Reconsidering evidence-based oncology: The need for clinical judgment and contextualized care
Year: 2025
Type: article
Abstract: After spending a quindecinnial in oncology, and witnessing the clinical discussions around including those in the major multispecialty oncology conferences, a question rose to my mind. Is it somewhere we are killing common sense, and basic human and oncology science under the pretense of evidence-based practice? Few such instances are discussed further under broad subheadings with an aim to focus on the need for individualized patient care and critical interpretation of the clinical guidelines and evidence. LIMITATIONS OF TRADITIONAL TERMINOLOGIES Pack-year: During the discussion at head-neck cancer (HNC) session the moderator started with—”The evidence says, Human Papilloma Virus (HPV) - associated oropharyngeal cancer (OPC) is more common in young men with high-risk sexual behavior, and smoking history of less pack-year while opposite is true for the HPV-independent OPC.” Isn’t it understood that the young men will have a history of relatively less pack-years and moderately high-risk sexual behavior?[1,2] Pack-years itself has its own limitations with respect to time and intensity of smoking. HPV-positive versus HPV-mediated malignancy: There is a difference between the HPV-positive/HPV-associated and HPV-mediated malignancy. HPV-associated tumors may not be HPV-mediated. Laboratory reporting of p-16 and sample collection has limitations[3] which are further aggravated in tobacco users.[4] This may affect the clinical staging and, hence, the treatment planning. Chemoradiation: Adjuvant or radical radiotherapy (RT) with or without concurrent chemotherapy (CT) using cisplatin (based on the cisplatin eligibility criteria) as a radiation sensitizer should be an ideal wording. But it is replaced with the term chemoradiation. Is it really right to write chemoradiation/CTRT? The evidence says CT given concurrently with RT is better than the radiation alone in HNC,[5] but it should not be a blanket statement, especially for the disadvantaged group.[6] Further, the basics of using chemotherapy as a radiation sensitizer, the mechanism of action of radiation, and the pharmacokinetics of the drug teach that carboplatin is not a replacement for cisplatin.[7] LIMITATIONS OF EVIDENCE APPLICATION Long- versus short-course neoadjuvant RT (NART) in rectal cancer: A session discussion was on long- versus short-course neoadjuvant RT (NART) in rectal cancer. Literature was referred in depth and debated.[8,9] The point raised was, looking at the post-RT hyperemia field during surgery planned shortly after short-course RT, the surgeon can make out whether the patient received NART at a center with higher experience in treating patients with short-course NART or at a peripheral center. The RT-portals for short- versus long-course RT are not mentioned in the literature. So, a question with respect to common sense was, “Will I be right if I say very early nodal or N0 disease to be treated with short-course, and hence, relatively small RT-portal, and advanced nodal disease with long-course RT with conventional RT-portal?” The opinion of the house was, “We still don’t have the evidence to say and practice so.” Trainees attending the conference were left in doubt. Regional nodal irradiation in breast cancer: During a case-based discussion on regional nodal irradiation in breast cancer, a case of a 60-year-old lady who underwent mastectomy and sentinel lymph node biopsy was discussed. One out of three lymph nodes was positive without extranodal extension. The pathological staging was pT2N1M0, IDC grade II, hormone receptor (HR) associated, HER2 negative. Negative for other pathological risk factors. The patient received Taxol-based adjuvant chemotherapy. So, the answer “no need of adjuvant RT, especially when the patient has received Taxol-based chemotherapy and is HR positive” was panned as there is no strong evidence to say so.[10] One need to consider the rate of false negativity of sentinel node biopsy,[11] and the phase of the cell cycle where RT, hormone therapy, and paclitaxel act. Further, if the sentinel node was positive, complete axillary dissection should have been an option to spare other treatment modalities, which in turn would have reduced the morbidity. BASIC HUMAN SCIENCE Arytenoid and larynx subsite: For HNC, if we revisit our basic training in human science and oncology, it does not concur with the evidence mentioned in the literature. Arytenoid forms the posterior one-third of the true vocal cord, and a posterior commissure, which are the subsites of the glottis. In the American Joint Committee on Cancer staging manual, arytenoids are mentioned as a subsite of the supraglottic larynx. A few millimeters of sub-centimeter-sized arytenoids are in the supraglottis.[12] BASICS OF (RADIATION) ONCOLOGY Organs at risk contouring and pathophysiology of radiation toxicities: According to the basic rules of radiobiology, that is, law of Bergonie and Tribonadeau,[13] one of the most radioresistant cell of human body is a nerve cell, and we struggle to contour and spare spinal cord, one of the dose limiting structures in HNC RT. The evidence says the main culprit for the spinal cord injury is compromised vasculature because of endarteritis obliterans and its consequences, like fibrosis leading to ischemia.[14] If we critically study the spinal cord anatomy at cervical, thoracic, and lumbar levels with respect to the distribution of white and gray matter, its radiosensitivity, and the evidence-based radiation tolerance constraints, concordance is lacking.[15-17] Similarly, to reduce the magnitude of post-RT swallowing dysfunction, pharyngeal plexus injury and epiglottic scarring need to be considered in addition to the pharyngeal constrictors. Parotid sparing RT is a well-established technique. Serous acini are said to be more radiosensitive than the mucinous acini. The serous secretions will ultimately come through a good vasculature of the gland, which is compromised post-RT, leading to xerostomia. The mandibular bone tolerance is defined as the maximum point dose, which should be less than 70Gy and for the femoral head RT constraint is 50% volume should receive less than 50 Gy.[15] Common sense and basic science say fovea/vasculature should be given a constraint that is practically difficult. Limitations of the rectal dose constraints were discussed earlier by the author.[18] Thus, ultimately the vasculature of an organ that is difficult to contour and spare during RT is the perpetrator of RT-induced toxicities.When the whole issue of Red Journal published long back on LENT-SOMA had discussed the pathophysiology of RT toxicities,[13] and the ALARA principle is well known, one should try to balance the risk versus benefit ratio. But the majority of us are seen struggling to achieve the radiation dose-volume constraints defined by others as guidelines. Yes, guidelines and not strict rules. Further, the chances of landing in local minima while searching for global minima are known with highly conformal RT.Concurrent versus sequential tamoxifen during RT: A question usually asked is with respect to adjuvant tamoxifen given during adjuvant RT in breast cancer. Few clinicians prefer starting tamoxifen at least 10 days after RT conclusion. Though there is no strong evidence stating tamoxifen should not be used during RT, common sense says so.[19] The explanation is that tamoxifen, a protein kinase-C inhibitor, causes G1-phase arrest,[20] and radiation acts on late G2- and early M-phase of cell cycle. Further, it is a usual practice to prescribe a calcium supplement with tamoxifen. Is it really useful and needed? Exogenous calcium supplement/medication (non-dietary source) may further add to the cardiotoxicity in breast cancer patients treated with cardiotoxic chemotherapy.[21] Tumor biology and mathematical model of tumor growth: While irradiating a tumor, one has to critically think when to target the tumor microenvironment and when to target a malignant cell or a tumor as whole, that is, conventional versus hypofractionated RT. The duration of symptoms and clinical tumor staging may not always be directly proportional. The tumor biology, that is, potential doubling time, cell loss factor, and surviving fraction, defines the tumor size irrespective of the duration of symptoms. Hence, duration of symptoms and mathematical model of tumor growth, along with other sociodemographic factors, should be considered while deciding the treatment intent, and RT dose-fractionation schedules to justify the right use of resources. Frequent pleural/peritoneal-centesis for palliation: Do we ever consider the pressure dynamics taught during secondary schooling while draining the seroma, pleural, or peritoneal fluid in an otherwise hemodynamically stable patient? The more you drain, the faster it will reaccumulate and will become loculated because of inflammation-induced fibrous bands. OVERLOOKED CLINICAL JUDGMENT OR INVESTIGATIONS HYPE PET scan: It is used as a common staging, response evaluation, or follow-up modality without critically evaluating its real benefit, limitations, or indication. Do we ever consider the dose of radiation received by the heart and kidneys during a PET scan, especially in patients treated or planned to be treated with cardiotoxic or nephrotoxic drugs or those with relatively curable malignancies expecting long-term survival? I highly respect the evidence and development in technology, which warrants its judicious use. Many oncology setups in India have limited access to full-length articles to critically evaluate them, especially the limitations mentioned by the authors themselves. Further, is it right to replicate the evidence and treatment protocols generated in a different set of populations with different patient physiques, etiological factors, sociodemographics, disease stage, treatment support, and facilities in Indian cancer patients? It is very much important to understand “why,” “how,” and “when” rather than just a “what” behind the evidence/technological advances to give the best out of it for the betterment of society. A mathematical model of tumor growth, and accordingly deciding treatment intent considering and balancing the patient’s psychosocial and financial toxicity, and return in outcome, is the best guide to decide patient-specific treatment, giving the best to the patient and family with a justifiable use of resources. Oncology practice should be patient-specific and based on common sense and basic oncology science while respecting the evidence. The need is to understand the concepts. Just doing it because it is said in the evidence and without really understanding the “why” behind it will lead to wastage of resources and more of a quack practice. A clinician should be able to balance between the disease cure/control versus the ability of a person to live a fruitful life ahead, respecting his/her life’s priorities.
Author: Chaitali S. M. Waghmare
Institution: All India Institute of Medical Sciences, Nagpur
Language: English
Field: Medicine
Domain: Health Sciences
Open Access status: diamond
OpenAlex ID: W7117691644