Cancer Screening Guidelines in An Indian Context

Screening for Cancer is a crucial part of Cancer Prevention and Control. Yet, screening is not integrated into our routine medical health care for our mass population. Dr Gauravi Mishra, of the Tata Memorial Hospital, Mumbai provides us with her expert guidance on advances and modifications in screening strategies for India including Genome Tests and Liquid Biopsy. And specific focus on Prostate Cancer.

There have been recent changes in cancer screening. What are the current guidelines for the various cancers for India?

India has still not rolled out the population based cancer screening programme in all States. Operational Guidelines of the role out of the integrated National Programme for Prevention and Control of Cancer, Diabetes, Cardiovascular Disease & Stroke (NPCDCS) are now available.¹

Guidelines in India (NPCDCS):

Benefits of screening are clear but are there any risks involved (test complications, radiation exposure, inconclusive results, overdiagnosis etc.)?

Every screening test can be harmful too. For example, x-ray examinations expose the body to radiation, and endoscopy of the bowel can lead to bleeding or (in rare cases) serious injuries.

In the PLCO trial, Minor complications such as fainting and bruising occurred at a rate of 58.3 per 10 000 women screened with CA-125 and 3.3 per 10 000 women screened with transvaginal ultrasound. Of women diagnosed with ovarian cancer, 95 in the intervention group (45%) and 91 in the usual care group (52%) experienced at least 1 major complication associated with their diagnostic procedures (i.e., infection, blood loss, bowel injury, cardiovascular events).²

Related Reading: Guidelines for Cancer Screening for Women Related Cancers

There are complications associated with radiation exposure. Radiation risks after exposure in younger individuals can initiate cancer process, whereas radiation risks after exposure at later ages are more influenced by promotion of preexisting premalignant cells.³

In a study by Yaffe MJ et al on the risk of radiation-induced breast cancer from mammographic screening it was found that for a cohort of 100 000 women each receiving a dose of 3.7 mGy to both breasts and who were screened annually from age 40 to 55 years and biennially thereafter to age 74 years, it was predicted that there will be 86 cancers induced and 11 deaths due to radiation-induced breast cancer. This risk is small compared with the expected mortality reduction achievable through screening. The risk of radiation-induced breast cancer should not be a deterrent from mammographic screening of women over the age of 40 years.⁴

Results from the Norwegian Screening program included a total of 39 888 patients with invasive breast cancer, 7793 of whom were diagnosed after the screening program started. The estimated rate of overdiagnosis attributable to the program was 15% to 25%. This translates to 6 to 10 women overdiagnosed for every 2500 women invited.⁵

What are the biggest screening challenges in the Indian scenario?

The cancer screening challenges faced in India are:

Population - The increasing population of India poses substantial challenges to the government’s capacity to provide consistent health-care infrastructure and delivery of care.

Limited data - The Indian Council of Medical Research has collected data about cancer incidence through several population-based cancer registries for the past 30 years. Although these registries cover only 7% of India’s cancer population, they provide the best available information to understand the effects of cancer on national morbidity and mortality rates, and for future planning of health expenditures on cancer

Limited health workforce - Provision of health-care workers for cancer control India’s existing health-care system is designed to prioritise infectious diseases, nutritional deficiencies, and maternal and child health

Sociocultural barriers to health and cancer care
Major sociocultural issues that affect approaches to health care in India include social taboos, castes, gender inequality, low regard for health as a priority, nihilistic approaches to cancer diagnosis (i.e., cancer fatalism), blind faith in traditional methods of healing, religious dynamics, and widespread superstitions.

Lack of awareness among population

Lack of mechanism to build capacity of the health services staff to take up the screening activity in terms of relieving the staff for longer duration for training and limited number of organisations that can conduct the trainings.¹⁶

What is Liquid biopsy? Is it a diagnostic or screening tool?

Liquid biopsy is a test done on a sample of blood to look for cancer cells from a tumor that are circulating in the blood or for pieces of DNA from tumor cells that are in the blood. A liquid biopsy may be used to help find cancer at an early stage. It may also be used to help plan treatment or to find out how well treatment is working or if cancer has come back. Being able to take multiple samples of blood over time may also help doctors understand what kind of molecular changes are taking place in a tumor.

Liquid Biopsy as a screening tool
Liquid biopsy has emerged as a promising avenue for cancer screening. Several circulating biomarkers such as circulating DNA, circulating tumor cells, circulating microRNAs and others have shown promise for patient monitoring. Early detection may help reduce cancer-related mortality and increase overall patient survival. The noninvasive nature of liquid biopsy represents an advantage over other approaches to define cancer biomarkers, particularly for the development of cancer screening tests. However, so far, no test developed from liquid biopsy proves to be both specific and sensitive enough to be used as a universal screening test.¹⁷

Liquid Biopsy as a diagnostic tool
Initially correlated to prognosis, liquid biopsy data are now being studied for cancer diagnosis, and most importantly for the prediction of response or resistance to given treatments. In particular, the identification of specific mutations in target genes can aid in therapeutic decisions, both in the appropriateness of treatment and in the advanced identification of secondary resistance, aiming to early diagnose disease progression.

Despite such high potential, a significant gap must actually be filled, since the systematic application of liquid biopsy in real practice is still hindered by many hurdles, such as unsatisfactory specificity and sensitivity, lack of standardization, and elevated economic and human resource costs, and still offers many challenges. In fact, due to the low concentration of CTCs, ctDNA, and EXOs currently recoverable from the patient, the analytical results sometimes suffer from unsatisfactory specificity and sensitivity. The use of different high-throughput analytical platforms often results in difficulty in reproducing results, and highlights the need for standardization and analytical validation of the method used for liquid biopsy. In the same way, computational analysis needs new tools that can elaborate complex algorithms of data interpretation and clinical correlation of molecular data. Finally, it is desirable that the current high personnel and infrastructure costs necessary for these methods are reduced in response to progress in biotechnology.¹⁸

One study estimated that there is steady rise in overdetection of Prostate cancer (DOI:10.1093/jnci/95.12.868). What are the concerns about PSA screening?

Detecting prostate cancer early may not reduce the chance of dying from prostate cancer. When used in screening, the PSA test can help detect small tumors that do not cause symptoms. Finding a small tumor, however, may not necessarily reduce a man’s chance of dying from prostate cancer. Many tumors found through PSA testing grow so slowly that they are unlikely to threaten a man’s life. Detecting tumors that are not life threateningis called “overdiagnosis,” and treating these tumors is called “overtreatment.”

Overtreatment exposes men unnecessarily to the potential complications and harmful side effects of treatments for early prostate cancer, including surgery and radiation therapy. The side effects of these treatments include urinary incontinence (inability to control urine flow), problems with bowel function, erectile dysfunction (loss of erections or having erections that are inadequate for sexual intercourse) and infection.

In addition, finding cancer early may not help a man who has a fast-growing or aggressive tumor that may have spread to other parts of the body before being detected.

The PSA test may give false-positive or false-negative results. A false-positive test result occurs when a man’s PSA level is elevated but no cancer is actually present. A false-positive test result may create anxiety for a man and his family and lead to additional medical procedures, such as a prostate biopsy, that can be harmful. Possible side effects of biopsies include serious infections, pain, and bleeding.

Most men with an elevated PSA level turn out not to have prostate cancer; only about 25% of men who have a prostate biopsy due to an elevated PSA level actually are found to have prostate cancer when a biopsy is done.

A false-negative test result occurs when a man’s PSA level is low even though he actually has prostate cancer. False-negative test results may give a man, his family, and his doctor false assurance that he does not have cancer, when he may in fact have a cancer that requires treatment.

Genome tests are considered the new frontier in screening? For which cancers is this applicable? Who is referred to genetic testing?

Not all cancers are hereditary cancers. Some families have an inherited gene fault (mutation) that can increase the risk of developing certain types of cancer. Tests are available for some inherited faulty genes. There are various important issues to be considered before making a decision to have a test.

Following features may suggest that the cancer may be hereditary:

• Unusually early age of cancer onset (e.g., premenopausal breast cancer).
• Multiple primary cancers in a single individual (e.g., colorectal and endometrial cancer).
• Bilateral cancer in paired organs or multifocal disease (e.g., bilateral breast cancer or multifocal renal cancer).
• Clustering of the same type of cancer in close relatives (e.g., mother, daughter, and sisters with breast cancer).
• Cancers occurring in multiple generations of a family (i.e., autosomal dominant inheritance).
• Occurrence of rare tumors (e.g., retinoblastoma, adrenocortical carcinoma, granulosa cell tumor of the ovary, ocular melanoma, or duodenal cancer).
• Occurrence of epithelial ovarian, fallopian tube, or primary peritoneal cancer.
• Unusual presentation of cancer (e.g., male breast cancer).
• Uncommon tumor histology (e.g., medullary thyroid carcinoma).
• Rare cancers associated with birth defects (e.g., Wilms tumor and genitourinary abnormalities).
• Geographic or ethnic populations known to be at high risk of hereditary cancers.
• Genetic testing candidates may be identified based solely on ethnicity when a strong founder effect is present in a given population (e.g., Ashkenazi heritage and BRCA1/BRCA2 pathogenic variants).

As part of the process of genetic education and counseling, genetic testing may be considered when the following factors are present:

• An individual's personal history (including ethnicity) and/or family history are suspicious for a genetic predisposition to cancer.
• Presence of genetic test that has sufficient sensitivity and specificity to be interpreted.
• The test will impact the individual's diagnosis, cancer management or cancer risk management, and/or help clarify risk in family members.

Currently tests are available for gene faults that increase the risk of breast cancer, bowel cancer, ovarian cancer, endometrial cancer and prostate cancer.

Tests are also available for rare gene faults that may increase the risk of kidney cancer, melanoma skin cancer, pancreatic cancer, thyroid cancer and a type of eye cancer called retinoblastoma.

Tests are not available for other types of cancer genes but research is finding more gene faults all the time and tests are being developed.^{20, 21}

References:

1. Directorate General of Health Services, Ministry of Health & Family Welfare. National Programme for Prevention and Control of Cancer, Diabetes, Cardiovascular Disease & Stroke (NPCDCS): Training Module for Medical Officers for Prevention, Control and Population Level Screening of Hypertension, Diabetes and Common Cancer (Oral, Breast & Cervical) 2017
2. Buys SS, Partridge E, Black A, Johnson CC, Lamerato L, Isaacs C, Reding DJ, Greenlee RT, Yokochi LA, Kessel B, Crawford ED. Effect of screening on ovarian cancer mortality: the Prostate, Lung, Colorectal and Ovarian (PLCO) cancer screening randomized controlled trial. Jama. 2011 Jun 8;305(22):2295-303.
3. Shuryak I, Sachs RK, Brenner DJ. Cancer risks after radiation exposure in middle age. Journal of the National Cancer Institute. 2010 Nov 3;102(21):1628-36.
4. Yaffe MJ, Mainprize JG. Risk of radiation-induced breast cancer from mammographic screening. Radiology. 2011 Jan;258(1):98-105
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7. Source: Association of Cancer Physicians. https://www.acponline.org/system/files/documents/about_acp/chapters/va/16mtg/hackney.pdf
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9. Kennedy DA, Lee T, Seely D. A comparative review of thermography as a breast cancer screening technique. Integrative cancer therapies. 2009 Mar;8(1):9-16.
10. Friedenson B. Is mammography indicated for women with defective BRCA genes? Implications of recent scientific advances for the diagnosis, treatment, and prevention of hereditary breast cancer. MedGenMed. 2000;2:E9
11. Osako T, Iwase T, Takahashi K, et al. Diagnostic mammography and ultrasonography for palpable and nonpalpable breast cancer in women aged 30 to 39 years. Breast Cancer. 2007;14:255-259
12. Screening Mammogram: 2D and 3D Tomosynthesis. Cedars Sinai. Available at https://www.cedars-sinai.edu/Patients/Programs-and-Services/Imaging-Center/For-Patients/Exams-by-Procedure/Womens-Imaging/Bilateral-Screening-Mammogram/
13. Mansour S, Adel L, Mokhtar O, Omar OS. Comparative study between breast tomosynthesis and classic digital mammography in the evaluation of different breast lesions. The Egyptian Journal of Radiology and Nuclear Medicine. 2014 Sep 1;45(3):1053-61.
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17. Med Sci (Paris). 2018 Oct;34(10):824-832. doi: 10.1051/medsci/2018208. Epub 2018 Nov 19.
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19. NIH. National Cancer Institute. https://www.cancer.gov
20. Cancer Research UK. Genetic testing for cancer risk. https://www.cancerresearchuk.org/about-cancer/causes-of-cancer/inherited-cancer-genes-and-increased-cancer-risk/genetic-testing-for-cancer-risk#Who%20can%20be%20tested%20for%20inherited%20faulty%20genes?
21. Board PC. Cancer Genetics Risk Assessment and Counseling (PDQ®). In PDQ Cancer Information Summaries [Internet] 2019 Mar 1. National Cancer Institute (US).

Dr. Gauravi Mishra is a Professor and Physician in the department of Preventive Oncology at the Tata Memorial Hospital, Mumbai. Dr. Mishra received her MD in Community Medicine from the Mumbai University. She has received fellowship in Cancer Prevention from the National Cancer Institute, USA and trained in Epidemiology at the IARC Summer School on Cancer Epidemiology at Lyon, France. Dr. Mishra specializes in screening and early detection of breast, uterine cervix and oral cancers. Her research interests involve investigating newer methodologies for early detection of cancers and working on different modalities of tobacco cessation. Some of her research work has been instrumental in shaping the National Cancer Control Policy in India.