I am sorry woody Lin to not be able to answer you, my research is most focus in radiotherapy

I am also very confused regarding the use of chemotherapy to treat a cancer patient. As per my experience with some near and dear one, I have found that after taking the chemotherapy they lost all of their hair. Moreover, they look very debilitating and mentally week.

Basing on sorrowful fates of many my closes suffered from cancer, I consider chemotherapy as a rather harmful and low effective approach in cancer treatment. Besides its under-question-effects on cancer cells, this way of treatment significantly eradicates internal resources of the affected organism impeding possiuble ways of recovery.

Dear all,

What I have mentioned might make people feel that I am criticizing chemo-therapy. I am sorry. I just wanted to make my thoughts more clear. Thanks for the replies.

Woody 

Does vemurafenib have advantages?

Life expectancy: The results of the trial indicate that vemurafenib can prolong life compared with dacarbazine. Half of the patients who used vemurafenib died after more than 13 months. For patients who received dacarbazine, this was the case after less than 10 months.

Symptoms: The comparison of vemurafenib with dacarbazine showed no difference in how they influence pain.

Quality of life: The trials showed no advantage for treatment with vemurafenib.

Does vemurafenib have disadvantages?

Side effects: Vemurafenib caused side effects more frequently than dacarbazine: out of 100 participants who took vemurafenib, 97 experienced side effects. In 50 out of 100, these side effects were serious. Out of 100 people who took dacarbazine, 90 had side effects. In 30 out of 100, the side effects were serious.

Treatment stopped because of side effects: Overall, there were no differences between vemurafenib and dacarbazine.

General information about other possible side effects can be found in the package insert.

http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0049526/

Dear Woody Lin,

Unfortunetly your question is not so clear. Usually chemotherapy was applied for agonist of cancer cell growth and/or metastasis to extend patient survival. But how long? nobody knows, it dependent to kind of cancer (for example in breast cancer chemotherapy has good effect but in pancreas cancer may be no), stage of cancer, patient suffer (young more prolong than old), and kind of chemotherapy ( light or aggressive) and treatment protocol. 

Hi Riccardo,

Thanks for the link. It answered some of my questions by providing how people understand the drug. I have no doubt that vemurafenib is better than dacarbazine since it prolonged a few months of overall survival. I have two questions remain:

1. BRAF V600E mutation seems to be a very popular feature of metastatic melanoma. Why didn't vemurafenib work better than that (e.g. >1 year of progression-free survival)?

2. Patients who took dacarbazine died about 20% already in the fist three months. Is it a sign that dacarbazine is bad for patients? Those patients have life expectancy > 3-months.

I know these are very general and pathetic questions, but I do believe that someone can answer them.

Sincerely,

Woody

Hi Woody,

Indeed Yours aren't pathetic questions but I'm a Molecular Biologist and I can't give you proper answers to both the points.

I can speculate that other genes mutations over BRAF (e.g. hTERT...)  could interfere with the TK inhibitor.

To find these mutations means to find negative predictive markers avoiding unnecessary treatment in unresponsive patients or to choose a more tailored therapy for each patient.

Sincerely,

Riccardo.

Why don't you check out my review article:

https://www.researchgate.net/publication/261327275_Targeted_Therapies_for_Cutaneous_Melanoma

Also, keep in mind that median survival is not the only measure of benefit.  Also consider response rates and bench mark survival (patients alive at 12, 24 and 36 months).

In regards to your second question, metastatic melanoma is very deadly - so 20% deaths at 3 months is simply a reflection of the natural outcomes for patients diagnosed either late or with aggressive disease.

Article Targeted Therapies for Cutaneous Melanoma

Woody:

To appreciate the survival benefit accrued from vemurafenib it is important to examine and appreciate more than just the raw overall survival numbers, which tell an incomplete story leaving out major themes of:

So let me try to clarify in order to more full appreciate the landmark importance of vemurafenib in the metastatic melanoma context:

The Phase III BRIM-3 RCT1 of vemurafenib for previously untreated with BRAF V600E mutated metastatic melanoma found the median OS (updated), presented at the ASCO 20127 to be 13.2 months with vemurafenib compared to 9.6 months for dacarbazine, but overall survival at 6 months was 84% for the vemurafenib arm as compared to just 64% for the dacarbazine arm, an impressive difference (and the hazard ratio for death in vemurafenib group was 0.37 while the hazard ratio for tumor progression was 0.26).

Furthermore, scope of objective response matters: objective response was dramatically higher - the vemurafenib arm had an ORR of 48% (compared to 69 - 81% in the Phase I BRIM1 trial and 53% in the Phase II BRIM2 trial) with a median PFS of 5.3 months, compared with a mere 5% response rate and 1.6 months median PFS for dacarbazine; that means that just one patient in 20 would see a response on dacarbazine, while close to half of all patients would see an objective response on vemurafenib, and this matters greatly in terms of clinically relevance. It is clear that an intervention (dacarbazine) that excludes as beneficiaries 95% of the patient population, regardless of what the survival would be for those rare (5%) lucky few showing response, is massively inferior to an intervention (vemurafenib) in which close to half of all patients will be beneficiaries of a complete or partial tumor (RECIST) response, and those half will in addition reap the benefit of a clinically relevant (defined by protocol as greater than 3 months) longer survival (and with longer time to recurrence). It must be agreed that 5% as a beneficiary pool is simply not a realistic clinical benefit load; vemurafenib enlarges the pool of beneficiaries by close to tenfold, and in the real world of the clinic, that's an overwhelming advantage.

But it is further worthy of separate note that subgroup analysis demonstrated a consistent PFS, even in patients with elevated baseline LDH levels, and that is an exceptional result.

I also noted that in the subgroup analysis, the benefit in overall survival was more dramatic in patients with stage M1c disease (HR for death in the vemurafenib arm being 0.32), While in patients with stage IIIC, M1a, or M1b melanoma, the OS benefit was more muted (HR of 0.64). It's furthermore again important to remember that in the subgroup analysis, the benefit in overall survival remained significant in patients with stage M1c melanoma (although there was no overall survival difference for patients with stage IIIC, M1a, or M1b melanoma).

And, we also now have evidence of activity in non-V600E BRAF-mutant metastatic melanoma from the just published (2014) reported results of BRIM-3 based on V600E and V600K2. In the 91% of patients with V600E, the median OS was 13.3 months in the vemurafenib arm versus 10.0 months in the dacarbazine arm, but the mutational breakout deserves attention here: in the 9% of patients who harbored a V600K mutation, the median OS was 14.5 months in the vemurafenib arm and half as much roughly, 7.6 months, in the dacarbazine arm, showing unambiguously that vemurafenib improves the survival in patients with metastatic melanoma who harbor either BRAFV600E or V600K mutation.

Collectively, based on these RCTs, the FDA3 and the EMA (European Medicines Agency)4 and NICE in the UK5,6, have judged that a clear survival benefit over dacarbazine (DTIC) has been convincingly demonstrated in the overall population, and furthermore the open-label extended follow-up of BRIM-3 makes clear that vemurafenib provides a significant survival benefit in patients with metastatic melanoma who harbor a either a BRAFV600E or V600K mutation.

And - critically - we are now including ten times as many patients for receipt of benefit - more even since a non-trivial number of patients experienced stable disease - from response when choosing vemurafenib over dacarbazine (DTIC), and the more patients who benefit, the greater the strength of the case for a clinically relevant advantage, and the greater the "ethics" of an intervention (one that helps more patients).

References

@Riccardo: Thank you for answering. I agree that cells might have ways to bypass the BRAF inhibition. It just made me wonder the effectiveness of targeting mutated genes (or precision medicine) in heterogeneous diseases like cancer.

@Damien Kee: Thanks for sharing your review paper. True, other benefits should be considered as well. For the second question, I think that 20% deaths at 3 months means the ineffectiveness of dacarbazine (or worse).

@Constantine Kaniklidis: Thank you so much for the detailed explanations. I agree that vemurafenib is better than dacarbazine in many ways as you mentioned. However, if dacarbazine is not actually helping patients from survival, a comparison of vemurafenib and dacarbazine is not meaningful. For example,  20% deaths within 3 months means the ineffectiveness of dacarbazine (or even worse). It simply makes vemurafenib a "better than nothing" option. I do believe that your clinical trail of vemurafenib is very likely to work. Vemurafenib is a good start for treating metastatic melanoma, but it is still very far from overrated statements like "having remarkable clinical efficacy" in recent papers.

Woody:

Thanks for your feedback. But although I share your yearning for further superior outcome benefits, I would respectfully take issue with your minimal perspective.

With:

• a significant prolongation of both the duration of disease control (median response duration was 6.7 months) and life expectancy, with median overall survival at 6 months of 84% and a 1-year survival rate of 58%
• and for M1c disease survival at 68%,
• and for patients harboring a V600K mutation, the median OS of 14.5 months in the vemurafenib arm of almost double that of 7.6 months in the comparator
• exceptionally high objective response rate (48%, approximately ten-fold greater than the comparator dacarbazine)
• symptomatic response improvement within days of starting treatment
• consistent PFS benefit, even in compromised-prognosis patients with elevated baseline LDH levels
• off-trial: substantial number of patients on vemurafenib treatment for over a year, suggestive of the potential for prolonged and durable disease control

the designation of important clinical advance in the treatment of metastatic melanoma is not appreciably hyperbolic, and certainly not just "better than nothing".

And I would add that we cannot:

Note in this connection that median TTR (time to response) for dacarbazine was 2.7 months (and with substantial numbers of patients exhibiting longer duration to first TTR), so we cannot confidently say that the mortality statistics reveal more about efficacy than about the natural history of high mortality in metastatic melanoma coupled with a TTR for dacarbazine of almost twice that of vemurafenib (whose TTR was only 1.5 months) [in general it is the case that given most TTRs, mortality/survival statistics at 3 months have negligible clinically meaningful relevance, and only 6 month and later stats allow sufficient time for response and significant outcome benefit, bearing in mind also that TTRs are medians and so large subpopulations may not even begin to acquire measurable benefits].

Finally, we cannot forget the context: this is just, after all, monotherapy, and combination therapy (I look forward to some positive results from the clinical trials combining it with anti-PDL1 therapy; with antiangiogenic therapy (bevacizumab); and with certain molecularly motivated promising vaccine immunotherapies) I would predict will translate to substantially greater outcome gains: the day is young.

So:

The above observations collectively suggest that although we have a long distance still to go before eroding the tragic toll of metastatic melanoma, and hence before grand festivity, a sober and dignified celebration for the literally thousands more patients who will survive, and longer, due to vemurafenib than would otherwise have, is not unseemly at this time.

However we are in decidedly strong agreement on one matter: hyperbole rarely serves the cause of science, and it would be better for the medical media to claim a significant but incremental advancement rather than "breakthrough" progress, so as not to fan immoderate expectations.

Dear Woody,

Dear Constantine,

Could I have your short comments / opinion on the attached comment?

Thank you very much

Robert

Hi Robert,

Thank you for sharing the article and the opportunity for me to comment on the paper. It is great that combination therapies might yield better outcome. I need to read the detailed numbers about the composition of the patients and how the distribution of survival days look like to actually give a comment. It is not my expertise and I have limited knowledge about how people design the clinical trials.

Sincerely,

Woody

Thank you very much Woody for your prompt response.

I think that I forgot to mention a "detail" in my previous message: I share at 100% your previous comments!!

Take care

Robert

Dear Robert and Woody:

Here are  my thoughts, such as they are:

This is a good "pipeline" review, mainly focused on market and commercial opportunities. It is good as far as that category of non-critical study goes, but necessarily misses many insights and opportunities:

(1)  First, a clarification: the author of the study is sketching  pipeline assessment of combination targeted therapies (two or more biological agents), not combination therapies in generally (which includes chemotherapy and endocrine therapy partners). 

(2)  The study overlooks some  of  the limitations of targeted therapies: to take just one of dozens of examples, if we look at the lung cancer, especially the NSCLC context, Phase III trials of targeted EGFR TKIs compared to survival outcomes of chemotherapy fail to show any overall survival (OS) advantage; that includes the Phase III EURTAC RCT, the Phase III WJTOG 3405 RCT, the Phase III OPTIMAL RCT, among several others. In all these cases, despite improvements  in response (ORR) and PFS, conventional chemotherapy, not targeted therapy, secured the clear OS  survival advantage.  There are comparable examples from other  malignancies.

Indeed, from my own research and reviews within breast cancer (and some other cancer types), to date the advantage goes not to targeted therapy  combinations, but to chemobiological combinations in which chemotherapy is partnered with a single targeted agent (like T-DM1, or  lapatinib + capecitabine, etc.), leveraging the best  of both  worlds. So the prediction of the author of the study as to the rosy future of dual-targeted combinations is arguable - we may, as present, still find that  conventional agents may be needed as partners to translate to optimal outcomes.

(3)  The study leaves us with something of an undifferentiated mass of regimens. But in studying the success and molecular motivation of combination targeted therapies, we need  to make fine categorizations to appreciate  the different molecular strategies at play: to give an example, in my own research, I differentiate:

• Dual Target/Single Pathway Combinations: the coinhibition of two or more targets within one and the same single pathway (like EGFR + MTOR)
• Coinhibition of two or more signaling pathways (like VEGF + EGFR)
• Coinhibition of Parallel or Compensatory Pathways (like HER2 and IGF-IR-mediated activation of the PI3K/AKT/mTOR pathway)

among other subcategories, and this "architectural refinement" allows one to discover and see patterns of the "logic" of combinations, and to also help predict even across malignancies which strategies are more optimal.

(4)  One final lack of differentiation is that these are a mixed of approved and experimental targeted combinations, but their outcomes are very different, some advancing  us in ORR and/or PFS with improvements  that are not only statistically significant but also clinical relevant (months to years), others only inching us up by bare  increments of a handful of weeks, and with potential high cost of  toxicity. So these are not all equally meritorious.

To defend the  author's study, as I said at the outset, within the narrow borders of a "what's-in-the-pipeline" review, it's a serviceable compilation. But to advance the field of  anticancer therapeutics, we - the oncology clinicians and researchers - need nuance, nothing else will move us forward in the rather slow  slog toward therapeutic breakthroughs to save or prolong the  lives of so many patients waiting for something better, on the real, not  just commercial, frontier edge of research.

Constantine Kaniklidis

Director, Medical Research, No Surrender Breast Cancer Foundation (NSBCF)

Breast Cancer Reviewer, Current Oncology  

Thank you very much Constantine for your very comprehensive response!

Best regards

Robert