The theme of the 2022 ASCO Gastrointestinal Cancers Symposium was “Accelerating Access to Precision Care Through Innovation.” Several studies presented at this meeting focused on older patients, who represent the majority of patients with gastrointestinal malignancies. Data reviewed at the meeting and featured here highlight several treatment approaches and alternatives to standard treatments that appear to be safe and effective in an elderly patient population.
De-intensification and Tolerability of Therapy in Colorectal Cancer
Several abstracts examined the benefit of de-escalating chemotherapy, focusing on tolerability, safety, and benefit in older patients. The use of oxaliplatin specifically remains controversial in an older population. Oxaliplatin-related toxicities, including neurotoxicity, remain of concern. The data presented further support either omitting or limiting the use of oxaliplatin in older patients.
The phase III RESPECT trial evaluated the addition of oxaliplatin to fluoropyrimidine plus bevacizumab as initial therapy in elderly patients, and it was presented during the oral abstract session.1 The Japanese trial evaluated FOLFOX7 (a simplified leucovorin and fluorouracil regimen with high-dose oxaliplatin) or CapeOX (capecitabine/oxaliplatin) plus bevacizumab vs fluorouracil/leucovorin or capecitabine plus bevacizumab. Patients between the ages of 70 and 74 with an Eastern Cooperative Oncology Group (ECOG) performance status of 2 or those at least aged 75 with a performance status of 0 to 2 were included. Of the 251 patients randomly assigned, 93% of patients were at least 75 years old, with a median age of 79.
“The data presented further support either omitting or limiting the use of oxaliplatin in older patients with colorectal cancer.”— Avni Desai, MD
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The primary endpoint was progression-free survival. Median progression-free survival was 9.4 months without oxaliplatin and 10 months with the addition of oxaliplatin (hazard ratio [HR] = 0.837, P = .086). Median overall survival was 21.3 months without oxaliplatin and 19.7 months with the addition of oxaliplatin. The response rate was 29.5% without oxaliplatin and 47.7% with the addition of oxaliplatin. However, the addition of oxaliplatin did not show a survival benefit. Improved quality of life and decreased treatment-related adverse effects were noted without oxaliplatin. Hamaguchi et al concluded that oxaliplatin is not recommended in addition to initial fluoropyrimidine-based chemotherapy as initial therapy for elderly patients with metastatic disease.1
A second oral presentation addressed the prognostic impact of early oxaliplatin discontinuation in patients treated with 6 months of oxaliplatin-based adjuvant chemotherapy for stage III colon cancer. Dr. Claire Gallois presented the ACCENT/IDEA pooled analysis of 11 trials.2 Early treatment discontinuation was defined as discontinuation of treatment before 75% of cycles of chemotherapy. Early oxaliplatin discontinuation was defined as discontinuation of oxaliplatin only before completion of 75% of oxaliplatin cycles while continuing fluoropyrimidine alone.
Of the 10,444 patients analyzed, 20.9% had early treatment discontinuation as defined above. Of the remaining 7,243 patients, 18.8% had early oxaliplatin-only discontinuation. Early treatment discontinuation or early oxaliplatin discontinuation was associated with frailty, older age, and a poor performance status of at least 1.
A decrease in disease-free and overall survival in the population who had early treatment discontinuation was noted (HR = 1.4, 95% confidence interval [CI] = 1.23–1.58, P < .001 and HR = 1.51, 95% CI = 1.31–1.74, P < .001 respectively). On the other hand, early oxaliplatin discontinuation was not associated with lower disease-free or overall survival (HR = 1.10, 95% CI = 0.77–1.58, P = .6 and HR = 0.97, 95% CI = 0.62–1.52, P = .9, respectively). Those who received at least 50% of oxaliplatin cycles had a 3-year disease-free survival of 78.1%, compared with 78.3% for those who received 100% of cycles. This study did not focus solely on elderly patients; however, the findings support early oxaliplatin discontinuation after 3 months as an option for older patients who are candidates for combination therapy with fluoropyrimidine and oxaliplatin.
The impact of previous adjuvant oxaliplatin combination therapy on survival in elderly patients with colorectal cancer with recurrence was reported by Nagata et al.3 This Japanese retrospective study included 127 patients older than age 70 who received adjuvant therapy for high-risk stage II and III colorectal cancer. A total of 75 patients were treated with fluoropyrimidine monotherapy, and 52 patients were treated with fluoropyrimidine and oxaliplatin combination therapy.
The 5-year disease-free and overall survival rates in the fluoropyrimidine group were 70.6% and 67.1%. The 5-year disease-free and overall survival rates in the group given fluoropyrimidine and oxaliplatin was 89.0% and 71.8%, respectively. The median overall survival from the date of relapse was significantly worse with fluoropyrimidine and oxaliplatin than with fluoropyrimidine alone (45.0 vs 14.4 months, P = .011). The authors noted that recurrence after combination therapy was a poor prognostic factor, possibly decreasing the benefit of adding oxaliplatin after recurrence.
Chen et al analyzed the efficacy of regorafenib with PD-1 inhibitors in elderly patients with colorectal cancer.4 This retrospective analysis included patients (median age of 68) treated with regorafenib and PD-1 inhibitors at a single institution in China. Median overall survival and progression-free survival were 15 months (95% CI = 7–23 months) and 4 months (95% CI = 1.8–6.2 months), respectively. The objective response rate was 8.3%. Disease control (partial response plus stable disease) was achieved in 70.8%. The analysis showed that elderly Chinese patients may benefit from a combination strategy similar to that used in patients of younger ages.
Safety and Efficacy of Esophagogastric Cancer Treatment
The results of a phase II trial of the efficacy and safety of neoadjuvant therapy with SOX (S-1 plus oxaliplatin) in elderly patients with locally advanced gastric cancer were reported by Uehara et al.5 This Asian study sought to evaluate the efficacy of neoadjuvant therapy in elderly patients given the difficulty tolerating chemotherapy after gastrectomy.
The primary endpoint was dose intensity, with rates of dose intensity for S-1 and oxaliplatin of 97.2% and 98.3%, respectively. A total of 26 patients were included, with a median age of 74.5 years. A total of 96.2% of patients received three planned cycles, and 88.5% underwent gastrectomy with D2 dissection. The authors concluded that SOX was feasible in elderly patients, with careful monitoring to manage possible adverse effects.
“G8 [Geriatric 8] is a useful screening tool to identify patients for whom S-1 and ramucirumab may yield longer overall survival as well as a higher response rate.”— Avni Desai, MD
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Hu et al reported the results of the Geriatric 8 (G8) screening tool–stratified efficacy of S-1 plus ramucirumab in elderly patients with advanced or recurrent gastric cancer.6 This post hoc analysis of the Japanese KSCC1701 trial sought to stratify the safety and efficacy of the treatment in patients 70 years or older. The primary endpoint was 1-year overall survival, and the exploratory endpoint was detection of differences of treatment response by the G8 screening tool (a higher score indicated a better health status). The 1-year survival for those with a high or a low G8 score was 82.6% and 26.7%, respectively. The study authors concluded that G8 is a useful screening tool to identify patients for whom S-1 and ramucirumab may yield longer overall survival as well as a higher response rate.
The phase II RAMONA trial assessed the use of nivolumab plus ipilimumab in the second-line setting for older patients with esophageal squamous cell cancer (AIO-STO-0117 trial) and also used geriatric assessment with the G8 screening tool.7 In this European multicenter trial, 66 patients, with a median age of 70.5 years (range = 55–84 years), were enrolled after geriatric assessment. Geriatric assessment was completed using the G8 screening tool in combination with the Deficit Accumulation Frailty Index. A total of 44 patients were treated with nivolumab and ipilimumab, and 22 patients were treated with nivolumab alone.
The study’s primary endpoint was met, with a median overall survival of 7.2 months (P < .006). Median progression-free survival was 2.7 months, and the objective response rate was 18.2%. Grade 3 or more treatment-related adverse events were observed in 25% of patients. In this trial, Ebert et al noted improved overall survival and safety of an elderly prescreened European population.
Hepatobiliary and Pancreatic Cancers
The differences in pretreatment frailty across gastrointestinal cancers in older adults were reported in a poster by Arora et al.8 The goal was to examine the differences in pretreatment frailty and geriatric assessment domain impairments among patients with pancreatic, hepatobiliary, and colorectal cancers. A total of 505 adults (at least 60 years of age) enrolled in the Cancer and Aging Resilience Evaluation (CARE) registry were included. Patients reported that geriatric assessment was completed prior to the start of therapy. Frailty was defined using the 44-item CARE frailty index.
Patients with pancreatic cancer had the highest incidence of frailty (23.3% for those with colorectal cancer, 40.6% for those with pancreatic cancer, and 34.3% for those with hepatobiliary cancer; P = .001), instrumental activities of daily living limitations (50.2% for those with colorectal cancer, 64.3% for those with pancreatic cancer, and 52.7% for those with hepatobiliary cancer; P = .018), and malnutrition (40.8% for those with colorectal cancer, 70.3% for those with pancreatic cancer, and 45.4% for those with hepatobiliary cancer; P < .001). The authors suggested that early intervention in patients with pancreatic cancer prior to and during therapy may improve outcomes.
“Durvalumab/tremelimumab represents a safe and effective treatment alternative for frail and older patients with unresectable hepatocellular carcinoma.”— Avni Desai, MD
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A phase II Taiwanese study evaluated S-1 and gemcitabine in elderly patients with locally advanced or metastatic pancreatic adenocarcinoma.9 The study enrolled 49 patients older than age 70, with a median age of 76 (range = 70–87 years), and an ECOG performance status of 0 to 2. Patient frailty was evaluated by the Vulnerable Elders Survey 13 score (median 5; range = 0–13) and G8 score (median 10.5; range = 3–15) at baseline. (A score of 3 or more on the Vulnerable Elders Survey 13 suggests vulnerability.)
The median progression-free survival was 6.6 months, and overall survival was 12.5 months. Patients had improved emotional function and global health status scores during S-1 and gemcitabine treatment. The most frequent grade 3 toxicities were anemia (20.4%), and decreased neutrophils (18.4%). Bai et al concluded that S-1 and gemcitabine was effective, with tolerable toxicity, in a frail group of patients.
The results of the multicenter phase III HIMALAYA study of first-line treatment with tremelimumab and durvalumab in patients with unresectable hepatocellular carcinoma were presented by Dr. Abou-Alfa.10 Durvalumab plus tremelimumab led to a significant improvement in overall survival vs standard-of-care sorafenib as first-line therapy. Durvalumab demonstrated noninferior overall survival vs sorafenib. The median overall survival was 16.4 months with durvalumab/tremelimumab, 16.6 months with durvalumab, and 13.8 months with sorafenib. Patients had a median age of 65. Durvalumab/tremelimumab and durvalumab monotherapy had manageable safety profiles, with lower grade 3 or 4 treatment-related adverse effects relative to sorafenib without any increase in liver toxicity or bleeding risk. Although this study included patients older and younger than age 65, durvalumab/tremelimumab represents a safe and effective treatment alternative for frail and older patients.
Treatment Disparities Between Older and Younger Patients
Elias et al reported on the disparities in comprehensive genomic profiling in older patients with gastrointestinal malignancies.11 Next-generation sequencing of tumor tissue was reviewed for patients with gastrointestinal malignancies (n = 92,802). Many patients, 55%, were younger than age 65. The association between age group (< 65: n = 51,652; 65–74: n = 28,972; 75+: n = 12,178) and biomarkers was evaluated.
An age-associated increase in high tumor mutational burden was found (≥ 10 mut/Mb; 5.6% vs 6.6% vs 10.7% for respective age groups, P < .0005). The overall incidence of mismatch repair deficiency or microsatellite instability (3.6% vs 4.0% vs 7.5%, P < .0005) and DNA damage repair mutations (13.2% vs 13.9% vs 16.4%, P < .0005) also increased with age. Patients aged 75 and older were underrepresented as compared with the Surveillance, Epidemiology, and End Results database (15.2% vs 31.6%, P < .0005). The study authors concluded that genomic profiling is underutilized in older adults, who represent the majority of patients with gastrointestinal malignancies. As biomarker-driven trials are often dependent on comprehensive genomic profiling, increased use may improve clinical trial enrollment of older adults with cancer.
The differences in molecular profile of hepatocellular carcinoma in older vs younger patients were reviewed in a poster by Arora et al.12 The authors sought to analyze the association of age with genomic alterations and therapeutic response to sorafenib. In the 487 hepatocellular carcinoma samples analyzed, increased CD8-positive T cells and B cells as well as increased alterations in oncogenic drivers were observed in the elderly population. A reduced time to disease progression was noted with sorafenib in those older than age 65.
Pain among older adults diagnosed with gastrointestinal malignancies was the focus of an abstract by Al Obaidi et al.13 Data were gathered from the CARE registry. A total of 714 patients up to age 60, with a median age at diagnosis of 70 (range = 60–96 years), were included in the study. A total of 53.1% of the participants reported none or mild pain (0–3), 25.6% reported moderate pain (4–7), and 21.4% reported severe pain (8–10). Those with moderate to severe pain were more likely to report limitations in instrumental activities of daily living, limitations in activities of daily living, falls, cognitive complaints, anxiety, and depression.
Alternative Treatments to Standard-of Care Surgery for Elderly Patients
Chuong et al reported the results of a retrospective multi-institutional analysis of outcomes of patients 75 years and older with pancreatic adenocarcinoma treated with ablative stereotactic magnetic resonance image–guided adaptive radiation therapy.14 The 49 patients evaluated had a median age of 81 years (range = 75–91 years). Most received induction chemotherapy for a median of 3.2 months. The median progression-free survival and 1-year progression-free survival rate were 13 months and 53.8%, respectively. The median survival and 1-year estimated overall survival rate were 23 months and 78.9%. The median local disease control and 1-year local disease control rate were 29 months and 88%. Acute and late grade 3+ toxicity rates were 8.2% and 4.1%, respectively. This was a well-tolerated treatment option in a frail elderly population, with good local disease control and overall survival.
“The study authors concluded that genomic profiling is underutilized in older adults, who represent the majority of patients with gastrointestinal malignancies.”— Avni Desai, MD
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Another poster reviewed palliative radiosurgery for patients with localized pancreatic cancer who were not candidates for standard-of-care therapy with surgical resection or systemic therapy.15 A total of 28 patients older than age 80, median age of 84, were identified in this retrospective evaluation. Patients received five fractions of stereotactic body radiation therapy with 35 to 40 cGy. Median overall survival was 10.8 months. At 6 months, 18 patients were alive. Grade 2 toxicity was noted in four patients in the first 3 months, with no late toxicity reported. A total of 14 patients developed distant metastatic disease, and 8 patients developed local disease progression. Six patients had no disease progression at least 1 year from treatment. Sckolnik et al found this to be an effective, well tolerated, and safe palliative option for older patients who are not candidates for standard-of-care therapy.
Long-term outcomes of contact x-ray brachytherapy following external-beam chemoradiation for rectal cancer to achieve higher clinical complete response rates were reported by Myint et al.16 Responders after 5 weeks of chemoradiotherapy with small residual tumors who were not surgical candidates or declined surgery received an x-ray brachytherapy boost of 90 Gy in three fractions over 4 to 6 weeks. Of 345 patients, 83 received x-ray brachytherapy. Of these 83 patients, 53 (64%) achieved clinical complete response. After clinical complete response, 15% developed local tumor regrowth. All underwent curative resection, 80% with R0 resection. Organ preservation was achieved in 75%. Metastatic disease developed in 14% of patients. The study authors concluded that this is an alternative treatment option for elderly or otherwise frail patients who are not surgical candidates. The phase III European randomized OPERA trial will evaluate this treatment further.
A few oral abstracts focused on PD-1 blockade and or checkpoint inhibition in microsatellite instability–high (MSI-H) cancers. The high rates of complete clinical response or pathologic complete response reported are intriguing and may provide an alternative treatment option for older patients with MSI-H or mismatch repair–deficient (dMMR) cancers who are not candidates for surgery or who desire organ preservation. The early results of a phase II study of PD-1 blockade alone for dMMR locally advanced rectal cancer was presented by Dr. Lumish.17 An objective response rate of 100% was reported in the 12 of 13 patients who had undergone at least initial 3-month evaluation. All seven patients who completed induction therapy with the monoclonal antibody dostarlimab achieved complete clinical response. The median age of patients enrolled was 52 (range = 26–78 years).
Results of the GERCOR NEONIPIGA phase II study on neoadjuvant nivolumab plus ipilimumab and adjuvant nivolumab in MSI-H/dMMR esophagogastric adenocarcinoma were presented by Dr. Thierry Andre.18 The primary objective was pathologic complete response rate. A total of 32 patients were included, with a median age of 65.5 years (range = 40–80 years). Of the 29 patients who underwent surgery, all had R0 resection, and 17 (59%) had pathologic complete response. With a median follow-up of 10.9 months, 30 patients were free of recurrence or disease progression.
DISCLOSURE: Dr. Desai reported no conflicts of interest.
REFERENCES
1. Hamaguchi T, Takashima A, Mizusawa J, et al: A randomized phase III trial of mFOLFOX7 or CapeOX plus bevacizumab versus 5-FU/l-LV or capecitabine plus bevacizumab as initial therapy in elderly patients with metastatic colorectal cancer: JCOG1018 study (RESPECT). 2022 ASCO Gastrointestinal Cancers Symposium. Abstract 10. Presented January 20, 2022.
2. Gallois C, Shi Q, Meyers PJ, et al: Prognostic impact of early treatment discontinuation and early oxaliplatin discontinuation in patients treated with 6 months of oxaliplatin-based adjuvant chemotherapy for stage III colon cancer: An ACCENT/IDEA pooled analysis of 11 trials. 2022 ASCO Gastrointestinal Cancers Symposium. Abstract 11. Presented January 20, 2022.
3. Nagata Y, Amano K, Mikuni H, et al: Impact of previous adjuvant oxaliplatin combination therapy on survival in elderly colorectal cancer patients with recurrence. 2022 ASCO Gastrointestinal Cancers Symposium. Abstract 48. Presented January 20, 2022.
4. Chen B, Zhao H, Huang J, et al: Efficacy analysis of regorafenib combined with PD-1 inhibitors in elderly patients with metastatic colorectal cancer. 2022 ASCO Gastrointestinal Cancers Symposium. Abstract 105. Presented January 20, 2022.
5. Uehara H, Ota M, Matsuda Y, et al: Efficacy and safety of neoadjuvant chemotherapy for locally advanced gastric cancer in elderly patients: A phase II trial (KSCC1801). 2022 ASCO Gastrointestinal Cancers Symposium. Abstract 254. Presented January 20, 2022.
6. Hu Q, Suyama K, Kobayashi K, et al: Geriatric-8 (G8) screening tool stratified the efficacy of S-1 plus ramucirumab in elderly patients with advanced/recurrent gastric cancer: A post-hoc analysis of the KSCC1701 trial. 2022 ASCO Gastrointestinal Cancers Symposium. Abstract 256. Presented January 20, 2022.
7. Ebert MP, Meindl-Benker NM, Gutting T, et al: Nivolumab plus ipilimumab in second-line combination therapy for older patients with esophageal squamous cell cancer (AIO-STO-0117 trial). 2022 ASCO Gastrointestinal Cancers Symposium. Abstract 303. Presented January 20, 2022.
8. Arora S, Fowler M, Harmon C, et al: Differences in pretreatment frailty across gastrointestinal cancers in older adults: Results from the Cancer and Aging Resilience Evaluation (CARE) registry. 2022 ASCO Gastrointestinal Cancers Symposium. Abstract 542. Presented January 20, 2022.
9. Bai LY, Li CP, Shan YS, et al: A prospective phase II study of biweekly S-1, leucovorin and gemcitabine in elderly patients with locally advanced or metastatic pancreatic adenocarcinoma. 2022 ASCO Gastrointestinal Cancers Symposium. Abstract 550. Presented January 20, 2022.
10. Abou-Alfa GK, Chan SL, Kudo M, et al: Phase 3 randomized, open-label, multicenter study of tremelimumab and durvalumab as first-line therapy in patients with unresectable hepatocellular carcinoma: HIMALAYA. 2022 ASCO Gastrointestinal Cancers Symposium. Abstract 379. Presented January 20, 2022.
11. Elias R, Kuang Z, Murphy JE, et al: Disparities in comprehensive genomic profiling in older patients with gastrointestinal malignancies. 2022 ASCO Gastrointestinal Cancers Symposium. Abstract 646. Presented January 20, 2022.
12. Arora SP, Gandhi N, Walker P, et al: Molecular profile of hepatocellular carcinoma in older versus younger adults: Does age matter? 2022 ASCO Gastrointestinal Cancers Symposium. Abstract 477. Presented January 20, 2022.
13. Al Obaidi M, Kosmicki S, Harmon C, et al: Pain among older adults diagnosed with gastrointestinal malignancies: Results from the Cancer and Aging Resilience Evaluation (CARE) registry. 2022 ASCO Gastrointestinal Cancers Symposium. Abstract 82. Presented January 20, 2022.
14. Chuong MD, Palm R, Herrera R, et al: Multi-institutional outcomes of patients aged 75 years and older with pancreatic ductal adenocarcinoma treated with ablative 5-fraction stereotactic magnetic resonance image-guided adaptive radiation therapy (SMART). 2022 ASCO Gastrointestinal Cancers Symposium. Abstract 569. Presented January 20, 2022.
15. Sckolnik, S, Fishel R, Borazanci EH, et al: Palliative radiosurgery for localized pancreatic cancer in the elderly. 2022 ASCO Gastrointestinal Cancers Symposium. Abstract 583. Presented January 20, 2022.
16. Myint AS, Rao C, Dhadda AS, et al: Improved organ preservation with dose escalation using contact x-ray brachytherapy for good responders following external beam chemoradiotherapy: Long-term outcomes from a single institution. 2022 ASCO Gastrointestinal Cancers Symposium. Abstract 131. Presented January 20, 2022.
17. Lumish MA, Cohen JL, Stadler ZK, et al: PD-1 blockade alone for mismatch repair deficient locally advanced rectal cancer. 2022 ASCO Gastrointestinal Cancers Symposium. Abstract 16. Presented January 20, 2022.
18. Andre TA, Tougeron D, Piessen G, et al: Neoadjuvant nivolumab plus ipilimumab and adjuvant nivolumab in patients with localized microsatellite instability-high/mismatch repair deficient oeso-gastric adenocarcinoma: The GERCOR NEONIPIGA phase II study. 2022 ASCO Gastrointestinal Cancers Symposium. Abstract 244. Presented January 20, 2022.
Dr. Desai is a Board-certified internist, medical oncologist, and hematologist specializing in treating patients with gastrointestinal malignancies at Memorial Sloan Kettering Commack, New York.
