Abstract: A standard treatment recommendation for esophageal cancer patients with stage IB-IIIB disease is for neoadjuvant chemoradiation followed by surgery. This trimodality therapy can be difficult for patients to tolerate, and the neoadjuvant therapy can impact the patients’ ability to undergo surgery without delays. Methods: We conducted a pilot quality improvement (QI) project, STRENGTH (Seeking To Reactivate Esophageal aNd Gastric Treatment Health), to implement supportive care interventions in the prehabilitation phase of neoadjuvant treatment. Our QI program included a standardized chemotherapy order template with supportive care interventions including medications, intravenous (IV) fluids, and nutrition consults and nurse follow-up phone calls implemented at specific time points. Patients were also enrolled in an exercise program specifically designed for cancer patients. Results: In the patients treated after implementation of the STRENGTH QI program, the following outcomes were improved: chemotherapy relative dose intensity, number of completed chemotherapy cycles, receipt of planned radiation doses, prescription of antiemetics and supportive care medications including IV fluids, hospitalization rate, time to surgery, pathologic response, and 18-month progression-free survival. Conclusion: Patients treated following implementation of the STRENGTH QI pilot program experienced improvements across multiple outcomes resulting in the pilot program being adopted as standard of care in this patient population. We plan to further optimize the STRENGTH program with implementation of standardized dose reduction and delay protocols for both chemotherapy and radiation, and assess the effects that the STRENGTH program interventions have on patient quality of life.
In 2019, it is anticipated that 17,650 new cases of esophageal cancer will be diagnosed in the United States.1 The majority of newly diagnosed esophageal cancer patients at the University of Colorado Cancer Center (UCCC) are seen in the Esophageal and Gastric Cancer Multidisciplinary Clinic (EGMDC). Approximately 75 patients are evaluated in the EGMDC each year who are diagnosed with stage IB-IIIB disease and would be appropriate for neoadjuvant therapy. Around one-third of those seen in the EGMDC elect to receive all of their cancer treatment at UCCC. In the EGMDC, patients undergo a comprehensive disease evaluation by a team of specialists and their trainees. Patients are then presented in the multidisciplinary conference, and treatment decisions are discussed by a panel of medical, surgical, and radiation oncologists and support staff. Once an optimal treatment course is determined for each patient based upon provider opinion, guideline recommendations, current evidence, and patient-specific factors, an individualized multidisciplinary consultation occurs in which treatment recommendations are presented to each patient by the team of oncology specialists. In addition, patients are provided with information on our cancer center’s support services including exercise programs, nutrition support, psychosocial services, and financial counseling.
For patients with stage IB-IIIB esophageal cancer, the typical treatment recommendation by the multidisciplinary team had been neoadjuvant chemoradiation utilizing the CROSS regimen (weekly doses of carboplatin intravenous [IV] area under the curve [AUC] of 2 and paclitaxel IV 50 mg/m2 with concurrent radiation 41.4-52.5 Gray (Gy) over 5-5.5 weeks)2,3 followed by surgical resection, as per standard guidelines.4 Unfortunately, even with a multidisciplinary approach, neoadjuvant treatment may be poorly tolerated, which can negatively impact surgical management. To address this concern, a team of practitioners from medical, radiation and surgical oncology, pharmacy, nursing, nutrition support, psychology, and social work developed the STRENGTH (Seeking To Reactivate Esophageal aNd Gastric Treatment Health) pilot quality improvement (QI) program with the primary objective of improving tolerance of neoadjuvant treatment through prehabilitation to facilitate surgical resection within 12 weeks of completing neoadjuvant therapy.
Methods
Assessment of Resources, Staff, Training Needed for Project
The STRENGTH team was led by a nutritionist and surgical advanced practice provider who were invested in improving outcomes for the stage IB-IIIB esophageal cancer patient population. They spearheaded this initiative and coordinated monthly meetings to discuss possible interventions that would be feasible and sustainable to achieve our goal. We focused on standardizing our process and automating it where we could. It was determined that full implementation of the QI pilot program required additional training and the investment of all staff involved in the care of these patients. No additional staff were hired for implementation of this program.
The EPIC electronic health record Beacon template for the CROSS chemotherapy regimen was adjusted to include standing orders for IV fluids and supportive care medications for home use. Modifications to this EPIC template took several months and approval from physicians treating patients with the CROSS regimen across the UCCC. All patients receiving treatment at UCCC were scheduled for education by a pharmacist on the CROSS regimen and use of supportive care home medications.
Additionally, patients had a referral placed for the exercise program dedicated to cancer patients at the Wellness Center on campus. The nutritionist scheduled her own patients, which allowed for weekly dietary consultation. The clinic receptionists were trained to distribute distress screenings to patients, and the medical assistants were educated to notify clinic practitioners of any scores indicating the need for social work consultation. The surgical nurses adapted their workflow to conduct follow-up phone calls after patients completed neoadjuvant treatment to assess symptoms while patients were not being routinely seen in the clinic, waiting to recover prior to surgical intervention.
Full Implementation of Pilot
This pilot QI program was implemented on August 31, 2015. All members of the EGMDC were on board and supportive of the implementation of this pilot program. This QI project was approved by the institutional review board.
Patients who were recommended to undergo neoadjuvant treatment with the CROSS regimen and planned to receive their treatment at UCCC were treated utilizing the STRENGTH program. This program was applied at the initial EGMDC visit when treatment with the CROSS regimen was recommended and continued through completion of neoadjuvant therapy. Essential elements of the prehabilitation STRENGTH program include:
- IV fluids twice per week starting week 3 of chemoradiation
- Standardized prescription of supportive care home medications in addition to standard, as-needed antiemetics, omeprazole twice daily at treatment onset continued for 60 days, lidocaine 2% oral solution, and/or sucralfate to use as needed for pain starting week 2
- Weekly dietician consultation
- Weekly distress screening with reflex social work support
- Enrollment in a strength-training exercise program for cancer patients
- Follow-up nursing phone calls following neoadjuvant treatment
A retrospective chart review was conducted on 11 patients who received the CROSS regimen prior to STRENGTH implementation (historical controls initiated neoadjuvant treatment May 12, 2014, to August 3, 2015) and 11 patients who were treated with the CROSS regimen following STRENGTH implementation (initiated neoadjuvant treatment between August 31, 2015, and June 9, 2016). Patients treated prior to implementation of the STRENGTH program had IV fluids and additional supportive care medications added per provider discretion. In addition, the nutrition follow-up was based upon referral as well as social work consultation on an as needed basis. Patients were not enrolled in the exercise program and did not have nurse follow-up phone calls after neoadjuvant treatment. Specific data gathered (on the entire population) included supportive care medications provided, administration of IV fluids, chemotherapy doses received, presence of dose reductions or delays, radiation treatment received, surgical outcomes, and disease status at 18 months.
Results
Patients initiated neoadjuvant treatment between 2014 and 2016. Demographics were similar between the two groups (Table 1). Individual patient treatments and results are summarized in Table 2. Overall, patients treated following implementation of the STRENGTH pilot program experienced improvements in the outcomes assessed.
Chemoradiation
There was a trend for patients treated following implementation of the STRENGTH program to receive a higher chemotherapy dose intensity with fewer dose adjustments.
During the pre-STRENGTH period, patients received an average of 5 chemotherapy doses (range 2-6) of carboplatin and paclitaxel, with average relative dose intensity of 91.8% for carboplatin and 86.7% for paclitaxel. In the post-STRENGTH program cohort, patients received an average of six doses (range 5-8) of carboplatin and paclitaxel, with average relative dose intensity of 111.4% and 112.9%, respectively. Patients achieving 100% relative dose intensity of chemotherapy received 5 weekly doses of carboplatin IV AUC 2 and paclitaxel IV 50 mg/m2.
Four patients treated pre-STRENGTH program implementation required a dose reduction, with two requiring more than one reduction. In the post-STRENGTH implementation cohort, five patients required a dose reduction with one patient requiring more than one. One patient in each cohort required a delay in therapy. The average time to dose reduction or delay was longer following implementation of the STRENGTH pathway; 3.6 weeks (range 2-5) vs 4.3 weeks (range 2-7). The reasons for dose reductions and delays in the pre-implementation group were leukopenia, thrombocytopenia, elevated bilirubin, dehydration/nausea, and decline in renal function; in the post-implementation group, reasons included leukopenia and thrombocytopenia.
Radiation fractionation differed between the two cohorts. In the post-STRENGTH cohort, 10 patients received 50.4 Gy in 28 fractions (fx) and 1 received 45 Gy in 25 fx. Planned doses in the group treated pre-STRENGTH program included 45 Gy/25 fx (2), 50 Gy/25 fx (6), 52.5 Gy/25 fx (1), and 50.4 Gy/28 fx (2). All patients in the post-STRENGTH group received their planned radiation dose. In the pre-STRENGTH cohort, one patient did not complete their planned dose due to nausea, vomiting, and dehydration, receiving 46 Gy of planned 50 Gy. Mean elapsed days for radiation tended to be slightly longer in the patients treated pre-STRENGTH (36.27 vs 35.27); however, on average, more fractions were prescribed for the post-STRENGTH implementation group vs the pre-STRENGTH implementation group (28 fx over 5.5 weeks, at 1.8 Gy/fx vs majority received 25 fx over 5 weeks at ≥2 Gy/fx).
There was a trend toward decreased hospitalization in the patients treated following implementation of the STRENGTH program. Five patients (45.5%) were admitted in the pre-STRENGTH implementation group whereas two (18.2%) were admitted in the post-implementation group. Three patients in the pre-STRENGTH implementation cohort and two in the post-STRENGTH implementation cohort required a treatment break or stopped radiation early due to symptoms; each of these five patients was hospitalized for their symptoms at time of radiation treatment break. Patients with neutropenia in the pre-STRENGTH implementation group continued radiation without a treatment break; two patients in the post-STRENGTH implementation group had a 1-day treatment break for neutropenia.
Supportive Care
Prescribed supportive care varied between the study periods. All patients assessed received chemotherapy pre-medications consisting of a serotonin antagonist, dexamethasone, famotidine, and diphenhydramine.
In the pre-STRENGTH implementation cohort, 100% of patients were prescribed prochlorperazine, 90.1% ondansetron, and 81.8% dexamethasone. In the post-STRENGTH cohort, 100% of patients were prescribed prochlorperazine and ondansetron but only 27.3% dexamethasone.
In the pre-STENGTH program cohort, 90.1% were prescribed a lidocaine-containing mouthwash vs 100% in the post-implementation cohort. In the pre-STRENGTH implementation group, 9.1% received sucralfate and 72.7% a proton pump inhibitor (PPI) vs 81.8% for both sucralfate and a PPI in the post-implementation group. There was a near doubling in the percent of patients who received IV fluids following STRENGTH implementation with 45.5% of patients receiving IV fluids before program implementation and 90.1% after.
Surgical Outcomes
On average, patients in both groups had surgery within 12 weeks of treatment onset, with a trend toward a shortened interval between neoadjuvant therapy and surgery seen in the post-STRENGTH implementation group; 11.0 weeks (range 6.3-37.0) vs 9.7 weeks (range 7.3-13.4). Improved pathologic responses and a trend toward longer progression-free survival were documented in the patients treated following implementation of the STRENGTH program.
In the pre-STRENGTH implementation group, one patient (9.1%) had a complete response (CR), five (45.5%) a near CR (nCR), two (18.2%) a partial response (PR), and three (27.3%) had no response. In the post-STRENGTH implementation group, three patients (27.3%) had a CR, five (45.5%) a nCR, and three (27.3%) a PR. At 18 months from surgery in the pre-STRENGTH implementation group, four patients had progression of disease. In the post-STRENGTH implementation group, only one patient had disease progression at 18 months.
Discussion
To our knowledge, this is the first reported case series exploring the impact of an integrated supportive care prehabilitation program on the neoadjuvant chemoradiation regimen CROSS for treatment of esophageal cancer. Though the benefits of multidisciplinary care in this population have been well-documented,5-7 the use of a multidisciplinary team specifically focused on supportive care in the neoadjuvant phase of treatment has not been previously documented. Also unique to the STRENGTH QI program is the provision of pre-specified supportive care at key time points in the patient’s neoadjuvant course.
When assessing the results of our small pilot, the integration of this supportive care program at our center resulted in a higher dose intensity of chemotherapy, as well as a prolonged time to first dose reduction. Furthermore, fewer patients required hospitalization for toxicity related to neoadjuvant treatment, and the time from completion of neoadjuvant therapy to surgery was decreased. Interestingly, the frequency of pathologic CR was also higher in this group, possibly correlating with higher chemotherapy dose intensity. At 18 months from surgery, recurrence data suggests fewer recurrences in the patients treated after implementation of the STRENGTH program. Though these findings are limited by the small cohort size and short follow-up period, these signals are worth further exploration.
Despite receiving an overall higher dose of chemotherapy, patients in the post-STRENGTH implementation group still had fewer dose reductions and hospitalizations. This suggests that increasing and standardizing supportive care measures allowed patients to receive therapy intensification and may have ultimately led to improved outcomes.
In addition to outlining the potential benefits of pre-specified supportive care for patients receiving neoadjuvant chemoradiation for esophageal cancer, this experience has also identified additional areas for practice improvement that the STRENGTH team plans to integrate into the prehabilitation program moving forward. Included among these are development of a standardized strategy for dose reduction and treatment breaks for both chemotherapy and radiation to ensure more uniform delivery of standard therapy, as well as further assessment of the effects the interventions have on patient quality of life.
Limitations
There are several limitations to analysis of this pilot program. The number of patients included in each cohort is too small to identify any significant differences in the treatment outcomes. The follow-up time of 18 months is also potentially too short to identify meaningful differences in recurrence rates. Additional limitations include the retrospective nature of chart review and inclusion of patients in a nonrandomized manner at a single center. Also, all patients treated following implementation of the STRENGTH program did not receive all recommended supportive care interventions. Some of the trends in outcome do raise questions to the benefit of this pilot QI program, which should be further analyzed on a larger scale.
Conclusion
In summary, this data suggests that integration of a multidisciplinary supportive care prehabilitation program into the neoadjuvant treatment regimen of patients with esophageal cancer may improve patient outcomes related to the ability to administer an increased intensity of chemoradiation. This simple, reproducible QI program is widely transferrable and could be integrated at any cancer center. Our pilot QI program demonstrated feasibility with a potential signal for improvement in treatment outcomes requiring further exploration. Our team will continue to evaluate the potential benefits of this supportive care program in a larger patient population while tailoring our approach to ensure maximum benefit to our patients.
References
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