- Clinical science
General oncology
Summary
Oncology is the science of tumors. This learning card explains basic concepts relevant to the development, progression, spread, complications, diagnosis, and management of cancer. Histological analysis helps to determine tumor type and grade, whereas the TNM classification system is used to assess staging. Because it is standardized and used internationally, the TNM classification helps unify oncological research and therapy protocols. Metastasis occurs via different pathways mainly by hematogenous or lymphatic spreading. Therapy can be curative (mostly in early tumor stages) or palliative (mostly later stages). In addition to surgically removing a tumor, it can be beneficial to perform neoadjuvant (before surgery) and/or adjuvant (after surgery) radiation, chemotherapy, or both. Response rates to these forms of treatment are highly variable.
In addition to local effects, such as compression or infiltration of neighboring structures, malignant tumors can also cause systemic complications such as paraneoplastic syndromes and cancer anorexia-cachexia syndrome. See the learning card on paraneoplastic syndromes for more information.
For more details about tumor markers and immunohistochemical markers, see the learning card on tumor markers.
Nomenclature
Terminology
Term | Definition |
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Normal cell | |
Neoplasia |
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Tumor |
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Carcinoma |
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Sarcoma |
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Hamartoma |
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Dysplasia |
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Carcinoma in situ (CIS) |
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Invasive carcinoma |
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Metastasis |
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Benign and malignant tumors
Benign tumor | Malignant tumor | |
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Differentiation (grading) |
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Growth |
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Macroscopy |
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Microscopy |
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Metastasis and relapse |
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Tumor origin
References:[1]
General epidemiology (United States)
In 2018, approximately 1.7 million people will be diagnosed with cancer in the United States. Cancer is the 2nd leading cause of death after heart disease. The most common type of cancer in both men and women is skin cancer, with basal cell carcinoma being more common than squamous cell carcinoma and melanoma.
Epidemiology of common cancer types in 2018
The following numbers are an estimation of new cancer cases and their mortality in the United States (excluding skin cancer).
Type | Incidence/year in men | Incidence/year in women | Mortality/year |
---|---|---|---|
Breast | 2,550 | 266,120 | 41,400 |
Lung and Bronchus | 121,680 | 112,350 | 154,050 |
Prostate | 164,690 | N/A | 29,430 |
Colorectal | 75,610 | 64,640 | 50,630 |
Bladder | 62,380 | 18,810 | 17,240 |
Kidney | 42,680 | 22,660 | 14,970 |
Uterus | N/A | 63,230 | 11,350 |
Pancreas | 29,200 | 26,240 | 44,330 |
Thyroid | 13,090 | 40,900 | 2,060 |
Non-Hodgkin lymphoma | 41,730 | 32,950 | 19,910 |
Leukemia | 35,030 | 25,270 | 24,370 |
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The most common cancer in men excluding skin cancer are:
- Prostate cancer
- Cancer of the lung and bronchus
- Colorectal cancer
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The most common cancer in women excluding skin cancer are:
- Breast cancer
- Cancer of lung and bronchus
- Colorectal cancer
- The cancer with the greatest mortality rate for both groups is cancer of lung and bronchus.
References:[2]
Carcinogenesis
- Definition: A multistep process by which normal cells develop and accumulate genetic mutations (inherited or acquired), resulting in a monoclonal expansion of mutated cells that can progress to the development of neoplasia.
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Process
- Initiation: DNA damage
- Promotion: DNA damage is passed on
- Latency: time between promotion and progression
- Progression: The neoplastic cell line proliferates with the acquired DNA damage, leading to malignant transformation.
DNA damage
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Mutations: duplication , insertion , deletion , point mutation
- Consequences: silent mutation, nonsense mutation, missense mutation
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Chromosomal translocation
- Example: translocation t(9;22) in chronic myeloid leukemia. There is reciprocal translocation resulting in an elongated chromosome 9 (9q+) and truncated chromosome 22 (22q‑), also known as Philadelphia chromosome.
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Amplification: increased gene expression
- Example: There is overexpression of the HER2/neu gene in several forms of breast cancer.
Key genes involved in carcinogenesis
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(Proto‑)oncogene
- Mutations of proto-oncogenes → formation of oncogenes
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Tumor suppressor genes
- Inhibits uncontrolled proliferation
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Apoptosis regulatory genes
- Loss of regulatory genes (e.g., Bax) leads to cell immortality and increased proliferation.
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Factors that affect key genes involved in carcinogenesis
- Exposure to risk factors
- Diet
Properties of malignant cells
- Uncontrolled cell proliferation
- Failure to differentiate
- Failure of normal apoptotic pathways
- Defective DNA repair pathways
- Lack of response to external growth inhibiting signals
- Increased angiogenesis
- Shift in cellular metabolism (e.g., Warburg effect)
References:[3]
Oncogene
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Oncogene: Gain-of-function mutation converts a proto-oncogene into an oncogene which leads to overexpression of signaling proteins and growth factors → uncontrolled cellular proliferation (e.g., dysplasia, neoplasia).
- Only one allele of proto-oncogene needs to be damaged to form an oncogene.
- A gene that is often present in cancer cells.
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Proto-oncogene: Genes that encode proteins that are important in normal cell division and cell differentiation. Examples include:
- Protein kinases, e.g., protein kinase B (PKB)
- PKB activates and inhibits various substrates and therefore suppresses, e.g., apoptosis, and activates translation and, indirectly, cell division.
- PKB is activated by phosphatidylinositide 3-kinase (PI3K).
- Ligand-directed transcription factors (intracellular hormone receptors)
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GTP-binding proteins
- G protein-coupled receptors
- Small G-proteins such as Ras
- Tyrosine kinase receptors
- Growth factors and cytokines
- Protein kinases, e.g., protein kinase B (PKB)
Proto-oncogene | Chromosome | Gene product | Associated malignancies |
---|---|---|---|
BRAF |
| Serine/threonine kinase | |
BCR-ABL |
| Tyrosine kinase | |
JAK2 |
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HER2/neu (c-erbB2) |
| Receptor tyrosine kinase | |
ALK |
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RET |
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c-KIT |
| Cytokine receptor | |
L-myc-1 (MYCL1) |
| Transcription factors | |
N-myc (MYCN) |
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c-myc |
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KRAS |
| GTPase | |
BCL-2 |
| Antiapoptotic molecule | |
CDK4 |
| Cyclin-dependent kinase | |
CCND1 |
| Cyclin D protein (regulatory protein of the cell cycle) |
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ERBB1 |
| Epidermal growth factor receptor |
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Tumor suppressor genes
- Definition: A gene that normally controls and suppresses cell proliferation. Loss of function or inactivation leads to an increased risk of developing cancer. Both alleles need to be mutated in order for complete loss of function of the gene.
Gene | Chromosome | Gene product | Associated malignancy |
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TP53 |
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Rb |
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CDKN2A |
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APC gene |
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BRCA1 |
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BRCA2 |
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MMR gene family |
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DCC |
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SMAD4 (DPC4) |
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MEN 1 |
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NF1 |
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NF2 |
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TSC1 |
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TSC 2 |
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VHL |
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WT1 |
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WT2 |
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Carcinogens
Chemical carcinogens
Substance | Occurrence | Malignancy |
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Benzene, Benzol |
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Vinyl chloride |
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Nitrosamines |
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Aromatic amines (β-Naphthylamine) |
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Asbestos |
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Wood dust |
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Ethanol |
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Alkylating agents |
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Cigarette smoke |
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Radon |
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Aflatoxin |
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Arsenic |
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Radiation
Type | Occurrence | Malignacy |
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Nonionizing radiation |
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Ionizing radiation |
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Oncogenic infections
Infective agent | Associated malignancies |
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DNA viruses | |
EBV | |
HBV | |
HHV-8 | |
HPV 16 |
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HPV 18 | |
RNA viruses | |
HTLV-1 | |
HCV | |
Nonviral pathogens | |
Schistosoma haematobium |
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Clonorchis sinensis (Chinese liver fluke) | |
H. pylori |
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Grading and staging
Tumor grading
- Definition: Process of classifying tumors based on their histological appearance (degree of differentiation).
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Indicators of poor differentiation
- High-proliferation index
- Presence of nucleoli
- Giant cells with multiple nuclei
- Hyperchromasia and heterogenous chromatin distribution
- Abnormal shape of cell or nucleus (nuclear atypia, enlarged nucleoli)
- Different cell polarity
- Different orientation of nuclei belonging to the same group of cells
- Increase in mitotic figures
- Anaplasia: loss of morphological features of malignant cells so that resemblance to normal cells of a particular tissue where tumor cell originated from is lost
Grading systems
AJCC grading system
- Most commonly used grading system for nonhematological malignancies
- Can be applied to a wide range of tumors
Grading | Differentiation of malignant tissue |
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G1 | Well differentiated (low grade) |
G2 | Moderate differentiation (intermediate grade) |
G3 | Poor differentiation (high grade) |
G4 | Undifferentiated/anaplastic (high grade) |
GX | Differentiation cannot be assessed |
Cancer-specific grading systems
- Gleason score for prostate cancer
- Nottingham grading system for breast cancer
Tumor staging
- Definition: Method of determining and classifying a tumor according to its spread throughout the body.
- Prognosis: Stage of the tumor is typically more important than the grade in determining the prognosis.
Staging systems
- TNM and AJCC systems are most commonly used
TNM classification
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T: size or direct extent of the primary tumor
- Tcis: Carcinoma in situ (no basement membrane penetration - no infiltration of submucosa)
- T1-4 based on the size and/or extent of the primary tumor
- T4 refers to infiltration of neighboring organs
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N: Involvement of regional lymph nodes
- N0: No lymph node involvement
- N1-3 based on type of tumor and lymph node involvement
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M: Presence of distant metastasis
- M0: No distant metastasis
- M1: Presence of distant metastasis
- Mx: Unknown if distant metastasis is present or not
- By adding a "C" to any category, it's possible to express the certainty of the diagnosis
- By adding a prefix to TNM it's possible to indicate additional diagnostic or clinical information
T, N, and M have independent prognostic values. N and M are typically the most important determinants of prognosis.
AJCC staging system
- Stage 0 (carcinoma-in-situ)
- Stage I–III: tumor spread into nearby tissues
- Stage IV: tumor spread to distant parts of the body
Cancer-specific staging systems
Spread determines Stage, and Stage determines Survival more than grade!
Metastasis
Overview
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Metastasis: spread of malignant cells to distant organs, tissues (e.g., colorectal cancer spreads to the liver)
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Lymphatic metastasis
- Dissemination of malignant cells via lymphatic vessels and lymph nodes
- Most common route of metastasis for most carcinomas
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Hematogenous metastasis
- Dissemination of malignant cells via blood vessels. Venous dissemination is more common than arterial dissemination because the thin wall of veins is easier to invade.
- Most common route of metastasis for most sarcomas.
- Seeding (oncology): spillage of malignant cells to neighboring structures → implants at a site adjacent to the primary tumor and subsequent growth
- Transcoelomic metastasis: spread of malignant cells into body cavities by penetration of surfaces such as the pleura, pericardium, and peritoneum
- Canalicular metastasis: spread of malignant cells via canalicular system (e.g. bile ducts, lactiferous ducts, urinary tract, and the subarachnoid space)
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Lymphatic metastasis
Most carcinomas spread lymphatically. However, renal cell carcinoma, follicular thyroid carcinoma, hepatocellular carcinoma, choriocarcinoma primarily spread hematogenously!
Mechanisms of Metastasis
- Complex genetic changes are responsible for the selection of tumor subclones that are capable of metastasis.
- All metastases can be understood as arising from a two-part process: invasion of local extracellular tissue → dissemination and colonization.
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Invasion of extracellular tissue: loss of cellular adhesions → adhesion to basement membrane → invasion through basement membrane → passage through extracellular tissue
- Loss of E-cadherin expression is associated with tumor metastatic potential
- Overproduction of proteases such as collagenase and matrix metalloproteinases degrade the basement membrane and interstitial matrix; → Neoplastic cells encounter various chemotactic and angiogenic factors in the newly exposed extracellular matrix.
- Autocrine signaling via tumor-produced cytokines and paracrine signaling by cleaved matrix components and extracellular growth factors stimulate tumor cell locomotion towards vasculature or lymphatics.
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Dissemination and colonization: encountering vascular or lympathic routes → evasion of host defenses → implantation with distant tissue
- Host defenses destroy the majority of circulating cancer cells. Mechanisms to avoid this include tumor cell aggregation, formation of platelet-tumor complexes, and binding of active coagulation factors to form malignant emboli.
- Disruption of cellular adhesion molecules (laminins, cadherins) enable extravasation at distant tissues. CD44 has been recently implicated in this process.
Common sites for cancer metastasis
- Brain metastases: appear in the white-gray matter junction as multiple well-circumscribed lesions
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Bone metastasis: usually involve the axial skeleton (e.g., vertebral column, pelvic girdle)
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Types of bone lesions
- Lytic: lung, kidney, multiple myeloma
- Blastic: prostate
- Mixed: breast
- For bone metastasis see the learning card on malignant bone tumors.
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Types of bone lesions
Organ with metastasis | Primary tumor located in |
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Liver | |
Bone | |
Brain |
Generally, tumors in the brain (approximately 50%) and in the bone are most often metastatic rather than primary tumors!
References:[4][5]
Cancer anorexia-cachexia syndrome
- Definition: A syndrome characterized by progressive wasting of skeletal muscle mass with or without loss of body fat that occurs in patients with advanced cancer.
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Pathophysiology
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Excess in proinflammatory cytokines (IL-1, IL-6, IFN-γ, and TNF-α) as a result of tumor growth → ↑ basal metabolic rate and catabolism
- Proteasomal activation and breakdown of myosin in skeletal muscle + loss of adipose tissue
- Negative nitrogen balance
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Excess in proinflammatory cytokines (IL-1, IL-6, IFN-γ, and TNF-α) as a result of tumor growth → ↑ basal metabolic rate and catabolism
- Clinical features: weight loss, poor appetite, ↓ adipose tissue, muscle wasting, fatigue
- Diagnosis: no formal diagnostic criteria available, but some features for diagnosis include
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Treatment
- Corticosteroids (e.g., prednisolone)
- Progesterone analogs (e.g., megestrol acetate)
- Cannabinoids (e.g., dronabinol)
- Nutritional counseling, parenteral nutrition
- Prognosis: poor prognostic indicator
References:[6][7][8][9]
Antineoplastic therapy
Definitions
- Curative therapy: therapy with the intent of curing the disease
- Palliative therapy: therapy with the intent of relieving symptoms and improving quality of life
- Neoadjuvant therapy: : chemotherapy and/or radiation before elective surgery (e.g., preoperative radio-/chemotherapy in advanced rectal cancer)
- Adjuvant therapy: chemotherapy and/or radiation after surgery (e.g., postoperative chemotherapy in advanced colorectal cancer)
Modalities of antineoplastic therapy
- Surgery (e.g., hysterectomy, mastectomy, prostatectomy)
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Chemotherapeutic drugs (e.g., BEP regimen in seminoma testicular cancer)
- Combinations of multiple classes of chemotherapy are often used to treat malignancy
- Cancers develop resistance by expressing multi-drug resistance protein 1 (also called P-glycoprotein)
- Radiotherapy: A treatment method where a machine delivers carefully targeted radiation beams from outside the body to destroy cancer cells, halt their growth, or offer palliative therapy of locally advanced unresectable or metastatic disease.
- Hormone therapy (e.g. antiandrogens in prostate cancer)
- Biological agents (e.g. CD20 antibodies in non-Hodgkin lymphoma)
Besides tumor grade and stage, it is important to consider the patient's performance status (Karnofsky score), general well-being, comorbidities, and the patient's wishes when choosing a treatment option.
Treatment evaluation
Assessing resection
Resection margin | Definition | Examined by |
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R0 |
| Pathologist |
R1 |
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R2 | Surgeon |
Assessing response
(CR) | No clinical or radiological evidence of tumor disease over a certain amount of time (depends on tumor type) |
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(PR) | Decrease in tumor volume by a certain percentage (depends on tumor type) |
Stable disease (SD)/ (NC ) | Minimal decrease or increase of all lesions/tumor volume |
Progressive disease (PD) | Increase of all lesions/tumor volume |