The main problem in cancer chemotherapy (in comparison with antibacterial chemotherapy) is a very close characteristics of cancer and host cells and lack of immune defense component  (host immune system can't eliminate cancer cells survived chemotherapy as it do in case of infection).  Eventually all targets for the anticancer drugs present in normal human cells. So, even you use very high dose of chemotherapy you can't kill most of cancer cells without fatal damage of the host organism. Only few of cancer types can be cured by chemotherapy (including high-dose chemotherapy with blood stem cells support) or targeted therapy - some type of leukemias, lymphomas, germ-cell cancer. Other ones - can't be cured, so they have resistance mechanisms more potent, than normal cells. You can't overcome this resistance with higher doses.  So, most of anticancer drugs have a temporary effect - suppression of cancer grows (or even tumor shrinkage) till resistant clones repopulate. In other word: if you use "absolute poison" disrupting really vitally for the cells targets  - you will kill patients with a tumor, if you use less potent drug - some cancer cells survive and cure isn't possible.

Hello

The dose of a cancer chemotherapy regimen is highly influenced by the pathways that the antineoplastic compounds adopt to enter the cancer cells. Studies have been performed that focused on the impact of efflux transporters and influx transporters in this regard. If the tumor has managed to increase the expression of efflux transporters (which drive the compounds out of the cell) or reduce or completely suppress the expression of uptake or influx transport systems, the regimen is bound to have more effect on the surrounding tissue, rather than on the tumor. These changes have been well documented in the literature and mechanisms underlying these changes in tumors need to be unraveled to achieve a better chemotherapeutic strategy. In short, the efficacy, and hence the maximum dose of a regimen depends a lot on the expression status of these proteins in the tumor tissue.

That is an interesting question but its possible that the resistant clone of the tumour already exists prior to the start of treatment. In this scenario one may give a lower dose of drug, which may be less effective against killing the tumour in general and would only enrich the resistant clone more slowly than a higher dose of a drug which will be more effective against the majority of tumour cells and enriching for the drug resistant clone more quickly.

It's an interesting question because you're trying to get an optimal dose that is maximally toxic to the tumour and not the patient. However, monotherapy is not likely to be the answer, but then the question remains whether dual- or multi-drug therapies reduce resistance. Perhaps if the right targets are chosen? Resistance of a clone to one drug might mean sensitivity to another, so utilizing synthetic lethality is an potential option.

For this issue,the dose of chemotherapy depends of the patient  resistance and the type of disease

There is NO standard level that somehow can be used to achieve the goal you note i.e.  prevent tumor resistance.  The answers already given make reasonable points re this question but the bottom line is that we use therapies that kill cancer and prolong survival by trial and error as well as by studies that indicate the dose tolerance that if exceeded will make the treatment worse than the cure.  The concept or principle involved is called the TI (therapeutic index).  TI (Therapeutic Index) is the ratio of Benefits to Patient ÷ Adverse Effects.

With the above said, a key issue is how to achieve a higher dose & yet not put the patient at risk 2° an increase in toxicity leading to an unacceptable TI.  The mode of drug (chemo) administration thus becomes a huge issue and we see this in various contexts:

1. High dose chemo with the patient rescued by bone marrow transplantation.  The downside of this is that even in great hands sometimes the bone marrow rescue (graft) does not take & the patient has very low blood counts indefinitely.  If the cancer is not cured then further treatment is usually a challenging option. 

2. Selectively directed chemo such as intra-arterial or intra-cavitary chemotherapy.  This brings a very high dose of chemo to the site of the tumor. It assumes the tumor has not metastasized elsewhere in sufficient volumes of tumor.  I treated a young woman with ovarian cancer that had spread all over her abdominal cavity (peritoneal metastases).  She had failed an extensive operation performed by an expert in gynecological oncology.  I used a special catheter (Port-A-Cath) that was placed into the abdominal cavity. I had previously obtained tumor cells from the fluid that collected inside the abdomen and done chemosensitivity testing.  I used the results of this test to select the agent (Adriamycin).  The patient had a dramatic response after two such administrations with negligible toxicity.  She was alive and free of disease over ten years after the above was done. 

3. Continuous infusion of chemotherapy using an ambulatory infusion pump e.g. CADD pump and connected via a Port-A-Cath. This allows for much higher doses of drug.  The patient is also given CSF (colony stimulating factors) to enhance bone marrow stimulation & production of white cells (granulocytes) & red blood cells (hematocrit ↑ ) to decrease toxicity & ↑ the TI.  I have used this successfully to induce a complete remission in patients failing more conventional chemotherapy.  The problem is that too few MDs use this because insurance companies were and possibly still are terrible at reimbursing for this novel approach to drug administration.  

There are other issues to enhance chemotherapy e.g. synergistic agents, circadian rhythm administration, combined modality approaches using chemo + immunotherapy or chemo + radiation.  This post is too long already.  

Stephen B. Strum, MD, FACP

Medical Oncologist, member of ASCO, ASTRO, AUA

DOI: http://dx.doi.org/10.2147/OTT.S55344

Myron's curt reply above is quite misleading in light of the very provocative work he has done if one simply clicks on the URL he has given and downloads his papers.  Reversing resistance mechanisms used by the cancer cell is highly desirable. There are a sizable number of peer-reviewed papers on this topic.  Searching my own computer I can see some using dipyridamole, quercetin, hydroxamic acid, melatonin, butyrates and more. To this list we can add the anti-viral oseltamivir phosphate (Tamiflu).  It would be meaningful to see a full review article on this topic with a focus on which of these agents used in humans actually translates into improved survival.  

Great response above; could be the basis for an important review article. I will state that as a practicing medical oncologist of 4 decades duration with another 10 years in pathology and immunology, that some of the more creative approaches to delivering chemotherapy have fallen, for the most part, by the wayside.  Jacob Lokich pioneered in  protracted intravenous infusion chemoRx and this used ambulatory infusion pumps and different dose schedules that delivered serious doses of chemo via a venous access device such as a Port-A-Cath. 

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I will never forget the young woman with refractory breast cancer post chemo with the major drugs who entered a complete remission using the above approach receiving 120 hour infusions of 5-FU and Cytoxan.  The latter drug was infused at 600 mg/m2 per 24hrs x 5 days while the former at 300 mg/m2 x 5 days along with 20mg of DXM (dexamethasone) in the pump reservoir to act as an anti-emetic.  CSF (colony stimulating factors) like Neupogen (G-CSF) were given on the known nadir day (5 days after infusion completed. No serious cytopenia nor other side effects but dramatic anti-tumor response.

Same considerations with intra-arterial chemo as well as intra-peritoneal chemo. These should have become mainstays but tragically, due to insurance reimbursement issues and out of pocket expenses that most oncologists would not endure, they treatment administration approaches have generally fallen by the wayside. 

heterogeneity of cancer cells is a unique feature of any cancer.  In vitro studies done either by chemotherapeutic strategies or immunotherapeutic strategies can not be extended to in vivo situation. There are several reasons for it. Number one reason is heterogeneity. You may kill some but not all cancer cells either at low dose or at high dose, but some may be resistant and some may escape chemo- or immunotherapy to become resistant.  One should study literature on chemoresistance and mechanisms and develop a sequential strategies to counter act resistance. Same logic would apply  for immunotherapy. Some are susceptible to antibody mediated therapy. some for monospecific monoclonals and some for polyspecific monoclonals, some for polyclonal antibodies.  Passive immunotherapy uses mono-and polyspecific monoclonals. Active specific immunotherapy induces generation of polysepecific antibodies of different kinds such as IgM and IgG. The nature of antibodies may differ depending on the nature of antigens such as peptides and glycoantigens. The antibodies may differ IgM, pentameric or polymeric, generated by CD5-/CD19+ or CD5+/CD19+ and so on. Totally different strategy is cell mediated killing. Again tumor cells have developed strategies to resist tumor mediated killing. The tumor cell surface molecules such as HLA-E can paralyze Cytotoxic CD8+ T cells or NK or NKT cells by interacting with their inhibitory receptors such as CD94/NKG2a.  Again some cells or susceptible and some are resistant. For example the resistant cells may overexpress HLA-E than the susceptible cells.  Just not one cell surface antigen but many.  Therefore  a combinatory therapy may be useful. Again there is scope for personalizing it depending on the cancer type and stage and aggressiveness.

Despite all the obstacles that many of the astute responses above highlight, what I have personally found is that some cancers are affected sufficiently by treatment to put the host-tumor balance into a state of homeostasis whereby the patient lives in peaceful coexistence with the cancer.  I found this early on in my path (autopsy) studies of patients "cured" of HD (Hodgkin’s disease), but who at autopsy still had microscopic evidence of HD.  Their cause of death was definitely not linked to HD in any way e.g. lab, clinical exam, imaging, etc.  But the cancer was there, albeit in microscopic volume. 

The patients I have treated over 4 decades that have done well may be in this same category.  I just do not know since autopsy studies have become rare and also because many of these patients cured by therapy in contemporary times are still alive.  

So the young man with advanced testicular cancer with uremia who was alive more than 10 years later after receiving the Einhorn regimen, the young woman with peritoneal metastases & malignant ascites who went into long-term survival & likely cure after intra-peritoneal chemo with adriamycin (also using results of chemosensitivity testing) and the many men with advanced PC (prostate cancer) who were told they had 6 months to live and are now alive and well and off ADT (androgen deprivation therapy) more than a decade later are in my opinion "CURES".  Add this to a former employee with AML and a colleague's wife with small cell ovarian cancer and you have an interesting list of patient's with usually ominous prognoses who were treated non-conventionally and are either cured or are having one hell of a durable response.  

Personally, I know there is a lot more work to be done a la the kind of contributions per Dr. Szewczuk et al, but I also firmly believe that we docs in the field are not using our creativity and the peer-reviewed literature to try novel approaches to treat malignant disease.  We have a lot of tools in the proverbial "Al Gore Lockbox" and there they sit, unused or hardly used. 

Article The persistence of Hodgkin' disease in long-term survivors

Article Erratum to: Case Report: Sodium dichloroacetate (DCA) inhibi...

Thankyou for all suggestions. Products, pathways, treatment have been performed for many stages of cancer and treatment are available for many stages of cancer and prevent cancer cells to reach highly resistant or aggressive stage where treatment is highly difficult. Treatment is still possible, could you please tell me the most aggressive cancer or cancer cell line that are highly resistant for anything?

There are several aggressive cancer cell lines but nothing parallels aggressive pancreatic adenocarcinoma. In general adenocarcinomas are aggressive.

Genomic screening of tumors is answer to this problem. Genetic analysis of particular tumor to determine the mutation and amplification of driver genes will help in deciding the drug combination for particular tumor.

Nut midline carcinoma has a typical life expectancy of 6.5 months after diagnosis and is usually diagnosed at stage 4. There is only 1 known survivor. No one survives it despite intensive therapy and it seems to target adolescents.

Hello Susan, Nothing is impossible.. I am sure that most of the researcher focusing on this part just like me. 

to address the issue of cancer cells developing resistance to the administered cancer therapeutics, pushing the dose even higher is not necessarily the best approach. this is exemplified by the failure of high dose chemotherapy for patients with breast cancer for example.

an interesting approach, for which only preliminary data exists and surely no clinical validation so far, is that of the adaptive treatment of cancer. this is a term used to describe a different conceptual approach of cancer treatment moving from the 'treat-to-eradicate' to a 'treat-to-stabilize' approach. according to this paradigm, cancer cell perturbations and tumor burden have to be followed on a continuous manner with the applied cancer therapeutics being adapted accordingly (dosing, agents and so on).

an interesting article on this concept can be found in the link below 

http://www.ncbi.nlm.nih.gov/pubmed/19487300

best

The reply by Dr. Zardavas above with the reference provided would probably be daunting to most clinicians treating cancer.   Back over 45 years ago, as a post-graduate fellow at the U of Chicago my review of autopsy specimens from long-term survivors of HD (Hodgkin’s disease) would now be supportive of the Gatenby et al reference above. 

"Our observations suggest that clinical cure of Hodgkin's disease docs not necessarily indicate eradication of the disease but may represent a state of equilibrium between host and neoplasm, particularly in the patients with the prognostically favorable histologic types."

Rappaport, H. and Strum, S.B.: Criteria of Cure: Clinical-Pathologic Correlations. Natl Cancer Inst Monogr 36:567-569, 1973. 

Recently, I have seen this same phenomenon in men with PC (prostate cancer) who have achieved an undetectable PSA on Rx, gone off Rx, and yet on highly refined staging studies still show persistence of metastatic disease over a period of years.  The only missing data is to document histologically that active PC is still present.  Nowadays, performing autopsies is just not remunerative nor cost effective.  We have lost a great teaching tool in comparison to my medical school days when autopsies were routinely done.

A real question would be do outstanding treatment protocols like the Einhorn protocol for testicular cancer, or many chemo regimens for Hodgkin's disease truly eradicate disease or are we left with the balance as Gatenby et al describe above: 

"Alternatively, if therapy is limited to allow a significant number of chemosensitive cells to survive, they will, in turn, suppress the growth of the resistant population. We hypothesized that under these circumstances, adaptive therapy should be designed to maintain a normal cohort of surviving sensitive cells."