Cancer: Symptoms, Causes and Treatments

Surgery Plus FLOT: A Game Changer For Esophageal Cancer?

Patrick Boland, MD, discussed the practice-changing implications of the phase 3 ESOPEC study comparing FLOT vs CROSS regimens for the treatment of esophageal adenocarcinoma.

The phase 3 ESOPEC study (NCT02509286) investigated the best approach for treating esophageal adenocarcinoma that can be surgically removed. The study was a head-to-head comparison of neoadjuvant chemoradiation, or CROSS, vs perioperative chemotherapy with fluorouracil, leucovorin, oxaliplatin and docetaxel (FLOT).

The study found that FLOT resulted in significantly better survival rates compared with CROSS. After a median follow-up of almost 5 years, patients receiving FLOT lived a median of 66 months, while those receiving CROSS lived a median of 37 months. The chance of surviving 3 years was also higher with FLOT (57.4%) compared with CROSS (50.7%). Additionally, FLOT showed a higher rate of complete tumor eradication after treatment.

"I do think these are data that should change practice for a portion of patients now…We saw that in all groups, there was no group that did better with some radiation," said Patrick Boland, MD, in an interview with Targeted OncologyTM.

In the interview, Boland, associate program director of gastrointestinal (GI) medical oncology at RWJBarnabas Health and Rutgers Cancer Institute, discussed the ESOPEC study and its practice-changing implications for GI oncologists.

Targeted Oncology: What are the FLOT and CROSS regimens? How are they used?

Boland: Right now, there are 2 general approaches for esophagus or [gastroesophageal (GE)] junction adenocarcinoma. In part, it depends on what part of the world you are in. But the major option is between getting radiation initially, with an often-chosen regimen being the CROSS regimen with carboplatin and paclitaxel, and the alternative being chemotherapy. With chemotherapy, we most often, for patients who are fit enough, think of FLOT, which is a 3-drug chemotherapy regimen. For some of these GE junction cancers, if there is a reason not to give radiation, we will give a less intense chemotherapy than FLOT like [leucovorin calcium (folinic acid), fluorouracil, and oxaliplatin (FOLFOX)]. The standard of care right now will be FLOT or FOLFOX. There [are] some institutional and provider biases between which to use. [ESOPEC] is really the first head-to-head comparison of these 2 regimens.

There was a study last year, the Neo-AEGIS trial [NCT01726452] that compared CROSS-type chemoradiation to chemotherapy, but the chemotherapy was dominantly more of a chemotherapy doublet, like [flouracil (5-FU)]/cisplatin, they allowed. The study was amended as it was going on to allow some patients to get FLOT, but it was a minority. That study suggested the regimen was similar in terms of efficacy, but it was predominantly comparing a doublet which is no longer the standard of chemotherapy, to CROSS. These [ESOPEC] results were then eagerly awaited to see [if] we were going to see superiority with a better systemic therapy.

What was the design of the ESOPEC trial and who was included?

[ESOPEC] was designed for esophageal adenocarcinomas and enrolled patients with early-stage disease to chemoradiation with carboplatin and paclitaxel vs FLOT. This is a relatively large study in this disease site. I think it was clean and well-designed otherwise. Patients were to have surgery afterwards, and then those in the FLOT arm would get [postoperative] chemotherapy, which is also the standard.

Can you summarize the findings of the study?

There were no major differences between the groups that went on either arm, and when they looked at like delivery of treatment, I think by and large, patients got the treatment that was planned.

One thing that was noted is that in the chemoradiation arm, a little bit under 70% of patients got the full planned chemo doses with the radiation, but 98% got all of the radiation therapy planned. [The investigators] did not give us this data but there may have been a dose or 2 of chemotherapy missed, one would imagine. I would estimate that would not have a huge impact on the results, but hard to say. That is less than we have seen; that is a lower rate of chemo completion in the original CROSS study and some of the other studies. I think it would be nice to see data on that. We saw it in the chemotherapy arm. As expected, patients got [preoperative] chemotherapy and a bit more than half got [postoperative] therapy. This is kind of typical, all these studies, and nothing surprising there.

The top results of the study showed is that in the FLOT arm, we had improvements in survival. The hazard ratio was 0.7 [with] significant improvements in survival. The difference was more than 10% difference at 5 years, almost 12%. The disease-free survival difference after about 3 years was about 15%. It seemed to be persistent there. That is a notable difference for us also. Things like rates of getting good surgery done by R0 resection looked looks similar between the 2. It was certainly no worse with chemotherapy than with FLOT. The pathologic response rate was numerically a little bit better with FLOT. So, it was not lower, which we tend to see more higher rates of [pathologic] response with radiation. I think all those things were highly encouraging.

Do you see these findings changing your practice?

I do think these are data that should change practice for a portion of patients now. We always look at the forest plots, the subset analyses, and try to find things that are perhaps problematic. But we saw that in all groups. There was no group that did better with some radiation. There is a benefit, really, across all groups, but especially younger patients, especially node-positive patients, especially those with T3/T4 tumors, there seem to be a clear advantage with FLOT. FLOT is, if you look at an ounce-for-ounce, more effective, but it is also a tougher regimen to give and to get, and just as a lot of patients do not get it [postoperatively], there are a lot of patients who are not candidates for FLOT [preoperatively].

The median age of patients with esophageal cancers is 68. [The median age of patients] was about 63 on this study. In real life, patients are a little bit older and so a lot of them are not going to tolerate it well, or we are going to have concerns when we are looking at quality of life. I think for older patients, there is still going to be some impetus to give chemoradiation as opposed to FLOT for them.

In the chemoradiation arm, patients did not get nivolumab [Opdivo] there. At least today in practice, patients who do not have a pathologic complete response, which is most of them, are given nivolumab, and we know that nivolumab provides a disease-free survival advantage. We are hopeful it gives us a survival advantage, but we do not know that piece yet. Follow-up with CheckMate 577 [NCT02743494] is going to be important as we figure out how to how to lay all these things out. That, of course, is a year of therapy, but it is a largely innocuous treatment for the majority of patients.

I think it would be nice to know outcomes by location. Sort of some of Siewert I, the more classic esophagus cancer where I think the bias is heavily towards chemoradiation, it would be nice to see whether that that trend that is upheld. I do not have a reason to expect it would not be, but it would be beneficial to see that as we try to convince people to change practice. I think already, Siewert III, we tend to treat like gastric cancers. Siewert II is where the big debate is, but I think a lot more Siewert II patients really should end up proceeding with FLOT now.

REFERENCE: Hoeppner J, Brunner T, Lordick F, et al. Prospective randomized multicenter phase III trial comparing perioperative chemotherapy (FLOT protocol) to neoadjuvant chemoradiation (CROSS protocol) in patients with adenocarcinoma of the esophagus (ESOPEC trial). J Clin Oncol. 2024;42(suppl 17)abstr LBA1. Doi:10.1200/JCO.2024.42.17_suppl.LBA1

New Hope For GI Cancers: Review Analyzes Molecular Targets And Treatment Advancements

Gastrointestinal (GI) cancers, encompassing esophageal, gastric, small bowel, and colorectal carcinomas, represent a significant global health burden due to their high incidence and mortality rates. This review by M. Jesús Fernández-Aceñero et al. Provides an in-depth analysis of the molecular characteristics, prognosis, and current therapeutic strategies for these malignancies, highlighting the latest advancements and challenges in the field.

Esophageal carcinoma is among the ten most prevalent tumors globally, with squamous cell carcinoma (SCC) being the most common subtype. Despite geographical variations, SCC accounts for approximately 85% of esophageal cancer cases. Adenocarcinoma, particularly arising in Barrett's esophagus, is on the rise in Western countries. Early-stage esophageal cancer is primarily treated with surgery, while advanced SCC relies on cytotoxic therapies. Neoadjuvant treatments are commonly employed to facilitate surgical resection. Despite these interventions, the prognosis remains poor, with less than 15% of patients achieving disease-free status at a five-year follow-up.

Recent genomic studies have provided valuable insights into the genetic alterations driving esophageal SCC. Technologies like whole-genome and whole-exome sequencing have identified potential therapeutic targets, such as the WNT/Notch1 pathway and the CCL2-CCR2 axis. However, targeted therapies, including EGFR inhibitors, have yet to demonstrate clinical efficacy in phase 3 trials, underscoring the need for predictive biomarkers to personalize treatment strategies .

Gastric cancer (GC) ranks as the fifth most common malignancy and the fourth leading cause of cancer-related deaths worldwide. The incidence of GC is particularly high in Eastern Asia and Eastern Europe, with significant differences in screening programs, clinical characteristics, and patient management between Asian and Western regions. Advances in molecular biology have led to the identification of key genetic alterations in GC, contributing to the development of molecular classifications like those by The Cancer Genome Atlas (TCGA) and the Asian Cancer Research Group (ACRG) .

A promising therapeutic target in GC is the tight junction protein claudin-18 isoform 2 (CLDN 18.2), which is overexpressed in up to 30% of gastric and gastroesophageal carcinomas. Zolbetuximab, an anti-CLDN 18.2 antibody, has shown efficacy in clinical trials, offering a new treatment avenue for HER2-negative gastric and gastroesophageal adenocarcinomas. Despite the potential of fibroblast growth factor receptor (FGFR) inhibitors, their success has been limited, likely due to the diverse genetic alterations affecting FGFR .

Small bowel carcinoma is relatively rare compared to other GI cancers. The molecular landscape of these tumors is less understood, but recent studies have started to uncover the genetic changes involved. Treatment strategies for small bowel carcinoma often mirror those for other GI cancers, including surgical resection and chemotherapy. The identification of specific molecular alterations could lead to more targeted therapies in the future .

Colorectal cancer (CRC) is one of the most common malignancies worldwide. Advances in molecular biology have identified several genetic mutations and pathways involved in CRC pathogenesis, including APC, KRAS, and TP53 mutations. These discoveries have paved the way for targeted therapies and personalized treatment approaches. Immunotherapy, particularly immune checkpoint inhibitors, has shown promise in CRC, especially in microsatellite instability-high (MSI-H) tumors .

The future of gastrointestinal cancer treatment lies in a deeper understanding of the molecular mechanisms underlying these diseases. Research is ongoing to elucidate the molecular pathogenesis of these cancers, which could lead to the development of more effective and personalized therapies. The integration of high-throughput molecular techniques and next-generation sequencing has the potential to identify novel targets and biomarkers, paving the way for personalized medicine in gastrointestinal oncology.

The molecular characterization of GI tumors has significantly advanced our understanding of these malignancies, leading to the development of targeted therapies and personalized treatment strategies. However, challenges remain, including the need for reliable predictive biomarkers and overcoming resistance to targeted treatments. Continued research is essential to improve the prognosis and treatment outcomes for patients with GI cancers.

This comprehensive review underscores the importance of integrating molecular findings into clinical practice to enhance the management of gastrointestinal tumors, ultimately aiming for better patient outcomes and personalized therapeutic approaches.

Source:

Journal reference:

Fernández-Aceñero, M. J., et al. (2024). A Review and Update on Therapy of Gastrointestinal Tract Tumors: From the Bench to Clinical Practice. Journal of Clinical and Translational Pathology. Doi.Org/10.14218/JCTP.2024.00007.

Agent Orange: A Widow Fights For Compensation

GREAT BARRINGTON>> When Pete Naylor was diagnosed with esophageal cancer early last year, he and his wife, Kate, leapt into action to make sure the government he had fought for in Vietnam would provide for his treatment — and, in the case of his death, for his family.

"Pete was going to beat this thing," Kate said. "But he wanted us to be protected just in case."

The disease moved quickly. Pete Naylor died on April 11, 2015, just three months after he was diagnosed.

For his wife and two daughters, Meghan and Erin, there's no question that the cancer was caused by his service in Vietnam. Now, they need to convince the Veterans Administration.

It's no small feat, given the VA's reluctance to officially acknowledge a tie between esophageal cancer and the Vietnam-era defoliant Agent Orange. The link has been the subject of scientific studies, litigation and political legislation for decades.

Kate has been fighting to receive death benefits for over a year.

"This is not just for my family," she told the Eagle recently in her kitchen, beside the brick façade her husband built surrounding the stove. "This is about the principle."

Agent Orange, a potent herbicide that kills leaves and foliage on bushes and trees, was used by the U.S. Military during the Vietnam War to take away cover from the North Vietnamese. The defoliant was sprayed across approximately 12 percent of the land in Vietnam.

The health effects of the chemical are well documented; the VA today recognizes 14 diseases with direct links to Agent Orange. But esophageal cancer is not on that list.

A soldier's experience

Pete Naylor was born in Long Beach, N.Y., on March 18, 1947. The second oldest of 13 children, he moved to the Berkshires in 1960. He found school difficult in the area and went to the Cardinal Farley military academy in Rhinebeck, N.Y., starting in 1961.

In July 1968, Pete joined the Army, serving until March 19, 1971. During his service, he spent 11 months in Vietnam as a helicopter crew chief. He met Kate Kane in 1973 after he returned to the Berkshires. They married on Oct. 4, 1975.

Pete was a stonemason by trade, retiring in 2008, though he would continue projects around the house for years. In October 2014, he began to feel unwell.

The disease moved quicker than the family expected. He had trouble eating and had to have food pureed. Within a couple of weeks he was using a feeding tube. The family knew the cancer had spread to his bones.

"It was Stage 4 immediately." Kate said.

The couple went to Dana Farber in Boston to see what could be done. Surgery was out, the doctors said, because the cancer had metastasized. Chemotherapy was the only option.

On April 2, after being met with silence from the VA on their claim, the Naylors asked U.S. Rep. Richard Neal, D-Springfield, for help.

Neal replied on April 6, 2015, that he was looking into the matter, but Kate has not heard back. Requests for comment from Neal's office were not returned.

Pete was admitted into Berkshire Medical Center on April 4, 2015; he died a week later.

"We had time. We talked," Kate said. "We said goodbye."

Doctor's diagnosis

A month later, on May 5, Kate filed for death pension and accrued benefits relating to the cancer.

On June 9, 2015, the VA denied the Naylors' claims for both accrued benefits and service connection related to the cancer. It cited a lack of evidence tying the disease to Agent Orange.

"The secretary [of the VA] has determined that there is no positive association between herbicide exposure and esophageal cancer," the decision read. "The evidence does not equal or outweigh the evidence against association."

There was no ambivalence in the analysis from Pete Naylor's oncologist at BMC, Dr. Michael DeLeo.

DeLeo's examinations show an otherwise healthy 67-year-old being ravaged by an aggressive cancer of the esophagus. The diagnosis took pains to point out that Pete looked younger than his age and was in excellent health.

The oncologist identified three risk factors he could see for the disease: smoking, alcohol use and Agent Orange. Pete Naylor quit his mild habit of smoking over 25 years before diagnosis and rarely drank alcohol. That only left one likely culprit, the doctor said: exposure to Agent Orange.

DeLeo made that link directly in his postmortem statement provided on April 25, 2015.

"It is my medical oncology opinion that advanced aggressive squamous cell carcinoma esophagus was directly related to Agent Orange exposure, given lack of other significant risk factors noted," DeLeo wrote.

The oncologist's medical opinion was dismissed in the June 9 denial from the VA, which argued that legal precedent allowed the administration to disregard the doctor's opinion when weighed against the "collective view of experts" that there is no link between Agent Orange and esophageal cancer.

The VA did not respond to requests for comment.

Legal opinion

A lawyer who represents veterans says based on the government's own standards, the decision should tilt the decision toward the Naylors.

"The VA uses National Academies of Sciences, Engineering, and Medicine Health and Medicine Division standards to determine if there are links between diseases and Agent Orange," said Adam Luck, a Texas-based attorney whose law firm, Glover & Luck, has represented families denied benefits after their loved ones die of service-related diseases.

Still, when it comes to esophageal cancer, the record is mixed.

On the one hand, Luck said, a connection between the disease and Agent Orange is hard to definitively prove. The sample size, exposure data, and controls for scientific study are complicated by the cancer's aggression and lethality. It's simply not realistic to look at the available information and draw any kind of conclusion.

But on the other hand, that lack of definitive conclusions doesn't mean there's no connection. In fact, data suggests there may indeed be a link between the defoliant and the disease. In the most recent report on the links between Agent Orange and diseases from 2014, the academies found that there was some indication that the defoliant caused cancer. But the report stopped short of making a definite connection due to a lack of overall evidence.

Luck says that leaves the probability for the VA's purposes at "50/50." In that case, he said, the tie goes to the veteran — or it should.

Kate Naylor received benefits for Pete's funeral on June 11, 2015. The VA gave some money to the family for funeral and cemetery costs. Six days later, the VA returned a final payment for the month of April's disability benefits for Pete's tinnitus and Agent Orange-related diabetes mellitus. It was cold comfort, Kate said.

So she filed an appeal with the VA.

That appeal is ongoing. Thus far Kate has only heard that the claim is being processed. She received the most recent update on July 28.

"It's the same old thing," she said. "Jumping through hoops."

Waiting for the VA

Local Vietnam veteran activist John Hardin has seen how slow the VA can be to process. He fought for years for his disability benefits due to service and is still in litigation with the VA over his level of compensation. Hardin said the VA will avoid paying for Agent Orange related illnesses if it can.

"The minute they hear something might not be related to Agent Orange, they cling to that," he said. "If your disease isn't on their list, you're in for a fight."

Rick Francis, a veterans activist from Washington state, agreed. In the early 1980s, Francis started the nonprofit The Blackdog Foundation in response to what he called poor outreach to and treatment of veterans by the VA. It provides post-traumatic stress treatment and domestic abuse prevention services to veterans and their families.

"When you give just enough funding to cover a number so small, when the need is vast, you never have healing," Francis said. "You have a demand for expedience, with an expectation of perfection, that never gets past the blame game."

But there is reason to hope that the VA might provide some healing for Kate Naylor. That hope comes from a former congressman from Wisconsin.

In 2009, U.S. Rep. Steve Kagen sponsored the Thomas G. Schubert Agent Orange Fairness Act. The bill, which was co-sponsored by then-U.S. Rep. Barney Frank, D-Mass., would have added esophageal cancer to the list of Agent Orange-related diseases eligible for compensation.

Unfortunately, the bill never made it to the floor. Kagen told The Eagle this was due to a rule the Democratic majority had instituted that mandated any bill that came before the House floor have secured funding. The bill would have cost $2.1 billion, Kagen said. He and Frank were unable to secure promises of funding. Frank did not return calls seeking comment.

Kagen has been an advocate for veterans in his district and nationally for years. Even now, six years removed from his congressional career, the impulse to help victims of Agent Orange still exists.

"There is no doubt in my mind that exposure to Agent Orange is bad for our health and that one consequence is development of esophageal carcinoma," Kagen said.

When veterans' families are faced with denial of death benefits for esophageal cancer that developed as a result of Agent Orange, he continued, there's a simple solution. The family needs to have the doctor amend the death certificate to read that the cause of death was esophageal cancer caused by Agent Orange.

One of Kagen's constituents did just that in 2008 and won her appeal against the VA. In the decision, the findings of fact clearly state that the amended death certificate was a factor in the decision to award benefits.

Kate is moving forward with amending Pete's death certificate to state that Agent Orange caused the cancer. She is waiting for DeLeo's office to reply to her request that he provide a notarized letter to the Pittsfield City Clerk announcing he wishes to amend the death certificate.

"Fingers crossed," she said.

Fighting for veterans

Kate hopes that her story will encourage other veterans and their families to fight for their compensation under the law.

"It took Pete a long time to embrace his status as a veteran," she said, sitting under a photo of her husband taken during a fishing trip.

Once he did accept his status, though, he embraced it fully. For Pete, she said, taking responsibility for his veterans status and other veterans in the community was part of his DNA.

Pete saw himself as a resource for young men in the area returning from Iraq and Afghanistan, Kate said. He would welcome them into their family home, she said, and let them know they had someone who understood where they were coming from. He would also encourage them to apply for benefits from the VA.

"That's why this fight isn't just for us," she said. "Other veterans should be encouraged to apply for their compensation, too."

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