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Series Editors: H.-U. Kauczor · H. Hricak · M. Knauth
Hans-Ulrich Kauczor
Tobias Bäuerle Editors
Imaging of Complications and Toxicity following Tumor Therapy
Medical Radiology
Diagnostic Imaging
Series Editors
Hans-Ulrich Kauczor
Hedvig Hricak
Michael Knauth
Editorial board
Andy Adam, London
Fred Avni, Brussels
Richard L. Baron, Chicago
Carlo Bartolozzi, Pisa
George S. Bisset, Durham
A. Mark Davies, Birmingham
William P. Dillon, San Francisco
D. David Dershaw, New York
Sam Sanjiv Gambhir, Stanford
Nicolas Grenier, Bordeaux
Gertraud Heinz-Peer, Vienna
Robert Hermans, Leuven
Hans-Ulrich Kauczor, Heidelberg
Theresa McLoud, Boston
Konstantin Nikolaou, Munich
Caroline Reinhold, Montreal
Donald Resnick, San Diego
Rüdiger Schulz-Wendtland, Erlangen
Stephen Solomon, New York
Richard D. White, Columbus
For further volumes: http://www.springer.com/series/4354
Medical Radiology—Diagnostic Imaging is a unique series that aims to document the most innovative technologies in all fields within diagnostic imaging and interventional radiology, thereby informing the physician in practice of the latest advances in diagnostic imaging and percutaneous imageguided minimally invasive procedures. The contents are intended to cover all organs, and all modern imaging techniques and image-guided treatment modalities, with special emphasis on applications in clinical practice. Each volume is a comprehensive reference book on a topical theme, and the editors are always experts of high international standing. Contributions are included from both clinicians and researchers, ensuring wide appeal. Medical Radiology —Radiation Oncology is a unique series that aims to document the most innovative technologies in all fields within radiology, thereby informing the physician in practice of the latest advances in diagnostic and treatment techniques. The contents range from contemporary statements relating to management for various disease sites to explanations of the newest techniques for tumor identification and of mechanisms for the enhancement of radiation effects, with the emphasis on maximizing cure and minimizing complications. Each volume is a comprehensive reference book on a topical theme, and the editors are always experts of high international standing. Contributions are included from both clinicians and researchers, ensuring wide appeal.
Hans-Ulrich Kauczor • Tobias Bäuerle Editors
Imaging of Complications and Toxicity following Tumor Therapy
Editors Hans-Ulrich Kauczor
Dept. of Radiology
University Hospital Heidelberg Heidelberg Germany
Tobias Bäuerle
Institute of Radiology
University Hospital Erlangen Erlangen Germany
ISBN 978-3-319-12840-5 ISBN 978-3-319-12841-2 (eBook)
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T. Bostel and F. Sterzing
Dimitri Psimaras, D. Leclercq, D. Ricard, and J.Y. Delattre
Part
John T. Murchison and Edwin J.R. van Beek
Rianne Wittenberg, Santiago Rossi, and Cornelia Schaefer-Prokop
Part
8
Maxim Avanesov, Andreas Block, and Gunnar K. Lund
G. Tallen, M. Warmuth-Metz, P. Hernáiz Driever, and Stefan M. Pfister
Imaging of Complications and Toxicity Following Tumour Therapy: Pelvis and Genitourinary (Male)
A. Shah, S.A. Sohaib, and D-M. Koh
Rosemarie Forstner and Teresa Margarida Cunha
Joana Ramalho and Mauricio Castillo
Björn Jobke and Hans Bloem
Chitra Viswanathan
Sharon Z. Adam, Michal Mauda-Havakuk, Ravit Geva, and Arye Blachar
Contributors
Sharon Z. Adam Department of Radiology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel
Department of Diagnostic Radiology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
Maxim Avanesov Department of Diagnostic and Interventional Radiology, Center for Radiology and Endoscopy, University Medical Center HamburgEppendorf, Hamburg, Germany
Edwin J.R. van Beek Queen’s Medical Research Institute, University of Edinburgh, Edinburgh, UK
Arye Blachar Computed Tomography and Magnetic Resonance Imaging Division, The Tel Aviv University Sackler School of Medicine, Tel Aviv, Israel
Department of Radiology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel
Andreas Block Department of Internal Medicine II and Clinic (Oncology Center), Center for Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
Hans Bloem Department of Radiology, Leiden University Medical Center, Leiden, The Netherlands
T. Bostel Department of Radiooncology and Radiation Therapy, Heidelberg University Hospital, Heidelberg, Germany
Mauricio Castillo Division of Neuroradiology, University of North Carolina, Chapel Hill, NC, USA
Teresa Margarida Cunha Department of Radiology, Instituto Português de Oncologia de Lisboa Francisco Gentil, Lisbon, Portugal
J.Y. Delattre AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Service de Neurologie 2-Mazarin, 47 Bd de l’hôpital, Paris, France
Centre OncoNeuroTox, Paris, France
Sorbonne Universités, Sorbonne Universités, UPMC Univ. Paris 06, Inserm, CNRS, UM 75, U 1127, UMR 7225, ICM, F-75013, Paris, France
P. Hernáiz Driever Department of Pediatric Oncology/Hematology, Charité-Universitätsmedizin Berlin, Berlin, Germany
Marco Essig Department of Radiology, University of Manitoba, Winnipeg, MB, Canada
Rosemarie Forstner Department of Radiology, Landeskliniken Salzburg, Paracelsus Medical University, Salzburg, Austria
Ravit Geva Department of Oncology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel
Ulrich Hacker University Cancer Center Leipzig (UCCL), University Hospital Leipzig, Leipzig, Germany
Björn Jobke Department of Radiology, Deutsches Krebsforschungszentrum (DKFZ), German Cancer Research Center, Heidelberg, Germany
D-M. Koh Department of Diagnostic Radiology, Royal Marsden Hospital, Sutton, Surrey, UK
D. Leclercq Centre OncoNeuroTox, Paris, France
Sorbonne Universités, Sorbonne Universités, UPMC Univ. Paris 06, Inserm, CNRS, UM 75, U 1127, UMR 7225, ICM, F-75013, Paris, France
Service de Neuroradiologie, Hôpital Salpêtrière, Paris, France
Michael M. Lell Department of Radiology, University Erlangen, Erlangen, Germany
Florian Lordick University Cancer Center Leipzig (UCCL), University Hospital Leipzig, Leipzig, Germany
Gunnar K. Lund Department of Diagnostic and Interventional Radiology, Center for Radiology and Endoscopy, University Medical Center HamburgEppendorf, Hamburg, Germany
Michal Mauda-Havakuk Department of Radiology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel
John T. Murchison Department of Radiology, Royal Infirmary of Edinburgh, Edinburgh, UK
Stefan M. Pfister Division of Pediatric Neurooncology (B062), Deutsches Krebsforschungszentrum (DKFZ), Heidelberg, Germany
Department of Pediatric Hematology and Oncology, Heidelberg University Hospital, Heidelberg, Germany
Dimitri Psimaras AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Service de Neurologie 2-Mazarin, 47 Bd de l’hôpital, Paris, France
Centre OncoNeuroTox, Paris, France
Sorbonne Universités, Sorbonne Universités, UPMC Univ. Paris 06, Inserm, CNRS, UM 75, U 1127, UMR 7225, ICM, F-75013, Paris, France
Joana Ramalho Division of Neuroradiology, University of North Carolina, Chapel Hill, NC, USA
D. Ricard Centre OncoNeuroTox, Paris, France
Sorbonne Universités, Sorbonne Universités, UPMC Univ. Paris 06, Inserm, CNRS, UM 75, U 1127, UMR 7225, ICM, F-75013, Paris, France
Service de Neurologie, Hôpital d’instruction des armées du Val-de-Grâce, Service de Santé des Armées, Paris, France
Santiago Rossi Centro de Diagnostico Dr Enrique Rossi, Buenos Aires, Argentina
Cornelia Schaefer-Prokop Department of Radiology, Meander Medical Center, Amersfoort, The Netherlands
Department of Radiology, Radboud University, Medical Center, Nijmegen, The Netherlands
A. Shah Department of Diagnostic Radiology, Royal Marsden Hospital, Sutton, Surrey, UK
S.A. Sohaib Department of Diagnostic Radiology, Royal Marsden Hospital, Sutton, Surrey, UK
Department of Diagnostic Radiology, Royal Marsden NHS Foundation Trust, Sutton, Surrey, England, UK
F. Sterzing Department of Radiooncology and Radiation Therapy, Heidelberg University Hospital, Heidelberg, Germany
G. Tallen Department of Pediatric Oncology/Hematology, CharitéUniversitätsmedizin Berlin, Berlin, Germany
Department of Pediatrics, Faculty of Medicine, University of Calgary, Calgary, AL, Canada
Chitra Viswanathan Division of Diagnostic Imaging, Department of Diagnostic Radiology, University of Texas MD Anderson Cancer Center, Houston, TX, USA
M. Warmuth-Metz Department of Neuroradiology, Universität Würzburg, Würzburg, Germany
Rianne Wittenberg Department of Radiology, Meander Medical Center, Amersfoort, The Netherlands
Part I
Basics of Toxicity of Tumor Therapies
2.1
Chemotherapy and Targeted Therapy
Florian Lordick and Ulrich Hacker
Abstract
A precise knowledge of antineoplastic drugs is an indispensable basis for the care of patients with cancer. The mechanisms of action and resistance, cross-resistance patterns, pharmacodynamics and pharmacokinetics, pharmacological interaction, and last but not least potential adverse effects should be part of this knowledge. As contemporary cancer care requires interdisciplinary and multiprofessional structures, the radiologist is an important and integral part of the oncological treatment team. He has several key roles. Besides the determination of an accurate clinical staging which is the basis for all treatment recommendations, he evaluates the response to anticancer treatment and defines the remission status following treatment. Importantly, he assesses acute and long-term treatment toxicities, both having a tremendous impact on patients’ safety and quality of life. This article summarizes the principles of medical anticancer treatment and outlines the major side effects associated with drug classes and specific antineoplastic compounds.
F. Lordick (*) • U. Hacker
University Cancer Center Leipzig (UCCL), University Hospital Leipzig, Liebigstr. 20, Leipzig D- 04103, Germany e-mail: direktion.uccl@medizin.uni-leipzig.de
Besides the locally active treatment modalities (surgery and radiation therapy), drug therapy is the third important column of anticancer treatment. Applied via the bloodstream, medical therapy can hit not only the primary tumor but also lymphatic and hematogenous disseminated tumor cells and metastases.
“Cytotoxic drug” denominates a compound that inhibits cell division and kills cells. By its effects on nucleic acid formation, DNA synthesis and repair, and protein synthesis and by the inhibition of particular protein functions that are associated with survival, proliferation, and migration, these drugs exert antiproliferative cytostatic effects or cytotoxic effects as programmed cell death (apoptosis), cell destruction (necrosis), and induction of senescence. Of note, all these effects do not only occur in neoplastic tumor cells but can alter also cells of the healthy tissue, depending on the susceptibility of particular organs to the cytotoxic drug effects. Therefore, cancer chemotherapy has transitioned from the use of cytotoxic drugs to the era of agents with an apparent selectivity for a cancer-specific target (Phelps and Sparreboom 2014). However, targets which are completely specific for cancer cells seem to be rare. And even if such characteristics exist, like the Philadelphia chromosome translocation in chronic myeloid leukemia coding for the cancer-specific bcr/abl tyrosine kinase (Heisterkamp et al. 1985), drugs hitting that target do not work absolutely target specific and do have an impact on functional structures of healthy tissue cells as well.
A classification of anticancer treatment into classical cytostatic or cytotoxic chemotherapy, antihormonal therapy, monoclonal antibody treatment, or treatment with tyrosine kinase inhibitors has historic reasons and appears arbitrary as the cell biological effects of those therapies are pleiotropic and have a great overlap. A certain relevance lies in the discrimination of the mostly non-cancer selective classical cytotoxic treatment (“chemotherapy”) and the so-called selective targeted treatment forms like antihormonal therapy, therapeutic
antibodies, and kinase inhibitors. The therapeutic index of classical cytotoxic drugs like alkylating agents is often smaller than that of biologically targeted forms of therapy (Fig. 1).
Classical cytotoxic drugs have different mechanisms of action which are outlined in Fig. 2
Hanahan and Weinberg described the hallmarks of cancer in a previous landmark article that was updated in 2011. These hallmarks include sustaining proliferative signaling, evading growth suppressors, resisting cell death, enabling replicative immortality, inducing angiogenesis, and activating invasion and metastasis. Conceptual progress in the last decade has added two emerging hallmarks of potential generality to this list – reprogramming of energy metabolism and evading immune destruction. The “tumor microenvironment” that consists of apparently normal cells adds to the complexity of current tumor characteristics which forms the basis for contemporary drug development and targeted treatment of cancer (Fig. 3) (Hanahan and Weinberg 2011).
Fig. 1 The concept of therapeutic index refers to the relationship between toxic and therapeutic doses. This pharmacodynamic parameter is relevant to clinical practice because it determines how safe or toxic a drug is. Both ED50 and TD50 are calculated from dose-response curves, which represent the frequency with which each dose of drug elicits the desired response or toxic effect in the population. The dose required to cause a therapeutic effect (positive response) in 50 % of a population is the ED50. The dose required to produce a toxic effect in 50 % of the studied population is the TD50 (Redrawn from Craig and Stitzel (2003))
Purine analogues
6-MP
6-TG
MTX
Pyrimidine analogues
5-FU
Raltitrexed
Pemetrexed
MTX
Ribonucleotide reductaseinhibitors
Hydroxyurea
DNA polymerase inhibitor
Cytarabine
DNA alkalyting agent
N-Lost-derivatives
Nitrosoureas
Oxaphosphorines
Platinum compounds
Da-/Procarbazine
Thiotepa
Mitomycine C
Topoisomerase inhibitors
Etoposide
Anthracyclines
Irinotecan
Topotecan
Proteine degradation L-Asparaginase
Vinca alcaloids
Vincristine
Vinblastine
Vindesine
Vinorelbine
Taxanes
Paclitaxel
Docetaxel
Cabazitaxel
Fig. 2 Target structures of classical cytotoxic drugs: DNA deoxyribonucleic acid, MTX methotrexate, 5-FU 5-fluorouracil, 6-MP 6-mercaptopurine, 6-TG 6-thioguanine
EGFR inhibitors
Aerobic glycolysis inhibitors
Proapoptotic BH3 mimetics
Deregulating cellular energetics
Sustaining proliferative signaling
Cyclin-dependent kinase inhibitors
Evading growth suppressors
Immune activating anti-CTLA4 mAb
Avoiding immune destruction
Resisting cell death
PARP inhibitors
Genome instability & mutation
Inducing angiogenesis
Inhibitors of VEGF signaling
Enabling replicative immortality
Tumorpromoting inflammation
Activating invasion & metastasis
Inhibitors of HGF/c-Met
Telomerase Inhibitors
Selective antiinflammatory drugs
Fig. 3 The hallmarks of cancer (Redrawn from Hanahan and Weinberg (2011)) are the basis for contemporary drug development and targeted anticancer treatment
Definitions of Anticancer Drug Therapy
2.1 Mono- Versus Combination Therapy
In principle, combination chemotherapy has advantages over monotherapy due to additive or multiplicative effects of tumor cell kill. Primary or secondary resistant tumor cell clones can be eradicated or suppressed by different mechanisms of action. Ideally, combinations have the following features:
• The combined agents are equally effective.
• Lack of cross-resistance.
• Different mechanisms of action.
• Additive or synergistic mechanisms of action.
• No overlapping toxicities.
For most combinations, this ideal situation does not exist. Especially with regard to side effects, some addition of toxicity must always be accepted when combinations are used.
2.2 Induction Chemotherapy
Induction chemotherapy is used when at the time of diagnosis no acceptable therapeutic alternative exists. Induction chemotherapy shall bring the cancer into a state of better therapeutic options. The goal is “the induction” of an optimal remission, which is at best a “complete remission.” High treatment intensities are usually necessary for an optimal induction. Therefore, the probability of inducing adverse effects is usually high.
2.3
Consolidation Therapy
The consolidation therapy shall provide the eradication of clinically occult residual tumor. It shall improve the rate of true complete remissions. Thereby, consolidation shall increase the chances of cure or increase the duration of response.
F. Lordick and U. Hacker
2.4 Maintenance Therapy
Maintenance therapy, in its classical sense used in the treatment of hematological malignancies like acute leukemia, follows consolidation and shall eradicate or control further residual tumor cells, e.g., those that – due to kinetic resistance –were not yet eradicated by the previous treatment. Maintenance therapy can increase the chance of cure or prolong the time interval until further tumor progression. The latter goal is nowadays often chosen in the palliative treatment of solid tumors when a remission has been achieved by a more intensive treatment period preceding maintenance.
Neoadjuvant (also primary or preoperative) therapy is a treatment in patients with localized or locoregional tumor extension in which the application of local treatment alone (operation or radiation therapy) may lead to an unsatisfactory outcome. Neoadjuvant chemotherapy is applied to reduce the extent of surgery (e.g., in breast cancer, where size reduction of large tumors allows for more breast-conserving surgery following neoadjuvant chemotherapy) and to increase the chances of cure (like in gastric or muscle invasive bladder cancer). In some cancers (e.g., osteosarcoma and Ewing sarcoma), postoperative treatment is tailored on the basis of the achieved response during neoadjuvant therapy. The goal of adjuvant chemotherapy is the eradication of subclinical metastases (“micrometastases”) following primary local treatment (operation or radiation therapy). The clinical goal of treatment is to increase the cure rate.
Accepted indications for perioperative chemotherapy are shown in Table 1. As increased cure rates are the goal of neo-/adjuvant chemotherapy, optimal dose intensity is necessary and some toxicity must be accepted. On the other hand, treatment safety is of utmost importance as patients may survive with the operation alone. In addition, long-term side effects should be avoided
Table 1 Examples for tumors with an established indication for perioperative (neoadjuvant or adjuvant) therapy
Breast cancer
Ovarian cancer
Esophageal cancer
Gastric cancer
Pancreatic cancer
Colon cancer
Rectal cancer
Lung cancer
Testicular cancer
Urothelial cancer
Ewing sarcoma
Osteosarcoma
Rhabdomyosarcoma
as they may lead to a significant impairment of quality of life of cancer survivors; alter physical, cognitive, and social functioning; and may even induce secondary diseases (cancers, leukemia, organ dysfunctions, cardiovascular diseases, etc.) leading to a negative impact on life expectancy.
2.6 Palliative Therapy
Palliative chemotherapy is a treatment intended to prolong life, to control symptoms, and to augment quality of life. In case of symptomatic disease, more intensive induction treatment regimens are often applied. For a further stabilization of the tumor, most often less intensive monotherapies are regarded as standard of care. Treatment-emergent side effects must be carefully weighed against potential treatment benefits.
3 Classification of Anticancer Drugs
The classification of anticancer drugs can follow different criteria. Traditionally, the World Health Organization (WHO) chose the mechanisms of action (e.g., alkylating agent) and the origin of compounds (e.g., antitumor antibiotics) as their leading criteria for classification. Table 2 groups the compounds predominantly according to their mechanisms of action.
4
Classification of Treatment Toxicity
Side effects of medical treatment have been classified according to uniform criteria as long as the drug is applied within a clinical study.
Internationally, the so-called Common Toxicity Criteria (CTC) or the newer Common Terminology Criteria for Adverse Events (CTCAE) as developed and published by the
National Cancer Institute (NCI, Bethesda, USA) are most commonly used. Meanwhile, these criteria have been well implemented into clinical practice and proved useful. Therefore, thorough oncologists and multidisciplinary teams use it outside of clinical studies in routine cancer care. The current version of CTCAE V4.03 can be downloaded from the Internet (http://evs.nci.nih. gov/ftp1/CTCAE/CTCAE_4.03_2010-06- 14_ QuickReference_8.5x11.pdf).
Table 2 Classification of anticancer drugs according to their mechanisms of action and biochemical properties
Drug class Group
Alkylating agent
N-lost-derivatives
Nitrosourea derivatives
Oxaphosphorines
Platinum derivatives
Tetrazines
Aziridines
Others
Antibiotics
Anthracyclines
Alkaloids
Anthracenedione
Others
Podophyllotoxin derivative
Vinca alkaloids
Taxanes
Camptothecin derivatives
Compound
Bendamustine
Busulfan
Chlorambucil
Nimustine (ACNU)
Carmustine (BCNU)
Lomustine (CCNU)
Cyclophosphamide
Ifosfamide
Trofosfamide
Cisplatin (CDDP, DDP)
Carboplatin
Oxaliplatin
Dacarbazine (DTIC)
Temozolomide
Thiotepa
Amsacrine (AMSA)
Estramustinphosphate
Procarbazine
Treosulfan
Daunorubicin
Doxorubicin
Epirubicin
Idarubicin
Mitoxantrone
Actinomycin-D
Bleomycin
Mitomycin C
Etoposide (VP-16)
Vinblastine
Vincristine
Vindesine
Vinorelbine
Cabazitaxel
Docetaxel
Paclitaxel
Irinotecan
Topotecan
F. Lordick and U. Hacker
Table 2 (continued)
Drug class Group
Antimetabolite
Antifolates
Purine analogues
DNA demethylation
Protein degradation
Aromatase inhibition
Other hormonal therapies
Pyrimidine analogues
Immune modulators
RNR inhibitor
Demethylating agents
Enzyme
Nonsteroidal inhibitors
Steroidal inhibitor
Antiandrogens
Monoclonal antibodies
Antiestrogen
Gestagens
Selective estrogen receptor modulators
Cytokines
IMIDs
Immune checkpoint inhibitors
CD20 antibodies
CD30 antibody-toxin conjugate
CD33 antibody
CD52 antibody
EGFR antibodies
HER2 antibodies
HER2 antibody-toxin conjugate
VEGF antibody
VEGF recombinant fusion protein
VEGFR2 antibody
Compound
Methotrexate (MTX)
Pemetrexed
6-Mercaptopurine (6-MP)
6-Thioguanine (6-TG)
Fludarabine
2-Chlordeoxyadenosine (2-CDA)
5-Fluorouracil (5-FU)
Capecitabine
Clofarabine
Cytosine arabinoside (AraC)
Gemcitabine
Hydroxyurea
Azacytidine
Decitabine
L-asparaginase
Anastrozole
Letrozole
Exemestane
Abiraterone
Bicalutamide
Flutamide
Nilutamide
Fulvestrant
Medroxyprogesterone acetate
Megestrol acetate
Raloxifene
Tamoxifen
Interferon alpha
Interleukin 2
Lenalidomide
Thalidomide
Pomalidomide
Ipilimumab
Lambrolizumab
Rituximab
Ofatumumab
Brentuximab vedotin
Gemtuzumab ozogamicin
Alemtuzumab
Cetuximab
Panitumumab
Trastuzumab
Pertuzumab
Trastuzumab emtansine
Bevacizumab
Aflibercept
Ramucirumab
(continued)
Table 2 (continued)
Drug class Group
Tyrosine kinase inhibitors
Bcr/abl
cKIT
EGFR
HER2
Histone deacetylase (HDAC)
mTOR
Multiple kinases
Proteasome
RAF
Smoothened receptor (hedgehog signaling)
Somatostatin receptors
Compound
Imatinib
Dasatinib
Nilotinib
Imatinib
Afatinib
Erlotinib
Gefitinib
Lapatinib
Romidepsin
Vorinostat
Temsirolimus
Everolimus
Axitinib
Nintedanib
Pazopanib
Regorafenib
Sorafenib
Sunitinib
Bortezomib
Carfilzomib
Vemurafenib
Vismodegib
Octreotide
Lanreotide
Compounds are listed with their generic names. Where appropriate, commonly used abbreviations are listed in parentheses
The NCI Common Terminology Criteria for Adverse Events is a descriptive terminology which can be utilized for adverse event (AE) reporting. A grading (severity) scale is provided for each AE term. System Organ Class (SOC), the highest level of the reporting hierarchy, is identified by anatomical or physiological system, etiology, or purpose (e.g., SOC Investigations for laboratory test results). Within each SOC, adverse events are listed and accompanied by descriptions of severity (grade).
An AE is any unfavorable and unintended sign (including an abnormal laboratory or imaging finding), symptom, or disease temporally associated with the use of a medical treatment or procedure that may or may not be considered related to the medical treatment or procedure. An AE is a term that is a unique representation of a specific event used for medical documentation and scientific analyses.
Grade refers to the severity of the AE. The CTCAE displays grades 1 through 5 with unique clinical descriptions of severity for each AE based on this general guideline (Table 3). Not all grades are appropriate for all AEs. Therefore, some AEs are listed with fewer than five options for grade selection.
5 Specific Toxicities Associated with Anticancer Treatment
All organ systems can be subject to treatmentemergent toxicities.
With classical cytotoxic treatment, myelosuppression (neutropenia, thrombocytopenia, and anemia) is a common side effect. Between 80 and 100 % of all patients undergoing chemotherapy have some grade of myelosuppression leading to
F. Lordick and U. Hacker
Table 3 Toxicity grades according to the “Common Terminology Criteria for Adverse Events” (CTCAE) reporting system provided by the National Cancer Institute, Bethesda, USA
Grade Severity
Grade 1 Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated
Grade 2 Moderate; minimal, local, or noninvasive intervention indicated; limiting ageappropriate instrumental activity of daily living (ADL)a
Grade 3 Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care ADLb
A semicolon indicates “or” within the description of the grade aInstrumental ADL refer to preparing meals, shopping for groceries or clothes, using the telephone, managing money, etc.
bSelf-care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking medications, and not bedridden Chemotherapy and
alterations of the differential blood counts. Severity and duration depend of course on the applied cytotoxic drug and schedule as well as additional risk factors, like age and general health status. In case of neutropenia, patients are at particular risk of acquiring infections. Febrile neutropenia is an emergency situation during antineoplastic treatment. It requires immediate clarification and start of empiric antibiotic treatment. In most cases (except low-risk neutropenia in otherwise unimpaired and compliant patients), this should be done following hospitalization, and intravenous broad-spectrum antibiotics should be given (Klastersky and Paesmans 2013). In more than two thirds of patients, the focus of febrile neutropenia remains unknown, but pulmonary infections, bloodstream infections, urinary infections, infections of the skin and soft tissues, as well as infections of the upper aerodigestive tract should be excluded by appropriate clinical, paraclinical, and radiological diagnostics.
Apart from myelosuppression, nonhematological adverse events are common and
need to be well known by the treatment team. Table 4 outlines a selection of substance- and group-specific non-hematological toxicities of anticancer drugs.
Our expectation was that with the introduction of new, more specific and biologically targeted drugs, the efficacy of anticancer treatment would increase, while the side effects would decrease. This hope was desperately disappointed (Niraula et al. 2012). International investigators analyzed all randomized controlled trials evaluating agents approved for the treatment of solid tumors by the US Food and Drug Administration between 2000 and 2010. Odds ratios were computed for three end points of safety and tolerability: treatmentrelated death, treatment discontinuation related to toxicity, and grade 3 or grade 4 adverse events (AEs). These were then pooled in a meta-analysis. Correlations between these end points and the hazard ratios for overall survival and progressionfree survival were also assessed. The investigators came to the conclusion that new anticancer agents that lead to improvements in time-to-event end points also increase morbidity and treatmentrelated mortality. The balance between efficacy and toxicity may be less favorable in clinical practice because of selection of fewer patients with good performance status and limited comorbidities. Patients’ baseline health characteristics should be considered when choosing therapy.
With the use of targeted therapies, novel side effects have emerged that are closely related to the specific mechanisms of action of the respective drug. Targeted therapies in general block certain signaling pathways that play important roles in promoting tumor cell survival and proliferation or interfere with stromal cells like vascular endothelial cells to inhibit tumor angiogenesis or with immune cells to modify antitumor immune responses. Monoclonal antibodies and tyrosine kinase inhibitors (TKI) represent the drug classes that are most commonly used for targeted cancer therapy. Furthermore, specific intracellular signaling checkpoints can be blocked by chemical compounds (i.e., mTOR inhibitors). Another group of drugs targets immune function to improve host anticancer immunity. CTLA-4 antibodies are used to enhance T-cell co-stimulation,
Table 4 Selection of substance and group-specific non-hematological toxicities of anticancer drugs
Substance/group
Alemtuzumab
Anthracyclines/mitoxantrone
Aromatase inhibitors
Bevacizumab
Bleomycin
Bortezomib
Busulfan
Cetuximab/panitumumab
Chlorambucil
Cytarabine
Docetaxel
Erlotinib/gefitinib
Fluoropyrimidines
Imatinib
Irinotecan
Methotrexate
Mitomycin C
Sunitinib/pazopanib/sorafenib/regorafenib
mTOR inhibitors (everolimus, temsirolimus)
Nitrosoureas
Oxazaphosphorines (cyclophosphamide, ifosfamide)
Paclitaxel/docetaxel
Platinum compounds
Tamoxifen
Trastuzumab/pertuzumab/lapatinib
Vinca alkaloids
Typical adverse effect
Opportunistic infection
Cardiomyopathy, cardiac arrhythmia
Bone and joint pain, osteoporosis
Arterial hypertension, proteinuria, impaired wound healing, gut perforations, bleeding
Pulmonary toxicity, lung fibrosis
Neuropathy
Pulmonary toxicity, veno-occlusive disease
Acneiform exanthema, allergic reactions
Pulmonary toxicity, lung fibrosis
Central nervous toxicity (especially high-dose AraC leads to cerebellar alterations)
Finger- and toenail alterations, edema, neuropathy, taste alterations
and drugs targeting the PD-1/PD-L1 pathway have been developed to block inhibitory immune checkpoints.
An overview of key side effects can be found in Table 2. Specific side effects resulting in pathological radiological findings are shortly summarized in the following section.
Agents Targeting the Epidermal Growth Factor Receptor (EGFR): The monoclonal antibodies (cetuximab, panitumumab) are used for the treatment of RAS wild-type metastatic colorectal cancer, while TKI (gefitinib, erlotinib, afatinib) represent a standard of care in the treat-
ment of EGFR-mutated non-small cell lung cancer (NSCLC) patients. Skin toxicities occur with high frequency in both groups of drugs. In contrast, interstitial lung disease (ILD) represents a rare complication, and the mechanism is not fully understood. Disruption of the alveolar epithelial function however may play a role. Based on this, the frequency of ILD is higher in smokers and in patients with preexisting lung disease (Ando et al. 2006).
Agents Targeting Her-2: Chemotherapy combined with monoclonal antibodies (trastuzumab, pertuzumab) represents a treatment standard in
F. Lordick and U. Hacker
Her2-positive breast cancer and in Her2 gastric cancer (trastuzumab). The TKI lapatinib targeting EGFR and Her2neu is approved for the treatment of breast cancer. An important side effect of this class of drugs is cardiotoxicity that is related to the expression of Her2 on cardiomyocytes. Mechanistically, Her2 signaling results in sarcomere stability and initiates repair processes that are important to counteract toxic stress (Tocchetti et al. 2012).
Agents Targeting Tumor Angiogenesis: The monoclonal antibody bevacizumab binds vascular endothelial growth factor (VEGF), and the fusion construct aflibercept binds VEGF and placental growth factor (PlGF). Both drugs are used in combination with chemotherapy for the treatment of metastatic colorectal cancer. Additionally, a large number of TKI targeting VEGF receptors and other receptors are in clinical use for the treatment of a wide variety of cancer types (Table 2). Hypertension and proteinuria represent common side effects of VEGF-targeting therapy. Furthermore, the rate of thromboembolic complications is increased. Other side effects are related to impaired tissue repair capacity and comprise gastrointestinal pneumatosis perforations and the formation of fistulas (Shinagare et al. 2012). Overall, bleeding is a rare side effect. However, frequent bleeding complications have resulted in the exclusion of the use of bevacizumab in squamous cell carcinoma of the lung. Progressive reversible encephalopathy syndrome (PRES) is a very rare (≤0.1 %) but severe neurological complication that has been reported in patient treatment with bevacizumab or aflibercept (Seet and Rabinstein 2012). The disruption of cerebrovascular endothelial cell signaling is related to the disruption of cerebrovascular autoregulation preferentially in the posterior circulation of the brain. Finally, pancreatitis (sunitinib, sorafenib, pazopanib) and acalculous cholecystitis (sunitinib) have been reported in the literature on a casuistic basis.
Anaplastic Lymphoma Kinase (ALK) Inhibitors: ALK inhibitors are used for the treatment of NSCLC harboring specific genomic rearrangements (EML4-ALK). Pneumonitis has been
reported with the use of the ALK inhibitor crizotinib and symptoms started within two months of treatment. The underlying mechanisms are not yet clarified.
RAF-Targeting Agents: RAF-targeting agents include the multi-TKI sorafenib for the treatment of renal cell and hepatocellular cancer as well as vemurafenib and dabrafenib, which are used for the treatment of melanoma harboring the B-Raf mutation V600E and other B-Raf mutations. An increase in the occurrence of cutaneous squamous cell carcinomas has been reported, and nodular panniculitis (Monfort et al. 2012) may result in increased radiotracer uptake during 18F-FDG positron emission tomography (PET).
Agents Targeting Mammalian Target of Rapamycin (mTOR) and Targeted Immune Modulators: These agents (everolimus, temsirolimus) are used for the treatment of breast and renal cancers and pancreatic neuroendocrine tumors. Mucositis and aphthous mucosal lesions are common side effects. Additionally, interstitial pneumonitis is an important side effect of this class of drugs with up to 36 % of patients showing any pulmonary abnormalities during treatment (Duran et al. 2014).
Ipilimumab is a novel targeted immune modulator that interacts with CLTA-4, thus fostering co-stimulatory function to improve host antitumor immune response. Due to immune function deregulation, autoimmune-related side effects like enterocolitis and hypophysitis may occur. Additionally, unspecific lymph node enlargement and soft tissue changes like myositis or fasciitis as well as retroperitoneal fat opacities due to lymphocyte infiltration may interfere with treatment response assessment (Bronstein et al. 2011).
As examples of “new toxicities” emerging from biologically selective targeted drugs, Fig. 4 displays a perforation at the rectosigmoid level that occurred during treatment of metastatic colorectal cancer with the anti-VEGF antibody bevacizumab. Another patient who was also treated for metastatic colorectal cancer received the monoclonal anti-EGFR antibody cetuximab plus chemotherapy and developed a grade 3 skin rash during weeks 4–6 of this combined treatment (Fig. 5).
Fig. 4 Gut perforation leading to an ileus and peritonitis, emerging from a pararectal abscess in a patient with colorectal cancer with simultaneous liver and lung metastases. (a) Is illustrating the coronary section through the abdomen; (b) is illustrating a transversal section through
the pelvis. The two white arrows in b are highlighting the formation of a pararectal abscedation. This patient was treated with the anti-VEGF monoclonal antibody bevacizumab in combination with chemotherapy
ab
Fig. 5 (a, b) Patient who developed severe (grade 3 according to CTCAE V4.03) skin rash during weeks 4–6 of chemotherapy combined with the anti-EGFR-directed monoclonal antibody cetuximab
F. Lordick and U. Hacker
Conclusions
For clinical practice, we have to state that medical anticancer treatment is more demanding than ever, as toxicities are very common, polymorphic and allotropic. They may lead to severe impairment of the patients’ safety and quality of life. All members of the treatment team, including the radiologist, need to do their best to support patients during anticancer treatment. Treatment-emergent as well as tumor-related complications may not be missed, and the severity of events must be appropriately classified. In addition, for drug development it has been advocated to move “Toward Patient-Centered Drug Development in Oncology” (Basch 2013).
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Ando M, Okamoto I, Yamamoto N, Takeda K, Tamura K, Seto T, Ariyoshi Y, Fukuoka M (2006) Predictive factors for interstitial lung disease, antitumor response, and survival in non-small-cell lung cancer patients treated with gefitinib. J Clin Oncol 24(16):2549–2556. doi:10.1200/JCO2005.04.9866
Basch E (2013) Toward patient-centered drug development in oncology. N Engl J Med 369(5):397–400. doi:10.1056/NEJMp1114649
Bronstein Y, Ng CS, Hwu P, Hwu WJ (2011) Radiologic manifestations of immune-related adverse events in patients with metastatic melanoma undergoing anti-CTLA-4 antibody therapy. AJR Am J Roentgenol 197(6):W992–W1000. doi:10.2214/AJR.10.6198
Craig CR, Stitzel CR (2003) Modern pharmacology with clinical applications, 6th edn. Lippincott, Williams & Wilkins, Philadelphia
Duran I, Goebell PJ, Papazisis K, Ravaud A, Weichhart T, Rodriguez-Portal JA, Budde K (2014) Drug-induced
pneumonitis in cancer patients treated with mTOR inhibitors: management and insights into possible mechanisms. Expert Opin Drug Saf 13(3):361–372. doi:10.1517/14740338.2014.888056
Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144(5):646–674. doi:10.1016/j.cell.2011.02.013
Heisterkamp N, Stam K, Groffen J, de Klein A, Grosveld G (1985) Structural organization of the bcr gene and its role in the Ph′ translocation. Nature 315(6022):758–761
Klastersky J, Paesmans M (2013) The Multinational Association for Supportive Care in Cancer (MASCC) risk index score: 10 years of use for identifying low-risk febrile neutropenic cancer patients. Support Care Cancer 21(5):1487–1495. doi:10.1007/s00520-013-1758-y
Monfort JB, Pages C, Schneider P, Neyns B, Comte C, Bagot M, Vignon-Pennamen MD, Viguier M, Lebbe C (2012) Vemurafenib-induced neutrophilic panniculitis. Melanoma Res 22(5):399–401. doi:10.1097/ CMR.0b013e3283570792
Niraula S, Seruga B, Ocana A, Shao T, Goldstein R, Tannock IF, Amir E (2012) The price we pay for progress: a meta-analysis of harms of newly approved anticancer drugs. J Clin Oncol 30(24):3012–3019. doi:10.1200/JCO.2011.40.3824
Phelps MA, Sparreboom A (2014) A snapshot of challenges and solutions in cancer drug development and therapy. Clin Pharmacol Ther 95(4):341–346. doi:10.1038/clpt.2014.15
Seet RC, Rabinstein AA (2012) Clinical features and outcomes of posterior reversible encephalopathy syndrome following bevacizumab treatment. QJM 105(1):69–75. doi:10.1093/qjmed/hcr139
Shinagare AB, Howard SA, Krajewski KM, Zukotynski KA, Jagannathan JP, Ramaiya NH (2012) Pneumatosis intestinalis and bowel perforation associated with molecular targeted therapy: an emerging problem and the role of radiologists in its management. ARJ Am J Roentgenol 199(6):1259–1265. doi:10.2214/AJR.12.8782
Tocchetti CG, Ragone G, Coppola C, Rea D, Piscopo G, Scala S, De Lorenzo C, Iaffaioli RV, Arra C, Maurea N (2012) Detection, monitoring, and management of trastuzumab-induced left ventricular dysfunction: an actual challenge. Eur J Heart Fail 14(2):130–37. doi:10.1093/eurjhf/hfr165
Radiotherapy
T. Bostel and F. Sterzing
T. Bostel • F. Sterzing (*) Department of Radiooncology and Radiation Therapy, Heidelberg University Hospital, Im Neuenheimer Feld 400, Heidelberg 69120, Germany
The focus of this chapter lies on the description of the general basics of early and late radiation effects and the translation of these pathogenetic processes into imaging; furthermore, a few short clinical examples including imaging patterns of those underlying pathogenetic normal tissue reactions are given to provide a better understanding. In addition, the margin concepts used in radiotherapy as well as the important radiation techniques are summarized, as it is very important for diagnostic radiologists to correlate posttherapeutic tissue and organ changes in follow-up examinations with dose characteristics of a certain treatment to achieve a higher degree of reliability in image interpretation. Furthermore, for
17
a better understanding of the cellular basis of the various radiogenic tissue effects, a short refresher about the underlying radiobiological principles is given. The detailed description of specific radiation effects and imaging patterns of clinically relevant organs and tissues, however, follows in the specific organ chapters in order to avoid redundancy.
Abbreviations
CLE Consequential late effects
COX-2 Cyclooxygenase-2
CT Computed tomography
CTV Clinical target volume
3D Three dimensional
4D Four dimensional
DNA Deoxyribonucleic acid
EBRT External-beam radiation therapy
e.g. Exempli gratia
GTV Gross tumor volume
Gy Gray
i.e. Id est
IL-1a Interleukin-1 alpha
iNOS Inducible nitric oxide synthase
IGRT Image-guided radiotherapy
IMRT Intensity-modulated radiation therapy
MRI Magnetic resonance imaging
mRNA Messenger ribonucleic acid
NTCP Normal tissue complication probability
OAR Organs at risk
PET Positron emission tomography
PTV Planning target volume
RBE Relative biological effectiveness
RR Relative risk
SBRT Stereotactic body radiation therapy
TD Tolerance dose
TGF-ß Transforming growth factor-ß
TNF-a Tumor necrosis factor alpha
VOD Veno-occlusive disease
1 Introduction
Radiotherapy plays a vital role in the oncological treatment concept besides surgical and systemic therapies. Moreover, it is an effective local cancer
T. Bostel and F. Sterzing
therapy like surgery, but beyond that it offers the chance for regional high-volume treatments of microscopic tumor deposits or lymphatic pathways as transition to systemic treatments. This pivotal role of radiotherapy is also supported by epidemiological data: More than half of all cancer patients can be cured nowadays, owing to improved efficacy of advanced and mostly multimodal cancer therapies, and around half of these patients receive either radiotherapy alone or radiotherapy in combination with other cancer treatments. Moreover, about two thirds of cancer patients gain valuable palliation by radiation to alleviate the symptoms and to improve the quality of life in the course of their advanced disease.
In recent years, substantial advances in radiological imaging as well as computer hardware and software along with improved design of medical linear accelerators have contributed significantly to the development in radiation therapy. Nowadays, existing modern radiation techniques enable the delivery of conformal dose distributions with steep dose gradients between the tumor and adjacent normal tissue structures. Thus, intensification of the radiation dose to the tumor and reduction of high-dose irradiation of sensitive organs and normal tissues are possible resulting in higher curing rates and lower rates of side effects (i.e., increased therapeutic ratio). However, despite these advances, modern radiotherapy still leaves significant proportions of healthy tissue structures exposed to relatively high doses. This is in part caused by the margin concepts used in radiotherapy. In general, the determination of the planning target volume (PTV) necessarily requires the inclusion of the visible or palpable extent of tumor (i.e., gross tumor volume, GTV) as well as an additional surrounding area without visible branches of the tumor in order to take microscopic disease into account (i.e., clinical target volume, CTV). Furthermore, a patient-specific safety margin is added, if necessary, to account for the range of target motion related to breathing, pulsations, or intestinal peristalsis (e.g., lung or liver lesions) that is often based on four-dimensional (4D) imaging information derived from the planning
Fig. 1 Dose dependency of tumor control (green sigmoid curve) and side effect (red sigmoid curve) probability (according to Holthusen): Due to the fact that both curves overlap, there is no chance for complete tumor destruction through radiotherapy without any risk of normal tissue complications – the third blue curve depicts the therapeutic window (Figure provided by courtesy of Dr. Dr. Thieke) Radiotherapy
CT. And finally, a margin to encompass variability in patient positioning (setup) and mechanical uncertainty is added to create the final PTV. This PTV concept accounts for all available radiation techniques, even though modern approaches such as stereotactic radiation therapy or intensitymodulated radiation therapy enable to adapt the dose distribution more precisely to the tumor boundaries than traditional radiation techniques, which in turn helps to spare the adjacent healthy organs and tissues. On the other hand, PTV can encompass extended areas of normal tissues, dependent on the tumor and disease stage, for example, irradiations of the whole body, whole brain, spinal column, or breast with or without the supraclavicular lymph nodes after breastconserving surgical treatment.
In the follow-up care of cancer patients, however, it is very important that side effects after therapeutic irradiations are not in general regarded as an indicator for medical malpractice. Moreover, it is an indicator for the best-possible treatment and maximum cure probability when these radiogenic effects manifest with only a defined low incidence of sequelae of defined severity in cured patients (Dorr 2009) (Fig. 1). Regarding the evaluation of side effects, it has also to be mentioned that radiotherapy is increasingly combined with other local and systemic therapeutic approaches such as operation, chemotherapy, or molecular targeting which may lead not only to additive but also to synergistic effects for the tumor response and for organ-specific injuries (Dische et al. 1989; Pedersen et al. 1994). Furthermore, it has to be considered that a certain number of pathological conditions may be triggered by other reasons than specific tumor therapies, such as comorbidities, the tumor itself, or other non-oncological treatments, for example, obstipation due to analgesia with opioids.
As a consequence of increased numbers of cancer survivors and prolongation of survival times, late radiation sequelae as well as secondary cancers are more frequently seen than in the past. This subject has therefore gained more relevance in oncological studies as well as clinical followup examinations in recent years. Therefore, it is of utmost importance that radiologists are familiar
Toleranz überscnritten
with the imaging patterns of these therapy-related tissue reactions as they may both mimic and obscure tumor relapses. Beyond interpretation of posttreatment imaging, diagnostic specialists can make further valuable contributions to increase the therapeutic ratio preceding the radiation treatment process (Terezakis et al. 2011). First of all, every cancer treatment, particularly radiotherapy, heavily relies on accurate staging of the cancerous disease in order to select an appropriate treatment regimen for each patient. It is obvious that misdiagnosis in staging may have fatal consequences for the patient with regard to therapy-associated complications and treatment outcome. For example, unrecognized local tumor extension in an early stage of the disease may result in an insufficient local therapy with persistence of residual tumor cells that trigger the further course of the disease, either with new local symptoms or with propagation of systemic spread of these cells. Similar devastating consequences may result from overtreatment, for example, through radiotherapy, with avoidable early and late therapy effects and worsening of the patient’s general condition. This is especially important, since late sequelae of any oncological treatment are therapeutically difficult to influence and characterized by a progressive pattern in many cases (see below). Taken together, accurate staging is an essential precondition for a successful treatment
of cancer patients. Further input of diagnostic specialists may be provided during the routine radiation oncology workflow: Delineation of the macroscopic tumor (GTV) often requires additional advanced imaging modalities such as MRI or PET/CT and reaches beyond the normal anatomic information. As tumor imaging has been increasing in both the amount and the complexity of information, an in-depth knowledge of oncologic radiology has become more and more crucial in recent times. Furthermore, tumor tissue is often difficult to distinguish from normal tissue changes, for example, due to prior treatments or stromal reactions seen in infiltrating cancers, radiologic input may add to the precision in delineating the GTV. In summary, radiation therapy has become increasingly based on multimodal imaging, and oncologically trained diagnostic radiologists are increasingly important for the successful application of modern radiotherapy treatments (Terezakis et al. 2011).
2 Radiation Delivery Techniques
For radiologists it is important to consider not only the delivered overall dose for image interpretation of normal tissue changes but also the used treatment technique. This means that depending on the irradiation technique, a given specific overall dose may be distributed in normal tissues in completely different ways, and thus the organ exposure can vary significantly with consecutive different image presentations in the follow-up. Furthermore, it would be extremely helpful for radiologists if dose overlays from treatment planning software could be integrated into PACS workstations in the near future to achieve a higher degree of safety in image interpretation.
2.1 Traditional External-Beam Radiation Therapy (EBRT)
First, therapeutic applications of ionizing radiation started early after their discovery by Conrad Roentgen in 1895. For many decades, irradiation of cancerous tissues was performed with X-ray
T. Bostel and F. Sterzing
devices, which allowed only relatively low energy doses with peak doses near the entrance site of the beam. Thus, major drawbacks were dose-limiting radiation effects in skin and epidermis and the rapid decline of the depth-dose curve being unfavorable especially for the treatment of deep-seated local tumors.
It was only in the 1950s until high-energy linear accelerators were developed – a milestone for the specialty of radiation oncology. From the 1950s to the 1980s, radiation treatment was administered by the use of planar radiographs in two dimensions, which visualized osseous landmarks. These bony landmarks were used for delineation of radiation portals and localization of therapeutic targets. Depending on the tumor site, the number of beams used for radiotherapy ranged from two to six. However, treatment planning was limited by poor tumor visualization of mainly X-ray-based imaging methods and techniques available for radiation delivery (Purdy 2008; Bortfeld and Jeraj 2011).
2.2 Conformal Radiation Therapy
In the 1980s, cross-sectional imaging procedures (i.e., CT and MRI) entered clinical routine, which were essential for a more accurate delineation of cancerous tissues and risk structures. These advances in radiological imaging were fundamental for further progress in radiation oncology with development of computerized treatment planning and delivery systems that enabled an exquisite tailoring of 3D radiation dose distributions to the cancerous tissues (Bortfeld and Jeraj 2011). These 3D conformal dose applications were reached by the use of a larger number of lower-dose radiation beams aimed at the target volume from different directions (up to 10 beams) (Fig. 2). As a consequence, the low-dose exposition of healthy tissues was increased, but the amount of tissues receiving high doses was significantly decreased (Bortfeld and Jeraj 2011); thus, the dose in the tumor could be escalated, while the surrounding healthy tissues and organs at risk could be protected better than with traditional EBRT helping to increase the therapeutic ratio. Furthermore, dynamic multileaf collimators were developed and clinically established for more
precise shaping of radiation beams compared to the previously used lead blocks (Purdy 2008).
Modern conformal radiation therapy plans may also include intensity-modulated radiation therapy (i.e., IMRT) and stereotactic body radiation therapy (i.e., SBRT), which are described in the next two sections.
2.3 Intensity-Modulated Radiation Therapy (IMRT)
The mathematical basis of IMRT was developed in the early 1980s to address the problem of irradiation of complex-shaped tumors in close
proximity to or within risk structures, for example, paraspinal tumors (Fig. 3). But it still took a while until theoretical knowledge was put into practice, with first IMRT treatments applied to patients in 1997. The concept of IMRT is based on two decisive pillars, which are inverse treatment planning and nonuniform photon intensities across each of several radiation beams – usually 5–9 in modern treatment plans (Brahme et al. 1982). In the pre-IMRT era, physical dose distribution was calculated by trial and error; this means by trying out different intensities and directions of radiation beams. IMRT, on the other hand, takes the abovementioned path of inverse treatment planning, that is, dose distribution is tailored exactly to the target volume at the beginning of the planning process. Subsequent modeling of the direction, contour, and intensity of each treatment beam follows this by computerized treatment planning systems. For this purpose, radiation beams are subdivided into many segments and subsegments (i.e., often more than 100), in which intensities can be specified independently of each other by the use of multiple overlapping field segments or moving collimator leaves. This enables reduction of the dose for a certain beam direction, if risk structures are included in the beam. However, this approach would result in underdosing of the target volume, if conventional radiation techniques were used (Fig. 4). In IMRT plans, the lack of dose in the target volume is compensated by additional dose through another beam (Sterzing et al. 2009; Paumier et al. 2011).
Fig. 2 Dose distribution for primary irradiation of an NSCLC in the right upper lobe. The purple- and redcolored inner region represents the high-dose region. The yellow, green, and blue areas represent decreasing isodose lines towards the periphery
Fig. 3 Presentation of a mass along the dorso-cranial thoracic wall left sided with infiltration of the paravertebral space, upper part of the thoracic spine and spinal canal in the planning CT (status post-laminectomy) (a). In
IMRT plan (b) with depiction of steep dose gradients to the surrounding normal tissues and the myelon (red area represent high-dose area; yellow, green, and blue areas represent decreasing isodoses)
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CHAPTER IV
THE CENTURIES AND THE CLASSES
The ancient authorities represent Servius Tullius as the founder of an organization at once military and political—on the one hand the army composed of classes and centuries, and on the other the comitia centuriata. According to Livy[383]
“From those whose rating was 100,000 asses or more he made 80 centuries, 40 of seniors and 40 of juniors, and termed them all the first class. The seniors were to be ready for guarding the city and the juniors were to serve in the field. The arms required of them were a helmet, round shield, greaves, and cuirass,—all bronze,—for the protection of the body. Their offensive weapons were a spear and a sword. To this class were added two centuries of sappers who were to serve without arms. Their duty was to convey the engines of war. The second class was made up of those whose rating was between 75,000 and 100,000 asses, 20 centuries of seniors and juniors together. They were equipped with an oblong shield (scutum) instead of a round one, and they lacked the cuirass, but in all other respects their arms were the same. The minimal rating of the third class was 50,000 asses, and the number of centuries was the same with the same distinction of age, and there was no change in arms excepting that greaves were not required. In the fourth were those appraised at 25,000 asses. They had the same number of centuries but their arms were changed, nothing being assigned them but a spear and a long javelin. The fifth class was larger, composed of 30 centuries. They carried slings and stones for throwing. Among them were counted the accensi, the hornblowers, and the trumpeters, 3 centuries. This class was appraised at 11,000 asses. Those whose rating was less formed one century exempt from military service. Having thus armed and organized the infantry, he levied 12 centuries of
equites from among the chief men of the state. Also the 3 centuries instituted by Romulus he made into 6 others of the same names as those under which the three had originally been inaugurated.” Afterward Livy speaks of the votes of the centuries in the comitia.
The ultimate source of this description, as well as of the similar account given by Dionysius, is the censorial document already mentioned,[384] sometimes termed the “discriptio centuriarum,”[385] sometimes “Commentarii Servi Tullii”[386] on the supposition that Servius was the author In reality it belonged to the Censoriae Tabulae[387] of the period immediately following 269.[388] The document gave a list of the classes, centuries, and ratings, and furnished directions for holding the centuriate assembly. As the military divisions and equipments mentioned by Livy in the passage above had been discarded long before this date,[389] they could not have been described in the document. The account of them found in our sources must, therefore, have been supplied by antiquarian study.[390] The annalist who first used these Tabulae in the censorial archives was Fabius Pictor.[391] Whether Livy and Dionysius derived their account directly from him or through a later annalist cannot be determined.[392] Though Cicero’s source may ultimately have been the same, he seems to have depended largely on his memory and is chronologically, though not in substance, less exact. In assigning seventy rather than eighty centuries to the first class he most probably has in mind a stage of transition from the earlier to the reformed organization.[393]
A brief analysis of this description, as presented by Livy or Dionysius, will prove that it could not apply at the same time to an army and a political assembly: (1) The century of proletarians, which formed a part of the comitia, and which according to Dionysius was larger than all the rest together, was exempt from military service. [394] (2) The unarmed supernumeraries termed accensi velati must in their military function have lacked the centuriate organization, as will hereafter be made clear.[395] (3) The musicians and the skilled
workmen who accompanied the army must also be eliminated from the centuriate organization of the army.[396] (4) The seniors, too, lacked the centuriate military organization.[397] (5) Thus the only pedites in the original centuriate system were the juniors. Even the military century of juniors was not in the beginning strictly identical with a voting century; and as time progressed, the one group diverged more and more widely from the other.[398]
Chiefly from these facts, which will become clear in the course of this study, we are warranted in concluding that the army was at no time identical with the comitia centuriata. As one was necessarily an outgrowth of the other, the military organization must have been the earlier. If therefore the original form of the centuriate system is to be referred to Servius Tullius, he will be considered the organizer of the phalanx, which the military centuries constituted,[399] not of the comitia.[400] This result harmonizes with the view of the ancient writers that the comitia centuriata exercised no functions—hence we have a right to infer that it had no existence—before the beginning of the republic.[401]
The following sketch of the development of the Roman military system from the earliest times to the institution of the manipular legion includes those features only which are essential to an understanding of the origin and early character of the centuriate assembly. The view maintained in this volume is, as suggested in the preceding paragraph, that the comitia centuriata in the form described by Livy and Dionysius developed from the early republican military organization, which was itself the result of a gradual growth. Reference is made to equipments chiefly for the purpose of throwing light on the relation of the Roman to the Greek organization and of the various Roman military divisions to one another.
I. The Primitive Graeco-Italic Army and the Origin of the Phalanx
Recent research has brought to light a period of Italian history during which the military system of the Latins and Etruscans closely resembled that of the Mycenaeans, the former doubtless being
derived in large part from the latter.[402] The nobleman,[403] equipped in heavy armor, rode forth in his chariot[404] to challenge his peer among the enemy to personal combat. The mass of common footmen were probably grouped in tribes and curiae (Greek phratries, brotherhoods),[405] as in Homeric Greece[406] and among the early Europeans[407] before the development of an organization based on a numerical system. The arms of the footmen must have been lighter, and probably varied with the individual’s financial resources. These common troops could have had no special training or discipline, as they counted for little in war [408] Yet in the Homeric age of Greece some attempt was made to keep the fighters in line, and to prevent the champions from advancing beyond it to single combat.[409] A similar tendency to even, rhythmic movement may be inferred for the Latin army.[410] The great innovators in this direction were the Lacedaemonians, to whom the honor of inventing the phalanx is chiefly due.[411] This improvement, which made an epoch in European warfare, could not have been later than the eighth century . . The phalanx was a line, several ranks deep, of heavyarmed warriors, who moved as a unit to the sound of music.[412] The depth varied as the occasion demanded; it was not necessarily uniform throughout the line, but for Lacedaemon eight may be considered normal.[413] The heavy-armed trooper carried a large shield, which covered the entire body, a helmet, and greaves; his offensive weapons were sword and spear.[414] Tyrtaeus mentions also a coat of mail though not as an essential part of the equipment. [415] The metal of their defensive armor was mostly bronze; their swords and spear-points were probably iron, which the mines of Laconia abundantly supplied.[416] Although it is well known that the phalanx was composed of smaller units, the original organization can only be conjectured. It is not unlikely that in the beginning there were tribal regiments,[417] divided into companies of fifty or perhaps a hundred,[418] which were made up of still smaller groups. The military age extended from the twentieth to the sixtieth year.[419]
The phalanx was readily adopted by other Greek states, which modified it to suit their several conditions. In Athens and probably elsewhere the army had a tribal organization,[420] but a census was introduced in order to determine who possessed sufficient wealth for service on horseback, in the heavy infantry, and in the light infantry; and when once the census classes were adopted, it was easy to extend them to political uses. In this way the four property classes at Athens, probably instituted about the middle of the seventh century . .,[421] became under Solon if not earlier a basis for the distribution of offices and other political privileges. Naturally the Greeks of Sicily and Italy adopted the phalanx, and it is reasonable to suppose that the Romans derived it, through the Etruscans,[422] from one of these neighbors.
II. The Servian Army
As the heavy troops of the Greek line were all armed alike, the Romans probably at first composed their phalanx in a similar way, without gradations of equipment. The complex system of census groupings in the army as we find it immediately before the institution of the manipular legion could only have resulted from a long development. The statement last made finds justification in the fact that the term classis[423] was originally limited to the first or highest census group, all the rest being “infra classem.”[424]
Not only was the organization like that of the Greeks, but the arms, too, were in the main Greek. The soldiers of the classis were equipped with helmet, shield, greaves, spear, and sword; as they wore a cuirass, they used a large round Etruscan buckler[425] instead of the man-covering Dorian shield. They were grouped in centuries,[426] forty of which composed the classis in the fully developed phalanx.[427] The age of service of the juniors, who alone fought in the field, extended from the completed seventeenth to the completed forty-sixth year,[428] whereas the seniors from the fortyseventh to the sixtieth year formed a reserve.
A still nearer connection can be found between the Roman and the Greek horsemen. As is proved by archaeology, the earliest Greek knights had no specialized weapons or armor and were not accustomed to fight on horseback, but were heavy infantry who used their horses simply as conveyance.[429] The same is true of the earliest Roman equites, whose equipment closely resembled that of the Greek horsemen. On account of their swiftness they were primitively called celeres.[430] Although these mounted footmen are generally known as equites, which in this sense may but loosely be translated knights, the Romans did not institute a true cavalry till the period of the Samnite wars.[431] It is a curious fact that some horsemen, Roman as well as Greek, were provided each with two horses,[432] one for the warrior and the other for his squire,[433] and that the mounted soldiers of Etruria were in these respects the same. [434] A further resemblance between the earliest Greek and Roman horsemen lies in the fact that they were noble.[435]
In their account of the growth of the mounted service during the regal period the ancient authorities show great inconsistencies. It seems probable that the early annalists pictured the increase in the knights in a way analogous to that of the senate: at first Romulus formed a troop, or century, from the Ramnes; afterward a second was added from the Tities; and still later the Luceres furnished a third.[436] Then Tarquinius Priscus doubled the number, making six in all, and Servius finally increased it to eighteen centuries. This simple development, itself a reconstruction, was complicated by the desire of the historians to make the number of knights under Servius agree with the number under Augustus, given by Dionysius[437] at about 5000; hence the assumption of 200 or even 300 knights to the century as early as the reign of Romulus.[438] It is possible by clearing away these evident misconceptions to discover the approximate truth.
When the chariot gave way to the horseback rider is not definitely known; at all events the change seems to have taken place under Hellenic influence, and could hardly therefore have been earlier than
the beginning of the seventh century . .[439] The idea of the sources is that there came to be three troops of horsemen, furnished by the tribes,[440] as well as three regiments of foot, that before Servius the number of troops of horse was doubled, and that the six troops thus formed were named accordingly after the tribes Ramnenses, Titienses, and Lucerenses priores and posteriores respectively.[441] The priores had each two horses, the posteriores one.[442] Hence the essential difference between these divisions was in rank and wealth rather than in the relative time of their institution. Long after Servius both divisions continued to be patrician.[443] As the centuriate organization of Servius applied to the infantry, the cavalry remained little affected by it. The six troops with their old names survived, and eventually became a part of the comitia centuriata. In the military sphere, however, the troop no longer retained its identity; but the whole body was divided into twenty turmae, each composed of three decuries commanded by decurions. [444] When with the institution of the republic the phalanx was split into two legions, ten turmae of cavalry were assigned to each legion. [445] As in historical time the number of horsemen to a legion did not exceed 300,[446] and as we have no reason to suppose that at an earlier period this arm of the service was proportionally stronger, we may conclude that in the Servian phalanx, or double legion, the number did not exceed 600.
From the foregoing discussion it appears clear that the Servian military system rested upon a division of the citizens into four groups, closely corresponding to the Athenian census divisions: (1) the equites priores, like the pentacosiomedimni, (2) the equites posteriores, like the hippeis,[447] (3) the classis, like the zeugitae, (4) the light troops infra classem, like the thetes. The distinction between priores and posteriores rested not upon an assessment but upon a less precise difference in wealth, whether determined by the individual concerned or by the state we cannot know; it represented, too, a gradation of nobility. The distinction between the knights and the classici was one of rank; that between the classis and the soldiers infra classem was alone determined by the census.
III. The Development of the Five Post-Servian Military Divisions on the Basis of Census Ratings
This arrangement was by no means final. Further changes were made in both foot and horse which were to have a bearing on the organization of the comitia centuriata. After a time[448] two additions of men less heavily armed than the classici were made to the phalanx, whether simultaneously or successively cannot be determined. There were now forty centuries of classici, and the additions comprised ten centuries each, the second less heavily armed than the first, though they may both be considered heavy in contrast with the light troops. Perhaps the state according to its ability made up the deficiency in the equipment, so as to render the entire phalanx as evenly armed as possible.[449] It numbered sixty centuries of heavy infantry, composed of three grades which depended upon the census rating.[450] The light troops were also grouped in two divisions on the same principle. The first comprised ten centuries; originally the second may have contained the same number, in which case four were afterward added to make the fourteen known to exist in the fully developed system.[451] There were five divisions of infantry amounting to eighty-four centuries of a hundred men each. Undoubtedly the growth of the army to this degree of strength was gradual, though the successive steps cannot be more minutely traced.[452]
In making the levy the military tribunes selected the soldiers from the lists of tribesmen, taking one tribe after another as the lot determined.[453] The early Romans must have striven to distribute the population as equally as possible among the tribes in order to render them approximately equal in capacity for military service. As long as this equality continued, the officials could constitute the army of an equal number of men from each tribe. These considerations explain the close relation in early time between the number of tribes and of centuries as well as the suggestions offered by our sources as to an early connection between the centuries and the tribes.[454] While there were but twenty tribes we may suppose that the legion
comprised but 4000 men, which was raised to 4200 when the twenty-first tribe was added. In this way can we account for the number of centuries to the legion. If but half the available military strength was required, the magistrates might draw by lot ten tribes from which to make the levy.[455] It was an easy matter as long as the heavy troops were limited to the classis;[456] but when two other ratings were added, and when meantime the tribes must have grown unlike in population, it became practically impossible to maintain for each rating a just proportion from the tribes;[457] and perhaps this was the chief reason for the modification in the method of recruiting. When therefore the tribes were increased to twenty-five, and it was deemed inexpedient to make a corresponding enlargement of the legion,[458] a new principle was adopted for the levy: after determining the ratio between the number of men needed and the whole number available, the officers drew from each tribe a number proportionate to its capacity.[459] It would agree well with all the known facts to suppose that the addition of the second and third ratings, followed by a more thorough organization of the light troops, belongs to the early republic (509-387),[460] when Rome needed all her strength in her life and death struggle with hostile neighbors. At the same time the purchase of armor and the increased burden of military duty would help account for the desperate economic condition of the poorer peasants of that epoch.
The proportions of the five ratings—20-15-10-5-2½ or 2—to be discussed hereafter,[461] suggest an explanation of their origin. It would be reasonable to assume that the normal holding of the wellto-do citizen was a twenty-iugera lot and that the Servian phalanx was composed of possessors of that amount, the light-armed being their sons and others distinctly inferior in wealth. In course of a few generations as the population grew, with no corresponding territorial expansion or colonization or industrial development, and with only a limited conversion of waste to arable land, many of the lots became divided and subdivided. The result was a weakening of the phalanx at a time when the state was in the most pressing need of military resources. The institution of the five ratings as a basis for the
reorganization of the army was a temporary expedient for meeting the crisis, to be superseded not long afterward by a better system founded on military pay. In all probability the introduction of the five ratings, or at least the beginning of the movement in that direction, should be closely connected with the institution of the censorship in 443 or 435.[462] The supposition would give us a sufficient reason for the creation of this new office at that time, and the strengthening of the army would explain the success of the Romans in the wars immediately following.
How the five ratings were arrayed in battle is unknown. If the front counted a thousand men (milites),[463] the classis comprised four ranks (4000), the second and third ratings one rank each, making in all six ranks of heavy troops (6000).[464] Twenty centuries could be drawn from the two ratings of light troops to complete the eight ranks when needed.[465] But the Romans undoubtedly exercised the same good judgment as the Lacedaemonians in varying their formation to suit the emergency;[466] and for that reason it is wrong to assume the same depth for all occasions or an even depth for any one occasion. The management of long lines one-man deep must have been extremely difficult, if not impossible.[467] The explanation already suggested, that the state supplied the deficiency in equipment,[468] would greatly simplify the case, for there would then exist no need of arraying the census groups in successive lines. Whatever may have been the tactic arrangement, it did not continue long, for soon after the introduction of regular pay, about 400 . ., [469] the distinction between the ratings ceased to have an importance for military affairs.
IV. The Question as to the Connection of the Supernumeraries and the Seniors with the Military Centuries
A number of supernumeraries termed accensi velati accompanied the army. The epithet accensi proves them to have been outside the five ratings, while velati describes them as wearing civilian dress. We are informed by the sources that they carried water and weapons to
the fighting men, stepped into the places of the dead and wounded, and acted as servants to the lower officers.[470] These men could not have been organized in centuries,[471] for they were drawn up in the rear behind the light troops; they extended along the entire breadth of the army,[472] and must have greatly exceeded one hundred or even two hundred. The musicians,[473] too, who accompanied the army were not grouped in two centuries, for they were distributed throughout the army.[474] There is no reason for assuming exactly two hundred musicians[475] or exactly two hundred workmen,[476] or for supposing that any of the men of this description were organized in centuries in the army. Reasoning in a similar way in regard to the seniors, we conclude that their organization in centuries could not have belonged to the original Servian system. A military century, as the name indicates, must have contained a hundred men.[477] But in any static population there are three times as many men between seventeen and forty-six as between forty-six and sixty[478]—in Rome there were three times as many juniors as seniors; and as the number of junior and senior centuries was equal, the latter could have contained only about thirty-three each, on the supposition that the whole male population between seventeen and forty-six years was organized in centuries.
The mere fact that the senior century contained so few men suggests that it was not a military institution. This impression is confirmed by the information that the seniors were reserved for the defence of the city, while the juniors took the field in active service. [479] When we reflect that even in the early republic the seniors could not often have been called on for defence, as the juniors were ordinarily sufficient for the purpose,[480] that the manning of the walls did not necessarily require a division into companies or an equipment like that for field service, and that when it was thought expedient for the seniors to serve in centuries or cohorts, their enrolment in these companies is especially mentioned, our conviction that the senior centuries did not belong to the original Servian organization grows into a certainty.[481]
V. Conclusions as to the Servian and Early Republican Organizations; Transition to the Manipular Legion
In our search for the Servian and post-Servian schemes of military organization we found it necessary to eliminate from the discriptio centuriarum all the centuries of pedites with the exception of the juniors. But even a military century of juniors could not have remained identical with a voting century; for the former comprised a fixed number and the same for all ratings, whereas in the comitia of historical time the centuries varied greatly in size, many of them containing far more than a hundred men each. In the four lower classes each century contained as many men as the entire first class;[482] and individuals constantly shifted from one class to another as their several properties increased or diminished.[483] It is a mistake, therefore, to think of the army as identical with even the junior centuries of the comitia.[484] Doubtless when the Servian army was first introduced, its organization was made to fit actual conditions, so that all who were liable to service found their place in it; but as the political assembly of centuries was instituted many years afterward, the army with its various enlargements could have kept meanwhile no more than approximate pace with the changing population, and at no time could it include the physically disqualified, who nevertheless had a right to vote in the junior centuries of the political assembly. On the other hand there were soldiers in the army too young to be in the comitia centuriata.[485]
The conclusion as to the strength of the army in the first years of the republic, before the latter had acquired any considerable accession of territory, corresponds closely with a moderate estimate of the population under the conditions then existing. The area of the state was about 983 square kilometers (equivalent to 379.5 sq. mi. or 242,899 acres).[486] Estimating the population of this agricultural community at its maximum of sixty to the square kilometer, we should have less than 60,000 for the entire area.[487] The number of men from seventeen to sixty, the Roman military age, should be about thirty per cent of the population[488]—less therefore than
18,000. If the ratio of juniors to seniors was about three to one,[489] we should have about 13,000 juniors to 5000 seniors. But a deduction must be made for slaves and for the physically incapacitated, leaving perhaps 9000 or 10,000 juniors and 3000 or 4000 seniors. These results are not unreasonable. Making allowance for several hundred supernumeraries,[490] we should then have no more than enough juniors to fill the eighty-four centuries of foot and the six troops of horse. It is clear, therefore, that all available forces were included in the army and that the junior centuries could not have contained more than a hundred men each.
Even before the phalanx had thus been brought to perfection, modifications were being made in the equipment under the influence of the Gallic invasion.[491] The introduction of pay, about 400 . ., as has been said,[492] broke down the distinction of equipment based on degree of wealth, and not long afterward, probably in the time of the Samnite wars, the phalanx gave way to the manipular legion, which reached its full development in the Punic wars.[493]
VI. The Five Classes and their Ratings
Though originally denoting the men of the first rating, who possessed the fullest equipment,[494] the term classis with an explanatory adjective came to apply to the entire army[495] or to its component parts.[496] The plural “classes” came finally to mean the five census groups, represented by the five timocratic gradations of the comitia centuriata. What had formerly been the classis then came to be known as classis prima, and the “infra classem” ratings were numbered downward second, third, fourth, and fifth. Probably this extension in the use of the word was not made till after the disappearance of the ratings from the army—how much later we do not know. In a speech delivered in 169 in favor of the lex Voconia the elder Cato more than once examined into the meaning of classicus and infra classem.[497] A hasty inference would be that at this late date classis was still strictly limited to the first rating. It is to be noted, however, that the early meaning might be retained in a legal formula
long after it had disappeared from general use, that classicus certainly preserved its original meaning notwithstanding the new development of the noun from which it is derived, and especially that the early sense of the terms classicus and infra classem was not generally known in 169, else Cato would not have taken such pains to define them. We know that the ratings were termed classes in 111, [498] and from what has just been said on the Voconian law it seems probable that the development took place long before 169. The circumstance that in their “discriptio centuriarum” Livy and Dionysius make no reference to the distinction between classis and infra classem would favor the supposition that they found no such distinction in their common source—ultimately Fabius Pictor. Hence it is not unlikely that classis was used in its historical meaning of property class in the censorial document from which Fabius derived his knowledge of the fully developed comitia centuriata, and which belonged to the period immediately following 269.[499]
Before the censorship of Appius Claudius Caecus, 312, military service within the census ratings was based on the possession of land, and the gradations of equipment, while they lasted, must therefore have been determined by the size of the estate reckoned in iugera.[500] Huschke[501] rightly inferred that the number of iugera marking the lower limit of each division must have been proportioned to the later money ratings, and assumed accordingly 20, 15, 10, 5, 2½ or 2 iugera as the respective minimal holdings of the five divisions. Although absolute certainty is unattainable, most scholars accept his conclusions as probable.[502] Before the change was made in the appraisements from amount of land to money, the census gradations ceased to serve a military purpose. In the further discussion of these groups reference is therefore solely to their political character, especially as expressed in the organization of the comitia centuriata. Till the time of Marius, however, the soldiers were ordinarily recruited from the classes—that is, from the citizens who possessed at least the qualification of the lowest group.[503]
The money ratings of 312 are not recorded; we know those only of the time following 269. The ratings of the earlier date must have
been in the nominally libral asses then current. For a long time, probably down to 312, the as remained at eleven to nine ounces in weight, then sank rapidly to four, three, and two ounces, reaching the last-mentioned weight in or shortly before 269. In this year or the following was legally adopted the lighter as, weighing two ounces, or a sixth of a pound, and hence termed sextantarian, and the heavier asses still in circulation were henceforth reckoned as sesterces, which now became the unit of value.[504] Two and a half sextantarian asses made a sesterce, and four sesterces made a denarius.[505] The as continued to be copper, whereas the sesterce and the denarius were silver. In consequence of the use of the sextantarian as the ratings must have been elevated to correspond with the decline of the standard; and the result of this change is the wellknown series, 100,000, 75,000, 50,000, 25,000, 11,000.[506] There can be no doubt that under the standard used in 312 the ratings were lower than those given. It is incredible that the classis should ever have been appraised so high as 100,000 asses of ten-ounce weight or even of the value of sesterces (5 oz.).[507] But the ratings of 312 have not been definitely ascertained. Assuming but one elevation between the two dates and in the proportion of 4:10:: sextantarian as: heavy as or sesterce, Mommsen[508] concludes that the appraisements of 312 were 40,000, 30,000, 20,000, 10,000, and 4400 asses respectively for the five classes. The adjustment however may have been gradual, as was the decline of the standard, and the former need not have corresponded exactly with the latter. But in so far as the Romans failed to bring about this adjustment, the censors must have found it necessary continually to advance the citizens from the lower to the higher divisions.
The ratings mentioned above as established on the basis of the sextantarian standard, namely 100,000, 75,000, 50,000, 25,000, and 11,000 asses for the five classes respectively, are those given by Livy.[509] Several variations affecting the highest and lowest classes are offered by other writers. Dionysius[510] states the appraisement of the fifth class at 12½ minae, which would be 12,500 asses. The usual explanation is that he is dealing in round numbers without
especial regard to accuracy, for which reason Livy should be given the preference. It is doubtful however whether Dionysius was so inexact. More probably his estimate depended ultimately on the idea that the minimal number of iugera of the highest class was twentyfive,[511] taken in connection with the decimal ratio between the extreme classes—an interpretation which would help explain variations in the rating of the highest class to be mentioned hereafter; or with less reason we might assume that the statements of Dionysius and Livy represent earlier and later conditions.[512] The limit of 400 drachmas given by Polybius[513] proves a lowering of the minimal rating between 269 and the publication of his history.[514] It may have been made in 217, when the money system was again changed. As Polybius probably considered the drachma, or denarius, to be worth ten asses,[515] the limit which he mentions would be 4000 asses. Cicero states the minimal limit at 1500 asses, [516] and a still lower sum of 375, mentioned by Gellius,[517] marked the line of division between the taxable proletarians and the capite censi, who were exempt from taxation. As the differentiation between the two groups last named must have been effected before 167, when the Romans were relieved of the tributum,[518] the rating given by Cicero could not have been later than that vouched for by Polybius. The limit of 4000 asses, accordingly, had reference merely to military service, whereas 1500 marked at once the political and tributary line of separation between the fifth class and the taxable proletarians.[519] The limit of 375 asses, on the other hand, was far below the fifth class, and had nothing to do with it.[520] The relation of these numbers to one another may be summarized as follows: Those assessed at 4000 or more asses belonged to the fifth class, enjoyed the political rights of that class, and were subject to military service as well as to taxation (tributum); those rated at 1500-4000 asses also belonged to the fifth class, enjoyed the political rights of that class, and were subject to taxation but exempt from military service; those rated at 375-1500 asses were proletarians, below the fifth class but subject to taxation; those rated below 375 asses, the capite censi, were exempt from taxation.
As regards the rating of the highest class, the elder Pliny[521] states it at 110,000 asses, which may be a copyist’s error for 100,000 or for 120,000; the estimate of Paulus Diaconus[522] is 120,000 and of Gellius[523] 125,000. If the manuscripts have correctly preserved these numbers, they may represent computations based on a varying number of iugera, from twenty-two to twenty-five[524] at the rate of 5000 asses a iugerum—a valuation which may have been given in the original annalistic source (Fabius Pictor). From the fact that Pliny assigns this rating to Servius as author, and that Gellius speaks of it in the past, we must infer that it was not due to a relatively late change. Indeed the rating must have remained unaltered to the time of Polybius,[525] who states that those appraised at 10,000 drachmas wore the cuirass—according to Livy[526] and Dionysius,[527] the distinctive equipment of the first class.[528] In the same age the Voconian law, 169, provided that a man registered by the censors as worth 100,000 asses or more should not bequeath his property to a woman.[529] While speaking in favor of the measure the elder Cato expounded the distinction between the classici and those who were “infra classem.”[530] Strictly following Cato’s definition, Gellius[531] explains the classici as those of the first class in contrast with the members of the lower classes, who are infra classem. Evidently the classici are to be identified with those rated at 100,000 asses, as given by Gaius.[532] The sum of 100,000 sesterces, in place of asses, represented by later writers[533] as the one fixed by this law, is due either to a late interpretation or to an amendment.[534] The minimal qualification of the first class must therefore have continued unchanged from 269 to the passing of the Voconian law, 169, and the composition of the History of Polybius.[535] From the latter event to the tribuneship of Tiberius Gracchus little time was left for an increase, which certainly the Gracchi and their successors would take no interest in bringing about. Further depreciation in the weight of the as, by the reduction to a half ounce through the Papirian law of 89,[536] had no effect on the valuation, as the standard was the silver sesterce, the as having
merely the fiduciary value of a quarter sesterce. Apart from the accounts of Livy and Dionysius already considered, no reference is made to the valuation of the intermediate classes, unless it be a passage in Livy[537] to the effect that freedmen possessing country estates worth at least 30,000 sesterces were enrolled in the rural tribes by the censors of 169, which is interpreted by Mommsen[538] to refer to the qualification of the second class. This is true if, as has been assumed above, the censors still reckoned two and a half asses to the sesterce.[539]
VII. Belot’s Theory as to the Ratings
Notice must be taken of a theory proposed by Belot,[540] that at the time of the First Punic War, owing to an economic revolution which enhanced prices, and to the decrease in the weight of the as, the five ratings as stated by Dionysius for the earlier period were multiplied by ten, giving for the future 1,000,000, 750,000, 500,000, 250,000, 125,000 asses for the five classes respectively.[541] The theory is supported with remarkable learning and skill. There can be no doubt as to the lowering of the weight of the as or of the economic revolution which increased prices. Large valuations of estates such as he mentions are found in the sources. For example in 214 the government ordered[542] that—
Those rated at 50,000- 100,000 asses should furnish one sailor
Those rated at 100,000- 300,000 asses should furnish three sailors.
Those rated at 300,000- 1,000,000 asses should furnish five sailors.
Those rated at above 1,000,000 asses should furnish seven sailors.
Senators should furnish eight sailors.
Belot’s attempt to identify the highest of these appraisements with the rating of the first class is unsuccessful, as will immediately appear. The object of the order issued by the government in 214 was to provide crews for the fleet of that year. Although the hundred and fifty ships to be manned[543] seem to have been triremes, we may consider them quinqueremes so as not to underestimate the number of men necessary. Reckoning 375 men to the ship,[544] we should have 56,250 men for the entire fleet. But according to Belot[545] there were 22,000 knights at this time, whose census rating was 1,000,000 asses, and who accordingly would have to furnish seven men each for the navy, which would amount to 154,000, or more than enough to man three such fleets as that of the year under consideration. But as the knights constituted only a twelfth of the total number of registered citizens of that period,[546] most if not all of whom must according to Belot have been assessed at 50,000 or above, we shall be obliged at least to double the 154,000 sailors furnished by the knights to obtain the whole number demanded by the government. The absurdity of the result condemns the premises. The minimal census of the knight could not have been materially if at all above 100,000 asses,[547] and the great mass of citizens must have been rated below that sum. Other features of his theory need not be considered here. The truth is that the great accumulation of wealth benefited but few; and notwithstanding the advance in the money value of property, the mass of people remained so poor that the state could not disturb the census ratings, however out of harmony with the new conditions they seem to have become. No suspicion should be thrown on the continuance of these small valuations by the circumstance that occasionally the state compelled the wealthy to contribute to the burden of war according to their ability, as in 214, and increased the penalties for the crimes and misdemeanors which the rich and powerful were wont to commit.[548]
VIII. The Post-Servian Equites
The classes, as developed after Servius, have now been considered sufficiently for an appreciation of their relation to the
comitia centuriata. It remains to discuss from the same point of view the post-Servian alterations in the equestrian organization.
In the earliest period when the warriors in general equipped themselves at their own expense,[549] the equites provided their own horses. But in time as the patricians ceased to be the only wealthy class in the community, and as they began to lose their political advantages, their duty of keeping one or two horses came to be felt as onerous, and some means of lightening it was sought for. The only private property which was free from the burden of supporting military service was that of widows and orphans. The government determined accordingly to levy a regular contribution on this class of estates in the interest of the equites. The eques was allowed ten thousand asses, or one thousand denarii (aes equestre), with which to purchase his horse or horses for the ten years of service and two thousand asses (aes hordearium) annually for maintenance.[550] He was not paid the money in advance, but was given security for the required sums,[551] which were gradually to be made good from the special kind of tax here described. When these equestrian funds were first granted cannot be absolutely determined. Cicero[552] assigns their institution to Tarquinius Priscus, Livy[553] to Servius, Plutarch[554] to Camillus in the year of his censorship, 377. For obvious reasons the earlier dates are suspicious, whereas the last has the advantage of connecting the institution of these funds with the general movement for the public support of military service. When in the war with Veii regular military pay was introduced, the eques on account of his more burdensome duty, perhaps too because of his higher rank, was allowed three times the pay of the legionary.[555] It was afterward decided to deduct the aes hordearium, probably also the aes equestre, from his pay.[556] Meanwhile as wars were waged on an ever increasing scale, the patricians, who were dwindling in number, could not furnish all the cavalry needed. This want was especially felt in the struggle with Veii, whereupon wealthy plebeian youths[557] came forward and offered to serve with their own horses.[558] This is the first known instance of voluntary equestrian duty, doubtless often repeated at
