portal films. For patients treated on the Varian Trilogy and TrueBeam (Varian Medical Systems, Palo Alto, CA) linear accelerators, patient setup was assisted by daily cone-beam CT imaging to match planned imaging, and final position verification with KV imaging was obtained before each fraction. In patients with a previous stent placement, this was used to help verify positioning. No patient had fiducial markers placed. Pretreatment factors including stage, size of the lesion, Eastern Cooperative Oncology Group (ECOG) performance status, and comorbidity scores were evaluated. The comorbidity score was obtained from the medical record and calculated using the Adult Comorbidity Evaluation-27 (ACE-27) instrument. Adverse events during treatment were collected and scored using the Radiation Therapy Oncology Group acute toxicity score, and late toxicities were scored using the common terminology criteria for adverse events (CTCAE) V4.0 toxicity grade. The primary aim of this analysis was to determine the overall survival time and recurrence-free survival time after pancreatic SBRT. Time-to-event data were calculated using the SBRT end-date to the date of death, date of recurrence, or date of last follow-up. Product-limit survival curves were used to estimate survival and time to recurrence. The data analysis for this paper was generated using SAS/STAT software, Version 9.4 of the SAS System for Windows. (SAS Institute Inc., Cary, NC).
RESULTS Twenty patients, older than 75 years of age, were identified. Detailed patient and tumor characteristics are listed in Table 1. The median age for the cohort at the time of SBRT was 83.2 (minimum 77, maximum 90) years. The ECOG performance status was 2-3 in 12 (60%) of the patients. The majority of patients had an ACE-27 comorbidity index of moderate-severe, with an ACE-27 score of 2 in 6 (30%) patients and 3 (severe) in 11 (55%) patients. The most common presenting symptoms were weight loss and other abdominal symptoms. The tumors were located in the head of the pancreas in 14 (70%) patients, in the body or tail of the pancreas in 6 (30%) patients. The median pretreatment CA 19-9 was 92.2 (minimum 23 months (Fig. 1).
DISCUSSION The optimal treatment of elderly patients with pancreatic cancer has yet to be elucidated. Pancreatic cancer is a disease of the elderly, with >40% of those diagnosed over the age of 75 years, and population data show that many do not receive any treatment. It is likely that the comorbidities found in this population preclude the use of curative surgery, prolonged courses of radiotherapy or systemic chemotherapy. Although systemic disease is the primary cause of mortality in these patients, local control is clinically important, as 30% of patients are found to have locally destructive disease at the time of autopsy.10 Tumordirected therapy appears to provide a survival benefit because as noted above with best supportive care, the median survival is only 2.5 months, and quality-adjusted survival of only 1 month.6 The use of SBRT for treatment of unresectable locally advanced pancreatic cancer has been described. Chang and colleagues reported on 77 patients treated with SBRT for unresectable pancreatic cancer. All patients were treated with a single fraction of 25 Gy. The median age of the cohort was 64 years, and 96% of the patients had received systemic TABLE 2. Toxicities
Acute toxicity (RTOG) Subacute toxicity (CTCAE V4.0)
GI bleed
Grade
N = 20 (n [%])
0
16 (80)
1
4 (20)
0
10 (50)
1 2
3 (15) 4 (20)
3 4 No Yes
2 1 18 2
(10) (5) (90) (10)
Description
Fatigue, nausea (2), decreased appetite Diarrhea, fatigue (2) Nausea, pain (2), GI bleed Dehydration (2) GI bleed Stent erosion (source unknown)
CTCAE indicates common terminology criteria for adverse events; GI, gastrointestinal; RTOG, radiation therapy oncology group.
r
2014 Lippincott Williams & Wilkins
Pancreatic SBRT for Elderly Patients
gemcitabine-based chemotherapy as part of their treatment regimen. Progression-free survival at 6 months was 26%, and 13% experienced local failure. Median survival from time of SBRT was 6.4 months.7 Another cohort reported by Rwigema and colleagues showed similar findings. Seventy-one patients were treated with a median dose of 24 Gy in single-fraction SBRT. The median age of the entire cohort was 71 years, and 90% received chemotherapy as part of their treatment regimen. Of this cohort, 36% experienced local failure. A total of 56% of the patients had locally advanced unresectable disease, and the freedom from local failure at 1 year was reported to be 38%. Median survival in the locally advanced unresectable group was 6.2 months.8 Outcomes of elderly patients treated for pancreatic cancer has also been reported. Horowitz and colleagues described the experience of patients over the age of 75 treated surgically with and without postoperative adjuvant chemoradiation therapy. Median survival was 22.6 months for patients treated with adjuvant chemoradiation therapy and 14.3 months for those treated with surgery alone. This was similar to results for the patients under the age of 75 treated at the same institution although performance status and comorbidity information was not reported in this study.11 Miyamato and colleagues reported on outcomes for patients over the age of 75 treated with chemoradiation therapy. Median age of the cohort was 78 years. Forty-two patients were treated, 24 with CRT alone, and 18 with adjuvant CRT after surgery. Median OS was 8.6 months in those treated with CRT alone, and 20.6 months when treated with adjuvant CRT. The median ECOG was 1, with 75% of patients with ECOG 0-1. ACE-27 comorbidity index scores were 0-1 for 57% of the population.12 These studies support the use of aggressive therapy for pancreatic cancer as tolerated, regardless of age. The question remains in how to best manage those patients who cannot tolerate aggressive curative therapy. Our cohort included patients who were deemed unable to safely undergo surgery or complete systemic therapy or prolonged radiation therapy. More than half of our patients had an ACE27 score of 3, signifying severe comorbidities. The performance status at time of treatment was ECOG 2-3 in 60%. The median survival of 6.4 months in this report is comparable with the previously reported patients with unresectable disease treated with SBRT and chemotherapy.7,8 Similarly, local control with SBRT was very good, comparable with previously reported experiences, with 3 patients experiencing local failure. Ten other patients (50%) developed distant metastases. Four of these patients developed evidence of systemic disease at the time of the first posttreatment CT scan. This is similar to the median time to distant recurrence or progression of approximately 3 months in the experience reported by Rwigema et al.8 A distinct advantage of SBRT over conventional radiation therapy is its short course of therapy. For patients facing a median survival of 6 months, being able to complete treatment in 2 weeks, and not spending up to a fourth of their expected lifespan under treatment, is a major quality-of-life consideration. SBRT in this elderly population was well tolerated, with minimal reported acute side effects. The toxicities experienced by our group of patients is comparable with previously reported studies, with minimal acute toxicity, and late grade 34 toxicity reported in 0% to 22% of the treated patients.7–9,13 The grade 3-4 toxicities seen in this population were considered unlikely to have been directly caused by SBRT, although as they were temporally related to the treatment, it was felt appropriate to attribute them to the SBRT. www.amjclinicaloncology.com |
3
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Yechieli et al
American Journal of Clinical Oncology
Volume 00, Number 00, ’’ 2014
FIGURE 1. A, Kaplan-Meier survival curve for overall survival. Median survival of 6.4 months (95% confidence interval [CI], 3.510.8 mo). B, Kaplan-Meier survival curve for recurrence-free survival (RFS). Thirteen patients had a recurrence. Median RFS is 6.8 months (95% CI, 1.3-23.5 mo).
This study is limited by the small size of the cohort and its retrospective nature. Although these patients were unable to tolerate systemic or aggressive surgical therapy, they were able to tolerate the immobilization and time required to treat with SBRT. Further study, including collection of patient-reported outcomes, are necessary to evaluate the impact of this treatment on quality-of-life. In conclusion, the use of SBRT in elderly patients with unresectable pancreatic cancer appears to be a safe and effective treatment. It is an excellent option for patients who otherwise would not have any other option for treatment, with median survival of 6.4 months comparable with other experiences where
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patients were treated even more aggressively, and providing a vast improvement from the 2.5-month median survival reported in those without tumor-directed therapy.6 Continued study with prospective evaluation of patient-reported quality-of-life outcomes, are an important next step to determine its value even in the most fragile patients. REFERENCES 1. Siegel R, Naishadham D, Jemal A. Cancer statistics, 2013. CA: Cancer J Clin. 2013;63:11–30. 2. Howlader NNA, Krapcho M, Neyman N, et al. SEER Cancer Statistics Review, 1975-2009 (Vintage 2009 Populations). r
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American Journal of Clinical Oncology
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Pancreatic SBRT for Elderly Patients
8. Rwigema J-CM, Parikh SD, Heron DE, et al. Stereotactic body radiotherapy in the treatment of advanced adenocarcinoma of the pancreas. Am J Clin Oncol. 2011;34:63–69. 9. Chuong MD, Springett GM, Freilich JM, et al. Stereotactic body radiation therapy for locally advanced and borderline resectable pancreatic cancer is effective and well tolerated. Int J Radiat Oncol Biol Phys. 2013;86:516–522. 10. Iacobuzio-Donahue CA, Fu B, Yachida S, et al. DPC4 gene status of the primary carcinoma correlates with patterns of failure in patients with pancreatic cancer. J Clin Oncol. 2009;27:1806–1813. 11. Horowitz DP, Hsu CC, Wang J, et al. Adjuvant chemoradiation therapy after pancreaticoduodenectomy in elderly patients with pancreatic adenocarcinoma. Int J Radiat Onco Biol Phys. 2011;80:1391–1397. 12. Miyamoto DT, Mamon HJ, Ryan DP, et al. Outcomes and tolerability of chemoradiation therapy for pancreatic cancer patients aged 75 years or older. Int J Radiat Onco Biol Phys. 2010;77:1171–1177. 13. Didolkar M, Coleman C, Brenner M, et al. Image-guided stereotactic radiosurgery for locally advanced pancreatic adenocarcinoma results of first 85 patients. J Gastrointest Surg. 2010;14:1547–1559.
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