Precision Radiation Oncology

Bruce G. Haffty, Sharad Goyal

• Publisher: Rutgers University Press Medicine
• Year: 2018
• ISBN:
  9780813592541
• Topic: Medicine
• Subtopic: Radiology, Radiotherapy & Nuclear Medicine

Precision medicine is a rapidly-evolving field in the management of cancer. The use of novel molecular or genetic signatures in local-regional management is still in its infancy. Precision Radiation Oncology demystifies this state-of-the-art research and technology.  By describing current existing clinical and pathologic features, and focusing on the ability to improve outcomes in cancer using radiation therapy, this book discusses incorporating novel genomic- or biology-based biomarkers in the treatment of patients moving radiation oncology into precision/personalized medicine. Precision Radiation Oncology provides readers with an overview of the new developments of precision medicine in radiation oncology, further advancing the integration of new research findings into individualized radiation therapy and its clinical applications.  
 

1

Combining Cytotoxic Chemotherapy and Radiation Therapy

Vivek Verma and Charles B. Simone II

THE CONCEPT AND RATIONALE OF COMBINED MODALITY THERAPY

A foremost principle explaining the potential benefits of chemoradiation (CRT) administration involves mechanistic themes. Most generally, because radiation therapy (RT) acts locally and chemotherapy (CT) is distributed throughout the body, combined CRT attempts to control both locoregional disease and potential distant micrometastatic spread, a notion known as spatial interaction. When delving into molecular mechanisms, however, RT is known to cause damage to neoplastic cells largely by free radical–mediated DNA double-strand breaks. Various CT agents, on the other hand, act via several different pathways. Many commonly utilized CT drugs act directly or indirectly on DNA. Alkylators/linkers of DNA, such as cyclophosphamide or cisplatin, directly modify DNA to create crosslinks, which can result in additional DNA damage beyond what RT causes. Indirect DNA agents act on proteins that themselves directly act on DNA; for instance, the anthracycline doxorubicin stabilizes the complex between topoisomerase II and DNA, thus preventing the reconnection of temporary DNA strand breaks that normally provide mechanical relief from the torsional forces caused by DNA unwinding. The commonly used compounds paclitaxel and vincristine act on microtubules, most of which are prominently involved in cytostructure and intracellular communication, whereas the antimetabolite methotrexate prevents the collection and use of folates needed for purine and certain amino acid synthesis. In part owing to these diverse mechanisms, combined-modality therapy (CMT) is radiobiologically favorable and may also promote cell cycle synchronization, DNA damage repair inhibition, hypoxic cell sensitization, and the impedance of rapid cellular repopulation.

Seminal clinical trials are often prime examples of these oncologic principles supporting CRT. In 2005 a landmark publication demonstrated the biological superiority of adding the DNA alkylator temozolomide concurrently and adjuvantly to RT alone (60 Gy/30 fractions) for patients with glioblastoma (1). In this randomized trial of 573 patients, most of whom had undergone surgery, the 2-year overall survival (OS) increased from 10.4% with RT alone to 26.5% with CRT. This highlights the appeal of CMT for biologically aggressive neoplasms. Many such tumors are associated with various degrees of radioresistance, owing to inherent (eg, genetic profiles of cancer stem cells) or acquired (eg, from hypoxia) reasons. Because these neoplasms have a higher risk of recurrence if unimodality therapy is performed, adding another agent may indeed improve outcomes; this was recently corroborated in a randomized trial of melanoma, a similarly aggressive and relatively radioresistant tumor, when the addition of RT to the surgical resection of lymph nodes demonstrated enhanced tumor control with CMT (2).

Some aggressive tumors for which there is a strong rationale for CMT lack or have less-convincing data for CMT. In these circumstances, although unimodality therapy is prevalent, CMT offers the opportunity to utilize a complete oncologic arsenal. Although overtreatment is a concern and more intensive (and potentially more morbid) treatment cannot be standard without compelling supportive data, undertreatment may compromise patient outcomes in diseases for which randomized trials have not been feasible or have not demonstrated clear results. A similar situation occurred regarding the optimal treatment of esophageal cancer; prior randomized trials between neoadjuvant CRT and surgery versus surgery alone were criticized and included no convincing numerical OS improvement. As a result, many patients received unimodality therapy. In 2012 the randomized Chemoradiotherapy for Oesophageal Cancer Followed by Surgery Study (CROSS) trial of neoadjuvant CRT (carboplatin/paclitaxel + 41.4 Gy in 23 fractions of RT) followed by surgery, versus surgery alone, demonstrated a doubling of OS, from 24.0 months in the surgery-only arm to 49.4 months in the CMT arm (3). Thereafter, combined CRT followed by surgical resection has emerged as the standard of care in virtually all patients meeting trial eligibility criteria.

Combining CT and RT, when delivered sequentially, can also assist in determining the response to one modality and potentially tailoring the other modality according to this initial response. For instance, cases of locally advanced breast cancer can benefit from neoadjuvant CT prior to surgery, largely for debulking purposes (eg, maintaining appropriate cosmesis and/or decreasing the risk of positive surgical margins). A retrospective analysis of 3,088 patients from two prospective breast cancer trials found that the extent of residual disease is a strong predictor of outcome (regardless of the type or extent of surgery) (4). Residual disease after neoadjuvant therapy is likely a marker for more aggressive biology and hence can result in changes in the management of postoperative RT. Although far from a consensus, the lack of an appropriate outcome after neoadjuvant CT may lead some radiation oncologists to administer slightly higher RT doses and/or electively treat certain nodal volumes owing to the proven higher risk of relapse.

Regarding head and neck malignancies, it has been proven advantageous to deliver CRT in patients with clinicopathologic characteristics portending a higher risk of failure. Two randomized trials from the Radiation Therapy Oncology Group (RTOG) and the European Organization for the Research and Treatment of Cancer (EORTC) demonstrated an OS benefit when adding CT to RT in high-risk head and neck cancers (5–6). Whereas the RTOG trial strictly included patients with extranodal extension, positive surgical margins, and/or two or more regional nodes, the EORTC trial also included pathologic T3 and T4 disease. Although both trials observed an improvement in locoregional control (LRC) and disease-free survival (DFS), only the EORTC trial showed an OS benefit. In a pooled analysis of both trials, the greatest benefit of adding CT to postoperative RT was exhibited in cases with positive margins and extranodal extension, and CRT is now routinely administered in these subgroups (7).

Lastly, an emerging area of combined CT and RT utilization is to prophylactically address cellular clones potentially resistant to standard therapies. Metastatic prostate cancer is often characterized by neoplastic cells that are resistant to hormonal (androgen deprivation) therapy (HT) and hence termed castrate-resistant prostate cancer. Therefore, there is biological rationale to suggest that this phenomenon can occur in high-risk prostate cancer and that prophylactically treating androgen- (and possibly radio-) resistant clones may be of benefit. The maturing RTOG 0521 trial addressed this question and randomized 562 patients between RT/HT and RT/HT/CT (docetaxel) (8). Preliminary results suggest a statistically significant improvement in 4-year OS, from 89% to 93%. Although a longer follow-up is needed, this trial may lead to a novel paradigm shift toward CMT in the management of select patients at higher risk of developing resistance to standard treatment options.

The usage of combined CT and RT continues to expand. With the growth of personalized medicine and the conception of precision radiotherapy, a pivotal effect of evidence-driven oncology has been the attempt to delineate specific subpopulations in which CMT is optimal. It is important to recognize that this entity remains ever changing, with future advances highly likely to revise and refine the current standards.

TECHNIQUES

This section will discuss the two primary methods for administering combined CRT: sequentially (Table 1.1) and concurrently (Table 1.2). The existence of high-level evidence regarding outcomes and expected treatment toxicities largely drives the clinical decision making for either technique. For some cancer types, but not for others, the synergy between CT and RT has been proven; radiosensitization has been well documented for many CT compounds (eg, platinum compounds, fluoropyrimidines/capecitabine, and gemcitabine). Although enhanced neoplastic destruction is the ultimate goal of oncologic management, these potential gains must be weighed against the toxicities that often amplify when CT and RT are given together. Seminal trials have quantified not only the magnitude of outcome benefits but also the increase in various toxicities with concurrent CRT. Hence, although various tumor types and clinical circumstances may lend themselves to CMT, clinicians must first decide whether a given patient is a candidate for it. Subsequently, they must determine, based on available evidence as well as several patient-specific factors, whether the expected benefits of concurrent CRT outweigh its potentially increased toxicity risks. These decisions may be best made, when possible, in a multidisciplinary fashion and on a case-by-case basis.

TABLE 1.1 Comparison of the advantages and disadvantages of sequential chemoradiotherapy over radiotherapy alone
Pros		Cons
• Control of both primary disease and potential micrometastases		• Increased toxicities over unimodality therapy alone
• Tailor second modality treatment to the response of the first		• Suboptimal tolerance of first treatment may impair complete receipt of secondary therapy
• Debulking of large tumor mass, possibly resulting in increased efficacy of the second modality		• Could promote the development of clones resistant to the initial therapy that are more difficult to treat with the second modality

TABLE 1.2 Comparison of the advantages and disadvantages of concurrent chemoradiotherapy over radiotherapy alone
Pros		Cons
• Simultaneous treatment of both primary disease and potential micrometastases		• Increased toxicities over unimodality therapy alone
• Potential radiosensitization, possibly leading to increased local control		• Possibility of not receiving a complete course of either treatment
• Possibly associated with needing lower doses of either modality or smaller radiotherapy fields		• No ability to cytoreduce the tumor burden

Sequential Chemoradiation

As previously mentioned, the goal of combining CT and RT—regardless of timing or technique—is to control both the primary disease and potential micrometastases. It is important to understand that each malignancy has a certain risk of metastatic spread that is influenced by several factors not limited to tumor histology, differentiation, genetics, location, and stage. Patient factors such as cancer history, prior RT and/or CT, and immune system status are also important to consider. The oncologist’s goal is to holistically estimate the risk of metastasis outside the primary site or the likelihood of local tumor control with and without CMT and add CT accordingly. Breast cancer, for which gene panels have been clinically validated to correlate with the risks of lymphatic and distant spread, is the most ubiquitous example of this concept (9). Hence, quantification of this risk has resulted in the administration of CT after RT in patients with genetics portending metastasis. Nevertheless, this section will elaborate on the advantages of sequencing RT before or after CT.

Two important rationales for the administration of CT followed by RT can be illustrated using the example of non-Hodgkin’s lymphoma. The Southwestern Oncology Group (SWOG) 8736 trial randomized 401 patients to eight cycles of CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) CT versus three cycles plus involved-field RT (40–55 Gy) (10). The addition of RT to CT resulted in a significant increase in 5-year progression-free survival (PFS) from 64% to 77% and a corresponding OS benefit from 72% to 82%. The first concept demonstrated in this trial was that the addition of RT allowed for a shorter CT course. Although often extrapolated to signify decreased CT doses if RT will be delivered, either method may result in fewer toxicities. Indeed, in the SWOG trial, there was a trend toward decreased life-threatening toxicities in the CMT group. Therefore, in patients who may not be able to tolerate a full course or dose of CT, CMT may be advantageous. Second, the evolution of RT for lymphoma has now moved to involved-site RT as the standard of care. The administration of CT prior to RT is therefore helpful to radiation oncologists to decrease treatment volumes, more sharply define the major foci of disease, and even reduce total RT doses.

Conversely, certain situations are best suited for the delivery of RT prior to CT. The central nervous system poses a challenge to the penetration of...

Table of contents

• Cover
• Title Page
• Copyright
• Contents
• Contributors
• Precision Radiation Oncology: An Introduction
• 1. Combining Cytotoxic Chemotherapy and Radiation Therapy
• 2. Molecular Targeted Therapy and Radiation
• 3. Current State of the Art in Intracranial Stereotactic Radiosurgery Technology: Accuracy, Precision, and Clinical Impact
• 4. Spine Radiosurgery in the Management of Spine Metastasis
• 5. Body Radiosurgery
• 6. Brachytherapy
• 7. Proton Beam Therapy
• 8. Intraoperative Radiation Therapy
• 9. Nanomedicines: Diagnostic and Therapeutic Applications in Radiation Oncology
• 10. Radiolabeled Spheres
• 11. Radiogenomics: Advancing Precision Radiation Oncology Through Development of a Genomic-Based Predictive Instrument
• 12. Combined Effects of Immunotherapy and Radiation Therapy
• 13. Radiomics
• 14. Big Data and Radiation Oncology
• Index