The development of target specific drugs for treatment for different kinds of cancers has opened an entirely new avenue for alternative treatments that are safer and more efficient. Multiple clinical studies have revealed that in the case of fast-growing tumours like pancreatic neuroendocrine tumours (PNETs), target specific drugs such as Everolimus and Sunitinib have shown significantly positive results with maximum tumour shrinkage and minimal side-effects in comparison to existing conventional treatments.
The Purpose of Opinion:
Targeted Drug Therapy (TDT) can contribute to the development of a more cell-specific and faster-acting method of PNET suppression. A treatment personalized to different stages of cancer is much more efficient in comparison to treatments that focus on using the same protocol to destroy tumours irrespective of its proliferative stage. TDT brings in the question of whether it is time to pave a new path for these target specific drugs or hold on to existing standardized treatments such as non-target specific chemotherapy (CC- Conventional Chemotherapy) and radiation for PNETs.
PNETs are rare tumours that occur due to the rapid proliferation of certain hormone-making cells(islet cells) and stem cells of the pancreas. These tumours are a diverse cluster with varying clinical manifestations, tumour biology, and prognosis.
The pancreas is a small glandular organ that lies behind the stomach, exhibiting both exocrine and endocrine functions . The exocrine functions are carried out by secretory cell clusters called acini that are present around small intercalated ducts . The acini secrete enzymes (e.g. amylases) that break down macronutrients . The endocrine functions include secreting hormones like insulin and glucagon by specific cells called pancreatic islets . These cells line multiple capillaries distributed throughout the pancreas and play a major role in sugar control and metabolism . The autonomic nervous system regulates the activity of islet cells via a feedback loop . Therefore, these functions make the pancreas a vital organ necessary for maintaining homeostasis.
PNETs arise from multipotent stem cells and islet cells present in the pancreatic ductal epithelium . They are known to be one of the rarest forms of cancer having an incidence rate of approximately one per 100,000 individuals per year . However, PNETs happen to be one of the deadliest forms of cancer having a mortality rate of 97% within five years of diagnosis and 99% within ten years of diagnosis . The lack of novel effective treatments and delayed prognosis makes it hard to treat these tumours . The tumour cells proliferate rapidly without presenting any clinical manifestations till the very end, thereby necessitating novel methods of prognosis as well as treatments .
PNETs are of two types: functional and non-functional. Functional PNETs present certain clinical syndromes of hormone excess that can be detected in the serum . This helps in the prognosis of the disease. However, these symptoms can be misdiagnosed as is many cases and result in many false negatives before an accurate detection is made . Non-functional PNETs on the other hand hardly present any clinical manifestations and goes undetected till the very end of metastasis, thereby lowering the chances of successful treatment . Metastasis possesses an even bigger danger in this case, as the cells migrate to the liver (hepatic metastasis) in most of these cases . The result is the malfunctioning of two organs that play a major role in homeostasis, the liver, and the pancreas. Moreover, a significant percentage of PNETs are of the non-functional type and sporadic which means that it can affect an individual at any age without any preference for gender, while some have a genetic predisposition [3, 9].
Current methods of prognosis include detection of chromogranin A in the serum and functional imaging techniques like somatostatin receptor scintigraphy (Octreoscan) . Chromogranin A is a precursor to several important peptides and promotes secretion of secretory granules containing hormones, like insulin in islet beta cells . It is overexpressed in tumour cells and acts as a diagnostic biomarker used for the detection of both types of PNETs, owing to its abundant secretion by tumour cells and high sensitivity . Octreoscan, on the other hand, is a radioactive labelling technique that is used to understand the behavior of the tumour and predict its biological urge to start metastasis . In this case, the technique involves using radioactively labelled octreotide (similar to somatostatin) to bind to somatostatin receptors on tumour cells. This technique relies on differential expression of somatostatin receptors at different stages of cancer .
Surgery is the most preferred mode of treatment followed by CC and radiation . However, surgery has been shown to be effective only in resectable microadenomas (tumour of glandular tissue <0.5cm) where over 95% visible tumours can be removed . In cases of unresectable macroadenomas, large cases of recurrence are seen post-surgery, thereby rendering this method risky . CC and radiation are often used for unresectable macroadenomas as they have a comparatively higher success rate of tumour shrinkage over multiple courses . On the other hand, these methods are associated with severe side-effects and tend to cause irreversible damage to tissue. Despite this, CC and radiation remain the most favored treatments for macroadenomas in PNETs . However, I believe that the advent of TDT over the past decade has made it possible to find specific markers for PNETs and therefore a gradual shift towards the usage of TDTs over conventional treatments is necessary. Tumour specificity helps in better prognosis and therefore ensures maximal drug delivery to the tumour cells, reducing collateral damage to surrounding cells.
EARLY PROGNOSIS OF METASTASIS:
The most important step in treatment is identifying the stage of cancer. Non-metastatic tumours are comparatively easier to treat as they are localized and therefore can be usually treated using surgery. Cancers that are metastatic become harder to treat, because they invade multiple organs, and hence CC is preferred. However, the success rate of CC is drastically low for PNETs as compared to other NETs [3, 6]. Therefore, it is important to be able to predict the onset of metastasis at its earliest and understand the differences between metastatic and non-metastatic PNETs concerning physiology and receptor expression profile. The problem lies in the fact that these cancers are known for their unpredictable rapid proliferation, where they sometimes turn metastatic much faster than other known tumours . The time gap is minuscule, and hence techniques such as Octreoscan and chromogranin A aren’t efficient enough to predict the onset of metastasis. However, in the past decade scientists have been able to localize a single nucleotide polymorphism in a gene, FGFR-4 (Fibroblast Growth Factor Receptor-4) that is necessary for the onset of metastasis. The Glycine->Arginine substitution in FGFR-4 (Gly388Arg) alters PNET progression and the receptor profile of these cells . Therefore, FGFR-4 Arg 388 acts as a predictive marker of metastasis as it is necessary for the initiation of metastasis and altering receptor profile. The above was confirmed when they noticed that Everolimus, a drug that targets mTOR receptor (mechanistic target of rapamycin), was ineffective on patients with Stage IV pancreatic NETs which consists of metastatic tumour cells . This shows that metastasis significantly modifies NET behaviour by changing receptor profile probably causing these cells to develop resistance to CC.
The changes in receptor profile that occur as the tumour cells progress from a non-metastatic to metastatic stage call for individualized treatment. Personalized treatment is the strong point of TDT. The possibility of changing receptor binding efficacy of TDT by making minor modifications ensures that despite changes in tumour cell receptor profile, the drug remains specific. Specificity is where CC and radiation are not so efficient. Non-specificity results in resistance and therefore recurrence of tumours is a high possibility. Moreover, non-specificity might lead to the death of neighbouring cells but does not guarantee the death of a significant number of tumour cells that are going to turn/ have turned metastatic.
The emergence of FGFR-4 as a predictive marker has led to the development of new drugs that target different receptors for non-metastatic and metastatic tumours. Non-metastatic tumours express many mTOR receptors and therefore drugs such as Everolimus and Temsirolimus that specifically target these receptors have been highly potent . These drugs have shown a tumour response rate of 70% and 63.9% respectively, in comparison to CC drugs that have a response rate of only 8-45% [3, 6, 10]. On the other hand, metastatic tumours require a different focus. Tyrosine kinase (TRK) inhibitors targeting the Vascular Endothelial Growth Factor (VEGF) pathway have been shown to inhibit metastasis . The VEGF pathway is a central pathway that plays a prominent role in metastasis, growth factor signaling and the cell cycle . Inhibition of TRK receptors like VEGFR1 and VEGFR2 (Receptor 1 and 2) which are involved in this pathway completely stops metastasis . TDTs such as Sunitinib that inhibit this pathway have been extremely effective and have shown a tumour response rate of around 68% in most patients taking part in clinical trials [3,7, 25]. These are significantly higher percentages than the ones seen in CC and radiation. Additionally, most target specific drugs have gone through multiple clinical trials, showing highly positive outcomes for PNETs as mentioned earlier.
However, the use of TDTs is restricted to only a few hospitals worldwide. Drug monopolization by pharmaceutical industries is the reason why doctors and medical insurance providers give preference to CC drugs for cancer over any other novel treatment in general . I will elaborate on this in the coming sections.
RISKS AND SIDE-EFFECTS:
A question that always arises when approaching a patient for treatment is about the side-effects. An important parameter to consider while deciding on a treatment is to minimize the side effects while maximizing treatment efficacy. Surgery, in the case of PNETs, is the treatment with the least number of side-effects if the tumours are microadenomas . However, macroadenomas are the most common manifestation of PNET cases, due to the rapid progression of tumour cells . CC and radiation exhibit substantial side effects, especially in the pancreas because it plays a major regulatory role in metabolism. Metastasis worsens the scenario as the first organ to fall prey to the tumour after leaving the pancreas is the liver . The susceptibility of the liver to PNETs makes the cancer potent as it can, in a short interval of time destroy not one, but two vital organs that play a significant role in metabolic regulation.
Therefore, the non-specific nature of CC/radiation as a treatment for metastatic tumours could lead to the destruction of remaining healthy cells in the liver and pancreas. These treatments cause severe side-effects such as peripheral neuropathy, hair and weight loss, metabolic distress, anorexia, and severe vomiting and nausea [8, 11]. The side-effects cannot be predicted accurately because the rate of metastasis influences the number of CC/radiation sessions required, increasing the collateral damage to other organs which in turn alters the observed side-effects. Due to high toxicity, the concentration of a CC drug must be diluted when given to elder individuals and is hence not very potent . On the other hand, it is shown that TDT does not require any change in concentrations when treating the elderly and therefore, is much more beneficial and safer for them . Moreover, the most common side-effects for TDT include stomatitis, skin rashes and diarrhea, all three of which can be controlled with adequate care .
DRUG MONOPOLIZATION AND EXPENSES:
Over the years, CC has turned into a lucrative business despite multiple governments and renowned researchers repeatedly emphasizing the fact that conventional cancer cure has its limitations. For example, the United States Government, in an effort to secure a patent for novel cancer treatment stated earlier on that “Current approaches to combat cancer rely primarily on the use of chemical and radiation, which are themselves carcinogenic and may promote recurrences and the development of metastatic disease.” [16,19]. The alliances formed between multiple hospitals, insurance companies, and drug manufacturers effectively monopolizes the industry and instead shuns novel treatments as ineffective and risky [14, 15, 16]. This was highlighted by Dr. Julian Whitaker (M.D. Founder, Whitaker Wellness Institute) and I quote “I find it very interesting that we have all these walks for the cure for cancer. We got all the risk factors. We got all the donations. We are going to find a cure in this decade. All this money keeps pouring in, and it all goes to the same guys.”. A decade ago, a new CC drug costed around $4500, and as of 2012 the prices have risen to over $12000 per month of treatment [13, 14, 18].
The general public is not aware of this and hence ignorantly assumes that CC is the best and only treatment available. This in turn leads to a presumption that TDTs or any other drugs are much more expensive than CC drugs owing to their high specificity and/or lesser media attention. However, this is only true for intravenous target drugs and not oral ones . This is also because several insurance companies regard intravenous as a different mode of treatment . On the bright side, the past decade has seen few sensible major insurance providers such as Medicare taking up major oral target specific drugs under insurance cover . Nevertheless, chemotherapeutic drugs are still cheaper overall and more widely available due to significant monopolization and mass production. Oral TDTs are only a bit more expensive than CC drugs, and hence a better insurance cover for these drugs could lead to a better awareness and increase in popularity. This would cause a dramatic shift, forcing companies and insurance providers to give a personalized oral TDT for specific tumours such as PNETs instead of CC and radiation. Therefore, for a small difference in price which could substantially reduce in the future, I believe that a person should choose TDTs for PNETs that make a significant difference to the treatment and chances of survival.
Over all areas of concern, TDT has important advantages over CC and radiation in treating rapid proliferating tumours such as PNETs. Still, this in no way indicates that TDT is a better choice for all kinds of cancers. CC and radiation are extremely useful and have a high tumour shrink percentage for certain types of cancer, which makes TDT unnecessary. Nevertheless, with reference to PNETs where CC has been highly unsuccessful, TDT has a significant advantage owing to its specificity and high efficacy rate. A personalized TDT ensures that metastatic and non-metastatic tumours are treated differently, thereby ensuring maximum tumour shrinkage. These factors along with minimal side effects, allows this drug to be used on all individuals irrespective of age and therefore appears to me that it should be the most obvious choice. In conclusion, I believe that TDT for PNETs with unresectable macroadenomas is a much safer and better option than CC or radiation.
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