1. Avoid colorectal stents and bevacizumab: Experience at the Mayo Clinic has shown that the risks of perforation after colorectal stenting in patients receiving bevacizumab are prohibitive.
2. It is Ok to give Cetuximab every-other week: Outside clinical trials, Cetuximab is given by Dr. Grothey at a dose of 500 mg/m2, every-other week (no loading dose is required).
3. Genotyping is essential to mCRC management: Thorough genotyping for - at least - KRAS, BRAF and NRAS is required prior to initiation of systemic therapy of metastatic CRC.
4. There is a thing called FoundationONE: A (somewhat) full genomic profile can be glimpsed with this genomic test for under US$ 5000.oo with FoundationONE by FoundationMedicine. Mayo devised a 50 gene genomic test for metastatic colorectal cancer (mCRC) under US $ 2000.oo.
5. FOLFOXIRI-Bevacizumab is active in BRAF mutant mCRC with acceptable OS: The added toxicity of FOLFOXIRI is warranted in BRAF mutant mCRC based on the TRIBE trial results.
6. Seek subclinical oxaliplatin-induced neuropathy with L'Hermitte's sign: L'Hermitte's sign is "an electrical sensation that runs down the back and into the limbs. In many patients, it is elicited by bending the head forward" (wikipedia). Dr. Grothey stops Oxaliplatin in patients with POSITIVE L'Hermitte sign as it is a herald of clinical neuropathy.
7. No need for the at least 1500 Absolute Neutrophil Count (ANC) rule to give oxaliplatin: The risk of febrile neutropenia with FOLFOX/XELOX is quite low. Therefore, some freedom is afforded.
8. Not all FOLFOXes are equal: There appears to be NO compelling evidence of the benefit of the bolus FU component in the FOLFOX platform. Therefore, In the palliative setting mFOLFOX7 (without bolus FU) is given. On the other hand, in the adjuvant setting, mFOLFOX6 (with some bolus FU) is administered to patients in order NOT to deviate too much from the (FU bolus containing) FOLFOX4 used in the (positive) MOSAIC that shaped our practice in stage III CRC.
9. Optimal dose of Oxaliplatin every two weeks is 85 mg: There is no reason to administer Oxaliplatin at a dose greater than 85 mg/m2 when it is given every 2 weeks. When Oxaliplatin is given every three weeks, it remains 130 mg/m2.
10. FOLFOX tolerability is FAR superior to XELOX's: In general, FOLFOX - particularly mFOLFOX7 - is better tolerated than XELOX.
11. LD-Capecitabine and Bevacizumab rules: An extremely effective and well tolerated way to deliver both capecitabine and bevacizumab is the CAIRO3's Continuous (ie, UNinterrupted) Low-Dose (LD) capecitabine at 625 mg/m2 q12h from days 1 to 21 with Bevacizumab 7.5 mg/kg every 21 days.
12. Some words on toxicity assessment: it is not only important to assess the grade of toxicity, but also to try to include a duration component to it. A non-resolving grade 2 toxicity can be more significant than a one-day grade 3 toxicity.
13. 10-point visual scales can be expanded: Patients are asked on every visit to grade PAIN, FATIGUE and WELL-BEING on 10-point scales. Pain scores 5, or greater, require immediate action.
14. Even if liver metastases can be resected, pre-operative chemotherapy is preferred: despite level I evidence to the contrary, Dr. Mark Truty provides compelling reasons to administer some (not too much) preoperative chemotherapy (ie, 3-4 months). I would need the presentation to recapitulate his arguments.
15. There is a thing called "The Kleiner Score" for Non-Alcoholic Steato-Hepatitis: See figure below.
(Kleiner DE, Brunt EM, Van Natta M, Behling C, Contos MJ, Cummings OW, Ferrell LD, Liu YC, Torbenson MS, Unalp-Arida A, Yeh M, McCullough AJ, Sanyal AJ; Nonalcoholic Steatohepatitis Clinical Research Network. Design and validation of a histological scoring system for nonalcoholic fatty liver disease. Hepatology. 2005 Jun;41(6):1313-21. - Medline)
16. A continuum-of-care approach to palliative systemic therapy in wild-type (wt) KRAS mCRC: This is what I understood as a reasonable approach for non-curative treatment for wtKRAS mCRC (I added a few notes to help ME, but they may include some - hopefully minor - imprecisions).
A. mFOLFOX7 x4 months: Start with mFOLFOX7 + Bevacizumab (q2 weeks x8, before neuropathy ensues). mFOLFOX7 is Oxaliplatin 85 mg/m2 2h-IV infusion, day 1, Folinic acid 400 mg/m2 2h IV-infusion, day 1, Fluoruracil 2400 mg/m2 in 46h IV-infusion (through an infusion pump).
B. Continuous LD-capecitabine + Bevacizumab: In non-progressors, follow with continuous LD-capecitabine + Bevacizumab until disease progression.
C. Either mFOLFOX7 or FOLFIRI + Bevacizumab: On progression, reintroduce mFOLFOX7 + Bevacizumab (similar to CAIRO3) or consider shifting to FOLFIRI+Bevacizumab (similar to TML). Caveat: For very early progressors (PFS no longer than 6 months, I surmise), anti-angiogenic therapy beyond progression may be of very little benefit.
D. Enter anti EGFR therapy: On progression, continue with Irinotecan + EGFR mAb (Cetuximab or Panitumumab).
E. Back to anti angiogenesis (?): Regorafenib:On progression, consider Regorafenib (for fit patients with PS0/1) or Best Supportive Care (if PS 2+).
F. Past performance may be herald of future results: going back to oxaliplatin: On progression, consider re-exposure to Oxaliplatin. Sometimes, it works AGAIN.
18. Unexpected results of FIRE-3 are still inconclusive: No firm recommendations can be extracted of the unexpected increase in OS observed in favor of Cetuximab+FOLFIRI (vs Bevacizumab+FOLFIRI) in wtKRAS mCRC. It did not shift current treatment approach. More date required.
19. We need to wait for the results of the CALGB 80405 at ASCO 2014: Despite several attempts we were not able to extract any information as to the results of the CALGB 80405 (head-to-head comparison of Bevacizumab + CT vs Cetuximab + CT in First-Line wtKRAS metastastic CRC). It is going to be a plenary presentation.
20. If you know, you can teach everything you know and still be far ahead: Thank you, Dr. Grothey.
Resources
In this link you will find the source code (in Python) for a dose calculator for mFOLFOX7, mFOLFOX7 + Bevacizumab, and Continuous Low-Dose Capecitabine + Bevacizumab (copy & paste this code into one of the Python engines - ie, CodeSkulptor located in the heading of the page. Execute it, and insert Height, in cms, and Weight, in kg. In Spanish, though).
About the First Colorectal Cancer Preceptorshi -GTG & Mayo Clinic
On April 4-5, 2014, I had the opportunity to attend the First Colorectal Cancer Preceptorship - GTG & Mayo Clinic in Rochester, Minnesota. I was invited by Dr. Anelisa Kruschewsky Coutinho, head of the Gastrointestinal cancer Tumor Group (GTG) from Brazil. The preceptorship was directed by Dr. Axel Grothey and it was imparted in the impressive Gonda Building, part of the Mayo Clinic complex. The faculty included Dr. Grothey (Management of patients with unresectable metastases: the role of prognosis and predictive factors, which chemotherapy backbone, optimal treatment duration. Non-surgical treatment of early colon and rectal cancer. Mayo Clinic approach to other GI malignancies), Dr. Chua (Surgery for colorectal cancer), Dr. McWilliams (Biomarkers beyond KRAS, NGS), Dr. Mandrekars (Clinical trials workshop: review of challenges with trial designd, designing new trials), Dr. Haluska (Future therapies and technologies with potential to improve on the SOC), and Dr. Truty (Liver resection: case-based presentation / Who, How, When?). The audience was composed of several latin-american clinical and surgical oncology delegates, including: Dr. Coutinho, herself (from Salvador, Bahia, Brazil), Carlos Vargas (Bogotá, Colombia), Gabriel Krigier (Montevideo, Uruguay), Gustavo Fernandes (Brisilia, DF, Brazil), Javier Castillo (Buenos Aires, Argentina), Juan Manuel O'Connor (Buenos Aires, Argentina), Luis Alberto Mattos (Recife, PE, Brazil), Marcelo Ferretti Fanelli (Sao Paulo, SP, Brazil), Maria Lourdes Oliveira (Rio de Janeiro, RJ, Brazil), Mariano Dioca (Buenos Aires, Argentina), Markus Gifoni (Fortaleza, CE, Brazil), Mighel Brandao (Salvador, BA, Brazil), Sergio Roithmann (Porto Alegre, RS, Brazil), Suilane Ribeiro Oliveira (Teresina, PI, Brazil), Rache Riechelmann (Sao Paulo, SP, Brazil), and Ulyses Ribeiro (Sao Paulo, SP, Brazil). One welcome deviation from "business as usual" was the total freedom from any commercial interest interference during the whole preceptorship. The sponsors were absent from the proceedings. I found this preceptorship of the utmost value for the future care of my patients with colorectal cancer, and I am thankful for the invitation of Dr. Coutinho and the generosity and kindness of Dr. Grothey and his friends who shared with us their immense knowledge. In the previous paragraphs, I conveyed some of the NEW things I learned that can be applied immediately to my patients with colorectal cancer. By no means, this pretends to be an exhaustive view since these are but few bullet points I wish to stress because: 1. I believe them to be important and 2. I tend to easily forget when I don't "write". Since these were notes jotted down during the preceptorship, no references were provided (at least as of now). I write in English because many of the delegates are non-spanish speakers, and I wish to share these notes with them (they could point out some mistakes I have made and remind me of other valuable lessons I forgot to include). I also describe a little bit the activity itself because it is an example of how "it should be done" and it can inform us for similar endeavo(u)rs in the future.
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