(Focus - India)
We had a discussion on NETs with Dr. Aparna, who mentioned about the signaling proteins, such as Vascular endothelial growth factor molecules (VEGF), that inhibits new blood vessel formation
for the tumor. She also mentions using injectable agents like bevacizumab which has been very useful, and it has given beneficial results in her clinical practice.
Dr. Aparna is a Consultant Medical Oncologist, currently serving in Nanjappa Hospitals, Shimoga, Karnataka, India.
Neuroendocrine tumors are very rare tumors, and they are not very common. All the primary care physicians and surgeons know about common cancers; when a person comes with a mass in the lung, it is obvious that it is cancer. But in neuroendocrine, it is very nonspecific and vague symptoms and neuroendocrine is a rare tumor. That is the reason diagnosis is getting delayed.
Doctor, a study on the clinical and epidemiological profile of neuroendocrine tumors from a regional cancer center in Western India reported that 66% of cases were metastatic at presentation. So, do you also see advanced cases of neuroendocrine tumor in your clinical practice?  Dr. Aparna - Yes, it is very sad and disheartening to know that in most cases, roughly 75% of our cases are already metastatic, and cancer would have already spread to different parts of the body where cure is not possible. We cannot offer a cure where we eliminate the tumor from the body. So, even in my practice, I see a similar percentage of patients. So, what are the reasons for underdiagnosis, doctor? Why are they presented at the last stage of their cancer? Dr. Aparna - The Oncologists do not diagnose most cancers, they are diagnosed by primary care physicians, surgeons, and generalists. For example, for breast cancer, usually, a patient goes with a breast lump to a gynecologist or a physician, who evaluates and finds out that it is cancer, then refers the patient to an oncologist. Similarly, in lung cancer, patients present with cough, and they don't know that they have cancer, so they go to a physician.
The physician diagnoses that patient has cancer. Similarly, when a patient has a neuroendocrine tumor, he will have multiple symptoms. They will have simple things like fatigue and weight loss; they are very nonspecific symptoms like fatigue or weight loss. The generalists have to pick up that it could be cancer or a neuroendocrine tumor.
Neuroendocrine tumors are very rare tumors, and they are not very common. All the primary care physicians and surgeons know about common cancers; when a person comes with a mass in the lung, it is obvious that it is cancer. But in neuroendocrine, it is very nonspecific and vague symptoms and neuroendocrine is a rare tumor. That is the reason diagnosis is getting delayed. Doctor, you mentioned that NETs symptoms are nonspecific, what all risk factors help in the timely diagnosis of neuroendocrine tumors? Dr. Aparna - The primary care physicians must be aware of this entity of neuroendocrine tumor (NET) as it has nonspecific symptoms; just like many stars make up a constellation, NETs have a constellation of symptoms. Patients might have flushing, itching, skin rash, and diarrhea, which are unrelated symptoms, but they occur in a constellation, the doctors must pick them up. If patients have any hereditary conditions of neuroendocrine tumors, like if someone was diagnosed with multiple endocrine neoplasia and had this hereditary genetic predisposition in their family, every effort should be made by the other family members to find out what cancer it is, is there a genetic predisposition, and get evaluated for such tumors. Doctor, an epidemiological study of neuroendocrine neoplasms shows that the most prevalent primary sites of gastroenteropancreatic NETs appear to differ between North America (small intestinal & colorectal NETs), Asia (gastric & pancreatic NET), and Europe (small intestinal & pancreatic NETs). So, what are your thoughts on this variance in primary tumor sites by geography? Are there any demographic factors that are contributing to these differences?  Dr. Aparna - It is challenging to say why a particular cancer is found more commonly in a specific region. Etiological studies to know the causative factor showed that there are geographical differences, but it may be due to some tropical risk factors like some infections. As the patient's immunity decreases, like suppose a patient has HIV, these neuroendocrine tumors can happen. It may be related to some infectious agents in our geography, or it may be racial also. There are differences in the different races because of genetic predisposition. So, being a tropical country, it may be due to the infectious agents or hereditary. Our genetic makeup possibly predisposes to different primary sites. Doctor, I understand that pancreatic neuroendocrine tumors are common in India, what do you see in your clinical practice? Is it mainly pancreatic neuroendocrine tumors? Dr. Aparna - Yes, pancreatic NETs are common; the next most common is lung because it is smoking-related. Both pancreas and lungs I see in my clinical practice.
These VEGF-directed therapies are making a very good impact not only on neuroendocrine tumors but also on many other tumors like colon and lung. For any tumor to grow, they need blood vessels, they develop their pipeline of blood vessels and start extracting blood from all different sources.
So now talking about the treatment part. We understand that the current standard of care for late-stage NET patients is peptide receptor radionuclide therapy with 177Lu-dotatate, which is flushed from patient's system rapidly after administration. Preclinical studies found that if a special dye (Evans blue) is added to the 177Lu-dotatate, the treatment can last longer in the body and be more effective. So, what are your comments? Do you see any limitations/challenges with this treatment approach?  Dr. Aparna - I think Evans blue tagging is seen to be very successful in preclinical studies. This lutetium dotatate being studied shows a very good promise in different studies. The problem is, once lutetium dotatate is infused into the system, it must bind to the peptide receptor on the tumor cell. After that, it must get inside the cell, and the receptor internalization will happen, and our killer machine will get into the tumor cell. So, for this to happen, sufficient time is required for dotatate to bind to the receptor. But the moment we infuse it, within a few minutes, the kidney will start to extract and start excreting it.
So, many efforts have been made to make the dotatate stay in circulation for some time. They use this technique called albumin hitchhiking. Albumin is normally present in our blood and is a carrier for different drugs. So, they have used this Evans blue to tag albumin and keep the dotatate in circulation for longer time so that it can bind to the receptor and get internalized, and it should have better tumor kill.
I think it is a very good effort that we are making, if it is successful in clinical trials, it is excellent since it is a costly treatment. Lutetium dotatate will cost at least two lakhs per dose, and the patient must take it for four to six cycles. It is a costly medicine we are giving, and if it can stay in the body for a little longer, it can provide a better cell kill with each dose we infuse, so it is very promising option. Doctor, studies show that surufatinib (a VEGF-directed therapy) in advanced pancreatic NETs improves progression-free survival and has an acceptable safety profile. Also, the Phase II TALENT trial (lenvatinib, a VEGF-directed therapy) results were considered compelling, due to the markedly higher response rates reported compared to what was observed commonly in pancreatic NETs. So, what are your thoughts on VEGF-directed therapies? How do you think they will change the treatment landscape of NETs?   Dr. Aparna - These VEGF-directed therapies are making a very good impact not only on neuroendocrine tumors but also on many other tumors like colon and lung. For any tumor to grow, they need blood vessels, they develop their pipeline of blood vessels and start extracting blood from all different sources. Suppose in the pancreas, when a tumor starts growing, it will make new blood vessels for itself, extract blood, oxygen, everything, and grow happily. This is called angiogenesis. This vascular epidermal growth factor (VEGF) is essential for the tumor to make the new pipelines for itself to enjoy its growth.
We are using these VEGF antagonist molecules to inhibit new blood vessel formation for the tumor. When we give this surufatinib, sunitinib, or lenvatinib, they are all oral agents, the patient must take it as a tablet, and it will go and block the new vessel formation in the tumor, and the tumor will start shrinking. This is the basic idea of the VEGF pathway, and we have multiple agents available. They are all oral medications, and we have them in India at affordable prices, say around INR10,000 per month. Sometimes the results we see in the trials may not be seen in the patient. But in this case, we see very good tumor regression in real-life practice. There are injectable agents like Bevacizumab, which also block the VEGF pathway and are very useful and give beneficial results in clinical practice.
The patients must understand that neuroendocrine tumor is a spectrum of diseases, some very mild and some aggressive, patients should never lose hope. We can control the mild neuroendocrine tumor, the grade one, even if they are metastatic, and patients survive for 3-4 years. Just by hearing the name of cancer or its stages, patients should not lose hope.
Doctor, you mentioned regarding the cost of peptide receptor radionuclide therapy, so what are the unmet needs and challenges in the treatment and management of neuro endocrine tumors in India? Dr. Aparna - There are many challenges that a patient faces. The delayed diagnosis is because of a lack of imaging. Unless you do a CT or MRI scan, you will not be able to pick up these pancreatic or lung problems. When a patient has a cough, we often do a chest X-ray, and the chest X-ray won't pick up anything. When they come with abdominal pain, we do just an ultrasound scan, which will not pick up the problem. It goes on and on; we do a chest X-ray and say there is nothing, you take this cough syrup. Sometimes patients cannot afford CT scans or MRIs, that is a challenge.
There are peptide receptor scans to see whether somatostatin receptors are there or not. Such scans are not available everywhere. You must come to metropolitan cities like Bangalore or Mangalore to get the scans done. That is one challenge that a patient faces to get diagnosed, to know whether the peptide receptors are present or not.
The cost is always a problem. Whether it is diagnosis or treatment, the price comes our way. Our government is helping in different ways to provide many of the therapies under government-run schemes. I think we still need help for these people. Sometimes some NGOs and charitable trusts also pitch in and help them with imaging and treatment. So accessibility and cost is one of the major challenges, right doctor? Dr. Aparna - Yes. Before we conclude, what are your key takeaway messages to patients suffering from neuroendocrine tumors? Dr. Aparna - The patients must understand that neuroendocrine tumor is a spectrum of diseases, some very mild and some aggressive, patients should never lose hope. We can control the mild neuroendocrine tumor, the grade one, even if they are metastatic, and patients survive for 3-4 years. Just by hearing the name of cancer or its stages, patients should not lose hope. Therapeutics have changed these days, and the outlook on cancer has changed, patients must be very hopeful. Many times, patients will not discuss their problems with the oncologist. I have seen patients committing suicide after they have got diagnosed at Stage IV. You should not take such hasty steps. Always feel free to discuss your fears with the Oncologist and the prognosis of the disease, the chances of survival, and the progression-free survival that we see with each therapeutic agent. Sometimes patients get scared and don't want to discuss it with doctors; they get afraid that the doctor may not tell the truth. It is not like that. If you want to understand and discuss with the Oncologist, we are always open to discussion. Caregivers should always be positive, give positive vibes to the patient, tell success stories, and motivate them to take treatment. If they have any suicidal thoughts or fear, the family members should discuss them with the Oncologist and motivate the patient. Thank you so much for your time and providing insights Dr. Aparna. Dr. Aparna - Thank you. It was a learning experience for me also; it was a very nice discussion.
1. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6699228/ 2. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8118193/#R12 3. https://jnm.snmjournals.org/content/early/2020/08/21/jnumed.120.248658 4. https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(20)30493-9/fulltext 5. https://pubmed.ncbi.nlm.nih.gov/33945297