Patients with liver-only metastatic colorectal cancer (CRC) who received adjuvant chemotherapy with modified fluoropyrimidine, leucovorin, and oxaliplatin (mFOLFOX6) in addition to hepatectomy achieved superior rates of disease-free survival (DFS), according to updated results from a phase 2/3 trial (JCOG0603) published in the 

 However, more research is needed to determine how these findings will translate into overall survival outcomes.

At a median follow-up of 59.2 months (range, 26.5-95.3), the updated 5-year DFS rate was 49.8% (95% CI, 41.0%-58.0%) with mFOLFOX6 vs 38.7% (95% CI, 30.4%-46.8%) with hepatectomy alone (HR, 0.67; 95% CI, 0.50-0.92; 

 = .006). However, adjuvant mFOLFOX6 resulted in an updated 5-year OS rate of 71.2% (95% CI, 61.7% to 78.8%) vs 83.1% (95% CI, 74.9% to 88.9%) with hepatectomy alone.

“Adjuvant chemotherapy with mFOLFOX6 improves DFS compared with hepatectomy alone but causes severe adverse effects [AEs] in approximately half of the patients,” lead study author Yukihide Kanemitsu, MD, of the National Cancer Center, and colleagues, wrote. “Further follow-up and study are needed to determine whether improved DFS translates into improved OS. At this point, routine use of adjuvant FOLFOX is not universally recommended after hepatectomy for liver-only metastatic CRC.”

Hepatectomy is currently considered to be the most effective therapeutic approach for patients with liver-only metastatic CRC, as long-term survival is often unachievable with other treatment modalities. However, hepatectomy alone does not always result in complete cure. Moreover, relapse occurs in 70% to 80% of patients at 5 years—even after curative resection.

In prior studies, post-hepatectomy adjuvant chemotherapy was found to improve DFS, but determining the OS benefit derived from this approach continues to be controversial. The current recommendations for adjuvant regimens of infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX) were extrapolated from the EORTC Intergroup trial 40983 (NCT00006479), which demonstrated that perioperative FOLFOX resulted in a progression-free survival benefit, but not an OS benefit.

In this trial, investigators sought to examine the safety and efficacy of post-hepatectomy, adjuvant FOLFOX compared with hepatectomy alone for patients with liver-only metastatic CRC.

The trial enrolled patients between the ages of 20 and 75 years who had histologically confirmed, liver-only metastatic CRC. To be eligible for participation, patients had to have an R0 resection for both the primary tumor and liver metastasis, an ECOG performance status of 0 or 1, and sufficient organ function.

Patients could not have extrahepatic metastasis or recurrence, nor could they have received prior chemotherapy with oxaliplatin or other chemotherapy or radiotherapy within 3 months of enrollment. Prior adjuvant therapy without oxaliplatin following primary resection was permitted if more than 3 months had passed since the last administration.

A total of 300 participants were randomly assigned in a 1:1 fashion to receive adjuvant chemotherapy (n = 151; eligible, n = 146) or hepatectomy alone (n = 149; eligible, n = 137) via a minimization method with a random component to balance the arms on the basis of liver metastatic status (synchronous vs metachronous), number of liver metastases (≤ 3 or ≥ 4), maximum liver metastatic lesion size (< 5 cm vs ≥ 5 cm), number of metastatic lymph nodes from the primary lesion (≤ 3 vs ≥ 4), and institution.

In the adjuvant chemotherapy arm, mFOLFOX6 was initiated 56 to 84 days following hepatectomy; this course was repeated every 2 weeks for 12 courses until progressive disease or intolerable toxicity.

Treatment was discontinued if recurrence was diagnosed clinically or based on imaging findings. Discontinuation was also elected if a serious AE occurred, if the treatment course was delayed for more than 28 days because of an AE, if a third dose reduction because of AEs was required, if the patient declined treatment, or if judged necessary by the attending physician for other reasons.

The primary end point of the trial was DFS, and the key secondary end points included OS, incidence of AEs, and patterns of recurrence.

Patient characteristics were well balanced between the treatment arms. The median age of the hepatectomy-alone group was 65 years (range, 58-69) compared with 63 years (range, 56-69) in the mFOLFOX6 group. In the investigative and control arms, 83% and 81% of patients, respectively, had 0 to 3 metastatic lymph nodes from the primary tumor and 17% and 19% of patients, respectively, had 4 or more nodes.

Regarding the number of liver metastases, 91% of patients in the hepatectomy-alone arm had 1 to 3, as did 90% of those in the chemotherapy arm; 9% and 10% of patients, respectively, had 4 or more. Moreover, in the control and investigative arms, 55% and 56% of patients, respectively, had synchronous liver metastasis, and 45% and 44% of patients, respectively, had metachronous liver metastasis. The maximum liver metastatic lesion size was less than 5 cm in 87% and 85% of patients, respectively; it was 5 cm or larger in 13% and 15% of patients, respectively.

In the chemotherapy arm, 85 patients (56%) completed the 9 courses of mFOLFOX6, and 67 (44%) completed the planned 12 courses. Additionally, 10 patients (7%) did not start treatment and were excluded from the safety analysis.

Additional data showed that the 3-year DFS rates with chemotherapy and hepatectomy-alone were 52.7% (95% CI, 44.0%-60.7%) and 42.6% (95% CI, 34.3%-50.6%), respectively. The 3-year OS rates in the investigative and control arms were 87.2% (95% CI, 80.2%-91.9%) and 91.8% (95% CI, 85.7%-95.4%), respectively.

DFS subgroup analyses revealed an advantage with chemotherapy over hepatectomy alone except primary site and prior treatment received. In contrast, OS subgroup analyses indicated that no subsets derived benefit from chemotherapy. Another observation was that those who received adjuvant chemotherapy without oxaliplatin following primary resection experienced poorer prognosis than those who did not have prior treatment.

“There was a tendency for an interaction between primary site and treatment for DFS and between prior treatment and treatment for OS,” the study authors noted.

Additionally, more patients who received hepatectomy alone experienced disease recurrence vs those who received chemotherapy, at 56% and 45%, respectively. Recurrence in the remnant liver proved to be more prevalent in the control arm vs the investigative arm, at 51% and 37%, respectively. However, recurrence in the lungs and other distant metastasis proved to be more prevalent in the investigative arm vs the control arm, at 63% and 48%, respectively.

In terms of safety, the most common grade 3 or higher severe AEs in the chemotherapy arm (n = 141) were neutropenia (50%), followed by sensory neuropathy (10%) and allergic reaction (4%). One patient died of unknown cause after receiving 3 courses of mFOLFOX6.

“A future prospective randomized study is needed to investigate the role of biomarkers in determining subgroups that might benefit from chemotherapy after hepatectomy for liver-only metastatic CRC,” the study authors concluded.

Kanemitsu Y, Shimizu Y, Mizusawa J, et al. Hepatectomy followed by mFOLFOX6 versus hepatectomy alone for liver-only metastatic colorectal cancer (JCOG0603): a phase II or III randomized controlled trial. 

. 2021;39(34):3789-3799. doi:10.1200/JCO.21.01032

Kemeny N. The management of resectable and unresectable liver metastases from colorectal cancer. 

. 2010;22(4):364-73. doi:10.1097/CCO.0b013e32833a6c8a

Nordlinger B, Sorbye H, Glimelius B, et al. Perioperative FOLFOX4 chemotherapy and surgery versus surgery alone for resectable liver metastases from colorectal cancer (EORTC 40983): long-term results of a randomised, controlled, phase 3 trial. 

. 2013;14(12):1208-1215. doi:10.1016/S1470-2045(13)70447-9

Nordlinger B, Sorbye H, Glimelius B, et al. Perioperative chemotherapy with FOLFOX4 and surgery versus surgery alone for resectable liver metastases from colorectal cancer (EORTC Intergroup trial 40983): a randomised controlled trial. 

. 2008;371(9617):1007-1016. doi:10.1016/S0140-6736(08)60455-9

This article was originally published on OncLive as “Hepatectomy Plus Adjuvant mFOLFOX6 Improves DFS in Liver-Only Metastatic CRC”

Articles

Disease-free survival in liver-only metastatic CRC was significantly improved by introducing adjuvant mFOLFOX6 chemotherapy to hepatectomy

Adjuvant mFOLFOX6 Increases Hepatectomy Efficacy, Improves DFS in Liver-Only Metastatic CRC

Despite years of negative clinical trials and minimal advancement, frontline immunotherapy regimens are beginning to show significant promise in revamping the treatment landscape of gastrointestinal (GI) malignancies, including upper GI cancer and hepatocellular carcinoma (HCC), explained Syma Iqbal, MD.

According to Iqbal, the next research steps involve determining optimal sequencing with these drugs.

“The biggest [advance] in GI oncology has been the addition of immunotherapy,” said Iqbal in an interview during an 

® Institutional Perspectives in Cancer (IPC) webinar on GI malignancies. “We have had VEGF inhibitor therapy in some format across tumors in GI oncology, including gastric and colon cancers, as well as HCC with the TKIs. Now, by incorporating immunotherapy we have made advances across these disease types in GI oncology.”

In the interview, Iqbal, co-chair of the IPC event, shared the main highlights from the meeting, which centered on the evolving landscapes and importance of implementing best practices for patients with hepatobiliary cancers, locally advanced and advanced pancreatic cancer, advanced gastric/gastroesophageal junction (GEJ) cancer, and metastatic colorectal cancer (mCRC). Iqbal is an assistant professor of medicine, assistant program director of the Oncology Fellowship Program, educational officer, co-director of the Liver Cancer Program in the Division of Oncology at the Keck School of Medicine at the University of Southern California.

®: During the IPC meeting, your presentation discussed the emergence of checkpoint inhibitors and targeted therapy in gastric/GEJ cancer. What have been some of the most significant changes to this paradigm?

: This has been a big year for upper GI tumors. We’ve had several positive studies after a very long time of multiple negative trials. We’ve been able to incorporate checkpoint inhibitors into the frontline setting in HER2-negative and HER2-positive disease. That has been the biggest change we have had this year.

Also, in the adjuvant setting, checkpoint inhibitors have been approved for patients with GEJ and esophageal adenocarcinoma, having shown a doubling in disease-free survival. That was a huge step forward for upper GI tumors.

Although it has been a good year, [the advances] have thrown a wrench into ongoing studies and studies that were designed. Oncologists who are working on those studies need to take a step back to figure out how we are going to deal with this new standard to still investigate new [strategies] for the future.

Do you foresee any of the protocols of the ongoing trials being amended to incorporate the new standards?

Many of the protocols are being amended to incorporate immunotherapy, at least into the standard-of-care arms. The trials that don’t include immunotherapy as standard of care are going to suffer. We are already seeing that because patients are coming in and asking for immunotherapy. Patients are aware of it; they see commercials on television. Now that there are data to support it, it is a hard discussion with patients to offer them something that doesn’t include [immunotherapy].

As it stands, the immunotherapy approvals are for all-comers, whereas the guidelines recommend the therapies for more specific indications. Do you anticipate modifications will be made to the guidelines to broaden the recommendations?

More is likely to come on that as these approvals get reviewed, but that is correct. The National Comprehensive Cancer Network guidelines came out prior to the FDA approvals. When the guidelines for [nivolumab (Opdivo)] in HER2-negative patients were proposed, they were based on CheckMate649 [NCT02872116], where the primary end point was a combined positive score [CPS] of 5 or greater. The guidelines reflected that and are recommended for patients who have a CPS of 5 or greater. The FDA gave a broad approval [to nivolumab plus chemotherapy] for all-comers as it appeared that all-comers benefitted. However, if we look at the subgroups, the benefit in the CPS less than 5 population is quite small, if at all.

This will continue to evolve because there may be some modifications around the approval. For now, [immunotherapy] is something that can be offered to all patients. At most academic centers in the upper GI oncology world, it seems that patients with a CPS less than 5 are receiving other therapeutics or non-immunotherapy combinations.

We also saw the FDA approval of fam-trastuzumab deruxtecan-nxki (Enhertu) in the second-line setting for patients with HER2-positive gastric/GEJ cancer paradigm. What is next for that agent?

We would like to hear more about trastuzumab deruxtecan in the second-line setting. Although [the approval was based on] phase 2 data, we also have data in refractory disease. We haven’t seen a positive trial for HER2 suppression after frontline HER2-directed therapy plus chemotherapy. That was also a promising step forward for second-line therapy for patients with HER2-positive disease that offers continued benefit.

During the IPC meeting, Heinz-Josef Lenz, MD, FACP, of the USC Norris Comprehensive Cancer Center, discussed the evolving treatment landscape of mCRC. How is the field navigating salvage-line treatment selection and sequencing?

The first thing that he emphasized was profiling these tumors to know exactly how best to treat specific populations. We’ve learned a lot more about the BRAF-mutant population with the use of encorafenib [Braftovi]. The combination [of encorafenib/binimetinib (Mektovi)/cetuximab (Erbitux)] showed more toxicity but not necessarily an improvement in outcome.

The other relevant information from his talk was regarding sequencing of the many therapeutics that we have. There has been hesitancy to use drugs like regorafenib [Stivarga] and TAS-102 [trifluridine/tipiracil; Lonsurf] based on the randomized data that we have because oncologists feel there isn’t much benefit to using these drugs. However, the regorafenib data that were presented [were encouraging], particularly with the ReDOS trial [NCT02368886] that showed that starting patients on a low dose of regorafenib [allows them to] tolerate the therapeutic better. This is likely because patients were able to stay on therapy.

We don’t pay enough attention to sequencing in CRC, and that is particularly so when going to the refractory setting to choose regorafenib or TAS-102. Dr Lenz’s presentation gave strong support for the use of appropriately dosed regorafenib up front in patients with good performance status and adequate albumin. Those patients tend to do better when started with regorafenib in the refractory setting vs starting with TAS-102.

Steven Grossman, MD, PhD, of USC Norris Comprehensive Cancer Center, discussed ensuring best approaches are utilized for patients with locally advanced pancreatic cancer in his presentation. What has been learned as a community about treatment selection between FOLFIRINOX or gemcitabine/nab-paclitaxel (Abraxane) in that setting?

For locally advanced and borderline resectable disease, we as a community have used modified FOLFIRINOX [mFOLFIRINOX], assuming it was better than gemcitabine/nab-paclitaxel. We learned from the SWOG-S1505 trial [NCT02562716] that in the perioperative setting, there was no difference in outcome whether patients got mFOLFIRINOX or gemcitabine/nab-paclitaxel up front.

Something about locally advanced disease is that we still must incorporate assessment of the whole patient when choosing a regimen. Otherwise, it seems that radiation remains controversial, and these patients are treated similarly to patients in the advanced-stage setting. We don’t have an optimal pathway for all-comers. These are unique, tailored approaches to individual patients in the locally advanced setting.

Are you more inclined to select mFOLFIRINOX or gemcitabine/nab-paclitaxel for fit patients with locally advanced disease?

To be honest, most people are still more inclined to use mFOLFIRINOX. We are swayed by the metastatic data, even though the local randomized data look similar. As we are evaluating patients, we are still looking at other factors like performance status, comorbidities, and [patient preference] knowing that it is not necessarily going to impact outcome if we use gemcitabine/nab-paclitaxel in that patient population. We always feared that it was inferior based on the metastatic data, but they’re 2 separate trials.

With that in mind, Diana Hanna, MD, of the Hoag Family Cancer Institute, gave a presentation on novel combination strategies for patients with advanced pancreatic cancer. What is the significance of profiling pancreatic cancer tumors to inform treatment selection with PARP inhibition?

For a long time now, we have become comfortable with the use of FOLFIRINOX or mFOLFIRINOX and gemcitabine/nab-paclitaxel as standard regimens in this disease. The steps forward are related to profiling these tumors, specifically [to identify] 

 mutations. This is the first time now in pancreas cancer where profiling has impacted outcome. The use of PARP inhibition with olaparib [Lynparza] as maintenance therapy in the 

-[mutated] population is relevant to care, so profiling should occur prior to starting patients on therapy. The protein profiling is also assessing for the very small number of patients who have microsatellite instability–high disease so we can try to incorporate immunotherapy.

It’s very disappointing that the study with the CPI compound that targeted the Krebs cycle was negative. People thought that was going to be positive, as we always do in the early phase when the data look so promising. That was disappointing, but it will be interesting to see the formal presentations to see if there was any subgroup that benefitted from that agent.

Finally, your co-chair Anthony El-Khoueiry, MD, of USC Norris Comprehensive Cancer Center, discussed shifting treatment strategies for patients with hepatobiliary cancers. How has this field evolved from an area of significant need to one with a crowded armamentarium? What challenges with regard to sequencing have arisen amid recent FDA approvals?

We’ve seen huge changes in hepatobiliary cancer. We have several positive trials now in the frontline setting combining immunotherapy with VEGF inhibitors, both using agents such as bevacizumab [Avastin] and TKIs. That has been a big change in how we approach clinical care in HCC. We now have options in the frontline setting for these patients, including the combination of atezolizumab [Tecentriq] plus bevacizumab and immunotherapy plus CTLA-4 inhibitors.

What this has done in HCC is confuse us because it has created an issue where we don’t know how to sequence these patients or pick the best first-line regimen. Why do we need another frontline regimen when we have atezolizumab/bevacizumab, which looks good? [It’s because] many of these patients may not be candidates for bevacizumab because of varices, history of recent bleeds, or platelet counts. Having an alternative frontline option opens the door for therapeutics to a population that wouldn’t have been candidates for [atezolizumab/bevacizumab].

The challenge now in HCC is [determining] how to sequence the TKIs and what to use in the second-, third-, and fourth-line settings. Many of these patients with Child-Pugh A cirrhosis can go through multiple lines of therapy. Anytime we have options, it confuses us more, but it is a great place for us to be. HCC has had huge changes and there is more to come here.

Given the heterogeneity of the patients who present with comorbidities related to varices, bleeding, or portal hypertension, having an alternative to a risky drug like bevacizumab [is important]. Now we just have to determine what do we do with everything else.

In cholangiocarcinoma, we have also seen significant changes. What is most relevant here is the importance of profiling these tumors. We know that 

 mutations are relevant to the treatment of this disease. This wasn’t a disease that most folks were profiling before, but now that we have interesting data looking at moving immunotherapy in the frontline setting for these patients, [profiling is important]. We are also awaiting results from a phase 2 trial [NCT02392637] evaluating the triplet of nab-paclitaxel plus standard gemcitabine/cisplatin. We will see whether there is a further change to our standard of care up front in cholangiocarcinoma.

This article was originally published on OncLive as “Immunotherapy Approvals Overcome Years of Stagnation in GI Cancers”

Event co-chair, Syma Iqbal, MD, discusses key points from a recent OncLive® Institutional Perspectives in Cancer webinar, which focused on the evolving landscapes in gastrointestinal cancer. 

Immunotherapy Approvals Propel the Future of GI Cancer Treatment 

Fast-mimicking dieting (FMD) was found to be safe, feasible, and potentially beneficial for patients with various solid tumor types and who were receiving different anticancer therapies, according to a study published in 

. The diet, which involved short-term, severe caloric restriction was associated with a decrease in blood glucose and growth factor concentration, as well as a reduction in peripheral blood immunosuppressive cells, and enhanced intratumor T-cell infiltration, among this population.

Among 99 evaluable participants, the median plasma glucose concentration reduction was 18.6%, the serum insulin reduction was 50.7%, and the serum IGF-1 reduction was 30.3%. Throughout the 8 consecutive cycles, these results remained consistent.

“Our results from a first-in-human clinical trial showed that a scheme of severe short-term calorie restriction was safe and biologically active in patients, and that its activity likely involved the activation of immune responses,” said co-author Claudio Vernieri, MD, PhD, Fondazione IRCCS Istituto Nazionale dei Tumori and the director of the Metabolic Reprogramming in Solid Tumors program at the FIRC Institute of Molecular Oncology, in Milan, Italy, in a press release. “Since calorie restriction is a safe, inexpensive, and potentially effective approach that could be easily combined with standard antineoplastic therapies, we think these findings might have relevant implications for cancer therapy.”

The study assessed a total of 101 patients. These participants had a variety of tumor types and were receiving various standard anticancer therapies. The global compliance rate among these participants was 91.8%; compliance in this case was defined as observing all 8 FMD cycles.

The most common adverse event (AE) associated with the dieting technique was fatigue and was rarely severe (12.9%). Thus, the trial met its primary safety end point.

The diet itself involved the following cycle: 5-days of low-carbohydrate, low-protein, plant derived dieting amounting to a total of 1800 calories (600 calories on day 1 and 300 calories on the subsequent 4 days). This cycle was followed by a period or regular eating for about 3 to 4 weeks and followed by another cycle. The study period involved 8 total cycles. When patients were not observing the FMD cycle, they were not restricted to any dietary regulations, but were encouraged to adhere to a healthy diet and lifestyle.

The loss of body weight that occurred during the 5 days of severe calorie restriction was reversible in most of the patients during the refeeding period.

“This is an especially important finding, because it excludes the risk that patients might undergo progressive weight loss and/or malnourishment, which are associated with reduced efficacy of anticancer therapies and reduced survival,” added Filippo de Braud, MD, director of the Oncology and Hematology Department of Fondazione IRCCS Istituto Nazionale dei Tumori and professor of medical oncology at the University of Milan in Milan, Italy.

Researchers determined that at the conclusion of the 5-day restricted calorie diet, patients had a significant decrease in circulating immunosuppressive myeloid subpopulations and an increase of activated CD8+ T cells. Notably, the various concomitant antitumor therapies did not impact these results. Additionally, a group of cancer-free volunteers also produced the same effects.

To corroborate the findings, researchers also performed an interim analysis of another ongoing trial (DigesT; NCT03454282). Patients in this trial were asked to complete a 5

day FMD cycle 7 to 10 days before undergoing surgery for early-stage breast cancer or melanoma. The tumor-infiltrating immune cells and transcriptomic immune profiles revealed a significant increase in tumor-infiltrating CD8+ T cells and other changes, suggesting that FMD induces an antitumor immune microenvironment.

The study authors concluded that the experimental diet generated favorable immunomodulatory effects at both the systematic and the tumor level. These findings indicate that a coherent immune response originates in the blood and consequently propagates to the tumor.

The main study limitations are related to the heterogeneous nature of the participants; because the patients all had different tumor type and concomitant anticancer therapies, researchers could not conclude the antitumor efficacy of the caloric restriction.

Consequently, the authors have helped to launch a series of new clinical trials, including the BREAKFAST trial (NCT04248998), which will seek to better understand the antitumor effects of the FMD diet among patients with solid tumors. Researchers hope to uncover ways in which diet and caloric restrictions may improve the potency of antineoplastic therapies and potentially prolong the life expectancy of patients in this population.

Fasting-mimicking diet is safe, may modulate metabolism and boost antitumor immunity in cancer patients. American Association for Cancer Research. News release. November 17, 2021. Accessed November 29, 2021. https://bit.ly/3ELIaZS

Patients with various solid tumor types experienced improved antitumor immunity after adhering to a diet with severe caloric restrictions.

Fast-Mimicking Diet Is Potentially Beneficial for Patients With Solid Tumors

Findings from a research letter published in 

 demonstrate that the number of pancreatic cancer incidences increased overall between 2000 and 2018.

 Moreover, the number of cases among woman younger than 55, particularly between 15 to 35 years, grew significantly.

The results showed a significant increase in the average annual percentage changes of the total pancreatic cancer cases in women (0.78%; 95% CI, 0.68%-0.88%; 

 <.001) and in men (0.90%; 95% CI, 0.82%-0.99%; 

 <.001). There was no statistically significant difference between sexes (0.12%; 95% CI, 0%-0.25%; 

The incidence rates were considerably lower among the 32,369 patients younger than 55 years (11.4% of cases; 43% women). However, the data showed a greater relative increase in incidence among women younger than 55 years (1.93%; 95% CI, 1.57%-2.28%; 

 < .001) vs men in the same age category (0.77%; 95% CI, 0.50%-1.05%; 

 < .001), indicating nonequal trends (

“These findings are important because this is the first time, using the most current data, that we are reporting that pancreatic cancer rates are increasing dramatically in women who are younger than 55,” lead study author and assistant professor of medicine at Cedars Sinai, Srinivas Gaddam, MD, said in a press release.

 “The findings are most dramatic in women less than 35 years old.”

Pancreatic cancer is the fourth leading cause of cancer-related mortality with a 5-year survival rate of approximately 10%. Noncomparative data from 2013 showed a rising increasing incidence of pancreatic cancer in older White women and men and in younger non-Hispanic White women. However, limited data exist regarding current patterns in pancreatic cancer incidence. As such, Gaddam and colleagues conducted an age- and sex-specific time trend analysis of pancreatic cancer incidence rates.

Pancreatic cancer incidence rates per 100,000 population were collected from 2000 to 2018 from the Surveillance Epidemiology and End Results database. A total of 283,817 diagnoses were recorded in the database, 50% which occurred in women. These data were age-adjusted to the 2000 United States population and adjusted for the reporting delay.

Patients younger than 55 years were termed younger adults and those aged 55 years or older were termed older adults. Investigators also conducted post-hoc analysis for patients aged the 15 to 34 years and for those aged 35 to 54 years.

Further results demonstrated that, among patients aged 55 years or older (n = 251,360; 51% women), the average annual percentage changes increased among women (0.62%; 95% CI, 0.51%-0.74%; 

 <.001) but more so in men (0.92%; 95% CI, 0.82%-1.01%; 

 < .001), reflecting nonequal trends (

To better understand the pattern reversal, the cohort of patients under the age of 55 years was split into 2 subgroups: 35 to 54 years (n = 30,831; 10.9%) and 15 to 34 years (n = 1538; 0.54%).

Women aged 35 to 54 years had a greater relative increase in incidence rates (n = 13,139; average annual percentage change, 1.56%; 95% CI, 1.24%-1.87%; 

 <.001) compared with men (n = 17,692; average annual percentage change, 0.65%; 95% CI, 0.38%-0.91%; 

 <.001). Investigators also reported nonequal trends (

Women aged 15 to 34 years also had a greater relative increase (n = 896; average annual percentage change, 7.68%; 95% CI, 6.21%-9.18%; 

 <.001) vs men (n = 642; average annual percentage change, 4.20%; 95% CI, 2.54%-5.90%; 

 <.001), again demonstrating nonequal trends (

“We don’t know the causes yet. Women with abdominal pain should not run to their primary care physicians and ask for a CT scan,” Gaddam said. “The incidence of this cancer is still very low in young people. We’ve identified this risk because we want to know what’s causing the significant upward trend. Also, are we catching it early? Will it continue for decades to come? Our goal is to find the answers to those and other questions.

“Future studies should validate these findings in other large population-based cohorts,” Gaddam concluded.

Gaddam S, Abboud Y, Oh J, et al. Incidence of pancreatic cancer by age and sex in the US, 2000-2018. 

. Published online October 24, 2021. Accessed October 29, 2021. doi:10.1001/jama.2021.18859

Study: incidence of pancreatic cancer rising in younger women. News release. Cedars Sinai. October 25, 2021. Accessed October 29, 2021. https://ceda.rs/3pPL9M0

This article was originally published on OncLive as “Pancreatic Cancer Incidence Rises, Notably Among Younger Women”

Between 2000 and 2018, the number of pancreatic cancer cases rose, particularly among women between the ages of 15 to 35 years.

 Pancreatic Cancer Cases Climbing, Especially in Younger Women

Ivosidenib (Tibsovo) was associated with a favorable overall survival (OS) and a tolerable safety profile in patients with advanced chemotherapy-refractory cholangiocarcinoma and an 

 mutation, according to updated findings published in 

. In addition, the findings indicate that patients receiving ivosidenib did not experience a decline in quality of life (QOL).

In the final analysis, ivosidenib was associated with a median OS of 10.3 months (95% CI, 7.8-12.3 months), compared with placebo which resulted in an OS of 7.5 months (95% CI, 4.8-11.1). After adjusting for crossover, the median OS associated with placebo was 5.1 months (95% CI, 3.8-7.6; HR, 0.49; 95% CI, 0.34-0.70; 

“The efficacy data and tolerable safety profile, as well as supportive QOL data, demonstrate the clinical benefit of ivosidenib compared with placebo for patients with this aggressive disease in which there is an unmet need for new therapies,” stated Andrew X. Zhu, MD, PhD, Department of Medicine, Massachusetts General Hospital Cancer Center, and colleagues in the study.

The ClarIDHy trial (NCT02989857) was a randomized, double-blind, placebo-controlled, clinical phase 3 trial which assessed a total of 187 pretreated patients with cholangiocarcinoma and an 

 mutation. Participants needed to have at least 1 but no more than 2 prior treatments for advanced disease (nonresectable or metastatic), gemcitabine or a fluorouracil-based chemotherapy regimen, and were not able to have received already received an IDH1 inhibitor.

The study incorporated 49 hospitals across 6 countries and ran between February 20, 2017, to May 31, 2020. All patients were 18 years or older and the median age was 62 years.

Notably, out of the 61 patients randomly assigned to receive placebo, 48 crossed over to treatment with ivosidenib following disease progression determined by radiographic findings.

The main outcome for this trial was progression-free survival (PFS), which was previously reported.2 Ivosidenib was associated with a 63% reduction in the risk of progression in this patient population.

The key secondary end point was OS, but additional secondary outcomes included objective response rate (ORR), safety tolerability, and QOL.

Notably, patients receiving placebo experienced declines of -12.6 (3.9) in QLQ-C30 physical functioning between day 1 of cycle 2 and day 1 of cycle 3. In comparison, patients receiving ivosidenib preserved their function and only lost -0.2 (1.9; 95% CI, 3.9-20.8; 2-sided 

 = .004). Ivosidenib was also favored in all other QLQ-C30 included subscales, including emotional function, cognitive functioning, and dyspnea, as well as in QLQ-BIL21 anxiety and tiredness.

Both treatment groups experienced treatment-related nausea. Forty-two percent of the ivosidenib group and 29% of the placebo group reported some degree of nausea. Ascites was the most common treatment-emergent adverse event (TEAE) reported at grade 3 or higher in both groups (9% with ivosidenib and 7% with placebo). Other TAESs experienced at grade 3 or higher included anemia (7% vs 0%, respectively), increased blood bilirubin level (6% vs 2%), and hyponatremia (6% vs 10%).

Six patients in the ivosidenib cohort died during the trial. These deaths are considered to be related to the underlying disease or comorbid conditions and ivosidenib-related complications. Forty-two patients receiving ivosidenib experienced a serious TEAE. Researchers believe that only 3 of those patients’ reactions were associated with treatment. Fourteen patients receiving placebo also reported serious TEAEs, none of which were treatment related. Twelve patients receiving ivosidenib and 2 patients receiving placebo reported Prolonged QT interval on electrocardiogram.

A total of 5 patients in the experimental arm needed a dose reduction, compared with none in the placebo group. A total of 9 patients on ivosidenib required drug discontinuation because of TEAEs, in comparison to 5 patients in the placebo group.

“To some extent, the population in this trial represents a real-world population in that patients receiving second-line and third-line treatment were included and there were no exclusions for comorbid conditions, such as ascites, pleural effusions, or biliary stents. In fact, more than 90% of patients had metastatic disease at baseline, and approximately 25% had baseline ascites,” summarized study authors. “Ivosidenib provides an alternative therapeutic option for patients in need of new noncytotoxic treatments that can target tumors, delay progression, preserve QOL, and potentially extend survival.

The study did include some limitations. Because crossover was allowed, the authors stated that it is likely the primary analysis of OS was cofounded. In addition, the findings on QOL were limited by the small sample sizes; data were on day 1 of cycle 2 and day 1 of cycle 3 in response to the rapid progression and subsequent withdrawal from the study which is associated with the disease.

Finally, the lack of on-site biopsy limited the ability to understand mechanism of resistance. Future studies should seek to assess the relapse mechanisms using circulating tumor DNA sequencing.

Zhu AX, Macarulla T, Javle MM, et al. Final Overall Survival Efficacy Results of Ivosidenib for Patients With Advanced Cholangiocarcinoma With 

 Mutation: The Phase 3 Randomized Clinical ClarIDHy Trial. 

 Published online September 23, 2021. doi:10.1001/jamaoncol.2021.3836

Abou-Alfa GK, Macarulla T, Javle MM, et al. Ivosidenib in IDH1-mutant, chemotherapy-refractory cholangiocarcinoma (ClarIDHy): a multicentre, randomised, double-blind, placebo-controlled, phase 3 study [published correction appears in Lancet Oncol. 2020 Oct;21(10):e462]. 

. 2020;21(6):796-807. doi:10.1016/S1470-2045(20)30157-1

A final analysis of the phase 3 ClarIDHy trial revealed that OS was superior in patients receiving ivosidenib, despite a high crossover rate from the placebo group. 



Ivosidenib Continues To Show Benefit for Patients with IDH1-Mutant Cholangiocarcinoma

Coordination between oncology and primary care teams to care for underinsured and uninsured cancer survivors remains a challenge, suggested a new study published in 

Investigators interviewed 93 health care providers in a qualitative study and asked them to describe opportunities and challenges to coordinate care between oncology and primary care teams. The study defined survivors as patients with a stage I, II, or II diagnosis, who have completed cancer treatment (including chemotherapy, radiation, and/or surgery) and who have initiated the surveillance stage of their cancer care journey.

Key challenges included difficulties accessing primary care providers (PCPs), a lack of communication between oncology and primary care teams, role delineation from both sides of the care continuum, and a lack of clinician knowledge and preparedness.

“These findings suggest that, given interdependencies between levels within a single health system, awareness and engagement by system leadership may be needed to create the conditions necessary to actualize and sustain communication across teams to support comprehensive cancer survivorship care,” wrote Bijal A. Balasubramanian, MBBS, PhD, and colleagues, in the paper. “One immediate target is closed-loop communication, ensuring both vertical and horizontal communication pathways. Health information technology tools may also foster team effectiveness by better identifying high-risk patients, monitoring outcomes, and managing task interdependence during transitions in care.”

Difficulty accessing primary care was 1 of the most common problems reported by patients, particularly for those without a preexisting PCP. Although oncology nurses routinely referred patients with chronic conditions such as diabetes and hypertension to primary care, many patients faced wait times longer than 6 months before being seen.

Communication was another critical issue that concerned both oncology teams and PCPs. Investigators noted that oncology teams often expect the patient to communicate treatment symptoms to their PCP; however, because patient’s communication with PCPs are often less frequent and/or regular than their communication with their oncology team, and because cancer therapies can worsen preexisting chronic conditions, substantial consequences are a potential concern.

The lack of communication often translated into role delineation for cancer surveillance testing. For example, in the case of mammograms for survivors of breast cancers, both groups agreed that the oncology care team should manage surveillance for the first 5 years, however, they disagreed on who should manage surveillance for survivors of 10 years or more.

“Who is supposed to follow that cancer follow-up frequency? Is Oncology [going to] do it or primary care has to do it?” remarked one PCP in the study. “So, if they can put ‘We continue to follow’ [in the EMR], or if the patient is discharged from oncology and primary care has to follow up or whatever, then make that really more clear.”

“The ideal thing would be a survivorship program to see all survivors, at all stages. But [the Medical Oncology Clinic] doesn’t have the bandwidth to take all survivors now,” added an oncology clinician.

Some PCPs felt that it would be better for the oncology care team to maintain surveillance because it is common for patients to fall out of their primary care routine. One PCP even expressed that “Cancer is not like any other disease. We really have to be very careful. If you leave [cancer surveillance] with the PCP … [patients] might not show up ... I don’t want patients to fall through the cracks.”

Furthermore, a number of PCPs expressed that they felt uncomfortable managing cancer-related pain and prescribing medications to help manage long-term treatment-related adverse events (AEs). Many PCPs shared that they were unfamiliar with the AEs their patients were experiencing and the prescriptions commonly used to treat them.

“I have a patient with [brain metastases]…and he was started on 3 seizure medications, and he doesn’t have seizures but I guess they have a role in treating headaches. He’s on 3 medications that I am not familiar with. The last 3 [or] 4 months, the medication refill comes to me ... I am uncomfortable with these 3 medications. I don’t prescribe 3 seizure medications to treat a headache,” said a PCP.

“Care coordination for underinsured and uninsured cancer survivors with comorbidities will continue to be an important issue given changing US demographics, early detection, and advances in cancer therapies that have extended cancer survivorship,” concluded the study authors. “Without robust communication systems and care pathways between primary care and oncology, such patients are at risk of increasingly poor outcomes, exacerbated by the patchwork nature of the US health care system. Closed-loop communication, role clarification, leadership support, and health information technology improvements to comanage patients during care transitions may provide a start toward enhanced team-based care.”

One notable limitation was that investigators spoke to providers whose patients sought oncology and primary clinics that were owned and operated under the same governance. The authors acknowledged that patients who seek specialty care independent of their primary care might face more severe access barriers. Future research should seek to assess how to better facilitate communication across external oncology practice partners, in addition to clinics operating under the same governance as the PCP.

Balasubramanian BA, Higashi RT, Rodriguez SA, Sadeghi N, Santini NO, Lee SC. Thematic analysis of challenges of care coordination for underinsured and uninsured cancer survivors with chronic conditions. 

 2021;4(8):e2119080. doi:10.1001/jamanetworkopen.2021.19080

A recent study identified some of the key challenges in coordinated care for underinsured and uninsured cancer survivors who have initiated the surveillance stage of their journey.

Stronger Coordination with PCP a Necessity in Caring for Cancer Survivors  

For this episode of “The Vitals,” we spoke with Kristin Barber, FNP-BC, AOCNP, Huntsman Cancer Institute, about understanding the MAP kinase signaling pathway and some of the ongoing trials targeting these mutations in gastrointestinal oncology.

Barber discussed some of the ongoing phase 1 trials she is participating in and how she hopes the results of these trials could change patient outcomes following targeted treatment.

Podcasts

“Previously, this mutation has been undruggable, but this is now changing.”



Targeting KRAS Mutations in Gastrointestinal Oncology 

Because salvage regorafenib (Stivarga) and trifluridine/tipiracil (TAS-102; Lonsurf) has only induced modest responses in metastatic colorectal cancer (mCRC) thus far, investigators are examining salvage therapy plus TKIs or checkpoint inhibitors as combination strategies for patients with mismatch repair proficient [pMMR] tumors, shared Kanwal P.S. Raghav, MBBS, MD.

Moreover, Raghav highlighted that molecular profiling is critical to identify patients with certain subtypes of mCRC, guide treatment decisions, and optimize available therapies prior to salvage options.

“These are essential discussions in the treatment of patients with mCRC because by the time most patients reach [the salvage-line setting], they have a larger burden of disease and may be sicker. Therefore, appropriate treatment selection is important to improve their outcomes and preserve their quality of life [QOL],” said Raghav, an associate professor in the Department of Gastrointestinal (GI) Medical Oncology in the Division of Cancer Medicine, and medical director of the Division of Ambulatory Treatment Centers at The University of Texas MD Anderson Cancer Center, in an interview with Oncology Nursing News®’ sister publication OncLive® during an Institutional Perspectives in Cancer (IPC) webinar on gastrointestinal malignancies.

The virtual meeting covered the evolving treatment landscape of mCRC, emerging options in hepatocellular carcinoma (HCC), and significant updates in gastroesophageal cancer.

In the interview, Raghav, who chaired the event, discussed nuances to treatment selection in mCRC, the significance of the phase 2 ReDOS trial (NCT02368886) with regorafenib, and how the paradigms for mCRC, HCC, and gastroesophageal cancers have expanded from areas of unmet need to ones with more robust armamentariums.

®: How do you approach treatment selection for patients with mCRC? Should molecular testing be considered in all cases?

: [Patients with] mCRC [are] treated with a wide variety of agents, and [treatment selection] is based on molecular profiling and what subset of mCRC [a patient] has. In most cases, patients will get first-line treatment or second-line treatment and subsequently third-line treatment. With recent developments, the definition of these lines of treatment is getting blurred; however, most patients with mCRC will progress through their initial lines of therapy and reach a point of salvage therapy.

Broadly speaking, CRC [management] is a compendium of cytotoxic chemotherapy, some targeted agents, immunotherapy, and some salvage [therapies]. In a general sense, if we think about the workup of a patient with mCRC, I am a big advocate of up-front molecular profiling [because] there are 2 advantages. [Molecular profiling] changes the patient’s standard-of-care management in a big way. Also, we can think ahead in the future to prep these patients for clinical trials, especially if we can identify rare subsets of tumors.

Broadly, when we start with CRC treatment, the first decision [depends on whether patients have] microsatellite instability–high [MSI-H] or mismatch repair deficient [dMMR] tumors. If we have [a patient with] a dMMR tumor—which [comprise] 4% to 5% of all mCRC—the treatment is up-front immunotherapy. This [is based on] the [KEYNOTE-177 study (NCT02563002), which evaluated] pembrolizumab [Keytruda] vs chemotherapy. [The] study showed a significant improvement in overall survival [with pembrolizumab]. All of these patients [with dMMR CRC] should receive up-front immunotherapy [because] that is more effective and better tolerated [vs chemotherapy].

Once we have removed the MSI-H/dMMR subset, we move to the pMMR group, which is larger. Within this group, there are a couple of subsets, including 

-mutant CRC, which [accounts for] about 50% to 55% of all CRC. That subset, unfortunately, has very limited treatment options, so they are essentially treated with cytotoxic agents and anti-VEGF agents, such as bevacizumab [Avastin]. In first-line treatment, we can discuss options regarding triplet and cytotoxic doublets depending on how [fit] the patient is.

 G12C–mutant CRC that should be identified early. Agents and clinical trials are available to [treat] that patient subset.

 wild-type patients are divided into 4 categories, including patients with 

 mutation go down the line of the BEACON CRC trial [NCT02928224] regimen of combination BRAF- and EGFR-directed [targeted] therapies for which there are clinical trials. Also, in the second-line setting, [this dual-targeted approach] is standard of care. Then, there is 

-amplified disease, in which the options include dual anti-HER2 therapy with trastuzumab [Herceptin] plus pertuzumab [Perjeta], trastuzumab plus lapatinib [Tykerb], trastuzumab plus tucatinib [Tukysa], or clinical trials. There is also fam-trastuzumab deruxtecan-nxki [Enhertu], which is an anti-HER2 antibody-drug conjugate, that can be used for this subset. [

-amplified CRC represents] a small subset, but many agents are available for those patients.

After we have removed those 2 subsets, what remains of 

 wild-type CRC can be divided into left- or right-sided CRC. In left-sided CRC that is 

 wild-type, I would use an anti-EGFR agent, up front if possible or at least in the second-line setting. Right-sided 

 wild-type tumors do not respond well to an EGFR-directed agent, so I would try to move them toward clinical trials or adopt the anti-EGFR approach in a later line of treatment. Of course, after all of this is done, [treatment selection] comes down to the third-line setting.

What considerations guide treatment selection between available third-line options?

A few options are available in this salvage-line setting that are standard of care, including regorafenib and TAS-102. Other strategies are also adopted in the clinic, but they are not supported with the same level of robust evidence as with a randomized phase 3 trial. One of [these alternative approaches] is to rechallenge with chemotherapy.

The safety profiles of the drugs guide most of the selection. If we look at the clinical trials, [the results] showed that these drugs were similar in design; therefore, there is not a whole lot of variability [to guide treatment decisions]. However, if I have been giving chemotherapy to someone and bone marrow depression has been a major toxicity, I am not going to use TAS-102 because [the agent’s] bone marrow toxicity is limiting. If somebody had peritoneal surgery or diarrhea as a major issue on prior lines of treatment, regorafenib is not the best drug to use in that situation. Otherwise, the most important factor is to choose patients carefully and make sure [decisions are informed by] what the trials have shown.

These drugs are effective, but they have only been shown to be effective in patients with good performance and clinical status. Fortunately, we have some clinical trials running at our center. One of them is looking at circulating tumor DNA monitoring and early signs of progression in patients in the salvage-line setting. We usually put [eligible] patients on that trial, in which regorafenib is generally used before TAS-102.

There are data about TAS-102 in a regorafenib-treated population, but no data exist [in the opposite sequence]. Most of these patients are coming through the first and second line of chemotherapy, so putting regorafenib in between [chemotherapy and TAS-102] changes the mechanism of action. Essentially, by the time we come [to the salvage-line setting], our primary emphasis is to encourage participation on clinical trials.

How are you incorporating the findings from the ReDOS trial into your approach to treatment with regorafenib? Is the goal of treatment to reach the maximum-tolerated dose or should dosing be individualized?

Even before the ReDOS trial, we were using a more dose-escalation–based strategy [with regorafenib] because most patients do not tolerate [the drug at] a very high dose. ReDOS also showed us that we probably don’t need [to treat] with the highest dose [of regorafenib], but rather] we need patients to be on [regorafenib] for a longer period. If we can achieve that by a dose-escalation strategy, we are more likely to keep patients on treatment.

An expert from The University of Texas MD Anderson Cancer Center recently highlighted the ramifications of the phase 2 ReDOS trial, the need for molecular profiling in mCRC, and ongoing research on the combination of TKIs and checkpoint inhibitors.   

Gastrointestinal Cancer