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Dr. Andrew Rynne
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Dr. Andrew Rynne

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Is BRAF trial a better treatment option compared to standard chemotherapy?

Answered by
Dr.
Dr. Ivan R. Rommstein

General Surgeon

Practicing since :2008

Answered : 9397 Questions

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Posted on Mon, 9 Oct 2017 in Abdominal Pain
Question: Hi Doctor Rommstein,

I am at a turning point in my treatment and time is not my friend.Chemotherapy for now unfortunately is my only option..So my choices are Folfox or Folfiri both with Avastin.I had 18 treatments of these drugs prior to my surgery.The second option is a BRAF colorectal test at the University of XXXXXXX and these are the drugs

     This a multicenter, randomized, open-label, 3-arm Phase 3 study to evaluate encorafenib + cetuximab plus or minus binimetinib versus Investigator's choice of either irinotecan/cetuximab or FOLFIRI/cetuximab, as controls, in patients with BRAFV600E mCRC whose disease has progressed after 1 or 2 prior regimens in the metastatic setting. The study contains a Safety Lead-in Phase in which the safety and tolerability of encorafenib + binimetinib + cetuximab will be assessed prior to the Phase 3 portion of the study

I have very much appreciated your advise to date and everything you have told me has turned out to be true.Could you please give me your opinion on which of these two treatments you think would be best for me.If you think there is another course I should consider please let me know.

Thank you,

XXXXXXX


Sorry to bother you again buy something just came to my atention.The BRAF trial at the University of XXXXXXX is a three arm test so you do not know which arm you will be receiving and since it is a test the outcome is uncertain.



I just read about a test at Northwestern which I am very interested in and would like your opinion.I know oxiplatin and irintecan work as thiose are the drugs that killed my cancer.I also know the TheraSphere works as that is one of the options some time ago that was recommended to me by my oncologist and since by a interventional radiologist.Thee are proven procedures that kill tumor cancer.Should I not investigate this option before I enter the BRAF truial? What is your opinion about the two approaches.?



Thank you,


XXXXXXX



Overview

TheraSphere is a medical device made by Nordion approved in the United States for the treatment of liver cancer called hepatocellular carcinoma. It consists of millions of microscopic glass spheres that are injected into the main artery in the liver to deliver radiation therapy directly to the tumor. Colorectal cancer is treated with combinations of chemotherapy agents, most frequently including drugs called oxaliplatin or irinotecan. In this study participants will be getting TheraSphere along with combination chemotherapy as a second line of treatment for their cancer.

doctor
Answered by Dr. Ivan R. Rommstein 43 hours later
Brief Answer:
hi

Detailed Answer:
Hi XXXXXXX
Good to hear you again.

Therasphere efficiency is still unproven and there is evidence on very small number of patients. It is used for primary liver tumors such as HCC or cholangiocarcinomas and in metastases,especially in diiseminated liver metastases, this is not indicated. I am sceptic about this, honestly. it works on the same principle as arterial pump.

Regarding BRAF trial, this would be best option. YOu had standard chemo and best possible surgery and at this point, your treatment options are limited and it is hard to expect that any conventional chemotherapy may be beneficial. Actually, I am pretty sure that another FOLFIRI or FOLFOX or cisplatina or irinotecan alone would not be efficient at all. You are lucky that you live in USA where clinical experimental trials are available. Unfortunately this is your only choice. This is experimental and no one knows what kind of results can be expected but encorafenib or binimetinib novel chemotherapeutics and if something can work, then these medications can.
Although, chances are not on your side, this should be clear so you should expect the worst, but hope for the best.

If this is double blinded randomized trial then you may get any of these chemos and you cant choose which one. If this is controlled trial then you can choose.
You should ask investigator about this. There is no point of repeating standard chemos such as FOLFIRI, since, even though it may have worked at the beginning, it is obvious that now tumor has mutated and became multi-resistant since otherwise, it would not have so many tumor satelites in liver.

So my suggestion is to try with trial, these are new drugs, uninvestigated and there may be response. these may be toxic, may have side effects and may have unexpected results, but this is the price that you should accept at this point. Unfortunately, the nature of this disease doesnt give you many options.

Sorry for being so direct, but from my experience, it is always better to face patients with the tumor behaviours and probable scenarios. I know that everyone will tell you some other story,but systemic chemotherapy is best option now. there are no miracle cures unfortunately and there are no therapies without side effects or complications. I know negative effects of chemo and that people cant stand it, but I am sure that you ll have strength for another one, considering what have you gone through already.


Above answer was peer-reviewed by : Dr. Raju A.T
doctor
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Follow up: Dr. Ivan R. Rommstein 1 hour later
Doctor Rommstein,

You have given me the best advice since we began communicating.THe two locl oncologists put tme on the standard colorectal metastasized drugs that any doctor would use.Folfox,Folfiri and Avstin however they were quick to tell me that most often BRAF does not respond.In my case 18 treatments killed 21 of the 22 tumors.The surgery removed the largest which was 1/2 dead and I was cancer free.The surgeon said he thought I would need some follow up chemotherapy my two oncologists said no and to come back in 90 days.When I asked the surgeon what to do he said follow your oncologists.Unfortunately this was the worst decision I have ever made and could be deadly.My oncologist before surgery told me not to get too excited as after surgery there would probably be undetectable cancer cells that would begin to grow and I would end up where I started.I have read several articles since and most say after a liver resection often times the patient is put back on chemo to kill the cells that were not detected and were still alive. 90 days later 7 lesions.THree weeks later 10 lesions including one on my pancreas.The 7 had doubled in size.

I have spent hours looking for a different route than the BRAF trial and have found many but your response tonight have convinced me that the trial may be the only option.I will be meeting with a new oncologist next week from Northwestern for one last look.THe trial is in its third stage which I guess is a good sign.I do not think this is a controlled trial but I will check.Shouldn't a third stage be controlled?

This is the trial my oncologists want me to enroll in at the University of XXXXXXX .I do not know if it is controlled


     This is a multicenter, randomized, open-label, 3-arm Phase 3 study to evaluate encorafenib + cetuximab plus or minus binimetinib versus Investigator's choice of either irinotecan/cetuximab or FOLFIRI/cetuximab, as controls, in patients with BRAFV600E mCRC whose disease has progressed after 1 or 2 prior regimens in the metastatic setting. The study contains a Safety Lead-in Phase in which the safety and tolerability of encorafenib + binimetinib + cetuximab will be assessed prior to the Phase 3 portion of the study.


My doctors are not aware of this trial.Doctor Kopetz is from MD XXXXXXX and is I am told the foremost authority of BRAF colorectal cancer.The three drugs that showed the best results was irinotecan/cetuximab/vemurafenib however he felt adding a MEK inhibitor could show even better results.
Vemurafenib Prolongs PFS in BRAF-Mutant mCRC XXXXXXX Kuznar
Published Online:9:08 AM, Wed January 25, 2017
4 35 0 0 << Back to all news
My doctors are not aware of this trial.Doctor Kopetz is from MD XXXXXXX and is I am told the foremost authority of BRAF colorectal cancer.The three drugs that showed the best results was irinotecan/cetuximab/vemurafenib however he felt adding a MEK inhibitor could show even better results. XXXXXXX Kopetz, MD, PhD
According to results from a randomized clinical trial,1 adding vemurafenib to the routinely employed combination of irinotecan and cetuximab prolonged progression-free survival (PFS) in patients with BRAF-mutant metastatic colorectal cancer (mCRC).

In the 106-patient trial, median PFS improved from 2.0 months in the arm randomized to cetuximab and irinotecan to 4.4 months in patients assigned to the combination plus vemurafenib, reported XXXXXXX Kopetz, MD, PhD, at the 2017 Gastrointestinal Cancers Symposium.

The data support the concept that vemurafenib “sensitizes BRAF-mutant colorectal tumors to cetuximab and irinotecan, and is consistent with the multiple preclinical and early phase 1 studies,” said Kopetz, Associate Professor of Gastroenterology Medical Oncology at the University of XXXXXXX MD XXXXXXX Center. “Overall, novel therapies such as this are needed for this rare and aggressive subset of colorectal cancers, where our standard chemotherapy regimens are failing to provide substantial and meaningful clinical benefit.”

BRAF V600E mutations are present in 5 to 10% of patients with mCRC. The biology is aggressive in this subset of patients, he noted. BRAF V600E mutations are associated with distinct clinicopathologic features such as proximal colon location, gene hypermethylation, and tumor microsatellite instability. Overall survival in BRAF-mutant mCRC is short and response to standard chemotherapy is limited.

The BRAF V600E mutation results in constitutive activation of MAP kinase signaling. In preclinical models, inhibiting BRAF V600E has been shown to transiently reduce MAP kinase signaling but with resultant feedback activation of EGFR, which can reactivate MAP kinase activity, explained Kopetz. As a result, single-agent vemurafenib has limited activity.2 Dual inhibition of EGFR and BRAF can shut down this signaling.

In preclinical models of BRAF V600E mCRC, a dual BRAF and EGFR blockade has generated an anti-tumor response. Adding irinotecan to vemurafenib and cetuximab led to a sustained anti-tumor response and prolonged survival compared with the vemurafenib/cetuximab doublet in a patient-derived xenograft model of BRAF V600E mCRC, which suggests additional clinical benefit by adding vemurafenib to standard irinotecan and cetuximab. Early results from a phase I clinical trial suggest that the triplet is safe and tolerable with efficacy in patients with refractory BRAF V600E mCRC.3

The 106 patients enrolled in the study Kopetz described in his presentation had histologically or cytologically documented BRAF V600E-mutated and extended RAS wild-type mCRC. Patients had to have ECOG performance status of 0/1 to be eligible. They were randomized to irinotecan, 180 mg/m2 IV every 14 days, and cetuximab, 500 mg/m2 IV every 14 days, with or without vemurafenib, 960 mg orally twice daily. Patients were allowed 1 or 2 prior regimens of systemic chemotherapy for metastatic or locally advanced unresectable mCRC. Prior irinotecan was allowed but prior anti-EGFR therapy or RAF or MEK inhibitors were not permitted nor was receipt of any chemotherapy within 14 days of registration. Thirty-nine percent of patients were treated with irinotecan prior to enrollment.

Crossover from the control arm to the triplet arm was allowed with documented progression. The primary endpoint was PFS.

Of the 106 patients, 7 were deemed ineligible due to inadequate hematologic function, not having a BRAF V600E mutation, or received chemotherapy within 14 days prior to randomization, leaving 99 available for analysis. The median age of patients was 62 years and >90% were white. More than half of the patients in each arm had 1 prior regimen for the treatment of mCRC, and about one third in each arm had 2 prior regimens.

PFS was improved with the addition of vemurafenib (HR, 0.42, P = .0002) with the aforementioned median PFS of 4.4 months in the triplet arm compared with 2.0 months with the doublet.

Four percent of patients in the cetuximab plus irinotecan arm and 16% in the triplet arm had a partial response. Seventeen percent and 48%, respectively, had stable disease, for a disease control rate of 22% in patients randomized to cetuximab and irinotecan, and 67% in patients randomized to vemurafenib, cetuximab, and irinotecan (P = .001). “Importantly, the durations of response were higher with the addition of vemurafenib, and the 2 responders in the control arm had very short durations of response,” Kopetz said.

The rates of grade 3/4 adverse events (AEs) that were higher in the experimental arm included neutropenia (28% vs 7%), anemia (13% vs 0%), and nausea (15% vs 0%), “but these rates may be attributed to increased duration of exposure, and are similar to a prior second-line study of cetuximab and irinotecan,” Kopetz said. Eighteen percent discontinued treatment due to AEs in the triplet arm compared with 8% in the doublet arm.

Future analyses will include overall survival. Crossover occurred in 48% of patients assigned to cetuximab and irinotecan; the outcomes of these patients remain immature. Subgroup analysis will be conducted to examine the role of irinotecan pre-treatment and to evaluate the outcomes of patients according to microsatellite instability, “recognizing that 25% of the BRAF population in metastatic disease has microsatellite instability,” Kopetz said.

If I am able to enroll in Doctor Kopetz trial would this be a better option.

There is one other option.A famous liver surgeon from the XXXXXXX Clinic believes that partial surgery with ablation and chemotherapy or the infusion pump could be a possible solution.

I don't feel right about you reading all of my posts and giving me your best advise and only paying $15.00 per month.I would like to transfer some money to your account or if you can use a credit card pay you some additional money for everything you have done for me.Please let me know.

Thank you,
XXXXXXX
doctor
Answered by Dr. Ivan R. Rommstein 15 hours later
Brief Answer:
hi

Detailed Answer:
Hello XXXXXXX
Thanks for your reviews, this means a lot for me, and I am sorry that these online advice are the most I can do. I would also like that my patients are informed and educated about their disease as you are. So maybe you have too busy oncologists but as I see, you are giving your best to be informed about new advances in oncology and you want to be involved in your treatment process. This is very commendable.

I ll need some time to analyse your last post and evaluate those studies that you mentioned. it would be helpful if you send me last CT image and report of your liver status and leave me email here if moderators will allow so that those larger data can be sent on email directly.
Earning is not my primary point here because I am particularly interested in your case since this is topic of my clinical and scientific interest. I am young surgical oncologist and hepatobiliary surgeon and I am dedicated to find new methods for treatment of liver malignancies so every new case in valuable experience for me. It is interesting for me to hear how would USA doctors treat liver metastases and I hope that in future I can contribute to development of surgical oncology.

So just give me some time to analyse your last post. meanwhile, provide me CT images of liver if you can and pathohistologic finding of primary colon tumor if available.

Warm regards. Dr Ivan Romic Rommstein
Above answer was peer-reviewed by : Dr. Prasad
doctor
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Follow up: Dr. Ivan R. Rommstein 3 hours later
Hi Doctor,

I have looked for the last year for an oncologist that specializes in BRAF colon cancer.Because there are very few patients with this type of cancer I was unable to find anyone until last night. She happens to be at the number 1 or 2 cancer clinic in the United States.Her specialty is BRAF colon cancer.Unbelieveable.I know time is not on my side as the tumors are growing quickly in both numbers and sizes however I think I would be foolish to enter into a three arm trial at the University of XXXXXXX that may include my previous drugs without first meeting this woman meeting this woman.I will send her an email today and call her office tomorrow morning to try and get an appointment.What do you think.My stools have been gray for the last few days so something is going on with my liver.

Here are two current tests she is running

Clinical Trials Led by XXXXXXX D. Yaeger
A Phase III Study of Encorafenib, Binimetinib, and Cetuximab for Patients with Metastatic Colorectal Cancer Containing Mutated BRAF
Clinical Trials Co-Investigated by XXXXXXX D. Yaeger
A Phase II Study of Ado-Trastuzumab Emtansine in Patients with Cancers Driven by HER2
A Phase II Study of Hepatic Arterial Infusion and Intravenous Chemotherapy versus Intravenous Chemotherapy Alone in Patients with Inoperable Liver Metastases from Colorectal Cancer

THis is her name and contact information

https://www.mskcc.org/cancer-care/doctors/rona-yaeger

THis was my cat scan on August 8th 2017

Details
Comments from the Doctor's Office XXXXXXX - there are several small new lesions in your liver. I will show you at our meeting. They are very small but look new and real.
A Hantel
Study Result
Impression
CONCLUSION:     
1. There are a few centimeter-sized and subcentimeter hypoenhancing hepatic lesions which are apparently new and highly suspicious for progression of metastatic disease.

2. Postoperative changes of wedge resection of the inferior right hepatic lobe.

3. Splenomegaly.

4. Status post right hemicolectomy.

5. Interval operative intervention of cholecystectomy. Minimal intrahepatic and borderline intrahepatic biliary dilatation noted.

6. At L2, there is a grossly stable hemangioma.

7. Lesser incidental findings as above.
Narrative
PROCEDURE:     CT CHEST ABDOMEN PELVIS (ALL CONTRAST ONLY) (CPT=71260/74177)

COMPARISON:     Elmhurst Memorial Hospital, CT CHEST+ABDOMEN+PELVIS(ALL CNTRST ONLY)(CPT=71260/74177), 2/04/2017, 10:36.

Additional comparison is made to outside CT of the chest, abdomen, and pelvis performed at Clay CT DMG on 05/31/2016, contrast enhanced CT of the chest, abdomen, and pelvis from M.D. XXXXXXX conducted on 11/23/2016, and contrast-enhanced CT of the
abdomen performed at Johns XXXXXXX on 04/05/2017.

INDICATIONS:     Malignant adenocarcinoma of the ascending colon, complicated by hepatic metastatic disease, and status post wedge resection of metastatic lesions involving segment V and VI (05/18/2017).

TECHNIQUE:     Multidetector CT images of the chest, abdomen and pelvis were obtained with intravenous contrast material. Automated exposure control for dose reduction was used. Adjustment of the mA and/or kV was done based on the patient's size. Iterative
reconstruction technique for dose reduction was employed.

FINDINGS:
DEVICES:     There is a left-sided Port-A-Cath with tip terminating in the distal SVC.
CARDIAC:     The heart is not enlarged. Atherosclerotic vascular calcifications are present in the coronary vessels. Trace pericardial effusion extends into the superior pericardial recess.
VASCULATURE:     The thoracic aorta has unremarkable configuration without aneurysm or dissection. Atherosclerotic vascular calcifications are present about the aortic arch.
LUNGS/PLEURA:     Minimal medial left apical and medial right paramediastinal paraseptal blebs are demonstrated. There is dependent subsegmental atelectasis bilaterally. Scattered reticular opacities may also represent atelectasis. Trace peri-fissural
nodularity along the minor fissure is stable and may represent an intrapulmonary lymph node (series 3, image 62).
No airspace consolidation, pleural effusion, or pneumothorax is detected.
AIRWAYS:     The tracheobronchial tree is without central mass or obstructing lesion.
MEDIASTINUM/HILA:     No mass or lymphadenopathy.
CHEST WALL:     Bilateral symmetric gynecomastia is present. No axillary mass or lymphadenopathy.

LIVER:     Postoperative changes of hepatic wedge resection are newly evident in segments V and VI.
There are several new hypoenhancing hepatic lesions which are suspicious for metastatic disease. There is a reference segment VIII lesion measuring 1.0 x 1.1 cm (series 2, image 84). A lesion at the border of segments VII and VIII measures 1.1 x 1.4 cm
(series 2, image 92). Subcentimeter lesions are present in the left hepatic lobe (series 2, images 95 and 96).
BILIARY:     The gallbladder is surgically absent. Mild intrahepatic and borderline extrahepatic biliary dilatation.
PANCREAS:     No lesion, fluid collection, ductal dilatation, or atrophy.
SPLEEN:     Enlarged, measuring 14.8 cm craniocaudally.
ADRENALS: No defined mass or abnormal enlargement.
KIDNEYS: Symmetric enhancement is seen without evidence of hydronephrosis or underlying solid masses.
GI/MESENTERY: A small hiatal hernia is evident. Distal esophageal wall thickening may be attributable to underdistention or could reflect esophagitis. There is no evidence of bowel obstruction. Postoperative changes of right hemicolectomy are
demonstrated with an ileocolic anastomosis in the right upper quadrant. Gross patency is demonstrated. Minimal scattered colonic diverticula are present in the descending and sigmoid colon. There is no colonic wall thickening or pericolonic fat
stranding.
URINARY BLADDER:     No visible calculus or focal wall thickening.
PELVIC NODES:     No lymphadenopathy.
PELVIC ORGANS:     No visible mass. Pelvic organs appropriate for patient age. Prostatic calcifications are present.
VASCULATURE: Heavy atheromatous plaque and scattered atherosclerotic vascular calcifications of the abdominal aorta are observed. No aneurysm is detected.
RETROPERITONEUM:     No mass or lymphadenopathy is apparent.
BONES: Multiapex scoliosis of the thoracolumbar spine is demonstrated. Multilevel degenerative changes of the spine are present. There is substantial wedging of mid thoracic vertebral bodies resulting in angulation of the thoracic kyphosis. Vacuum disc
phenomenon is present.
There is a lucent lesion of the L2 vertebral segment with prominent vertical trabeculations. This appears unchanged from previous imaging and is most compatible with a hemangioma.
Degenerative changes of the shoulder joints are observed bilaterally.
ABDOMINAL WALL:     Minimal periumbilical scarring/infiltration is present.
OTHER:     No free air or fluid is seen in the abdomen or pelvis.

Dictated by (CST): XXXXXXX XXXXXXX MD on 8/08/2017 at 15:18
Approved by (CST): XXXXXXX XXXXXXX MD on 8/08/2017 at 15:39

Impression
IMPRESSION:

NEW AND ENLARGING HEPATIC METASTASES.

INDETERMINATE PANCREATIC UNCINATE PROCESS MASS. THIS MAY BE AN
ADDITIONAL METASTASIS OR PRIMARY ISLET CELL TUMOR OF THE PANCREAS.






This was my last scan an MRI on August 30th


Transcriptionist: PSCB
Transcribe Date/Time: Aug 30 2017 1:01P

Dictated by : XXXXXXX KICZEK, DO

This examination was interpreted and the report reviewed and
electronically signed by: XXXXXXX HERTS, MD on Aug 30 2017 3:34PM EST

Narrative
* * *Final Report* * *

DATE OF EXAM: Aug 30 2017 12:23PM

QBM 0727 - MRI LIVER WO/W IVCON / ACCESSION # 0000

PROCEDURE REASON: Secondary malignant neoplasm of liver and intrahepatic
bile duct

* * * * Physician Interpretation * * * *

MRI ABDOMEN WITHOUT AND WITH IV CONTRAST

CLINICAL HISTORY: History of metastatic colon adenocarcinoma. Status
post hepatic wedge resection in the RIGHT lobe.

COMPARISON: CT from outside hospital 08/07/2017.

TECHNIQUE: Siemens 1.5 T Avanto scanner. Using the torso phased array
coil, axial STIR and T1 weighted in- and out-of-phase images were
obtained. Then, using a 3-D GRE T1 weighted sequence, dynamic images were
obtained before, during and after the administration of intravenous
contrast. Subsequently, axial and coronal HASTE, axial diffusion
weighted and axial T2 weighted images were obtained. Flow sensitive
imaging of the portal vein was performed. Finally, a delayed
post-contrast phase was obtained using the same 3D GRE sequence.

Contrast:
IV: 10 ml of Eovist
Oral Contrast: None

RESULT:

Liver: There are at least 10 hepatic metastases, several new and others
increased from the comparison study. These are well-circumscribed,
peripherally enhancing and T2 hyperintense lesions within both hepatic
lobes:

* 1.1 x 1.0 cm segment III lesion (22:24).
* 1.7 x 1.6 cm segment III lesion (22:30).
* 2.0 x 1.4 cm segment III lesion (22:30).
* 1.5 x 1.0 cm segment III lesion) 22:34).
* 1.9 x 1.8 cm segment II lesion (22:39).
* 1.1 x 0.9 cm segment IVa lesion (22:48).
* 1.9 x 1.5 cm segment V lesion (22:47).
* 2.1 x 1.6 cm segment VI/VII lesion (22:51).
* 1.3 x 1.0 cm segment VI lesion (22:38).
* 1.8 x 1.5 cm segment VII lesion (22:62).

There is a peripheral parenchymal defect in segment VI with associated
susceptibility artifact from surgical clips, from prior wedge resection
(16:40).

Patent hepatic vasculature..

Spleen: Borderline splenomegaly, 14 cm in length. No focal splenic mass.

Pancreas: There is a 1.7 x 1.6 cm avidly enhancing lesion at the uncinate
processes (16:10). There is no vessel encasement or narrowing. The rest
of the pancreas is normal. There is no pancreatic duct dilation.

Biliary: No bile duct dilation. No cholelithiasis choledocholithiasis.
The gallbladder is normal.

Adrenals: Normal.

Kidneys: No solid or cystic mass. No hydronephrosis.

Other: There is no ascites or fluid collection. There are a few
scattered subcentimeter retroperitoneal lymph nodes.

doctor
Answered by Dr. Ivan R. Rommstein 7 minutes later
Brief Answer:
Hi XXXXXXX

Detailed Answer:
Hi XXXXXXX
Yes,i ll evaluate this report and then comment this.I need some time,day or two maybe. in future you can attach reports in this site,you don't have to rewrite it in your question. also,provide me an email so that you can send me images if I will need it in future.
Above answer was peer-reviewed by : Dr. Raju A.T
doctor
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Follow up: Dr. Ivan R. Rommstein 3 hours later
Hi Doctor,

I spoke with my daughter tonight.She is a nurse practitioner and has spent hundreds of hours over the last 1-1/2 year on my case.Since the trial at the University of XXXXXXX and the test from the Doctor at XXXXXXX Kettering that specializes in BRAF are the same she feels I should start the test as soon as possible and at the same time maybe meet with the doctor at XXXXXXX Kettering.

The one thing that confuses both of us is the liver surgeon at the XXXXXXX Clinic.He is rated above the surgeon at XXXXXXX XXXXXXX who resectioned my liver.He actually transplants livers or implants portions of a liver from another person.He continues to say he thinks surgery in conjunction with albasion and the hepatic infusion pump still could be the way to go.It is hard for me to believe that is a viable option based on the number and locations of my tumors however I am not a liver surgeon and I may only have one more chance to treat my disease.

My email is YYYY@YYYY

Thank you again for all of your help and advise.
XXXXXXX

Hi Doctor Rommstein,

This is from the Doctor from XXXXXXX Kettering that specializes in BRAF colon cancer.I guess this is the route I must take but I still wonder about the liver surgeon at the XXXXXXX Clinic.
XXXXXXX

Hi XXXXXXX

I am sorry to hear about what you are going through. I assume the clinical trial you are referring to is the BEACON trial - a randomized phase 3 trial that is testing targeted therapies versus standard chemotherapy for BRAF mutated colon cancer. We are participating in this trial too. I don't know of other trials currently enrolling for BRAF V600 mutant colorectal cancer. This is a good trial and the targeted drugs being tested are supported by early clinical trial data, suggesting they may have some activity in this setting. There is a 1 to 1 randomization into each of the 3 arms, so there are 2 out of 3 chances of getting on a targeted therapy arm. The standard arm, as you mention, is irinotecan + cetuximab or FOLFIRI + cetuximab. In terms of treatment options, we wouldn't have something additional to offer you at MSK.

Hi Doctor Rommstein,

One of my concerns with the three arm BRAF trial at the University of XXXXXXX is which arm I would be enrolled in.One of the arms is very similar to the chemo drugs I had been previously taking.I spoke with Northwestern University today and they are running a trial using TheraSphere NCT0000 for metastasized colon cancer.Also Doctor Kopetz ran a trial SWOGS1406 using Irinotecan,Vermurafenib and Cetuximab that was successful.He said if he added a MEK inhibitor the test may be even more successful.
XXXXXXX
doctor
Answered by Dr. Ivan R. Rommstein 24 hours later
Brief Answer:
hi again

Detailed Answer:
Hi again.

I f you reject surgery completely, focus on new drugs. MEK inhibitors for example. Vemurafenib and Dabrafenib are new medications which some showed nice results so far, but this is still in early phase of clinical trials and results are mostly related to melanoma treatment.
But, these are worth of try.
Or TheraSphere as well, but Therasphere trial uses Irinotecan and Oxaliplatin. Ask them if newer medications can be used in combination with it...

It doesnt matter if targeted therapy is still at the beginning of research.YOu have nothing to lose. Irinotecan alone wont help, be sure about this. In combination with other chemo, results are much better. Cetuximab is promising...should be added as well.

I'll need some time for evaluation of those trials that you have mentioned and I will contact you soon.
Above answer was peer-reviewed by : Dr. Yogesh D
doctor
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Follow up: Dr. Ivan R. Rommstein 1 hour later
Hi Doctor Rommstein,

I don't reject surgery completely.What is confusing is when I told the surgeon who did the liver resection I had seven new lesions he said he could not help me.To me that meant he did not think another surgery was an option.Then I found a surgeon at the XXXXXXX Clinic.He also does full or partial liver transplants.

He told me I must have an MRI to make sure the cancer did not spread from August 8th.From looking at the August 8th cat scan his initial feeling was a partial resection coupled with ablation and the hepatic arterial infusion pump.

So now the MRI shows more and larger liver tumors and one on my pancreas.As recently as this weekend he still feels surgery could still be an option.

My local oncologist warned me before surgery about the cells that were not detectable growing after surgery.This is exactly what happened.So what concerns me if I have surgery again what do I do about the invisible tumor cells? Unfortunately the same doctor who warned me about the left over tumor cells did not suggest post surgery chemotherapy which many oncologists feel is the standard of care.

Tomorrow and the next day I am to have several tests to make sure I qualify for the BRAF test.The BRAF test I only have one chance in three that my drugs will not contain Folfiri or Irinotecan.Those are in the first two arms the third arm is encorafenib + cetuximab plus or minus binimetinib but I have no way to make sure I receive this.So do I take this risk?

I know the TheraSphere is an option however the only tests I can find using it in conjunction with chemotherapy is with Irinotecan or Oxalplatin.So I do not know if I should consider just the TheraSpheres.I do not think I can because of the tumor on the pancreas.

Do you think if I can find someone who would administer TheraSpheres with Encorafenib and or Cetuximab this would be better than the three arm trial?

Back to the trial at the University of XXXXXXX You think it is too dangerous to try?

Two legs are irinotecan/cetuximab or FOLFIRI/cetuximab and if irinotecan or Folfiri can not be effective why would I take the risk of the trial.Also why would both of my oncologists tell me the trial is my only viable option? But these are the same two that did not think post chemo was necessary and to come back in 90 days for a cat scan.If after six weeks a cat scan was taken by July 1st. I would be on some kind of systemic chemotherapy instead of my current condition.

I do not have to make a decision today so it does not hurt to at least take the tests tomorrow.

Thank you,
XXXXXXX

Hi Doctor Rommstein,

I posed the question of the test to the doctor at Kloan kettering who is an expert on BRAF colon cancer. Her comments:

The study has three arms:
(1) encorafenib + binimetinib + cetuximab (targeted therapy triplet of BRAF, MEK and EGFR inhibitors)
(2) encorafenib + cetuximab (targeted therapy doublet of BRAF and EGFR inhibitors)
(3) standard therapy (you and your doctor choose before randomization if you want this to be FOLFIRI +cetuximab or irinotecan + cetuximab)

Patients are equally distributed into these three arms. You have a 2 out of 3 chance of getting a targeted therapy combination
doctor
Answered by Dr. Ivan R. Rommstein 4 hours later
Brief Answer:
Hi

Detailed Answer:
Hi,again

First, it is ridiculous for me that someone is specialized in BRAF colon cancers exclusively. Every oncologist should be able to follow most recent advancements in oncologic therapy for all types of tumors. Here, we have oncologists that specialize digestive tumors for example, but then they are able to treat all types and cancer mutations. But this is not important now...

Second, BRAF mutation is not so rare. this is seen in 10-15 percent of metastatic colorectal tumors. There is increasing number of research papers that study this particular type of cancer and this is one of not many reasons which should contribute to your optimism since these studies may identify some extra-effective chemotherapy protocol. You dont have much time to wait for this, this is true, and chances for cure are minor, but don lose your hope.

You went through extensive and dangerous surgeries, chemos and all these tests, and I am sure that there is enough strength in you to keep fighting.

You are right, there is no purpose to repeat any drugs from FOLFIri Or FOLFOX group especially after 14 chemo cycles. This would be waste of time. They usually suggest this as a last palliation in terminal stages and this is not your case. You, as a citizen of such modern and rich country, deserve more specific and novel chemotherapy protocol, even if this is part of a trial. These include so called "molecular targeted approaches".

I am not familiar with XXXXXXX D. Yaegers work, but as I can see form her publications, she is leading some new projects which are closely related to your tumor type and course of the disease.

Regarding CT scan and surgery... These new liver lesions are really bad sign unfortunately.these are located in all segments, except in the 8., but as I remember,this segment was removed in last surgery. However, good sign is that there is no ascites and no extrahepatic metastases. This may indicate that tumor may have "stabil intrahepatic course". If this will be limited to liver parenchima for some time, we may get some time to test new chemos. If at least 2 segments were clear of tumor, I would have some standard surgery recommendation for you .

Although, there are reports about survival when only 1 of 8 liver segments are left (usually 7th or 8th segment). If those lesions in 6th and 7th could be killed by chemo or ablation, then ALPPS could become an option in your case...


We performed ALPPS liver resection after 2 TACE procedures in one patient with diffuse carcinoma similar to you, and she survived (https://www.ncbi.nlm.nih.gov/pubmed/0000).
However, that was hepatocellular carcinoma...

Maybe, if portal vein emobilzation prior to last surgery was performed, there would be some better outcome and chances for complete tumor resection.

I am not smart at this point either, when talking about surgery.
If you dont have cirrhosis or hepatitis then even 25-30% of healthy liver tissue may be sufficient for survival. Since you had chemo, then we need 35-40%. Can we remove tumor and save this amount of tissue? Few years ago, we wouldnt even think of surgery in such cases,but today,there are some methods: for example, ALPPS, portal vein embolization or newly reported transarterial radiation (https://www.ncbi.nlm.nih.gov/pubmed/0000), are promising surgical methods. We have some experience with these but safety and feasibility has yet to be evaluated.

Theoretically, we could focus to save 50-60% of the right lobe (there is no way to cure 2,3 and 4. segments). We can do portal vein embolization or ALPPS of left portal vein, wait for 2 weeks till right lobe hypetrophy, and then perform some percutaneous procedure (ablation/TACE/ethanol injection) on rest of the lesions in hypertrophied right lobe. Then you would need another surgery to remove atrophied and diseased left lobe. In this case, if hypertrophy is sufficient and if ablation works, it may be beneficial and in perfect circumstances, it may be curative.

Practically, I have never seen something like this. i have seen portal vein embolization+ 2x surgery+ TACE but patient had less lesions than you have...

If your surgeon's plan is to resect every single lesion in one surgery, then you would suffer postoperative liver failure for sure. Only strategies for liver hypertrophy induction can be considered (ALPPS, poertal vein ligation or 2 stage hepatectomy).

Also, these surgical procedures have high morbidity and mortality rates and statistics show that around 20% of patients die in early postoperative period and only 30% survive 1 year.
These should be considered only if you are fit enough, with no cardiac lung or kidney diseases and in good nutritional status. There is also a risk that hypertrophy and ablation wont work..Also, more tumors may occur in meanwhile.

Liver transplantation? This is an option only if extrahepatic metastases is ruled out for sure.
For unresectable colorectal tumors, results are not so good as for cirrhosis or primary tumors. However, there are reports of 50% 3 year survival. Mortality for transplantation has improved and only 5% patients die postoperatively. Cadaveric (whole liver) is better option always, but there is a lack of donors. Living-donor transplantation is another option where just one part of healthy liver is removed from another man. It carries a risk for both donor and recipient, but if you have some possible donors on your mind who has same blood type as you, then this may be an option.

If you are ready to take this risk, ask your surgeon about this that I have mentioned.
But what to say, sorry XXXXXXX but I cant give you more specific advice about surgery and I am not sure what I would do at your place, even though I know all advantages and limits of surgery.

Otherwise, if you reject surgery completely, focus on new drugs. MEK inhibitors for example. Vemurafenib and Dabrafenib are new medications which some showed nice results so far, but this is still in early phase of clinical trials and results are mostly related to melanoma treatment.
But, these are worth of try.
Or TheraSphere as well, but Therasphere trial uses Irinotecan and Oxaliplatin. Ask them if newer medications can be used in combination with it...

It doesnt matter if targeted therapy is still at the beginning of research.YOu have nothing to lose. Irinotecan alone wont help, be sure about this. In combination with other chemo, results are much better. Cetuximab is promising...should be added as well.

Above answer was peer-reviewed by : Dr. Kampana
doctor
default
Follow up: Dr. Ivan R. Rommstein 35 hours later
Hi Doctor,
I am sorry I did not see this response until just now.I th\ank you very much for analyzing my case to this degree and showing me all of the options.

What if I start the trial at leesast for now to at least get some medication in my system?You know beforehand which drugs you will be receiving.

In the meantime I am trying to set up an apointment with Doctor Yaeger at XXXXXXX Kettering as well as the doctor at the MD Andersion in XXXXXXX and Northwestern in XXXXXXX If they come up with a better approach I could always stop the trial.

If I take the route of liver surtgery I must find the best liver surgeon in the U.S.I am not sure that Federico Aucejo from the XXXXXXX Clinic is the one.

I have completed all of the required tests for the trial and it should start next week

This is what one of my oncologist told me yesterday

If you get assigned to the third arm and it doesn't work, we can try to get the drug vemurafenib for you outside a clinical trial - no guarantee it will be covered or supplied. Having said that the trial is the only way you can get a MEK inhibitor added to the mix. You have a 2/3 opportunity. That's the nature of studies - if we knew ahead of time what was better, we wouldn't have to do the trial.

I cant express my feelings for you after all that you have done for me.
XXXXXXX

Hi Doctor,

I have sent you letter to two surgeons and three oncologists.I am quite interested in hearing their responses.

Thank you again
XXXXXXX

Hi Doctor Rommstein,
I dont know if it is true but the reason I went to the XXXXXXX Clinic is I was told the liver surgeon was one of the best in the US.Here was his response to your letter


Aucejo, Federico
1:45 PM (4 minutes ago)

to XXXXXXX me
I totally agree with this person.

Mr. Regnery you should make a decision. If you are inclined to receive surgery I am happy to evaluate you for that. The only thing that I require is that we have to rule out as we discussed that the pancreas tumor is not a metastasis from your colon cancer because if that’s the case surgery won't help much.

Let me know how you would like to proceed.

Thank you.


Federico N. Aucejo, M.D.
Liver Cancer Program, Director
Liver Tumor Clinic, Surgical Director
Liver Tumor Center of Excellence, Co-Director
Associate Professor of Surgery, XXXXXXX Clinic Lerner School of Medicine
Digestive Disease and Surgery Institute XXXXXXX Clinic 9500 Euclid Avenue XXXXXXX OH 44195 Tel 216-445-7159

Hi Doctor Rommstein,

This is from one of my local oncologist.he is old school and almot exclusively works with chemotheraphy.
XXXXXXX

Sorry

His response



Hantel, XXXXXXX
1:44 PM (8 minutes ago)

to me
I would not recommend any surgery now given the short benefit you got from the first approach. If you were to have a great response to treatment and one area were left, you might consider an ablative procedure, but right now you are playing whack-a-mole with local measures.


Hi Doctor Rommstein,

All of my Doctors that I sent your write up to are very curious who you are. All said your letter was very professional. That is a big deal coming from another doctor. All said I should start the BRAF trial. Doctor He who was the surgeon from XXXXXXX XXXXXXX said he does not do ALLPS but he said I should look into it.I am dealing with some of the best doctors in the US.Some are surgeons some are oncologists but none know both except you.

Thank you so much
XXXXXXX

Hi Doctor,

This just came fro Doctor He the surgeon at XXXXXXX XXXXXXX They just sent me another email asking what country you are from.
XXXXXXX

From: Jin He
Sent: Wednesday, September 13, 2017 6:47 PM
To: XXXXXXX Espin
Subject: Re:

Very interesting.
Who wrote this to him?
Unfortunately we don’t do ALPPS.
Can he go to Europe?

Hi Doctor Rommstein,

Here are the results of my cat scan two days ago along with the CEA and the CA-19-9 is <2.Hw can I have a 1.7 lesion in my pancreas. It does not even mention one.

These are the results of the cat scan from earlier this week. It is somewhat misleading as it compares it to the scan you gave 8/7 not the MRI on 8/30 at the XXXXXXX Clinic so there is no way to determine If there has been any growth.

CEA 5.3 I think on 8/7 maybe 3.0 on 8/7 scan

I do not understand CA 19-9 <2 U/mL I read the normal value is <37.It does not even mention or show a lesion on my pancreas.





Details

Comments from the Doctor's Office

Things getting bigger in the liver but still plenty of normal liver.(from Doctor Polite)

Study Result

Narrative

CT CHEST ABDOMEN PELVIS W 9/12/2017 7:46 PM

CLINICAL INFORMATION: Colon cancer. Screening. Research protocol.

TECHNIQUE: Enhanced CT of the chest, abdomen, and pelvis using 120 cc of intravenous
Omnipaque 350

COMPARISON: Outside study dated 8/7/2017

FINDINGS:

CHEST:

LUNGS AND PLEURA: Scarring and atelectasis at both lung bases.

MEDIASTINUM AND HILA: Trace mediastinal fluid.

CORONARY ARTERY CALCIFICATION: Mild.

CHEST WALL: Left internal jugular vein chest port.


ABDOMEN:

LIVER, BILIARY TRACT: Numerous hepatic metastases, larger compared to previous with
reference measurement given below. Presumed surgical ablation scar of segment 6 lesion.

SPLEEN: No significant abnormality noted

PANCREAS: No significant abnormality noted

ADRENAL GLANDS: No significant abnormality noted

KIDNEYS, URETERS: No significant abnormality noted

RETROPERITONEUM, LYMPH NODES: No significant abnormality noted.

CALCIFICATIONS IN ABDOMINAL AORTA AND ITS BRANCHES: Mild

BOWEL, MESENTERY: No significant abnormality noted.

BONES, SOFT TISSUES: Degenerative changes throughout the spine. T7 compression fracture.

OTHER: No significant abnormality noted


PELVIS:

PROSTATE, SEMINAL VESICLES: No significant abnormality noted

BLADDER: No significant abnormality noted

LYMPH NODES: No significant abnormality noted

BOWEL, MESENTERY: No significant abnormality noted

BONES, SOFT TISSUES: No significant abnormality noted

OTHER: No significant abnormality noted

Current exam date/time: 9/12/2017 18:57:34
INDEX LESION MEASUREMENTS

RIGHT HEPATIC DOME METASTASIS: 2.4 x 2.1 cm (Image 60, Series 201); 1.0 x 1.0 cm on prior
(8/7/2017) (Image 84, Series 2).

IMPRESSION: Enlarging hepatic metastases.

Report Electronically Signed: 9/13/2017 8:29 AM XXXXXXX Funaki, MD
doctor
Answered by Dr. Ivan R. Rommstein 2 days later
Brief Answer:
Hi, my friend.

Detailed Answer:
Hi XXXXXXX
Sorry for the delay, but I was pretty busy these days.

Thanks for the nice words, but I haven't done anything special for you. these are just advice. It's the least I can do for you, and if I hope I can help just a bit to give you some hope in future.

It is nice to hear that other colleagues in USA appreciate my opinion, although I have much less experience than they have. I am Ivan Romic-Rommstein. I have finished my surgical specialization few years ago, and I work for the last 7 years work as a Abdominal surgeon in a Department of surgical oncology and hepatobiliary surgery, University hospital Zagreb, Croatia. This is a small country in the southeastern Europe, if you wonder where it is.

I have spent some time as a part of an educational fellowship in MM Universitätsmedizin Mannheim, Germany and University hospital Zurich, Switzerland, where I have heard of ALPPS for the first time.
Now I am back in my country.

Here, we must have a wide knowledge since there is a lack of doctors so you must be surgeon, oncologist, and gastroenterologist in one.

However, my special field of clinical and scientific interest is oncologic surgery, especially liver surgery, liver neoplasms and liver hypertrophy induction. I have some personal reasons for this, because someone close to me, died of metastatic colon cancer. I hope that in future, we will establish and improve radical liver surgery which should be a cornerstone in treatment of liver malignancies.

So you have a malignant disease which is my area of expertise, so this is the only reason why it seems that I know something more about this. So if you were here, probably my team would handle your case.

But let's go back to the present scenario.

Not all hospitals and liver surgeons accepted ALPPS. There is a high mortality rate after this surgery and new studies are required to evaluates its feasibility and safety. We have some experience with this, but Zurich has done many ALPPS procedures as well as some surgeons in Argentina, and some centres in Germany.

This is not some complex surgery, with regards to technical issues so every HPB surgeon should be able to perform ALPPS. This is more like a surgical strategy that induces liver hypertrophy and for the time being, this is the only curative treatment for metastatic liver tumors that are diffusely spread in the liver.

It can be combined with preoperative chemotherapy or TACE and there are successful cases in some patients with a similar story as you have.

But still, I have to emphasize again that ALPPS is physiologically demanding procedure and many patients die in postoperative period or there is no sufficient liver hypertrophy. So I would need your CT or PET images uploaded here to tell if ALPPS is justified in your case because I should have a look into relation of tumors and major vascular structures in liver. . Considering CT written description, I am afraid that there are higher chances that it is not, since no sufficient healthy liver volume can be preserved. YOu can see what ALPPS is in this short video: https://www.youtube.com/watch?v=VQuegI_wGhk

There is no purpose of going to Europe or other places to have ALPPS performed. As I said, you are probably not a candidate for it at this point, unless you are ready to take a very high risk. It is better to wait for chemo response.

SO if chemotherapy work a bit and kill few of these metastases then, surgery can be reevaluated again. So, just start with trial. It doesn't matter if you get to wrong arm; you just need to start any chemo so that we have some opportunity to see response. LAter, we will see if some other options are possible. There is no need to insist on MEK inhibitors at this point, especially if you have to pay for it.
You ll get Cetuximab in every case, and you have great chance to get some of the newer chemos.

Your markers are surprisingly low, this is very good. Normal values are below 37 don't worry.

Size progression is expected.
Pancreatic lesion would be a bad sign but it reports negative as I see.
Alos, there is no paraaortic lymphadenopathy which is a good sign too.

Have faith and be strong.

Inform me about further steps, I am always at your disposal.

Warm regards
Dr. Ivan Romic R.


Above answer was peer-reviewed by : Dr. Arnab Banerjee
doctor
default
Follow up: Dr. Ivan R. Rommstein 3 hours later
Hi Doctor,

Thank you again for all of the time you have spent on my case.I was not kidding about sharing your last letter with several oncologists/surgeons and how impressed they were especially XXXXXXX XXXXXXX

So the surgeon at the XXXXXXX Clinic thinks he should resection my liver,use ablation on the smaller lesions and an infusion pump.This is pretty radical especially when you do not know if the chemotherapy medicine in the pump will kill the invisible BRAF cells.That is what happened aft my liver surgery.

So I guess unless you disagree if I qualify I should start the trial next week and hope the new drugs are as effective as the Folfox.Folfiri and Avastin.

The oncologist at MD XXXXXXX also recommended the trial.I am very relieved that the radiologist at the XXXXXXX Clinic made a mistake in analyzing my MRI and that I have no cancer in my pancreas.

Thank you again
XXXXXXX
doctor
Answered by Dr. Ivan R. Rommstein 6 hours later
Brief Answer:
Hi

Detailed Answer:
Hi.
Yes, I agree with oncologist at MD XXXXXXX You have to start with trial and see the initial response. Starting with surgery may just be too risky and you may not even reach pump or chemo. If there are no any results after starting trial,you can still go back to your surgeon and have this hazardous surgery as a last hope.
Above answer was peer-reviewed by : Dr. Kampana
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