"Conversion therapy" = the use of induction chemotherapy in patients with isolated but initially unresectable CRC liver metastases. 12-33 percent of patients with “initially unresectable” hepatic metastases have been reported to achieve a sufficient objective response to permit a subsequent complete (R0) resection. Five-year survival rates average 30 to 35 percent, results that are substantially better than expected using chemotherapy alone (10 to 11 percent five-year survival, even with the most active regimens).

The definition of “initially unresectable” in these reports was apparently subjective. The frequency of converting a patient with truly unresectable disease to the point of resectability through the use of neoadjuvant chemotherapy is reported to be only 5-15%. Even with the most effective regimens, the complete pathologic response rate after neoadjuvant chemotherapy is reported to be only 4 to 9 percent.

There are several treatment options, including: FOLFOX), FOLFOXIRI, or FOLFIRI plus cetuximab or panitumumab (for patients whose tumors lack K-ras mutations).

Some studies have used Mitomycin + Xeloda combination. Other studies used intraarteial therapy (see reference 2 below)

References:

1. Blazer DG 3rd, Kishi Y, Maru DM, et al. Pathologic response to preoperative chemotherapy: a new outcome end point after resection of hepatic colorectal metastases. J Clin Oncol 2008; 26:5344.

2. Goéré D, Deshaies I, de Baere T, et al. Prolonged survival of initially unresectable hepatic colorectal cancer patients treated with hepatic arterial infusion of oxaliplatin followed by radical surgery of metastases. Ann Surg 2010; 251:686.

3. Adam R, Aloia T, Lévi F, et al. Hepatic resection after rescue cetuximab treatment for colorectal liver metastases previously refractory to conventional systemic therapy. J Clin Oncol 2007; 25:4593.

4. http://www.uptodate.com/contents/management-of-potentially-resectable-colorectal-cancer-liver-metastases?source=see_link&anchor=H9#H9

There was a brilliant presentation by Leonard Saltz in this year in the Annual ASCO Meeting in Chicago about this topic.

Challenging the statement of Dr. Uckun above regarding recommended chemo options, the thumb rule is that for conversion therapy you should use a protocol which produces good response. This can include oxaliplatin or irinotecan, has to include a fluoropyrimidin, and incorporating a biological is always almost a must. Bevacizumab can be used in all cases, cetuximab and panitumumab could be appropriate for KRAS wild type patients only.

Never forget, that conversion therapy in some cases is not an appropriate neoadjuvant chemo, and it will not kill micrometastases. Irinotecan, cetuximab and bevacizumab are failed to show activity in adjuvant trials, so conversion protocols containing these drugs can not be considered as effective antimicromet chemo combos. Only FOLFOX or CAPOX can be used as a conversion and as a neoadjuvant therapy in the same time. It means that if the conversion chemo was successful and the patient's mets succesfully resected to R0, it has to be considered to deliver an adjuvant treatment with 12 cycle of FOLFOX os 8 cycles of CAPOX, or you should increase the cycle number up to 12 if you used FOLFOX or up to 8 if you used CAPOX preoperatively. On the other hand, this kind of setup has never been tested in phase III trials.

Regarding your statement about oligometastatic state: if a met will disappear during a conversion therapy, it is always advised to resect its previous place, because even it can not be seen on CT scans, remaining tumor nests can be present on the former site of the visible met.

Dear Laszio:

The optimal chemotherapy regimen is not established. Upfront chemotherapy is an appropriate option for patients with initially unresectable liver metastases; however, the likelihood of downstaging a patient with truly unresectable disease to the point of resectability is only 10 to 15 percent. Furthermore, longer durations of preoperative chemotherapy increase the potential for liver toxicity and postoperative complications.

The optimal regimen for conversion therapy is not established. because of the potential for treatment-related toxicity with bevacizumab and because of the only modest improvement in overall response rate when this agent is added to oxaliplatin, many opinion leaders prefer an oxaliplatin-based systemic combination regimen WITHOUT bevacizumab.

It is NOT PROVEN that the addition of a biologic agent (ie, cetuximab or panitumumab or bevacizumab) to a chemotherapy backbone containing oxaliplatin or irinotecan can increase the number of patients potentially eligible for resection and improve outcomes

Notably, bevacizumab only moderately improved resectability rates when added to XELOX or FOLFOX in a large randomized trial (8.4 versus 6.1 percent with chemotherapy alone), as reported by Dr. Saltz himself (Reference: Saltz LB, Clarke S, Díaz-Rubio E, et al. Bevacizumab in combination with oxaliplatin-based chemotherapy as first-line therapy in metastatic colorectal cancer: a randomized phase III study. J Clin Oncol 2008; 26:2013).

An excellent summary can be found at: http://www.uptodate.com/contents/management-of-potentially-resectable-colorectal-cancer-liver-metastases?source=see_link&anchor=H9#H9

If you have access to the Cochrane collection, there is an excellent selection of colorectal cancer reviews, including one of anti-angiogenic drugs (e.g. bevacizumab, tyrosine kinase inhibitors) in colorectal cancer, and a review of options for downstaging liver mets with a view to making them resectable.

You'll find the Cochrane library here:

http://www.thecochranelibrary.com/view/0/index.html

Dear Fatih, I guess, in that situation the choice could be extremely difficult. The conversion chemo is basically about uncertanity in terms of you can not be sure that patient will be resected. As You also mentioned, the conversion rate is about 10 to 15 percent, which means that remaining patients has to be treated further in thee palliative setting.

Considering this fact, and keeping in mind, that mixing the treatment lines, changing the running protocol is always problematic, I personally strongly believe that the best conversional therapy is which can be easily continue as palliative therapy. Due to its neurotoxic feature, I guess, oxaliplatin is not the best candidate for first line long lasting palliative care, so this is the reason why I'm using FOLFIRI+bevacizumab for this patients.

The discussion above has been exceptional with some very shrewd and informative exchanges from Fatih Unkun, Laszlo Torday and Alisa Ratcliffe (and with respect to the first two of these authors who are known to me from other discussions, this quality is unsurprising (Alisa I am encountering for the first time)). Here I want to push the borders of the issues raised, and present a contrarian point of view, arguing for some important nuances, enhancements, and new perspectives that I hope will enrich the discussion. I first briefly offer a comment on the potential benefit of biological therapy on resectability in colorectal liver metastasis, and then turn to my real main focus on extrahepatic disease and augmented conversion therapy, finally returning to the complex role of oligometastatic disease in these contexts.

THE ROLE OF BIOLOGICAL THERAPY: BEVACIZUMAB BACKBONES

For the sake of this discussion, I will restrict my attention to bevacizumab but the case of cetuximab may also prove feasible, and I will only briefly note the definitive results from the preoperative chemotherapy for hepatic resection (POCHER) trial that revealed a complete resection rate of 63% achieved by FOLFOXIRI plus cetuximab in unresectable colorectal liver metastases [J Clin Oncol, 2009)].

I first note that despite the above cited early marginal findings of the Saltz trial, more recent data suggests greater viability for bevacizumab + chemotherapy in patients with hepatic-only metastases, with more encouraging rates of conversion to resectability: thus, in the Phase II trial conducted by Federica Bertolini and colleagues in Moderna Italy (Br J Cancer 2011), bevacizumab + FOLFOX6 yielded high rates of resectability (and pCR), converting 66.6% of patients with colorectal liver metastases (CLM) from non-optimally resectable to resectable disease status, and in addition in line with other studies finding that the use of bevacizumab in neoadjuvant setting did not affect complication rates (major postoperative complications stood at 23%) if the precaution of an interval of >5 weeks between the last bevacizumab administration and surgery is observed. And in the recent BOXER (Bevacizumab, Oxaliplatin, Xeloda in unresectable livER metastases) trial, David Cunningham's team at Royal Marsden more recently (Wong et al., Ann Oncol. 2011) conducted a multicentre study of CAPOX-Bv (CAPOX + bevacizumab) as perioperative therapy for poor-risk patients with colorectal liver-only metastases not selected for upfront resection, finding that 40% of patients with initially unresectable liver metastases were able to be converted to resectability. Even given the apparent inconsistencies across the Saltz versus the Bertollini study and the BOXER trial, these and other pending findings I am aware of at least suggest that bevacizumab-enhanced therapies show promising potential to raise rates of resectability without appreciable harm, and I fully expect maturing and emerging data to further confirm that.

A REVIEW OF RESECTABILITY IN COLORECTAL LIVER METASTASIS

1. EXTRAHEPATIC DISEASE (EHD): NO ABSOLUTE CONTRAINDICATION

I reviewed the literature to date on the resectability of hepatic disease with concomitant extrahepatic disease (EHD), and uncovered and appraised 37 studies to date meeting the inclusion criteria establishing the viability and safety of resection of hepatic and concomitant extrahepatic disease, with increasing evidence of long-term survival post-resection (all studies are given in my Appendix below on Hepatic Resectability in the Presence of Extrahepatic Disease).

Collectively, the aggregated critically appraised data to date demonstrates that resection of colorectal liver metastases with extrahepatic disease is a safe surgical option, showing median mortality rate < 1% - I note here that Simmonds et al. (Br J Cancer, 2006) in a systematic review of published studies of hepatectomy for colorectal cancer found the median postoperative mortality rate to be 2.8% - and median post operative complication 28%, with a median of 42% of patients undergoing hepatectomy and resection of extrahepatic disease at the time of initial colorectal surgery, in line with the previous review of Terence Chua and colleagues in Australia (Eur J Cancer, 2012) who analyzed data and results of 22 studies (all included in my own expanded review of 37 studies).

From an efficacy perspective, resection of colorectal hepatic metastasis with concomitant extrahepatic disease results in a median DFS of 12 months and a median OS of 30 months, translating into a median 5-year survival of ~19%, but - and this is critical - with a median 5-year survival of 25% for patients in whom a R0 hepatectomy was achieved. It is also however important to note that patients multiple site extrahepatic disease who undergo resection do not appear to benefit other than marginally, with an estimated median 5-year survival of only 7%.

I note also that in both my review (37 studies included) and that of Terence Chua and colleagues (22 studies), survival when stratified according to the sites of extrahepatic disease was most favorable in patients with lung metastases compared those patients with lymph node and peritoneal metastases, but - again critical to note - nonetheless, the median 3-year survival in patients with lymph node or peritoneal metastases was still in excess of 28% (patients with portal lymph node metastases generally have worse survival than those with either lung or ovarian metastases).

To take the example of outcomes in the liver + pulmonary metastases cases, the expected 5 year survival rate ranges from ~30% (Kobayashi et al., J Thorac Cardiovasc Surg 1999); Headrick et al., Ann Thorac Surg 2001); Neeff et al., J Gastrointest Surg 2009), Miller et al., J Am Coll Surg 2007) to as much as 40% (Murata et al., Cancer 1998), an appealing level given the challenging scenario of hepatic and extrahepatic disease.

2. THE OLIGOMETASTATIC CONNECTION

Therefore, it would be important that only patients with highly limited extrahepatic disease be selected for surgery, and based on my review of the 37 relevant studies to date, such limited disease would have to be defined as (1) single-site and (2) oligometastatic within that site, in keeping with Yozuru Niibe's seminal work in this arena. Note however that this oligometastatic requirement is applicable solely to single-site extrahepatic disease, and NOT to the resectability requirement for the intrahepatic metastatic disease itself, since my review uncovered the feasibility of non-oligometastatic intrahepatic disease being resectable to outcome advantage, as I note more fully below where it is shown that Hassan Malik and colleagues in the UK (Eur J Surg Oncol, 2007) found that patients with 4 - 7, and even > 7, liver lesions do in fact gain a favorable outcome from liver resection, with a survival disadvantage appears to be only present in patients with 8 or more lesions, with confirmation from Timothy Pawlik and colleagues at MD Anderson who found that in 159 patients with four or more colorectal liver metastases (median = 5, range = 4-14) who underwent curative resection, a median survival of 62 months and a five-year survival of 51% was achievable (J Gastrointest Surg, 2006), while Peter Kornprat and colleagues at Memorial Sloan-Kettering found median survival of 44 months and five-year survival of 33% in 98 patients with resection of >=4 colorectal liver metastases (median 5, range 4-15) (Ann Surg Oncol, 2007). Since under Yozuru Niibe's definition of oligometastatic disease the upper boundary is stipulated to be 5 lesions, yet with my critical review of the evidence, especially that of the Malik, Pawlik and Kornprat studies, showing no survival disadvantage emerging until >= 8 lesions, it is clear that we cannot accept oligometastatic disease as a criterion for resectability in intrahepatic disease, although as I have demonstrated, it should be equally clear that single-site oligometastatic disease is in fact appropriate as a requirement for extrahepatic disease, with my review uncovering no contradicting data among any of the 37 studies reviewed to date. One final note: although clearly oligometastatic disease has a far more subtle intersection with colorectal liver metastasis resectability than assumed or seen at first blush, it is neither a prerequisite for such resectability - as in fact I just demonstrated - nor an explicit goal of it, although admittedly successful colorectal liver metastasis resection would, one would assume, typically induce an oligometastatic state. It's real importance I posit is as a necessary condition of resectability for limited, that is, single-site extrahepatic (but not intrahepatic) disease.

3. CANDIDACY FOR HEPATIC RESECTION

Collectively, therefore, the data from the 37 studies I reviewed suggest that patients:

(1) harboring limited extrahepatic disease - which I propose to define based on my review as single-site oligometastatic disease - itself amenable to surgical resection (isolated portal lymphadenopathy, etc.) or

(2) who have reasonable expectations for long-term control via adjuvant therapy, such as those, say, with small volume lung involvement which would again meet my proposed definition of single-site oligometastatic disease, and

(3) who have been responsive to pre-operative systemic therapy,

could be rational candidates for hepatic resection.

At this point therefore, the data supports a new perspective, that patients with limited and favorably located extrahepatic disease that is durably controllable under another treatment modality, as well as patients with minimally progressive existing disease during pre-operative systemic therapy, may yet benefit from a hepatic resection, and should be deemed resectable.

And this new perspective (although the consensus fails to make the association with oligometastatic disease) has now been adopted an the Expert Consensus Statement 2012 of the International Hepato-Pancreato-Biliary Association at the just held Proceedings of the Consensus Conference on Multidisciplinary Treatment of Colorectal Cancer Liver Metastases. sponsored by the Americas Hepato-Pancreato-Biliary Association and co-sponsored by the Society of Surgical Oncology, the Society for Surgery of the Alimentary Tract, and the M.D. Anderson Cancer Center (HPB, 2012).

It should furthermore be noted that such augmented conversion therapy as I call it (not just chemotherapy and/or biological therapy) is not only also an option as indicated, but that many institutions like Memorial Sloan-Kettering Cancer Center (MSKCC) offer HAI therapy, that is, hepatic artery infusional (at MSKCC using floxuridine and dexamethasone) combined with systemic chemotherapy for those patients with extensive liver disease not amenable to resection, and the combination of systemic chemotherapy + HAI was able to convert to resectability 47% of patients initially deemed unresectable and 57% in those who are chemotherapy-naïve, with promising long-term outcomes (median survival from the start of HAI therapy being 35 - 50.8 months [Kemeny, J Clin Oncol, 2009; Weiss & D'Angelica, J Gastrointest Oncol, 2012]. This entails that we must expand our customary definition of conversion therapy (Fatih above put it succinctly: the use of induction chemotherapy in patients with isolated but initially unresectable CRC liver metastases) to include hybrid modalities such as HAI + systemic therapy (there are others too, but I leave that for another time).

4. SUMMARY OF FINDINGS ON EXTRAHEPATIC DISEASE RESECTABILITY

Thus:

(1) we can attest on the evidence (37 confirmative studies to date) the viability at a clinically relevant level of long-term survival in patients with CLM (colorectal liver metastasis) with EHD (extrahepatic disease) after surgical resection;

(2) we have provided compelling motivation for an expanded (augmented) definition of conversion therapy (see above, re HAI inclusion); and

(3) we motivate the requirement of resectability of limited extrahepatic disease as definitionally

(1) single-site, and

(2) oligometastatic within that site.

5. RESECTABILITY: A NEW FRONTIER

The criteria against resectability until recently have been (1) >3 liver lesions, (2) sub-centimeter estimated resection margin, (3) extrahepatic disease (EHD), (4) no anticipated remnant liver volume. However I will argue that these resectability contraindications are far too restrictive, and increasingly counterfactual. For example, concerning the first contraindication (>3 lesions), Hassan Malik and colleagues (Eur J Surg Oncol, 2007) in the UK found that patients with >3 liver lesions do in fact gain a favorable outcome from liver resection: those with 4 - 7 lesions have 5-year OS of 34.8% while even those with > 7 lesions had 24.2% 5-year OS. Similarly, as to the second criterion of an at least 1-cm resection margin, it has been demonstrated (Altendorf-Hofmann & Scheele, Surg Oncol Clin N Am. 2003; and Pawlik et al., Ann Surg, 2005) that actual clearance margin does not impact survival as long as R0 resection is achieved; indeed, the observed width of a surgical margin neither affects survival, recurrence risk, or site of recurrence, and therefore a sub-centimeter margin after resection of hepatic colorectal metastases should not be used as an exclusion criterion for resection.

Coupling these considerations with my discussion and review above of the issue of extrahepatic disease (EHD), it becomes clear that:

(1) resection of extrahepatic disease, including pulmonary, peritoneal carcinomatosis and hepatic hilar lymph nodes can achieve long-term survival and even cure in some patients,

(2) even under scenarios multiple hepatic tumors, of 4 - 7 or more hepatic lesions and

(3) a narrow (sub-centimeter) negative surgical margin, and that

(4) qualification for resectability should now be seen as primarily dependent on whether R0 resection for all tumors is achievable, and secondarily on the existence of 2 contiguous liver segments with adequate inflow, preservable outflow and biliary drainage, and adequate residual liver remnant volume with respect to hepatic disease-specific resectability.

Appendix: Hepatic Resectability in the Presence of Extrahepatic Disease

Murata et al., Cancer 1998; Kobayashi et al., J Thorac Cardiovasc Surg 1999; Minagawa, Ann Surg. 2000; Headrick et al., Ann Thorac Surg 2001; Nagakura, J Am Coll Surgeons. 2001; Jaeck, Ann Surg Oncol. 2002; Elias, Br J Surg, 2003; Mineo, J Am Coll Surgeons. 2003; Carmignani, Eur J Surg Oncol. 2004; Laurent, J Am Coll Surgeons. 2004; Tocchi, Int J Colorectal Dis. 2004; Elias et al., Ann Surg Oncol. 2005; Capussotti, Br J Surg. 2006; Shah, J Am Coll Surgeons. 2006; Figueras, Dis Colon Rectum, 2007; Kianmanesh, Ann Surg, 2007; Miller et al., J Am Coll Surg 2007; Niu, Ann Surg Oncol. 2007; Tamandl, Eur J Surg Oncol. 2007; Aoki, Surgery 2008; De Haas, Dig Surg 2008; Rees, Ann Surg Oncol 2008; Tanaka, Surgery. 2008; Barlow, Eur J Surg Oncol. 2009; Byam, Ann Surg Oncol, 2009; Carpizo, Ann Surg Oncol, 2009; Elias, J Clin Oncol. 2009; Kemeny, J Clin Oncol, 2009; Marudanayagam, HPB (Oxford), 2009; Masi, Ann Surg. 2009; Neeff et al., J Gastrointest Surg 2009; Oussoultzoglou, Ann Sur, 2009; Viana, J Surg Oncol. 2009; Garufi, Br J Cancer, 2010; Mise, Ann Surg. 2010; Pulitano, Ann Surg Oncol 2010; Adam, Ann Surg, 2011.

Constantine Kaniklidis

Director of Medical Research, No Surrender Breast cancer Foundation (NSBCF)

European Association for Cancer research (EACR)

I would like to bring up two additional points: 1. I found it very helpful to involve a liver transplant surgeon perform the resections. The head of liver transplant program at the University of Wisconsin (current head of Surgery at Memorial Hospital in Istanbul): Munci Kalayoglu was very successful in resections of liver mets previously deemed unresectable by colorectal surgeons or general surgeons.

2. Following a presentation from Canadian researchers, we had looked at Mitomycin + xeloda combination and found it very effective in shrinking liver mets. The mitomycin dose was 8 mg/m2 given with premedications (Benadryl, dexamethasone).

http://www.asco.org/ASCOv2/Meetings/Abstracts?&vmview=abst_detail_view&confID=41&abstractID=316

http://www.asco.org/ASCOv2/Meetings/Abstracts?&vmview=abst_detail_view&confID=36&abstractID=10043

However, others reported a lack of benefit of mitomycin in metatstatic colorectal cancer: http://www.asco.org/ASCOv2/Meetings/Abstracts?&vmview=abst_detail_view&confID=102&abstractID=82526.

Because of the conflicting results, a nice review article summarized the available data and showed that mitomycin combinations should also be considered in treatment of metastatic colorectal cancer. The reference is attached.

http://www.ncbi.nlm.nih.gov/pubmed/20433364

Here is a publically available opinion from one of the opinion leaders in this field:

What is the best ‘conversion therapy’?

Most data in this setting are available for a FOLFOX-based treatment approach, although recent data suggest that FOLFIRI could also serve as backbone.

A few studies have also demonstrated that combining all active chemotherapy agents – 5-FU, irinotecan, and oxaliplatin (FOLFOXIRI) – can achieve high response rates and can lead to a high rate of liver resections in previously unresectable tumours.

I personally routinely use FOLFOX in this setting and would add an EGFR antibody to the treatment if the tumour has been characterised as KRAS wild-type.

EGFR antibodies have routinely been associated with an increase in response rate when added to chemotherapy (FOLFOX or FOLFIRI), which is exactly what is required in a conversion therapy setting.

I add bevacizumab to FOLFOX in KRAS-mutated tumours, although I could envision that using FOLFOXIRI without any biological agent could also be an attractive alternative in KRAS-mutated colorectal cancer.

Unfortunately, I do not have a lot of experience yet with this aggressive chemotherapy combination, although this might change with the emergence of FOLFIRINOX as one of the standard therapies for advanced pancreatic cancer, which uses even higher dose of irinotecan in the combination than FOLFOXIRI.

Back to Top | Article Outline

When do I consider neoadjuvant therapy in resectable stage IV disease?

In patients with resectable metastatic disease, one could wonder if neoadjuvant therapy was indicated, or if surgical resection would be the preferred first step followed by postoperative adjuvant therapy.

In my eyes, the optimal sequence of treatment steps depends on the clinical situation we are facing. Two different patient cases might outline the different scenarios I have in mind here:

The first case is a patient who presents with colon cancer and synchronous, albeit resectable liver metastases. The clinical information we have on this patient at the time of diagnosis is a one-time snapshot of his disease; we have no real understanding of the particular biology of this cancer.

We could be facing yet undetected metastases, which could declare themselves if treatment was withheld for some time – but I don't think that any patient or oncologist would be willing to wait long before initiation of therapy.

In patients with synchronous metastases, I routinely use neoadjuvant therapy to administer hopefully effective cytotoxic treatment early on to target occult micrometastatic disease and – most importantly – to obtain information on the chemosensitivity of the cancer.

This approach provides an in vivo test of chemo-responsiveness of this particular disease, which can help guide post-operative adjuvant therapy, too.

It is important to note that an asymptomatic primary tumour can be safely left in place for resection at a later point. In addition, the preoperative treatment duration does not need to be long. After two to three cycles of FOLFOX, a response should be visible on CT scans.

With regard to biologics, I do not think that bevacizumab is needed in this setting, since it would have to be discontinued six weeks before planned surgery anyway. Similarly, the use of EGFR antibodies in KRAS wild-type cancers is not mandatory here.

The decision with regards to potential neoadjuvant therapy in resectable stage IV disease can be different in the following scenario: a patient who has undergone colon resection for a stage II cancer four years ago and now presents with a solitary liver metastasis.

In this case, the tumour has taken four years to declare itself as metastatic disease – and then come up with a solitary, easily resectable metastasis. This scenario provides us with a lot of information on this patient's tumour biology and no neoadjuvant therapy is indicated. In such cases, I get a liver surgeon involved right away and offer postoperative adjuvant therapy, mainly FOLFOX (or XELOX).

Of course, a lot of patients will fall somewhere in between these two scenarios and individual decisions on the most appropriate approach have to be made in agreement with my surgical colleagues.

Back to Top | Article Outline

Should biologics be used in the postoperative setting after curative resection of stage IV disease?

Since the goal of postoperative, adjuvant therapy is to prevent the recurrence of macrometastatic disease, I consider patients with R0-resected Stage IV disease to be in the same clinical situation as patients with resected high-risk Stage III colon cancer.

Unfortunately, all recent Phase II trials on the use of cetuximab and bevacizumab as adjuvant therapy in Stage III colon cancer have been completely negative, with no identifiable subgroup who might have benefited from the antibodies. Therefore, I do not add bevacizumab or EGFR antibodies to the postoperative therapy, even if I had used them successfully before as part of a preoperative therapy as outlined above.

http://journals.lww.com/oncotimesuk/Fulltext/2011/02000/How_do_I_treat___a_patient_with_metastatic.11.aspx

Here is a summary from the 2012 ASCO meeting. In particular, I would like to draw your attention to the MD Anderson Cancer Center data in 159 patients with ≥4 liver mets who underwent resections. They had a 5-year survival rate of 51% and a 5-year disease-free survival of 22%.

Curative-Intent Treatment of Colorectal Cancer

Complete resection remains the optimal therapy for treatment of patients with colorectal cancer (CRC) metastases, according to Steven A. Curley, MD, of the University of Texas M. D. Anderson Cancer Center. Dr. Curley opened the Sunday morning Education Session “Curative-Intent Treatment of Colorectal Cancer Metastases” by giving a surgeon’s point of view, which was followed by viewpoints from an interventional radiologist and a medical oncologist.

In his presentation on liver surgery for patients with CRC, Dr. Curley said that complete resection can be done safely, with low morbidity and mortality rates, and that the timing of the procedure should be determined by a multidisciplinary treatment team that includes hepatobiliary surgical oncologists, medical oncologists, pathologists, and diagnostic imaging specialists.

“Some patients may have a lesion in a critical location where, if they were to progress on systemic chemotherapy, [it] could become a borderline resectable case, so they should probably undergo resection followed by adjuvant therapy. Other patients may benefit from a neoadjuvant approach that looks at their treatment response,” Dr. Curley said.

Data Dr. Curley reviewed in his presentation showed that aggressive surgical management combined with neoadjuvant and adjuvant chemotherapy regimens have yielded 5-year survival rates that exceed 50%. With better surgical staging, patients treated with resection in four clinical trials since 2002 have survival rates of 58% at 5 years. Those data have encouraged more surgeons to become more aggressive about attempting resections, he said.

Researchers at the University of Texas M. D. Anderson Cancer Center looked at data on 159 patients with more than four CRC liver metastases who underwent resection. Overall survival at 5 years was 51%, and disease-free survival was 22%.

“This suggests that the dogmatic belief that if you have five, six, or 12 metastases you are no longer a surgical candidate really should be questioned,” he said. “We encourage that all patients with CRC metastases undergo assessment by a hepatobiliary surgeon as part of multimodality planning and management to see if it is possible for them to have surgical treatment.”

A multivariable analysis of the longterm probability of survival found that the factor with prognostic significance was the patient’s response to neoadjuvant chemotherapy, he said.

Although local hepatic tumor ablation techniques play a role in treating patients with unresectable disease, Dr. Curley said, “We do not have any indicators that ablation techniques, such as radiofrequency ablation (RFA), microwave ablation, laser ablati...

http://chicago2012.asco.org/ASCODailyNews/curativeCRC.aspx

Here in the UK, we have guidelines for treatment of colorectal cancer produced by NICE. You can find them here:

http://pathways.nice.org.uk/pathways/colorectal-cancer

They also offer a helpful summary of the literature, and reviews of the efficacy of certain of the biological agents.

I have an interest in this topic both as an oncology professional (I'm a clinical scientist working in an NHS/university oncology department) and a patient. Personally, I found FOLFIRI easier to tolerate than FOLFOX + bevacizumab until I ended up with neutropenia and had to stop, although I think that with the knowledge I have accumulated since then, if I were to have FOLFOX + bevacizumab again, I would probably have more chance of avoiding the neuropathy I now have. Ultimately, toxicity and tolerability are things we need to think about carefully.

With my patient hat on, while it's very valuable to know what treatments are most efficacious, it's also important to get helpful advice on how best to help your body withstand the onslaught of different treatments (this has been an interesting lesson for me! :o). This is an area we're not yet very hot on, and I've had to do a lot of digging through pre-clinical research to find ideas. But if we can help our patients to tolerate treatments better, we may see better results and a better probability of downstaging. So as well as which chemotherapy (or other options) to use, we need to bear in mind tolerability and toxicity when we are looking at the best options for conversion therapy, as they can significantly affect the patient's quality of life, and I think most patients figure quality of life is just as important as length of life...

Dear Fatih, my experiences with mitomycin C are extremely disturbing. Shortly: no therapeutic effect, even in within a short term, and almost uncontrollable early and late toxicity on heavily pretreated patient, resulting some very sad deaths to..

Dear Constantine! Quite a comprehensive review of data. I have also some experience with the literature and, as a "critical forever" I believe that one of the most important part of the conversion therapy is the patient selection. Unfortanetely, as I know, to date there are no definite guidelines regarding the assessment of potential resectability. It would be useful to develop a scoring system by which (taking lots of variables into account) we could guess the chance of successful conversion.

What is Your opinion about that? What do You think, is it possible to develop such kind of scoring system?

If we would have it, probably it would help us to determine the agressivity of the applied chemo, I mean, if the chance for resectability after chemo is high, I would go for like FOLFIRINOX+/-biological, but if the chance would be low, I would go for a conventional palliative treatment.

Dear Dr Torday

Mitomycin can cause pulmonary toxicity at 15 mg per m2 dose level. This has been reported for breast cancer patients and can have a fatal outcome. if you use premedications and half of that dose, it is well tolerated in heavily pretreated patients.

obviously not to be used in patients with liver or kidney failure.

Dear Dr. Torday,

Here is what I recall as general info: Mitomycin is given as a 15-20 min infusion; It is given every 6-8 weeks. Premeds: The night before: Benadry 50 mg PO, Zantac 150 mg PO, decadron 20 ng PO; then 15 min before Mitomycin: Benadryl 20 mg IV, Decadron 20 mg IV, Anzemet 100 mg IV. Do not use any other chemotherapy on the day of Mitomycin.

But again, as the review article I referenced earlier shows, this is not as active as the new generation standard drugs available.

What I've seen several times was a deep, and long lasting neutropenia, sometimes pancytopenie and when it was ended and hope started to raise a rapidly developing hepatorenal insufficiency put the point above the "i".

One of the considerations = for colorectal cancer patients with liver mets is to have a biliary tract visualization done and preemptively involve interventional radiologists to have percutaneously stents placed if it is likely for the patient to develop jaundice in the near future due to the location of the liver mets. The stent placement may sometimes prove helpful in administering therapy without having to deal with jaundice.

Laszlo:

An uncommonly shrewd suggestion! And yes, I do indeed believe in the feasibility of a resectability metric for optimal patient selection. There have been some early pathology-based metrics based on Yuman Fong's (at Memorial Sloan-Kettering) 5-point preoperative assessment scale, and independently on Fenella Welsh's (Hampshire, UK) predictive index for quantifying likelihood of positive resection margin (R1), which has come to be known as the Basingstoke Index, but such metrics were designed before an avalanche of data has forced (or nearly so) the revision of our thinking that I outlined above on extrahepatic disease and also on tumor volume and number, on which Fatih Uckun above has added some further data and insight, so these early metrics remain primitive, and now largely against the weight of the evidence.

My own interest now hugs the refinement of the OncoSurge decisional model for quantifying via ra ating scale of patient resectability in individual patients with colorectal liver metastases (it also identifies the appropriateness of local ablation and/or chemotherapy, another useful feature), first presented by researchers at Royal Liverpool University and at RAND and validated by expert assessment of 252 cases being considered for hepatic resection, showing exceptionally high concordance (Poston et al., J Clin Oncol, 2005; O'Reilly et al., Eur J Surg Oncol, 2008). It remains to my mind the most useful tool for hepatobiliary surgeons to facilitate management decisions, particularly in scenarios of uncertainty as to the risk–benefit ratio of liver resection, and being a relative straightforward computer program, it has more than adequate ease-of-use. It also is less rigid and dogmatic about absolute contraindications, setting these relatively permissively at (1) liver failure, (2) >70% liver involvement, (3) surgically unfitness, and - in the only effort I am aware of to date to accommodate the new perspective on the bounded but non-trivial potential resectability of extrahepatic disease - (4) unresectable extrahepatic disease; this is a unique advance in any resectability metric (although I would like to seeing a weighted approach to the lesion number cutoff (

Fatih, Laszlo, Ailsa:

That is indeed, Fatih, a very good review of the role of mitomycin C in mCRC, up to and including 2009. I would however note that since that terminus, several other studies plus the largest retrospective review and reported series of unselected refractory metastatic CRC patients treated with mitomycin C provides, albeit not as yet dispositive, nonetheless strongly compelling, data suggesting negligible if any benefit in this context.

So the AGITG Randomized Phase III MAX Study (Tebbutt et al., J Clin Oncol, 2010; subanalysis: Price et al., Ann Oncol, 2012) evaluated capecitabine, bevacizumab, and mitomycin (designated "CBM") as first-line therapy in metastatic colorectal cancer, and although the investigators concluded that "Adding bevacizumab to capecitabine, with or without mitomycin, significantly improves PFS", nonetheless a close reading shows that the mdian PFS was 5.7 months for capecitabine alone, compared to 8.5 months with the addition of bevacizumab ("CB") and 8.4 months when mitomycin was added to both agents concurrently, demonstrating a null contribution from mitomycin, with comparable null results in overall survival (OS). Similarly in the Phase I dose escalation study (Tanios Bekaii-Saab et al., Cancer Chemother Pharmacol, 2010) of a capecitabine + mitomycin C in patients with gastrointestinal malignancies, there was no objective responses at all (only stable disease). And most recently, in the largest reported series of unselected refractory metastatic CRC patients treated with mitomycin C (most having received it in combination regimen with capecitabine), the multicenter Brazil-MD Anderson retrospective review (), the observed median survival was 4.5 months, which is not significantly different from survival expected from best supportive care, the review authors concluding from this that "this lack of activity strongly suggests that MMC should not be routinely used in refractory mCRC", although it may have some modest activity in non-refractory contexts as yet to be clearly identified.

But I would speculate cautiously that the facts are somewhat more muted: there may be some appreciable benefit in non-advanced and non-refractory CRC settings, but that the pharmacokinetics and pharmacodynamics of mitomycin mediators may be systematically confounding efficacy in a context-dependent manner. In this connection, the human aldo-ketoreductase AKR1B10 is under-expressed in colon, gastric, and head and neck cancers, and is upregulated in colon cancer SW-480 and HT29 cell lines, inducing resistance toward certain chemotherapeutic agents including both cyclophosphamide (CTX) and mitomycin c, suggesting that the enzyme functions as a chemoresistance marker, given that aldo-keto reductases can reduce a broad spectrum of substrates including the cytotoxic aldehydes induced by several chemotherapies. For these reasons there is considerable current interest in designing or discovering AKR1B10 inhibitors (curcuminoids; propolis-derived caffeic acid phenethyl ester (CAPE); and olive oil-derived oleanolic acid have all shown strong preclinical activity of AKR1B10 inhibition). We also know that mitomycin C requires activation by the reductive enzyme NQO1 (NAD(P)H:quinone oxidoreductase 1), and that cells with elevated NQO1 levels are generally more chemosensitive to mitomycin, with NQO1 levels themselves being highly sensitive to dietary factors (such as fumaric acid levels in fruits and vegetables).

However, we must await confirmative studies beyond the in vitro and in vivo preclinical levels before we can evaluate the viability of AKR1B10 inhibitors and dietary NQO1 enhancers in the true human clinical context vis a vis mitomycin and other dependent chemotherapeutics. Until such time, given the arguable efficacy data and the near-unarguable and daunting safety data, the role of mitomycin C and its clinical benefit-harm ratio in mCRC remains equivocal at best and cautionary given some adverse experiences to data. Nonetheless, given these suggestive dependencies, I would venture that the final chapter in the saga of mitomycin in mCRC has not yet been written.

I neglected to add that some while ago some colleagues in Italy sent me a PDDF of a PowerPoint presentation Graeme Poston did on OncoSurge at a local conference, which although a bit dated (done I believe in 2007) you may still find of some value:

I neglected to add that some while ago some colleagues in Italy sent me a PDDF of a PowerPoint presentation Graeme Poston did on OncoSurge at a local conference, which although a bit dated (done I believe in 2007) you may still find of some value: http://www.asl2.liguria.it/pdf/atti_convegno_varazze/Approccio_Poston.pdf

Just an add-onn for the mitomycin C question:

"The Oncology Top Five List

1. For patients with advanced solid-tumor cancers who are unlikely to benefit, do not provide unnecessary anticancer therapy, such as chemotherapy, but instead focus on symptom relief and palliative care. "

http://ascoaction.asco.org/Home/tabid/41/articleType/ArticleView/articleId/246/Oncology-Top-Five-List-Identifies-Opportunities-to-Improve-Quality-and-Value-in-Cancer-Care.aspx

I challanged several times this recommendations, but finally I ended up to believe it true.

it is important that no futile therapy is offered to anyone and palliation should bebthe focus of any treatment in end stage patients. i am certain we all agree. but this was not the discussion. The question and discussion was about the most active agents that can be used as part of conversion therapy prior to resection of liver mets. and in that context it is important to be aware of the mitomycin option in case you encounter a patient you cannot treat with your most active drug combination. Very few oncologists have hands on experience with mitomycin because they are concerned of toxicity. As i pointed out treatment outcomes varied and no biomarkers were reported to guide a tailored use of this old chemotherapy drug.

Mitomycin should not be used, or should not even be considered for conversion therapy. f a patient can not tolerate oxaliplatin or irinotecan, mitomycin will not be an option too. And, on the other hand, there is not a single respected guideline which considers mitomycin as a first line treatment for mCRC or as a conversion therapy.

thank you for making your position very clear. you should consider writing an efitorial and sending it to the journal that published the review article. Thanks for sharing your insights. May i also ask how many patients you treated with mitomycin and what did your treatments consist of. You mentioned that some of your patients died. i think it would be very helpful to know more about the details. Was this reported.

i am signing off and heading to an NCİ conference. Enjoyed the discussion

And by the way:

Transhepatic Arterial Chemotherapy (TAC) Versus Transcatheter Arterial Chemoembolization (TACE) Plus Folfox4 as the Treatment of Unresectable Liver Metastasis of Colorectal Cancer

Phase: Phase IV

Type: Treatment

Status: Active

Age: 18 to 74

Sponsor: Other

Protocol IDs: 2009-03, NCT00868569

2.

Preoperative Transhepatic Arterial Chemotherapy (TAC) in the Treatment of Liver Metastasis of Resectable Colorectal Cancer

Phase: Phase IV

Type: Treatment

Status: Active

Age: 18 to 75

Sponsor: Other

Protocol IDs: 2009-04, NCT00874406

http://www.cancer.gov/clinicaltrials/search/results?protocolsearchid=6424623

Here is another study. Does this mean there is still some interest in Mitomyicin.

http://www.cancer.gov/clinicaltrials/search/view?cdrid=700275&version=HealthProfessional&protocolsearchid=6424623

Did anyone see a follow-up to the following work presented at ASCO meeting:

Mitomycin C and UFT/leucovorin as salvage treatment in patients with advanced colorectal cancer.

Print Print this page

Sub-category:

Multidisciplinary Treatment

Category:

Cancers of the Colon and Rectum

Meeting:

2009 Gastrointestinal Cancers Symposium

Session Type and Session Title:

General Poster Session F

Abstract No:

486

Author(s):

C. G. Gennatas, V. Michalaki, S. Gennatas

Faculty Disclosures

Abstract Disclosures

Abstract:

Introduction: The purpose of this study was to determine the efficacy and toxicity of UFT plus oral leucovorin (LV) and mitomycin C as salvage chemotherapy for heavily pre-treated patients with metastatic colorectal cancer. Methods: A total of 44 patients treated with mitomycin C (6 mg/m2 on day 1) and UFT (350 mg/m2)+ leucovorin (90 mg) both divided into three daily doses from day 1 to day 14 every 3 weeks. All patients had failed prior first-line and second-line treatment with oxaliplatin, bevacizumab, irinotecan, cetuximab and 5-fluorouracil. Results: Forty-three patients were evaluable for the response. The overall response rate (intent-to-treat) was 9.3% and disease stabilization was achieved in 26.3%. Median time to progression was 5 months (range, 2-13) and median overall survival was 7.5 months (range, 4-16). Fatigue and myelosuppression were the most frequent side effects. The most common non-hematological toxicities consisted of mild and reversible nausea, and diarrhea; again, severe symptoms were only occasionally seen. Conclusions: These data show that the combination of mitomycin C/UFT/leucovorin provide an acceptable and safe therapeutic option in extensively pretreated metastatic colorectal cancer.

http://www.asco.org/ASCOv2/Meetings/Abstracts?&vmview=abst_detail_view&confID=63&abstractID=10338

Dear Fatih,

It is not needed to write an aditorial about this. You can also find appropriate guidelines on the net.

Conversion therapy as it is defined is a systemic treatment of hepatic mets, and this is usually continued as first line chemo. Mitomycin is used in later lines, not in the first line, as salvage treatment as you have also mentioned and cited several times here.

This was my practice too, I used mitomycin in third or fourth line after running out established first and second line regimens containing oxaliplatin and irinotecan.

The used protocols were FEM (MMC: 5 mg/m2, q4w) or highdose 5FU+MMC (MMC dose: 15 mg/m2, q4w)

I treated approximately twentysome heavily pretreated mCRC patient with salvage MMC when I stopped this practice based on my experience and after consulting other well reputated oncologists in my country.

TACE is also an option for conversion, but it is far away from to be a routine procedure. So investigations with MMC in this conversion therapy setting could be interesting, but nowadays not influencing the routine practice for delivering conversion chemo.

I'm eagerly waiting your phase III proof about the first line use of an MMC based chemo in the treatment of mCRC or as a conversion therapy.

Constantine, I agree that development of AKR1B10 inhibitors looks like an interesting and hopeful line of enquiry. Frankly, I'm underwhelmed by the small benefits we have seen with EGFRs and VEGFs so far, especially given the controversy over the cost/benefit ratios of these drugs and the willingness of different healthcare systems to pay for them.

Given that a significant proportion of patients are KRAS mutant at codon 12 and therefore not likely to benefit from cetuximab and the like, we really need to be looking for targeted agents to give us real gains in overall survival and PFS over and above what we see with FOLFOX, FOLFIRI etc. I'd also be interested to see how the pre-clinical research into use of various phytonutrients and their derivatives as adjuvants to current chemotherapies, either to reduce toxicity or as synergistic therapeutic agents (e.g. curcumin, genistein, quercetin) pans out once some of these agents go to clinical trial (e.g. NCT01490996) - it remains to be seen whether this will turn out to be fruitful or a sideshow.

But as Constantine alluded, as we start to enter the world of individualised treatment, it would be interesting to see how we would answer this question in a few years time, and how we will go about evaluating the responses of the different genetic sub-populations to different regimens. If we think the situation is confusing at the moment, it's probably about to get a lot more complex...

Dr Torday I understand why you are eagerly tring to turn this into a discussion on Mitomycin . that is quite transparent. However, you are asking questions as if others like myself claimed sth that we did not. i suggest that you try to overcome your ego and read the info i provided and carefully read what i wrote

Then you will perhaps recognize that my e mail did not promote the use of mitomycin or any other drug for conversion therapy. İ listed publically available info and references. i also included statements and reviews from various scholars. and in this case I did so because Metastatic colorectal cancer affected my family and therefore i have a personal interest. We should all try to communicate about existing knowledge. and please remember this is ResearcgGate. this is not NCCN or another practice guidelines website.

Dear All:

It appears (based on Mitomycin questions from Dr. Torday) that some may not have seen my previous posts regarding the best treatments for conversion therapy earlier. Therefore I am repeating these:

HERE IS MY FIRST POSTING:

The optimal chemotherapy regimen is not established. Upfront chemotherapy is an appropriate option for patients with initially unresectable liver metastases; however, the likelihood of downstaging a patient with truly unresectable disease to the point of resectability is only 10 to 15 percent. Furthermore, longer durations of preoperative chemotherapy increase the potential for liver toxicity and postoperative complications.

The optimal regimen for conversion therapy is not established. because of the potential for treatment-related toxicity with bevacizumab and because of the only modest improvement in overall response rate when this agent is added to oxaliplatin, many opinion leaders prefer an oxaliplatin-based systemic combination regimen WITHOUT bevacizumab.

It is NOT PROVEN that the addition of a biologic agent (ie, cetuximab or panitumumab or bevacizumab) to a chemotherapy backbone containing oxaliplatin or irinotecan can increase the number of patients potentially eligible for resection and improve outcomes

Notably, bevacizumab only moderately improved resectability rates when added to XELOX or FOLFOX in a large randomized trial (8.4 versus 6.1 percent with chemotherapy alone), as reported by Dr. Saltz himself (Reference: Saltz LB, Clarke S, Díaz-Rubio E, et al. Bevacizumab in combination with oxaliplatin-based chemotherapy as first-line therapy in metastatic colorectal cancer: a randomized phase III study. J Clin Oncol 2008; 26:2013).

An excellent summary can be found at: http://www.uptodate.com/contents/management-of-potentially-resectable-colorectal-cancer-liver-metastases?source=see_link&anchor=H9#H9

Here is a publically available opinion from one of the opinion leaders in this field:

AND HERE IS MY FOLLOW-UP POSTING:

What is the best ‘conversion therapy’?

Most data in this setting are available for a FOLFOX-based treatment approach, although recent data suggest that FOLFIRI could also serve as backbone.

A few studies have also demonstrated that combining all active chemotherapy agents – 5-FU, irinotecan, and oxaliplatin (FOLFOXIRI) – can achieve high response rates and can lead to a high rate of liver resections in previously unresectable tumours.

I personally routinely use FOLFOX in this setting and would add an EGFR antibody to the treatment if the tumour has been characterised as KRAS wild-type.

EGFR antibodies have routinely been associated with an increase in response rate when added to chemotherapy (FOLFOX or FOLFIRI), which is exactly what is required in a conversion therapy setting.

I add bevacizumab to FOLFOX in KRAS-mutated tumours, although I could envision that using FOLFOXIRI without any biological agent could also be an attractive alternative in KRAS-mutated colorectal cancer....

https://www.researchgate.net/go.Deref.html?url=http%3A%2F%2Fjournals.lww.com%2Foncotimesuk%2FFulltext%2F2011%2F02000%2FHow_do_I_treat___a_patient_with_metastatic.11.aspx

The Final Word?

With respect solely to Phase III evidence on mitomycin, we do in fact have limited Phase III data on mitomycin C efficacy in this context (such as David Cunningham's group at Royal Marsden Hospital: Phase III study (Price et al., Clin Colorectal Cancer, 2004) of protracted venous infusion (PVI) 5-FU plus mitomycin C in patients with advanced colorectal cancer, with high response (38%) and survival (15.8 mo.) rates confirmed), but this decidedly limited data is countered by several other Phase III trials showing lack of appreciable efficacy gain via the addition of mitomycin C, such as the AGITG MAX Trial I have already noted above, and the Piedmont Oncology Association Phase III Trial which failed to find any therapeutic advantage for MMF (mitomycin + 5-FU) over 5-FU therapy monotherapy in advanced colorectal cancer (Richards et al., J Clin Oncol, 1986).

But note that no decisive conclusions can be drawn until a comprehensive systematic review (SR) and properly and tightly pooled meta-analysis (MA) is undertaken and completed, with - and this is always the vital component, as I have seen and demonstrated many SRs and MAs to be themselves methodologically bankrupt (including Cochrane Reviews, often retired hastily when studies are discovered that demonstrably met their inclusion criteria but were omitted) - with individual critical appraisal of each component study included, completed with, as is my approach, a MQ (methodological quality) score assigned to weight the pooling, these founding the basis for a motivated conclusion on what the balance of the evidence supports.

And in the here and now, without such an authoritative and current SR/MA and associated critical appraisals, which I and no one else has undertaken, we are left with a weak interim working conclusion presumptive of some modest efficacy in combination regimens in certain mCRC settings not wholly identified to date. Furthermore, given the fact that the studies supporting this have predominantly been combinative (concomitant mitomycin) but not contrastive (measuring response and outcome with versus without mitomycin) of efficacy, we can draw no motivated conclusion as to the clinically relevant intrinsic benefit of mitomycin over either (a) the backbone regimen or agent to which it is added, or (b) over best supportive care, and there would be a presumption of the lack, or marginal level, of such benefit, given that I have cited that the overwhelming weight of the data from studies designed to measure this contrastively (with/without) have failed to manifest significant benefit.

This is what an authoritative evidence based review (neither SR nor MA, but with some critical appraisals I have ad hocly conducted) supports, and against this we have (1) the wide and rich experience apparently to the contrary of numerous clinicians especially in Japan (what I call experience-based medicine, in contrast to evidence-based medicine (EBM)), and (2) the deep-seated beliefs again to the contrary by many prominent practitioners (what I call eminence-based medicine), and here the chemosensitivity biomarkers AKR1B10 and NQO1 may be at play here along with ethno-genetic variables as yet identified to confound the efficacy landscape (and research on these are intensive and may bear fruition in the nearer horizon).

I should add that in numerous consults I have participated in (I deal mainly with highly advanced disease that has been judged approaching but not satisfying futility to further interventions), I have counseled and the primary oncologists have implemented under my guidance and direction, after full and explicit informed consent - indeed insistence - by the patient, an integrative approach to mitomycin as salvage therapy coupled with high-dose curcuminoids and melatonin both for synergy and as chemoprotectants, with an additional supportive role for melatonin against thrombocytopenia (I have elsewhere provided the evidence for an anti-thrombocytopenic effect of melatonin), often with dramatic benefit. This remains a rare intervention (perhaps a couple of dozen times in the last 5 years), in extremis, and under manifest patient directive to that end, with full oncologist sanction, and no claim is made beyond those highly near-anecdotal boundaries (one of my relations is one, now celebrating NED after almost two decades post-Dx of advanced CRC liver metastatic disease).

So for these reasons here and above severally, I will repeat my prediction: that the final chapter in the saga of mitomycin in mCRC has not yet been written, although perhaps here, and in the here and now, we have spilled enough words on the matter.

Now an appeal, and admonishment, which I trust will be taken in the spirit in which it is offered, putting on my schoolmarmish "hat" (by your pictures, I have the advantage of seeing I am older - and of course vastly, immeasurably wiser (!), than all of you (Ha!)): I cannot help but perceive that the discussion above has been intense and has generated perhaps more heat than our professionalism would otherwise sanction. My counsel is that:

(1) we avoid veering into any ascription of motives to each other, not only because these are unknowable despite our misperceptions to the contrary, but more importantly because it is irrelevant in any objective exchange among fellow professionals, which we all are, or

(2) couching less than charitably any judgments of each other. Discussants understandably can and obviously do have strong personal connections to some of these issues - in terms of the always affecting loss of lives (my dear colleague Laszlo Torday), or the unwelcome touch of disease on the lives of those near to us (my dear colleague Fatih Uckun) - but we are all professionals bending to shared goals, even with strongly divergent opinions (which on close read are less divergent than first appears, I would suggest).

I have rarely encountered such valuable contributions as I see, and re-read, above and we are leaving, I would challenge anyone to contradict, the topics of conversion therapy and the cloudy role of mitomycin, I think, the better and more nuanced for all these exchanges. We will all serve ourselves and our contributions better by leaving the personal dimension at the door, to the extent possible. I include myself in this. Enough said.

Dear Ailsa:

There is certainly efficacy-relevant heterogeneity in KRAS mutations: in their study (J Clin Oncol, 2012) of the association of KRAS G13D mutations with outcome in mCRC Patients when treated with cetuximab in the first-Line, Sabine Tejpar and Eric Van Cutsem in Belgium and colleagues in Germany found that the addition of cetuximab to first-line chemotherapy seems to benefit patients with KRAS G13D–mutant tumors to the same relative degree of treatment effects as those in patients with KRAS wild-type tumors.

But more importantly, the KRAS codon 12 mutation itself harbors intrinsic heterogeneity in mCRC under cetuximab-based first-line therapy, with patients with the KRAS p.G12D mutation showing a highly marked trend (almost two-fold, at overall survival of 23.3 vs. 14–18 months) towards more favorable outcome in comparison to other mutations (from data analyzed from the CECOG, AIO KRK-0104 and AIO KRK-0306 trials, Modest et al., Oncology, 2012).

Furthermore, as to the larger question of EGFR biomarkers (prognostic and predictive, from the cumulative evidence to date (most only pending publication), it appears that, beyond KRAS mutations, identification of patients with compromised likelihood of benefit from anti-EGFR monoclonal antibodies may be vitally dependent also on:

- BRAF,

- EGFR gene copy number (GCN),

- the NRAS oncogene,

- PIK3CA mutations

- PTEN expression loss, and

- microRNAs (miRNAs),

with for example, (1) increased miR-200b expression and/or (2) decreased miR-143 expression and/or (3) copy number losses of the KRAS locus, being associated with favorable PFS, and these appear to serve to identify patients with mutated KRAS tumors who will be good responders to anti-EGFR therapy like cetuximab, while in wildtype, not mutated, KRAS patients, copy number gains appear on the other hand predictive of cetuximab resistance. I would recommend to your attention the fact as I uncovered in my own research that high-dose curcuminoids influence all three of these parameters and critically modulate expression profiles of microRNAs in several epithelial malignancies, especially pancreatic cancer where we have human clinical data of therapeutic benefit from curcuminoids, activity they share most closely, and synergistically, with EGCG (I am wary of quercetin and its vast in vivo, or higher, potential for extensive adverse pharmacokinetics across the CYP3A4 hepatic P450 cytochrome, and genistein has eluded resolution of its many contradictory mechanisms in endocrine / hormonal carcinomas and I would wait for further maturity of pre-clinical and clinical data).

All in all, from the lessons I take away, I would predict that over the next year to 18 months, based on accelerated and translational research, we will be close to a workable fingerprint of anti-EGFR therapeutic response, and resistance, and that a new generation of mCRC patients will have expanded options for clinically meaningful benefit from such biological therapy, finally unlocking the clinical potential of an to-date underwhelming and lightly leveraged molecular pathway.

I could not agree more. I truly enjoyed your posted explanations. I will no longer participate in this forum. It is my considered opinion that sometimes it is best to walk away from persons who do not value civility and genuine respect for others and their views as much as I and the people i associate with do. What Socrates could not accomplish, I do not dare to think I could.....

With my kindest regards and very best wishes.

I deleted my pprevious comment., because it was too long.

Firsly, Dr, Kaniklidis, your contribution is excellent! I absolutely agree with you, we do not have to throw away old drugs, and on the other hand old drugs can not be included into mainstream oncological treatments without compellingg evidence.

Dr. Uckun, You are a highly reputed researcher, and as being in this position You have to be aware that miffing at something and and emotionally driven poisonous classification of your opponent rarely helps in pushing a debate forward. In any cases, during this session I have avoided your written valuation as a person. I have expected tha same, unfortunately without avail.

Hi Constantine,

I would agree that research on phytonutrients is at a relatively early stage, and it is difficult at the moment to see the wood for the trees. What works in a mouse or a petri dish may have no clinical effect in a human, or worse still, may have unintended consequences (as you allude to with regards to the complexity of pharmacological interactions involving P450 cytochrome). I keep an active eye on the literature in this area. And yes, we will only find out what is useful by doing the trials, and a few are already being done (including one in the department I used to work in). It will be interesting to see if anything useful comes out of it all or not. If it does, I hope we may be able to target specific signalling pathways, expression of tumour suppressor genes etc., and thereby improve efficacy, which may allow us to give lower doses of chemotherapy drugs. We need more factors which can introduce a degree of tumour specificity in comparison to the blunderbuss approach we currently have, in which you may get a good tumour response (or not), but often at the expense of neurotoxicity, bone marrow suppression and other such nasties. If not - well, that's research for you. Some you win :o), some you lose :o(

I have read quite a number papers on KRAS mutation, BRAF mutation and others, including the ones you are citing. It's particularly interesting looking at similarities and differences in the mutation profile across both the primary and secondary tumours e.g. J Clin Oncol Vol 30(24), p2956-2962, Aug 20, 2012 (and at the inhomogeneities in mutation subpopulations within individual tumour masses). I think that understanding these issues is key to the job of overcoming chemo- and radio-resistance, and also to tailoring treatment to individual patients. And that's why I think (or at least hope) that we may be giving different answers to this question in the future. Just my two-penny worth...

Fatih, not the outcome that I had wanted, but I must respect your decision, and only regret that differences between two such exceptional professionals who I both value greatly has led to a loss, I think, for all of us. The consolation is that I continue to look forward to your contributions elsewhere in the ResearchGate community, and to future productive interactions and exchanges.

Constantine

Ailsa:

Two-penny worth, it is clear from your contributions, buys a lot of insight! I'll in the near future share with you and the others here you some of my thoughts and discovery on some of the intriguing themes you raised: more precision-targeting of oncogenic molecular pathways, natural chemosynergizers and chemo- and radio-protectants against myelotoxicity, and tumor and receptor discordances and their therapeutic implications (among other frontier topics).

Exciting time for researchers and clinicians alike.

Constantine

a question for you: for persons who failed and eventually died after conversion therapy, was the cause of failure local ie new or progrssive liver mets or mets someplace else. in other words, specifically were the failures caused by systemic disease or resistant local disease. And if especially for rectal cancer the failures are local, can a different resection strategy be helpful. any articles from liver transplant surgeons in this regard? also in your review of literature have you seen data on radiofrequency ablation or cryoablation plus chemo. I know it has been done but was it reported?

Constantine

look at the linked paper

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3026051/

Joachim

any info you are able to find in this regard?

Dear Dr. Uckun, I completely agree with Constatntin that leaving Research Gate is not an appropriate solution, and I decided to do all what I can to change your previous decision.

To achieve this goal, in case of you felt harmed by my style, I would offer you my full sorry hoping in your remission.

Lüften, sekür ederim!

Dear Laszio

I look forward to reading and learning from your many contributions. very best fatih

Fatih Uckun wrote:

> any info you are able to find in this regard?

I've never heard the word conversion therapy before.

A list of treatment options, causes, biomarkers I've bookmarked:

http://www.augos.com/temp/Temp-ColorectalCancer.html

Regards,

Joachim

Joachim, i meant cause of treatment failure after liver resection (the recent question i posted)

Sorry i was not explucit

Sorry, I found only these articles in my RSS collection.

http://7thspace.com/headlines/359776/a_randomized_two_arm_phase_iii_study_in_patients_post_radical_resection_of_liver_metastases_of_colorectal_cancer_to_investigate_bevacizumab_in_combination_with_capecitabine_plus_oxaliplatin_capox_vs_capox_alone_as_adjuvant_treatment.html?utm_source=feedburner&utm_medium=feed&utm_campaign=Feed%3A+7thspace+%287thSpace+Interactive%29

http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0045493?utm_source=feedburner&utm_medium=feed&utm_campaign=Feed%3A+plosone%2FPLoSONE+%28PLoS+ONE+Alerts%3A+New+Articles%29

http://www.sciencecentric.com/news/09052717-study-finds-dramatic-increase-metastatic-colon-cancer-survival.html

Regards,

Joachim

First and most important: I am very much gratified that we have our team back!, thanks to Fatih and Laszlo, and our gain.

Now, back to work:

Questions from Fatih Uckun

Constantine

a question for you:

Query: For persons who failed and eventually died after conversion therapy, was the cause of failure local ie new or progressive liver mets or mets someplace else? in other words, specifically were the failures caused by systemic disease or resistant local disease.

Response: Failure following conversion therapy and curative resection show different natural histories and "architectures" for colon cancer versus rectal carcinoma (RC), with locoregional failure commonly being the sole or major recurrence site in rectal cancer (note: median 75% (range 66–84%) of locoregional recurrence presented during the first 2 years after resection), as opposed to distant (non locoregional) metastases being most common in colon cancer, especially in the peritoneum, lung, and liver, accompanying far lower rates of local failure. Its for that reason that local therapy such as irradiation, is a core aspect of the treatment of rectal tumors but uncommonly used for colon cancers.

Query: And if especially for rectal cancer the failures are local, can a different resection strategy be helpful.

Response: The facts are knotty and nuanced, so let me try to provide a distillation of what the best evidence determines to date.

First, as I note above, post-resection locoregional failure in rectal cancer runs as high as approximately 75% (range 66–84%) during the first 2 years after resection (Susanne Merkel and colleagues, Colorectal Dis. 2011), but this has been radically "kicked" back with the introduction of total mesorectal excision (TME) surgery coupled with deployment of neoadjuvant treatment, yielding highly favorable reductions in the frequency of local recurrence as well as a prolongation of the time to local recurrence (TTLR), with best results today being seen after neoadjuvant long-course radiochemotherapy (known by the clumsy acronym of "LCRTCT") or radiotherapy (aka, LCRT), with now median 24% (range 8–40%) of all local recurrences presenting later than 5 years after primary therapy, something of a breakthrough advance.

Second, as to alternative resection techniques that might matter, at this time, the best that can be said stems from the recent comprehensive systematic review by Basingstoke investigators of 24 eligible studies, which found that within total mesorectal excision (TME), there is strong evidence that anterior resection (AR) for rectal cancer is an oncologically superior operation in comparison with abdominoperineal resection (APR), with lower local recurrence rates for AR, and non-inferior rates of distant metastasis (How et al., Surg Oncol, 2011).

Finally, there is also the special case of low rectal cancer where intersphincteric resection is the standard of surgical care, and here the forms of such surgery, open versus laparoscopic were not differentiated as to outcomes, neither local recurrence nor DFS at the 5-year boundary (Christophe Laurent and colleagues, Colorectal Dis. 2012), and similarly the two alternatives of ultralow anterior resection (ULAR) and abdominoperineal resection (APR) yielded similar long-term outcome in lower rectal cancer, in contrast in this special low form of rectal cancer than the clear superiority of AR over APR in standard rectal cancer as per the Basingstoke findings, but I would comment here that, unexpectedly, APR was more effective than ULAR in terms of tumor local relapse, but they were equi-efficacious as to distant metastases (Yang et al., Hepatogastroenterology. 2012). This demonstrates that low rectal cancer behaves differently than standard rectal cancer, with a clear advantage in both local recurrence and distant metastases in rectal cancer, but the advantage shifting to (UL)AR in low rectal cancer for local recurrence, but outcome equivalency for distant metastases.

Query: Also in your review of literature have you seen data on radiofrequency ablation or cryoablation plus chemo. I know it has been done but was it reported?

Response: This issue is exceedingly complex issue generating phenomenal controversy. Right now, as I am writing this I am called away on a virtual tumor board (at least I don't have to travel - the oncologists are in AU/NZ) for an emergency case of IBC which demands my immediate attention but I should be able to get back to you over the next 24 hours or so, and help clarify what the weight of the methodologically robust evidence says as the roles of RFA and cryoablation in this context (some considerable promise).

Dear Constantine

thank you for this very informative summary. Much appreciated. Those patients who had ulcerative colitis appeared to have a particularly high risk of recurrence. Have you had a similar experience.

i am hopeful that new funtional imaging methods used intraoperatively may enable a more effective and complete removal of the involved tissue and thereby reduce the local tecurrence rate. Are you aware of any photoacustic imaging studies in colorectal cancer.

Deep sequencing apparently revealed discriminating microbiota profiles in women with female genital tract cancers. Are you aware of any microbiome studies in rectal cancer patients aimed at identifying either a biomarker or contributing biological element.

Fatih Uckun has raised several important issues above, and I will address these individually in this and succeeding responses:

Query:

Those patients who had ulcerative colitis appeared to have a particularly high risk of recurrence. Have you had a similar experience.

Response: No. Many of my patient-consults elect under my guidance to use my case- and patient-customized anticancer CAM regimen, which includes (1) as one component high-dose AKBA, a boswellic acid derivative which incidentally exerts powerful 5-LOX inhibitory and anti-inflammatory activity (besides cytotoxicity), with human clinical data of benefit in inflammatory bowel disease including ulcerative colitis, and (2) as another component a pharmaceutical grade of RYR (red yeast rice) with equivalency to lovastatin, and I note in my review that we again have human clinical data that the risk of colorectal cancer in patients with inflammatory bowel disease is reduced by use of statins (Samadder et al. Cancer 2011).

And more specifically to the concern you raised, I remain unconvinced of an essential association: most of the claims of an association of ulcerative colitis (UC) and CRC/RC (colorectal cancer / rectal cancer) stem from studies and population-based cohorts with methodological limitations, and similarly for studies going beyond this claim to the claim that recurrence and outcome may be adversely affected by UC disease. Therefore, whether CRC/RC with underlying UC is prognostically poorer remains undemonstrated, and by weighting methodological quality of the studies, appears to be against the evidence.

So, in one of the most recent and comprehensive meta-analyses, conducted by the Tine Jesse and colleagues (Clin Gastroenterol Hepatol. 2012), the authors concluded that UC increases the risk of CRC 2.4-fold, but that in fact represents an overall CRC occurrence of just 1.6% during the first 14 years of follow-up, including sporadic cases, and in addition my own critical appraisal found that the meta-analysis contained small sample sizes in some of the included cohorts (from 89 to 4125). Furthermore, there was significant heterogeneity between studies potentially reflective of many confounders such as regional/geographic differences in patient care or uncontrolled factors such as differences in smoking habits among UC patients from different regions.

But if we instead look at population-based survival data of patients with CRC with or without inflammatory bowel disease (IBD), and as I always advise, use statistical techniques to normalize and control for confounders, than a different picture I would conclude emerges. Thus, Laurence Egan's team at the National University of Ireland (Galway) investigated from the National Cancer Registry survival of IBD CRC and non-IBD CRC in all patients diagnosed with CRC over a 12-year period (Raja Affendi Raja Ali et al., Clin Gastroenterol Hepatol. 2011) but, near to my heart in terms of tight methodological control of confounders, they employed tree-based propensity score matching (tree-based PSM). What this highly robust review found was: (1) that under Cox proportional hazards analysis IBD was not a significant prognostic factor for CRC, and (2) more importantly, when tree-based propensity score matching was used to analyze outcome results, the survival times of CRC patients with IBD compared to those without IBD did not in fact differ significantly. Indeed, in this rare high methodological quality study with confounder control, the most striking finding was a 3-year median survival advantage of IBD CRC patients compared with non-IBD CRC patients, contradicting the earlier widely cited Danish and Norwegian studies, and that the natural history of CRC after diagnosis for IBD and non-IBD groups are very similar, not suggestive of any clinically relevant differences in treatment response or refractoriness.

Thus, re the association of IBD disease with compromised risk or outcome in CRC patients, we must concluded that the case is not proven, and that high methodological quality data (as that discussed above using sophisticated tree-based propensity score matching) argues against such adverse association, with survival outcomes not significantly different between CRC patients with IBD versus those without.

Dear Constantine

thank you very much about pointing out the Egan study. Did they look at IBD to include both Crohns and UC. equally interesting are your comments regarding red yesst rice. please educate me about the molecular mechanism/premise. thanks and kind regards

Fatih:

Yes, with about 82% ulcerative colitis and 18% Crohn's.

CRC, IBD, and Statin and RYR (Red Yeast Rice) Therapy: Where We Stand

As to RYR and statin therapies, accumulated data over dozens of studies including meta-analyses, systematic reviews, randomized and prospective data, has shown that use of statins (vs never use of statins) was associated with a significantly reduced risk of CRC overall with a significant duration- and dose–response relationship with greater statin exposure offering more protection against CRC, remaining significant even after adjustment for age, ethnicity, vegetable consumption levels, , history of CRC in first-degree relatives and other potential confounders, and even more impressively, statin use is associated with a profoundly reduced risk of IBD-associated CRC (we are talking about an OR = 0.07). Cross-confirmative is the Israeli study finding statin therapy risk-reductive in sporadic CRC, with a 94% risk reduction in patients with IBD, via pleiotropic effects that include cell growth modulation, pro-apoptotic and strong anti-inflammatory activity, reduction of invasion, most plausibly consequent to the inhibition of the mevalonate synthetic pathway (inhibiting cellular availability of substrates critical to isoprenylation of small signaling G-proteins) with resultant inhibition of multiple pro-carcinogenic and pro-survival pathways.

In addition, in my own specialization of epigenetic reprogramming and transformational oncology, there is recent evidence that red yeast rice (RYC) and the statin class act as strong DNMT inhibitors inducing BMP2 promoter demethylation and BMP signalling activation which collectively induce CRC cell differentiation, hence reducing ‘stemness’. These epigenetic mechanisms I will note are critical since it's been established (1) that the BMP (bone morphogenetic protein) pathway is an important tumor suppressor pathway in colorectal cancer (CRC), (2) that the BMP2 promoter is methylated in a large proportion of gastric cancers, including colorectal and rectal cancers and is silenced by promoter hypermethylation in a subgroup of CRCs, and (3) that activation of the BMP pathway induces powerful pro-apoptotic response, while concurrently increasing the chemosensitivity of CRC cancer cells to 5-FU and likely also 5-FU prodrugs (capecitabine (Xeloda) and gemcitabine (Gemzar). The most prominent CRC subtype thus favorably affected is CRC with the CIMP (CpG island methylator) phenotype, which may represent from 25 - 50% of CRC cancers (and CIMP is also found in colonic polyps). There also is some evidence of a closely related mechanism via upregulation of miR-33b expression, reduced cell proliferation and impaired c-Myc expression - all exhibited by lovastatin - important given that c-Myc dysregulation and overexpression is an abnormality of CRC and several other epithelial cancers and c-Myc is regulated by multiple miRNAs as well as intertwined with epigenetic mechanisms.

Red yeast rice (RYR) contain several monacolins including monacolin-K otherwise known as lovastatin, and the hydroxy acid form of monacolin-K known as monacolin KA which is the activated form of lovastatin after it passes through the liver. But RYR, as opposed to commercial lovastatin (as in Medacor) contain additional components allowing it to be effective in patients otherwise non-responsive to marketed pharmaceutical statins and with reduced adverse events (only 7% muscle pain on RYR), as randomized data has confirmed may be effective in people who do not respond to marketed pharmaceutical statins. The RYR / lovastatin action via monacolin-K and monacolin-KA is known to induce DNA demethylation and the re-activation of BMP2 gene expression as well as TIMP3 and HIC1 promoters silenced by hypermethylation in CRC cells, also leading to increased expression of markers of intestinal epithelial cell differentiation and decreased expression of cancer stem cell CSC) markers. And like statin drugs themselves which interfere with production of ubiquinone Aka CoQ10, supplementation with CoQ10 (90 - 120 mg/daily) should be concurrent with RYR or statin therapies. Furthermore, retrospective cohort data shows that statins are associated with reduced need and use of steroids in inflammatory bowel disease (ulcerative colitis and Crohn's Disease), especially of benefit to CRC patients with IBD, and potentially sparing immunosuppressant therapy or ameliorating flares. And some preclinical data suggests that statins and RYR may overcome cetuximab resistance in mCRC harboring KRAS mutation (via BRAF activity modulation and the induction of apoptosis), as well as being a strong natural DNMT inhibitor which beneficial epigenetic reprogramming activity in several malignancies.

Therefore, despite some divergent data, at this juncture the accumulated evidence to date supports the benefit of RYR or statin therapy in reduction of CRC risk as well as IBD-associated CRC, and may independently also exerts powerful anti-inflammatory activity in inflammatory bowel diseases with or without CRC. (As a footnote, within the last 18 months or so, we have passed an evidence threshold where we can draw comparable conclusions for breast carcinomas), and we are awaiting maturity of data that may ultimately show a therapeutic and not just chemopreventive benefit (by blocking of several components of the metastatic cascade).

I hadn't come across red yeast rice before - it sounds like a promising idea. I'd be interested to read more about the possibility of it (or statins) overcoming cetuximab resistance in KRAS mutated tumours - do you have any references?

Ailsa:

As I noted it is a preclinical (but in vivo as well as in vitro) study (Lee J, Lee I, et al. Effect of simvastatin on cetuximab resistance in human colorectal cancer with KRAS mutations. J Natl Cancer Inst 2011 Apr 20; 103(8):674-88), and although some of its methodology has been questioned (Brandi G, Biasco G, Tavolari S. Re: Effect of simvastatin on cetuximab resistance in human colorectal cancer with KRAS mutations. J Natl Cancer Inst 2011 Aug 17; 103(16):1278), I am not convinced that these objections are all well taken (the authors declined to respond), but note also we have some further data suggestive to the same effect from other malignancies. We await human clinical data.

Since it has been compelling demonstrated that the effects and benefits of the individual statins are a class, not an agent-specific mechanism, applicability transfers directly to RYR which of course is pharmaceutically equivalent to lovastatin.

Query (from Fatih Uckun): Also in your review of literature have you seen data on radiofrequency ablation or cryoablation plus chemo. I know it has been done but was it reported?

Local Therapies for mCRC: RFA, Cyroablation, and SBRT - A Review

Response: I would strongly suggest expanding this query to include another form of interventional local treatment, namely stereotactic body radiotherapy (SBRT) typically delivered by CyberKnife technology, in addition to radiofrequency ablation (RFA) and cryoablation (CA), and the reasons for this will become clear when I report (below) the results of my comparative efficacy review.

RFA

According to the ASCO Clinical Evidence Review of RFA in CRC Hepatic Metastases, the yields for RFA are highly variable, but with 5-year survival rates ranging between 14%–55% and local recurrence rates of 3.6 – 60%, all with low morbidity and mortality (Wong et al., J Clin Oncol 2010), but at these levels resection yields superior results (Abdalla et al, Ann Surg 2004), and I would agree with the ASCO committee quality evidence is quite sparse on the ground so that we require more clinical data to draw any decisive conclusions about the efficacy and role of RFA in these contexts. And randomized data is less positive for RFA when combined with systemic therapy in patients with non-resectable colorectal liver metastases; the EORTC Intergroup phase II study (EORTC 40004) was the first randomized trial of RFA efficacy, with significant improvement in median PFS from combination treatment but benefit on overall survival was indeterminate (Ruers et al, Ann Oncol, 2012; see also Gillams et al, Cardiovasc Intervent Radiol. 2012 where combination RFA + systemic therapy yielded a 3 year survival of 57 % in patients with inoperable colorectal lung metastases). In any event the data support the limitation that RFA provides the best results in cases of CEA or CA19-9 ≤ 100, absence of extrahepatic disease, solitary hepatic lesion, and unilobar hepatic lesion (Gwak et al., J Korean Soc Coloproctol. 2011, in agreement with others), although weaker evidence may support broader application in cases where other local treatments prove infeasible, and in the special case of resectable hepatic CRC metastases, laparoscopic RFA especially can produce comparable long-term survival to hepatic resection in carefully selected patients and may provide a constrained alternative to surgery in highly chosen populations (Hammill et al., Ann Surg Oncol, 2011; van Tilborg et al, Br J Radiolog, 2011; Evrard et al, Br J Surg, 2012).

Thus it still remains that the weight of the evidence to date, in agreement with the latest Cochrane Review failed to support a recommendation for the efficacy of RFA in CRC hepatic metastasis (Cirocchi et al, Cochrane Database Syst Rev. 2012), and a subsequent high methodological quality meta-analysis (Weng et al., PLoS One. 2012) comparing RFA to resection in CRC hepatic metastases which included 1 prospective study and 12 retrospective studies concluded that resection was significantly superior to RFA with superior OS and DFS, even when conditions limited to tumor

Thanks Constantine, I'll take a look at that.

There was quite a nice review of radiotherapy for liver mets in the red journal earlier this year (Int. J. Radiation Oncology Biol. Phys., Vol. 82(3), p1047–1057, 2012). It includes SBRT and SIRT (as well as palliative whole liver treatment), with a summary of trials.

One radiotherapy option for liver mets that is is often overlooked is brachytherapy. It can be a good option if you don't have the equipment and infrastructure for SBRT. Unfortunately, there isn't much good quality data, and little in the way of trials, but there are certainly some centres getting decent results. It has the advantage, compared to ablative therapies, that it can be used in some patients who are awkward to treat with RFA / HIFU etc. due to the proximity of major blood vessels (where cooling due to the blood flow can reduce efficacy) the hilum (risk of damage to the bile duct), as these can be spared by treatment plan optimisation if using remote afterloading. It's reasonably straightforward to do under CT, fluoroscopic or MRI guidance. It's also a good option for unresectable hepatocellular carcinoma, and for patients with larger mets (i.e. bigger than 5cm or so). Pech et al (Strahlentherapie und Onkologie

June 2008, Vol 184(6), p302-306) report local control in a small matched pair series (18 patients, 36 colorectal hepatic mets, comparing HDR brachy vs laser ablation) of about 72% for the brachy treated lesions compared to 44% for the laser treated lesions, but the median followup was only 14 months (range 3-24mo). Ricke et al (Int. J. Radiation Oncology Biol. Phys., Vol. 78(2), p479–485, 2010) did a 73 patient prospective study with three different doses. It's a little confusing, as there was quite a bit of crossover from one dose to a lower dose on the basis of certain criteria. But for the doses actually given, the median local recurrence-free survival was 25.6 months in the 15-Gy group, 31.1 months (median not reached) in the 20-Gy group, and 46.4 months (median not reached) in the 25-Gy group. So it can be a good option for patients with large lesions, or mets in awkward positions.

Query (from Fatih Uckkun): Deep sequencing apparently revealed discriminating microbiota profiles in women with female genital tract cancers. Are you aware of any microbiome studies in rectal cancer patients aimed at identifying either a biomarker or contributing biological element.

Response:

Microbiota and Colorectal Cancer (CRC)

Although we lack decisive cross-confirmed evidence of any single microbe as causally linked to CRC, contributions of the gut microbiota to colorectal carcinogenesis are now manifest. Based on the evidence that the microbiota and its collective genome, the microbiome, constitute a complex ecological community profoundly impacting intestinal homeostasis and disease states. And although colorectal cancer has not been linked to any specific microorganisms, some species have been identified as cancer-promoting bacteria (for example, H. hepaticus augments both experimental colitis-associated colon cancer and spontaneous colorectal cancer in mice, while Bacteroides fragilis is a common intestinal commensal, yet an enterotoxigenic variant induces spontaneous colonic tumorigenesis in mice). This explains the interest in and benefits of prebiotic and probiotic therapy which:

(1) induces host production of biofilms that prevent adhesion or invasion of pathogenic species,

(2) maintains gut barrier function by blocking redistribution of host tight junction proteins,

(3) inducing host cytokines to modulate both inflammation and immunity, and

(4) neutralizes carcinogens and toxins (Janelle Arthur and Christian Jobin, Inflamm Bowel Dis. 2011, among dozens of others). But although intriguing, these observations have not yet moved beyond the descriptive phase into full functional and clinical fruition except in the form of lifestyle interventions which I summarize latter below.

What we do know is that the structures of the intestinal lumen microbiota and mucosa-adherent microbiota were different in CRC patients compared to matched microbiota in healthy individuals. Lactobacillales was enriched in cancerous tissue, whereas Faecalibacterium was reduced. In the mucosa-adherent microbiota, Bifidobacterium, Faecalibacterium, and Blautia were reduced in CRC patients, whereas Fusobacterium, Porphyromonas, Peptostreptococcus, and Mogibacterium were enriched. In the lumen, predominant phylotypes related to metabolic disorders or metabolic exchange with the host, Erysipelotrichaceae, Prevotellaceae, and Coriobacteriaceae were increased in cancer patients. Coupled with previous reports, these results suggest that the intestinal microbiota is associated with CRC risk and that intestinal lumen microflora potentially influence CRC risk via co-metabolism or metabolic exchange with the host. However, mucosa-associated microbiota potentially affects CRC risk primarily through direct interaction with the host.

[Chen et al., PLoS One, 2012]

The Continuous Update Project of the World Cancer Research Fund (CUP/WCRF) [Aune et al, J Epidemiol Community Health 2011] undertook a systematic review and meta-analysis of seven cohort studies on whole grain consumption and CRC risk, finding a favorable association. The intersection of this with microbiota stems from the fact that diets generating large amounts of colonic carbohydrate residues, which includes high fiber and high complex carbohydrate diets, are demonstrated to increase microbial fermentation and butyrate production and reduce CRC risk, in contrast to diets rich in meat and fat which alternatively stimulate sulfate-reducing bacteria (SRB) production of hydrogen sulfide, which is known to be genotoxic and which promotes methylation of DNA, and microbial conversion of bile acids to carcinogenic secondary bile acids, collectively and effectively increasing CRC risk (Vipperla & O'Keefe, Nutr Clin Pract. 2012), underlying the fact CRC risk is substantially determined by complex interactions between the diet and the colonic microbiota so that even despite an evidenced direct causal link between microbial infection and CRC, overwhelmingly studies support the inducive involvement of these microbiota in oncogenesis.

Targeted intervention can therefore be of benefit, as shown in a preclinical in vivo study that found that both conjugated linoleic acid (CLA) and a commercial avialable high-potency probiotic mix known as VSL#3 suppress colon carcinogenesis and therefore can help prevent of colitis-associated CRC via probiotic intervention, with CLA mechanistically modulating COX-2 expression levels in colonic mucosa, in contrast to the probiotic mixture VSL#3's targeting of regulatory mucosal CD4+ T cell responses, with VSL#3 showing more pronounced anti-carcinogenic and anti-inflammatory activities than CLA itself [Bassaganya-Riera et al., PLoS One, 2012], leveraging the existing evidence that probiotics like Lactobacillus acidophilus and Bifidobacterium longum inhibit carcinogen-induced colon tumor development (Manning & Gibson, Best Pract Res Clin Gastroenterol 2004; among many others to date). And the large Bellvitge Colorectal Cancer Case-Control Study was, and remains, the first study that showed a significant inverse association between total flavonoid (particularly flavones) and lignans intake and colorectal cancer, likely as the investigators acknowledge through modulation of colonic microbiota (Zamora-Os et al., Cancer Causes Control. 2012).

What we can therefore now take away as early clinical pearls is the probable benefit on both CRC risk and its natural course of prebiotic and probiotic therapies coupled with high-fiber, high complex carbohydrate dietary shift and the increasing avoidance of high-meat and high-fat consumption, via favorable microbiota modulation, and that collectively these interventions may dramatically decrease CRC and other disease, and appear to be similarly beneficial in several other epithelial malignancies.

Dear Constantine,

Thank you very much for this very high quality and instructive narrative. May I suggest that you take the lead to put together an editorial/short review that summarizes/details the various items we discussed so far and perhaps we could combine it with nanomedicine strategies that are emerging for personalized treatment of metastatic disease. What are your thoughts in this regard ?

Separately, I would like to share with you that in the Min mouse model in which a JAK3 inhibitors was protective (Reference: https://www.thieme-connect.com/ejournals/abstract/10.1055/s-0031-1296626), we have unpublished data showing an unexpected and dramatic increase of number and size of neoplastic lesions when the flavonoid genistein was used for chemoprevention. Genistein was shown to have Topo-II activity and we had speculated that this could have been the reason for our observation.

Kind regards

Fatih Uckun

https://www.thieme-connect.com/ejournals/abstract/10.1055/s-0031-1296626

Talking about RFA I would like only to note that the results coming from different groups are usually incomparable and frequently misleading. Contrary to SBRT which can be reproduced as a technique and dose, RFA represents a wide spectrum of different procedures (percutaneous, open, laparoscopic, with or without vascular control), performed with different equipment (monopolar, bipolar; single or multiple, or expandable electrodes etc.) and different security margins targeted by the teams. So unfortunately it is impossible to talk about RFA generally – as we don’t talk about radiation therapy generally.

http://www.intechopen.com/books/liver-tumors/expanding-local-control-rate-in-liver-cancer-surgery-the-value-of-radiofrequency-ablation

Hi Fatih,

Excuse me if I'm maybe being a bit dense here (wouldn't be the first time)... :o)

I'm a bit puzzled about what you said above, "...an unexpected and dramatic increase of number and size of neoplastic lesions when the flavonoid genistein was used for chemoprevention", and you thought it may have been because "Genistein was shown to have Topo-II activity ".

I had thought that as well as showing some action against tyrosine kinase, genistein acted as a topo II poison, although from what I've seen, not very strongly when given as part of the diet. I can see how it might not improve the survival of the min-mouse because it doesn't seem to stabilise the cleavage complexes for as long as, say, etoposide, but I can't quite figure why the "sudden and unexpected increase" in tumour lesions is due to topo II activity. Am I misunderstanding something?

Hello Ailsa,

While we expected an improvement in outcome, we got the exact opposite. Mice developed more tumors that also were larger !

We did not understand the reason for this observation. How can genistein promote cancer. Is there any way that it might decrease genomic stability due to its TOPO-II inh activity ? Other than speculations, I have no mechanistic insights for the aforementioned observation.

Practical relevance: As you might know, a large population of men consume genistein products or soy products containing a lot of genistein. Is that a safe practice for those at high risk for CRC ?

Fatih

Thanks for that, Fatih. I guess we will have to wait for answers to that question! It is very puzzling.

Soy gets into so many food products these days, and without reading the labels closely, you wouldn't notice...

Hi Ailsa,

We have since prepared a synthetic genistein for cancer prevention and it very actively prevents cancer development in the Her2 transgenic mouse model of metastatic breast cancer. But we have not tested it in a colon cancer model. If anyone is interested, I could provide it for collaborative research.

I wish all participants and of course their families Happy Holidays !!!

Very interesting discussion Dr. Uckun and Dr. Ratcliffe! The regulatory pathways are so complex that we always missed something.

The situation in your discussion is similar to that observed in breast cancer models where genstein inhibits tumor growth in ER-HER2+ cells through TK-inhibition, but promotes tumor growth and tamoxifen resistance in ER+HER2+ cells.

http://www.ncbi.nlm.nih.gov/pubmed/20067990

Thanks Alexander, I hadn't seen that paper. It's a very interesting parallel which does appear to give some helpful clues in regard to Fatih's team's observations.

BTW, it's very kind of you to give me a PhD :o), but I only have an MSc.

I would advise several cautions here:

(1) as always, in a mature evidence-based context, single studies are irrelevant but rather what only matters is what the preponderance, the weight, of the data indicates from a critically appraised and systematic reviewed full Evidence Matrix, the aggregate of preclinical in vitro and in vivo, and human clinical data that bears on the issues;

(2) that rodent studies in this context are pharmacokinetically oblique and clinically irrelevant to the genistein, and soy isoflavones in general, issue in humans (see below); and

(3) that in the strength of evidence hierarchy, we must be careful to always escalate lower-level (in vitro, and then in vivo) apparent concerns in the data to the higher levels including human clinical, if available, to assure we found conclusions on the best and highest level of relevant evidence.

Exercised in this way, I will argue below that the critically appraised and systematic reviewed evidence matrix on genistein and soy isoflavones is reassuring:

THE IN VIVO TRAP: DIVERGENT METABOLISM OF HUMAN Vs RODENT

It is now well-established that sharp and important differences in isoflavone metabolism - especially Phase II metabolism which is by glucuronidation and is a major pathway for the elimination of isoflavones as well as endogenous steroid hormones - exist between rodents and humans, particularly as they pertain to circulating concentrations of biologically active unconjugated forms of genistein, given that the conjugated forms of isoflavones have relatively little or no relevant biological activity (Yan Zhang and colleagues at Iowa State University (J. Nutr. February 1, 1999)) and the fact that the extent of phase II metabolism has a vital impact on the physiologic effects of soy constituents. The RCT conducted by Kenneth Setchell at the University of Cincinnati and colleagues (Am J Clin Nutr 2011) demonstrated that the capacity to conjugate isoflavones differs markedly intra-rodent (between rats and mice), as well as interspecies between rodents and humans. It is now dispositively established that humans have a much greater capacity for conjugating isoflavones via highly efficient phase II metabolism than do rodents, numerously demonstrated (Santell et al., J Nutr 1997; Hsieh et al., Cancer Res 1998; Santell et al., J Nutr 2000; Setchell et al., Am J Clin Nutr 2011). Importantly, the steady state percentages of unconjugated genistein concentration in plasma from (1) Sprague-Dawley rats and three strains of mice, namely (2) the C57BL/6 strain, being the most widely used strain, (3) the athymic (nude) mouse commonly used in cancer research, and (4)) the transgenic AngptL4B6 mice strain used in angiogenesis-specific research, all of these rodent strains being fed soy-containing diets, were:

4.0 ± 0.6% (Sprague-Dawley),

4.6 ± 0.6% (C57BL/6),

11.6 ± 0.9% (athymic/nude), and

30.1 ± 4.3% (transgenic AngptL4B6),

compared to the mean percentage of genistein in human plasma which was shown to be just 0.2% in steady state. What's vital to note here is that these rodent concentrations are at least:

20 times higher (Sprague-Dawley),

23 times higher (C57BL/6 strain)

58 times higher (athymic/nude mouse)

150 times higher (transgenic mouse)

than those in humans.

These findings demonstrate that rodents including the "standard" of nude mice may not really be fruitful or reliable for gaining insight into the beneficial or adverse health effects, including on tumor progression, and recurrence risk, of isoflavones in humans, because of the dramatically higher circulating concentrations of the biologically active form of genistein in rodents compared to humans.

To take one of hundreds of possible examples, the largest preclinical study investigating the toxicology, multigenerational reproductive effects, and influence of genistein on de novo carcinogenesis was sponsored by the National Toxicology Program (NTP). [National Toxicology Program. NTP toxicology and carcinogenesis studies of genistein (CAS No. 446-72-0) in Sprague-Dawley rats (feed study). Research Triangle Park, NC; 2008 Jan. Report No.: 0888-8051 (Print).] The studies administered genistein to Sprague-Dawley rats in various concentrations for 2 years. Among females, after 2 years of exposure to 100 ppm, the incidence of mammary adenoma or adenocarcinoma was significantly increased compared to female rats on the control diet, so that although there was a decrease in benign, possibly premalignant fibroadenomatous nodules, there was an observable increase in the incidence of histologically determined mammary adenomas and adenocarcinomas, but the NTP reports themselves characterize this as “equivocal evidence”. But more to the point is the fact that its findings are non-translatable to genistein therapy in peri- and post-menopausal women for two main reasons: (1) the concentration of genistein that was associated with elevated adenoma or adenocarcinoma risk in female rats was at least 29-fold higher than that taken by peri- and postmenopausal women in human clinical studies on the influence genistein on bone mineral density and vasomotor symptoms (and f we take in into account the new findings on the divergent Phase II metabolisms of rodent to humans, that adds another 20 fold higher concentration in Sprague-Dawley rats than in humans); (2) the timing of exposure in the NTP studies was equivalent to life-long exposure to high genistein levels from conception until sacrifice, an unrealistic assumption in the human clinical context.

Thus it must be concluded that the radically diverse phase II metabolisms of isoflavones between rodents and humans undermines the value and pertinence of the use of the common rodent strains used in preclinical research for providing any clinically relevant insight into the safety or efficacy of isoflavones, and genistein, in humans. So given the limitations of the in vitro research arena (and I have more fully documented this elsewhere in these forums (and in my review: The Boundaries and Limitations of Preclinical Research: A Mini-Review), and the translation failure of rodent to human findings from the in vivo arena, we must step beyond the preclinical data and mine the more dispositive human clinical data, where after over a dozen prospective trials and RCTs, and many more robust systematic reviews and meta-analyses, as large recently reported epidemiological cohorts (all reviewed by me elsewhere), there remains no convincing safety signals raised by soy isoflavone consumption in humans even in the several cases of prospectively examined active malignancies, using whole soy products not genistein monotherapeutic supplementation.

AN IN VITRO TRAP: GENISTEIN, TAMOXIFEN AND RECEPTOR STATUS

In much preclinical research and especially in genistein research, it is a truism that if there is any specific research finding - such as that genistein is tumor-promoting in low but not high does, or that genistein inhibits tamoxifen efficacy, etc - then you can always find at least one study concluding precisely the opposite, that genistein is tumor-inhibitory in low, and tumor-promoting, in high doses, or that genistein synergizes tamoxifen efficacy, etc. (as an exercise given in evidence-based classes, participants easily uncovered over several dozens of these dueling findings). We can also easily uncover cross-strata contradictory findings, meaning in vivo data in contradiction of in vitro data, and of course human clinical evidence, the final arbiter, in contradiction of both in vitro and in vivo preclinical results.

So although the preclinical in vitro study (cited above, Alexander Julianov), of genistein-treated erbB-2-transfected ER+ MCF-7 cells conducted by Xiaohe Yang and colleagues (Carcinogenesis, 2010) at the University of Oklahoma claims to have found that ER / HER2 coexpression in tumor cells enhances their susceptibility to genistein-induced growth-promotion and tamoxifen resistance, and although the authors in their abstract of conclusions claim, hyperbolically, this to have been observed "across a wide range of doses", a close reading of the full study does not bear out such a dose-independent conclusion, which would have been a first in preclinical history, in that the weight of the evidence overwhelmingly supports strong and unambiguous dose-dependent activity of genistein, which the authors in their own study, despite the counterfactual abstract conclusions, also supports: they conclude that "our results suggest that genistein at lower concentrations may induce growth promotion and tamoxifen resistance in ER+/erbB-2+ cells, as compared with ER− cells and ER+/erbB-2 normal cells" and they explicitly acknowledge that genistein-mediated inhibition, not growth promotion, was observed at high concentrations (>10 μM). And we note as an aside, complicating matters further, that at high doses, absorption, biotransformation, and excretion of genistein appears not only to operate in a dose-dependent, but also a nonlinear, manner (Zhou et al. J. Agric. Food Chem, 2008), among others].

The authors, Xiaohe Yang and colleagues, go on to claim that their own in vivo data (in never published research) support the notion that physiological concentration of soy/genistein may stimulate erbB-2-overexpressing mammary tumor/cells, but this was in transgenic mice, and as I documented, steady state unconjugated genistein concentrations have been shown to be 150 times higher than those in humans, making the transgenic mouse model wholly irrelevant to the physiological realities of genistein metabolism in humans given radically divergent phase II conjugation metabolisms in rodents versus humans - indeed, significant interspecies differences in the isoflavone metabolic phenotype has been numerously shown, with the overall metabolic profile of women being far closer to that of the porcine model than to that of rats (such as female Sprague-Dawley, or mice) [Liwei Gu et al., J Nutr, 2006].

Furthermore, the Yang in vitro study on MCF7 breast cancer cells is directly contradicted by the University of Illinois in vivo study (Constantinou et al. Nutr Cancer, 2001) using DMBA-induced mammary tumors female Sprague-Dawley rats (against which however I will make the same rodent-to-human non-translatability argument as I did the transgenic mouse model), and more relevantly, also contradicted by

the Zhiming Mai Harvard study (Mol Carcinog, 2007) using HER2-overexpressing BT-474 breast cancer cells, a more suitable choice I would argue given that BT-474 cells are intrinsically both ER-positive and HER2-positive as opposed to MCF-7 cells which are only ER+ and had to be erbB-2-transfected to make them coexpress HER2 positivity, and in addition I would further argue, the erbB-2-transfected ER+ MCF-7 cells used in the Yang study exhibit reduced levels of ER in comparison to their parental MCF-7 cells (Julia Gee and colleagues at Cardiff University, Endocr Relat Cancer July 1, 2005, among dozens of others) while BT-474 cells retain their full ER expression. Whereas in the Yang study the conclusion drawn was that ER / HER2 coexpression in tumor cells enhances their susceptibility to genistein-induced growth-promotion and tamoxifen resistance (but only as I noted in "lower concentrations - higher concentrations were growth inhibitory), in the Mai Harvard Study it was found that genistein actually sensitizes the inhibitory effect of tamoxifen on the growth of ER+/HER2+ overexpressing human breast cancer cells.

Most critically, however, we know from robust human clinical, not preclinical, data that soy intake (nor its genistein component) does not, as claimed by Yang and others, inhibit the efficacy of tamoxifen, and for AI therapy, enhances the efficacy of the aromatase inhibitor anastrozole (Arimidex), as shown by Xinmei Kang and colleagues (CMAJ, 2010) in China (and note this is not contradicted by the Hae Dong Woo study which was underpowered given the observation of only 8 breast cancer recurrence events in the 8 HER2+ patients, as the authors themselves admit). In addition this question is precisely tested in the LACE trial (Guha et al., Breast Cancer Res Treat, 2009) which found that soy isoflavones consumed at levels comparable to those in Asian populations - which I and my many patient/consults consume daily, at 3 - 4 glasses of soy milk, a serving of soygurt, and at least some tofu or tempeh or soy nuts, but then again as I have previously stated, I do not advise genistein, but rather soy, consumption - do not interfere with tamoxifen efficacy and may reduce, not elevate, the risk of cancer recurrence in women receiving tamoxifen therapy, and in both these studies sub-analysis fails to show contingency on HER2 status. In addition, the Shanghai Breast Cancer Survival Study found that soy consumption reduced both the risk of death and the risk of recurrence, and improved breast cancer survival prognosis, in both ER‐positive and ER-negative breast cancer patients and in both users and non-users of tamoxifen (n = 5000+ pre- and post-menopausal women). Finally, despite the putative adverse signals in some preclinical studies, in numerous human clinical studies estrogenic effects (that is, on ERa) are not observed (as in the bone metabolism RCT from Marini and colleagues (Ann Intern Med. 2007) and the bone loss follow-up study (Marini et al., J Clin Endocrinol Metab, 2008)). It is clear therefore that the preclinical data of adverse genistein-tamoxifen interaction is not supported in the realities of the human clinical context, but rather its opposite.

THE IRRELEVANCE OF TOPO II

As to the issue of topo II activity, and the claim that genistein can produce mutagenic or clastogenic effects under some in vitro experimental conditions, the facts are different from what is often suggested: genistein operates in in vivo, as opposed to in vitro, models most characteristically as a topo II poison (inhibiting both topo I and topo II), as opposed its soy co-component diadzein which operates as a (catalytic) topo II inhibitor (neutral to topo I) by which it (diadzein) can antagonize and hence countervail the clastogenicity of topo II poisons like genistein; in this sense, the mutagenic / clastogenic activity of genistein may be mitigated or abrogated by the co-consumption of diadzein in soy products (as opposed to elemental genistein alone) [Snyder & Gillies, Food Chem Toxicol, 2003]. In addition, it is important to note that topo II poisons are a structurally and functionally heterogeneous class and that a "classic" topo II poison such as the anthracycline doxorubicin operate primarily by inhibition the ability of topo II to ligate ("reseal") enzyme-linked DNA breaks (Walker et al. Cancer Invest, 2002); this is in contradistinction to agents such as genistein which have minimal effect on DNA ligation, acting primarily by stimulating the forward rate of topo II-mediated DNA scission (that is, strand division, as in the comparable process of antiproliferation and DNA scission induced by Vitamin C in the presence of copper chelates).

From this and other data, it appears that genotoxicity via topo II activity is simply not clinically relevant in the human clinical context, as noted numerously, as by Miltyk et al (Am J Clin Nutr, 2003) who concluded that while that genistein appears to impair DNA in vitro, it does not induce DNA damage in humans, with no human clinical data of any increase in genistein-induced DNA-strand breaks, nor chromosome deletions or translocations. Thus from the genotoxicity / mutagenicity and clastogenicity point of view, genistein is not an enabler in the human context and no human clinical data to date has ever shown any clinically relevant adverse DNA / chromosomal activity.

Dear Fatih, how do you believe this synthetic genistein acting? Is it acting like something which prevent cancer formation, or is it acting on micrometastases?

Hello Laszio,

The synthetic genistein has a specific effect on heat shock proteins and induces their depletion. It is acting as a cytotoxic agent. We used the MMTV-Her2 transgenic mouse model and it prolongs the latency/prevents breast cancer development. I am not sure if it has any effects on transformation or evolution of precancerous lesions. We have done quite a bit to study its targets as an anti-cancer drug candidate but not much about its context-dependent activity profile.

Hello Constantine,

What we have observed is not that genistein did not have much effect. It appeared to have a significant effect on the outcome in the Min mouse model (not NOD or SCID mice) but the effect was the opposite of what we hoped. It made things worse. I am not sure how this can we explained by free genistein levels etc. It suggests to me that genistein like many other drugs can have context-dependent effects. Its effects of the tumor macrophages and other elements of the tumor microenvironment could alter tumor biology.

Fatih:

Thanks for your feedback, and for introducing the springboard for these intriguing issues. Let me therefore try to further clarify my intention in my commentary above. The discussion and implications I marshaled were general: the interspecies differences observed are critically consequent to phase II metabolic divergence, and hence circulating concentration levels of the biologically active unconjugated genistein, shown to be massively higher in rodent models and strains than in humans human tumors; the specific strains referenced in the studies I cited have not been demonstrated to differ in the dynamics of Phase II metabolism from rodent species metabolic dynamics in general, they just happen to be the only strains for which - at least to date - we have rodent-human relative concentration ratios (from 20 to 150 fold) comparisons, as cited. Thus, the seminal study from Liliane Massaad's team compared the main phase I and phase II drug-metabolizing enzyme systems in both tumoral and nontumoral colon tissues, and found that for most phase II drug-metabolizing pathways the mouse model (via the widely used mouse colon adenocarcinoma Co38 model), was qualitatively and quantitatively different from human colon tissues, concluding that the drug-metabolizing enzyme systems of rodents versus humans in both tumoral and nontumoral colon tissues are so markedly divergent that this non-translatability can dramatically influence the sensitivity of organs or tissues to any under-study anti-cancer effects so as to differentially determine tumor response to anticancer agents, natural or traditional. Hence, unless we have dispositive data to show that any particular rodent strain, say Sx, is NOT subject to the same rodent-human divergence in Phase II metabolism, than any extrapolation from rodent to human remains tainted.

Since the data show that the Phase II glucuronidation of genistein sharply distinguishes rodent from human models, this induces proportionately high circulating plasma concentrations of biologically active unconjugated genistein in rodents that are not correspondingly physiologically achievable in humans who are "ultra-metabolizers" in Phase II kinetics and dynamics and hence present (humans) with maximal and highly efficient clearance of these active forms. The profoundly inefficient rodent clearance-metabolism of isoflavones in turn leaves many fold higher concentrations, and as I noted, the studied dose-dependencies of genistein are non-linear in the upper ranges, allowing for either strongly stimulatory, or strongly inhibitory, effects depending on where in the non-linear space the higher concentrations fall. And neither effect - tumor-inhibition versus tumor-stimulation - has been established as more probable, as we have studies divided on showing either one of these, the phenomenon of non-linear upper-range dose-dependency most powerfully demonstrated by Siyuan Zhou and colleagues who showed that the absorption, biotransformation, and excretion of high doses of genistein occurred in a nonlinear dose-dependent manner (cited above, this non-linear dose dependency ("ceiling" effect) also confirmed in the dietary isoflavone / colorectal adenoma risk study from the National Cancer Center in Japan (Akhter et al, Br J Cancer, 2009)). The totality of these findings calls into question rodent modeling of isoflavone antitumor activity, a suspicion confirmed by the fact that the observations seen in the rodent models are wholly dissonant with, and contradicted by, human clinical data, primarily consequent to the radical divergence of Phase II metabolisms for isoflavones (including genistein, diadzein, and equol (a diadzein-bacterial derivative)) [note: this is agent-specific - other agents may have largely congruent metabolic kinetics and dynamics between rodent and human models, but isoflavones decidedly do not].

Recently one of our paper entitled "Life and Consciousness - The Vedāntic View" has been published in the Journal Communicative & Integrative Biology. An interesting discussion on this paper can be found at: https://groups.google.com/forum/#!topic/online_sadhu_sanga/Mcv2O-yhqLE

From paper:

"The scientific confirmation of the existence of consciousness in unicellular organisms and plants certainly establishes that the brain is not the source of consciousness. Several decades back, research in medical science has also proven that the brain is not the source of consciousness. In 1970, Robert White and his team successfully transferred the head of a rhesus monkey to the headless body of another monkey. The monkey survived for 8 days.68 Researchers are also attempting to perform the same scenario with human beings.69 It is reported that if a human head has been detached under controlled conditions, it must be reconnected to the circulatory flow of other person's body (which is conscious or living) within one hour.70 Therefore, brain-based analysis for understanding consciousness (neuronal analysis) does not have very bright prospects."

Paper: Life and Consciousness - The Vedāntic View

DOI: http://dx.doi.org/10.1080/19420889.2015.1085138

Journal: Communicative & Integrative Biology

Publication date - 09 Oct 2015

Author: Bhakti Niskama Shanta - http://orcid.org/0000-0002-2039-3249