Xeloda dosing

[Rock_Robster]

Hi all, I’ve seen some recent chat in threads including Xeloda (capecitabine) dosing, but rather than hijack those I thought best to start here and ask my questions.

After 4 years managing stage IV rectal cancer, I’ve recently stated on Xeloda + Avastin (capecitabine + bevacizumab). Plan is to stay on this long-term if I can, interspersing with things like SABR/ablation or trials, as appropriate. Initial dosing in Australia is 1250mg/m2 twice daily, so as a 185cm / 83kg guy that works out to 5,000 mg/day. 2 weeks on and 1 week off. The onc said we would almost certainly need to dose reduce at some stage, likely to maybe around 70-80% of this, based on side effects.

I’ve just finished the first 2 weeks and have had to skip a few doses (as he suggested) due to side effects - mainly early appearance of early stage hand/foot syndrome, and early mouth ulcers. So I expect I’ll get a dose reduction next cycle. Wondering where most people end up with their dosages? (eg on a mg/m2 basis).

I’m avoiding added folate / folic acid and doing the topical treatments for the HFS (urea cream, etc) but wondering what peoples’ views on systemic treatments for side effects are that don’t interfere with efficacy? I’ve seen decent data for celebrex (celecoxib) which seems to be synergistic with Xeloda anyway so will restart that, but also hearing melatonin? I was taking 30-40mg nightly anyway but the onc pharmacist suggested I stop due to antioxidant effects on the Xeloda. Any thoughts welcome!

Cheers,
Rob

[beach sunrise]

Definitely find high dose IVC and add celebrex and vitamin E with selenium.
30 min's before breakfast I take my cancer pathway blockers, then eat breakfast and take xeloda, celebrex, vitamin E with selenium 15 min's after, wait another 15 min's and take the phenols. Repeat the pathway blockers and antioxidants a few hrs later. In between the celebrex dosage of 200mg B.I.D I take melatonin. It is also an anti inflammatory and free radical scavenger.
I have not heard of ulcers before. Thanks for sharing that side effect. I make my own toothpaste using baking soda, peppermint or spearment oil and rinse with coconut oil so maybe that is why I never had that. I also keep my hands and feet moisturized with a combo I make using olive oil or avocado oil with cocoa butter. My dogs go crazy wanting to eat it, lol.

[Jacques]

...
I’m avoiding added folate / folic acid and doing the topical treatments for the HFS (urea cream, etc) but wondering what peoples’ views on systemic treatments for side effects are that don’t interfere with efficacy? I’ve seen decent data for celebrex (celecoxib) which seems to be synergistic with Xeloda anyway so will restart that, but also hearing melatonin? I was taking 30-40mg nightly anyway but the onc pharmacist suggested I stop due to antioxidant effects on the Xeloda. Any thoughts welcome!

Cheers,
Rob

Rob - Thanks for starting this thread. This thread should eventually yield a lot of useful tips on how to deal effectively with the various Xeloda side effects, both proactively and retroactively.

I don't have much to contribute as far as systemic treatments for Xeloda side effects go. But I did notice an alert against using the oral steroid dexamethasone along with celebrex (celecoxib). Apparently, the two don't mix well:

"Using dexamethasone together with celecoxib may increase the risk of side effects in the gastrointestinal tract such as inflammation, bleeding, ulceration, and rarely, perforation. Gastrointestinal perforation is a potentially fatal condition and medical emergency where a hole forms all the way through the stomach or intestine. You should take these medications with food to lessen the risk. Talk to your doctor if you have any questions or concerns. Your doctor may be able to prescribe alternatives that do not interact, or you may need a dose adjustment or more frequent monitoring to safely use both medications. Your doctor may also be able to recommend medications to help protect the stomach and intestine if you are at high risk for developing serious gastrointestinal complications. You should seek immediate medical attention if you experience any unusual bleeding or bruising, or have other signs and symptoms of bleeding such as dizziness; lightheadedness; red or black, tarry stools; coughing up or vomiting fresh or dried blood that looks like coffee grounds; severe headache; and weakness. It is important to tell your doctor about all other medications you use, including vitamins and herbs. Do not stop using any medications without first talking to your doctor."
Reference: https://www.medicine.com/interaction-checker/result?drugs=celecoxib+dexamethasone#interaction-drug

Apparently, oral dexamethasone is sometimes used to attenuate HFS symptoms, but if it is used, it must be used cautiously.

[rp1954]

Yeah steroids are something we avoided for all 8 chemo years.

In most cases, through the use of IV vitamin C (IVC) for almost 12 years, and/or NSAIDs, usually celecoxib, post-surgically and chemo years, 2.7 ~ 9 (into post chemo time).

In our IVC circle, one woman (not a cancer patient) totally stopped her years long daily Prednisone requirements with IVC. Another broke his severe COVID storm fever with IV vitamin C, then got a lung infection later when dexamethasone was unnecessarily added (1st choice methylprednisolone was unavailable).

Other patients have long used IV vitamin C with various CRC chemo, especially Folfiri when they are wanting to quit.
I am not sure about current data on Avastin + celecoxib, definitely a review/research area for interactions and safety.

One of our starting points was the willingness to use IV vitamin C to reduce the need for Avastin because Vegf-A is mediated through histamine. Histamine is modulated by ascorbate on both sides of creation and destruction of histamine, to reduce histamine and VEGF-A levels. In 2010-2011, I looked at the possibility of extending Avastin and reduced Avastin total dose with IV ascorbate, but we never needed Avastin as it turned out. We didn't need celecoxib until 2012-13 because of the other inhibitors and improved 5FU (UFT) dosing with natural folate and oral leucovorin (LV for UFT but probably not Xeloda).

Working 5FU formulas are additive affairs to maintain chemosensitivity. Essentially, we were able to totally "trade" oxi-, iri- and Avastin for IVC, generic drugs and potent nutraceutical doses, on an individualized test basis, while still oxi-iri naive.

As for oral ulcers, from the earlier 5FU-folic acid toxicity era (3Q2010) and occasionally after, we used a powder blend of buffered ascorbates, glutamine, zinc carnosine, glucosamine and MK4 to hold as long as possible in the mouth or externally, swish and swallow to address GI integrity/injuries, too.

[Jacques]

• Initial Diagnosis and Staging, October 25, 2018
  

  Initial diagnosis: Stage IV-A --Rectal Cancer with 4 mets to liver.
  Liver mets considered resectable. Primary tumor considered resectable as an ultra low anterior resection (ULAR). The two surgeries planned as sequential: liver surgery first after some cycles of FOLFOX neoadjuvant therapy, followed by primary tumor surgery after 5 weeks of chemorad.
  
  https://coloncancersupport.colonclub.com/viewtopic.php?f=1&t=61050&p=483475#p483475
  

  
  
• Initial Treatment Plan as of November 9, 2018
  

  Sequence:
  1. Port installation
  2. Chemo - FOLFOX, 4-6 rounds
  3. CT scan and a 4 week break pre-surgery
  4. Liver resection
  5. CT scan
  6. 6 weeks chemoradio therapy - 5FU or Xeloda, with long course radiation on primary tumour (2x25 Gy)
  7. CT scan
  8. 4 week break pre-surgery
  9. Rectal resection - ultra low anterior resection, temp Ileostomy
  10. Chemo - FOLFOX, remaining doses to get to 12 in total (but only 8-9 in total with oxy)
  11. CT scan
  12. Ileo reversal
  
  Reference: https://coloncancersupport.colonclub.com/viewtopic.php?f=1&t=61175&p=484233#p484233

  
  
• Actual Treatment Sequence (according to December 2022 signature)
  

  40M Australia
  2018 RC, 12cm high
  G2 EMVI LVI. 4 liver mets
  pT3N1aM1a Stage IVa MSS NRAS G13R
  CEA: Nov-18: 14 then <2. Jun-22: 5. Sep-22: 10. Nov-22: 19
  11/18 FOLFOX
  3/19 Liver resection
  5/19 Pelvic IMRT
  7/19 ULAR
  8/19 Liver met
  8/19 FOLFOX, FOLFOXIRI, FOLFIRI
  12/19 Liver resection
  NED 2 yrs
  11/21 Liver met, sub-cm lung things
  3/22 3 Liver mets & PALNs. Lymphadenectomy
  4/22 Liver SBRT
  9/22 Small liver spot, PALNs
  10/22 PALN SBRT
  11/22 Liver mets, possible peri nodules. Xeloda+Avastin

[Rock_Robster]

Hi Jacques, you’re very thorough as always and ask great questions!

I’ve been grappling with this myself lately. First I might give a little context on the most recent developments in my case.

Following SBRT treatment on the distant lymph nodes in October, the plan was to start a phase 3 trial - specifically the RELATIVITY trial combining a LAG inhibitor (Relatlimab) with a PD-1 blockade (Nivolumab). Unfortunately I didn’t qualify for the trial as I have not had recent progression on irinotecan, nor have I ever had a biologic/targeted therapy. I am in the strange (good?) situation that although I’ve now been dealing with stage IV cancer for 4+ years, I haven’t actually progressed on any lines of chemo yet (though I am now allergic to oxaliplatin). I currently have the right and central lobes of my liver (left lobe removed).

So the plan remains to try to find a trial I can qualify for now, and given the likely delays I restarted systemic chemo as maintenance in the interim. Given the (thought to be) relatively low disease burden at that point, we elected for Xeloda+Bev in the hope this may be sufficient to maintain stability without destroying my performance and immune system, particularly given I hadn’t had Avastin before, and holding back the bigger guns for when needed.

I had baseline scans done at the start of this treatment, which unfortunately showed progression in the liver (multiple lesions through remaining segments), lungs (more nodules), and fat stranding in the omentum with potential early peritoneal nodules. Some lymphadenopathy remained as well. So this was clearly objectively a bad scan. In addition to this my blood work showed a similar jump - CEA rising from 15 to 20, CA19-9 up to 80, and a big jump in LDH from 180 to over 400.

At this point I and one of my oncologists was very concerned we may be undertreating this, given recent rate of progression. We debated adding irinotecan to the current cocktail to make XELIRI-Bev, but agreed with the other onc to do more bloods before changing the plan, given the current treatment has only really had 1 (almost 2) cycles to show effect. Fortunately last week this showed a modest CEA drop (to 17), a decent CA19-9 drop of 20 points, and a huge drop in LDH back to 270. So with this considered, the plan now is to do one more Xeloda+Bev cycle (making 3 in total) and then scan for response.

Given the highly systemic nature of my disease at present, none of my doctors are supportive of locoregional treatments like radiation or ablation unless a particular area is becoming symptomatic or life-threatening (eg pain, or impacting liver drainage or bowel obstruction). I can understand this - local targeted treatment would not be curative now, and the time off chemo could be devastating for other mets without systemic control. My disease has shown itself to be highly radiosensitive (complete responses both to IMRT and SBRT x 2), however there is a restriction that the liver can’t be re-irradiated within a ~6 month period - so if I did liver SBRT now and something popped up in 3 months that was impacting liver function, then I would have very few options for treatment.

Fortunately at the moment I have zero pain or symptoms really, my liver function is decent (t-bili is a bit high), performance score of 0 and I’m still working full time. I’m 40 years old with no comorbidities, BMI 26.

In addition to the above I am doing my usual off-label and supplementary regimen, and start IVC treatment tomorrow as well. I am also planning a trip to Japan next month to start autologous NK / dendritic cell therapy.

So the short-term priority remains: (1) get systemic control of disease by any means necessary, and (2) find a good trial that I might qualify for sooner. The options on the latter in Australia are unfortunately a bit limited, but there are a couple of novel molecules and combination therapies being explored that are interesting. I am meeting some additional trial leads next week to review.

Any additional questions, thoughts or input welcome!

Thanks,
Rob

[Nor Cal]

Following this thread as you and I seem to be in similar positions (treatment has gone well but now what?)

I'm currently on Xeliri, and the Xeloda dosing is 1,800 twice a day, which is low for my surface area (1.99). Irinotecan dose is standard. No Avastin as I've had bleeding and blood clot issues on it historically.

[rp1954]

the time off chemo could be devastating for other mets without systemic control.

I fully agreed in 2011. So for wife's surgery #2, the conglomerated para aortic LN removal, we got the UFT (oral 5FU drug) tx time off, down to ca 36 hours off. UFT is a faster acting/draining oral chemo than Xeloda. I figure Xeloda equivalent times off might be about double.

So is it possible for your peri-operative time off chemo to be shaved from 12 weeks to ca 72 hrs?
We took the initiative here.

A lot of factors are at play: the chemo drug(s) close in; no surgical complications (IVC etc) for us (final chemo decision for timing was based on good/great post surgical recovery quality); location/organs involved; expected treatment result - large met growth/reduction vs "just" metastatic spread suppression. A lot of early metgastatic spread steps might be suppressed by lower chemo levels without as much control of growth in the largest mets. Since our precise point was surgical removal of the biggest ones, a little more growth might not matter - very little resistance to sharp steel.

So your questions might include whether there is enough spread suppression from ADAPT+++ in the 6 weeks before surgery, after hardening by Xeliri-Bev, to use surgery more successfully than typically expected even if typically declared inoperable due to metastatic spread risk of "std" surgical practices. Also we tried a "+++" only, chemo naive approach for surgery #1 (2010) that may have slowed things down post op for almost 7 weeks, after the big pre-op necrosis with less stuff and no IVC yet, "++".

my liver function is decent (t-bili is a bit high)...

I found a Japanese paper where some of their drs used up to 6 grams (6000 mg/d) taurine to clean up excess bilirubin levels from 5FU based chemo damage (not sure of the other adjuvants). When my wife's bilirubin started drifting up, I added 200 mg/d of taurine to her daily formula and Bili normalized back.

[Rock_Robster]

Thanks RP, appreciate the detailed comments as always and thanks for the tip on taurine - I’ll definitely check it out.

Interesting one today - the clinic wanted to add glutathione to my IVC infusion. I said no until I had a chance to research it more - my memory was that elevated glutathione could potentially be chemoprotective and promote progression/metastasis. They promoted it was as a ‘detoxifier’ than a direct cancer treatment. Very interested if anyone has any views on this for next time.

Thanks,
Rob

[Jacques]

... I’ve just finished the first 2 weeks and have had to skip a few doses (as he suggested) due to side effects - mainly early appearance of early stage hand/foot syndrome, and early mouth ulcers. So I expect I’ll get a dose reduction next cycle. Wondering where most people end up with their dosages? (eg on a mg/m2 basis).

Hi Rob -

I was just looking back at your first post on this thread and noticed your comments about emerging Xeloda side effects.

In case you haven't seen these already, here are a couple posts on products for treating some Xeloda side effects:

Some treatments for mouth sores
https://coloncancersupport.colonclub.com/viewtopic.php?f=1&t=50402&p=386196#p386196
.
Some treatments for hand foot syndrome (HFS)
https://coloncancersupport.colonclub.com/viewtopic.php?f=1&t=59396&p=471025#p471025

[beach sunrise]

I wouldn't add glutithione until I researched it fully.

[Jacques]

Hi Rob -

Thanks for posting your long update above. It helps clarify the last line in your signature.

I had another look at your signature and I annotated a copy of it by stratifying the events by year (see below). The red highlights refer to the middle two years, which are basically the COVID pandemic years.

I was wondering if the recent flurry of recurrences over the past year or so might be related to a reduced access to full medical support during the COVID lockdown era resulting in a possible under-treatment of your cancer during that time frame.

What do you think? Have your doctors or your multi-disciplinary team members had anything to say about the recent rise in recurrences over the past year or so?

December 2022
Rock-Robster's signature -- annotated
40M Australia
2018 RC, 12cm high
G2 EMVI LVI. 4 liver mets
pT3N1aM1a Stage IVa MSS NRAS G13R
CEA: Nov-18: 14 then <2. Jun-22: 5. Sep-22: 10. Nov-22: 19
===== 2018 - DX Stage IV-A, potentially curable, with surgery
11/18 FOLFOX
===== 2019
3/19 Liver resection
5/19 Pelvic IMRT
7/19 ULAR
8/19 Liver met
8/19 FOLFOX, FOLFOXIRI, FOLFIRI
12/19 Liver resection
===== 2020
NED 2 yrs
===== 2021
11/21 Liver met, sub-cm lung things
===== early 2022 - DX Stage IV-B (liver+lungs)
3/22 3 Liver mets & PALNs. Lymphadenectomy
4/22 Liver SBRT
9/22 Small liver spot, PALNs
10/22 PALN SBRT
11/22 Liver mets, possible peri nodules. Xeloda+Avastin
===== late 2022 - DX Stage IV-C (liver+lungs+PALN+possible peri mets)?

[Rock_Robster]

Thanks very much for this Jacques. Sometimes it’s difficult to capture the full narrative in the space available for signatures. Apologies the below is a bit of an essay as I’m bored on a plane…

I don’t believe Covid impacted my care, as thankfully I was NED through most of the restrictions in Australia, and still able to access routine surveillance scans and bloods. I did however definitely have a strange turn of events in Nov 2021 when my recurrence was first picked up. I had recently moved interstate from Victoria to Queensland, but was still under the care of my Victorian team (remotely) while I got myself set up with a treating team in my new state. When I had the PET-CT that detected the recurrence, my original surgeon misread the scan report and only picked up the sizeable liver lesion (~3cm), and missed the moderately avid celiac node, and avid periportal node. On this assessment, he considered me possibly resectable and referred me to a top liver surgeon nearby where I now lived. This liver surgeon then accessed my scans electronically, however read the wrong patient’s scans (same name and presentation, wrong DOB). On this basis, he recommended surgery now. It was only a PCP/GP who raised a concern about the nodal disease, and I brought it to the attention of the surgeon. By this point however he was very much invested in my case, and agreed to do a PVE first and then right hepatectomy if possible, plus a nodal resection. This whole chain of events, whilst alarming, was actually serendipitous - my original surgeon later told me if he had have seen the celiac node he probably wouldn’t have referred me for resection at all.

So although my history looks like a serious of rapid recurrences, this hasn’t really been the case. I had been considered oligometastic since diagnosis, and up until Nov 2021. After this point it was fairly clear we were dealing with extensive systemic disease (liver, lymph nodes, likely lung nodules). Fortunately the lung modules were very small and slow-progressing, but the liver was a big concern. While I ended up having an extended lymphadenectomy in Mar 2022 (11 peri-aortic nodes taken, 5 positive), they knew they weren’t able to remove all the nodal disease in this procedure. This followed up with SABR on the liver lesions, to which I thankfully had a great response. However at no point from there was I considered NED.

The liver remained clear and the lungs stable, however unfortunately the celiac nodes were putting pressure on my celiac plexus causing 6/10 pain, so we agreed to prioritise SBRT radiation on those nodes for symptom relief. Again fortunately the response to this was almost immediate, and pain went to zero within a week.

The plan then was that I would start a clinical trial for the remaining systemic disease, provided it was measurable. I explained the outcome of that process in my earlier comment. So this basically brings us to now - restarting chemotherapy to try to get some systemic control. Unfortunately my baseline scans at the start of treatment showed another ‘flare’ (correlated with blood work), although most recent bloods are more promising so hoping to confirm response to treatment soon, and start the hunt for another trial.

To your question - I don’t think this is actually an issue of ‘why all the recurrences’ (as I say, it’s really been one occurrence which we’ve been unable to fully control), but the bigger question I have is - why does my disease seem happy to stay dormant stable for months, even years on end without systemic treatment - then sporadically flare with rapid progression?

Biologically I have several factors that should suggest more aggressive progression - NRAS+, EMVI, LVI, distant nodal disease, etc. However this has not consistently been the case (thankfully). My concern now, in addition to getting systemic control, is keeping my performance score well enough that I can tolerate treatment and qualify for trials - even if I have some progression. I’m relieved that both my radiation oncologist and surgeon are happy to be aggressive and intervene if there is something threatening my life/QoL, but I do see their point that we are likely beyond local treatment as our primary weapon. Systemic disease needs a systemic response, so I’m focussing on I/O trials with novel molecules / MAs, which also doing what I can to support immune response in the meantime (autologous NK/DC therapy, IVC, PSK, Vit D, etc) and metabolic/inflammatory defence (eg metformin, celecoxib, curcumin, melatonin, niacinamide, aspirin).

[rp1954]

How far back do your various inflammation series go? e.g. CRP, ESR, fibrinogen, D-dimer, IL6, IL8, ceruloplasmin, ferritin

[Jacques]

How far back do your various inflammation series go? e.g. CRP, ESR, fibrinogen, D-dimer, IL6, IL8, ceruloplasmin, ferritin

Hi Rob -

When you had the problem with DVTs, did they test you for systemic inflammation? If so, which markers did they use? Any of these ... ?

D-DIMER = https://www.mayocliniclabs.com/test-catalog/Clinical+and+Interpretive/40936
FIBRINOGEN = https://www.mayocliniclabs.com/test-catalog/Clinical+and+Interpretive/40937
CRP = C Reactive protein = https://www.mayocliniclabs.com/test-catalog/Clinical+and+Interpretive/9731
FERRITIN = https://www.mayocliniclabs.com/test-catalog/Clinical+and+Interpretive/88153
INTERLEUKIN-6 https://www.mayocliniclabs.com/test-catalog/Clinical+and+Interpretive/63020
CERULOPLASMIN https://www.mayocliniclabs.com/test-catalog/Overview/113561#Clinical-and-Interpretive

Another question: When you take long flights in an airplane, do you do anything special to mitigate against the onset of DVTs?

DVT and Flying
https://www.theclinicone.com/post/dvt-and-flying