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Combining radiation and systemic therapy
Introduction
Historically, systemic therapy played the primary role in the management of metastatic disease, while radiation therapy (RT) was primarily reserved for palliation of symptoms and sequelae of metastatic disease including pain, bleeding, compression, risk of fracture, and neurological compromise. Emergence of data supporting the use of ablative RT in the oligometastatic setting and the potential for radiation to enhance antitumor immunity in combination with immunotherapy agents further expands the use of radiation in metastatic disease and provides the rationale for combining radiation with systemic agents in certain settings. As the number of systemic agents increases at a staggering rate, there is frequently a lack of rigorous safety data for combining radiation with a given agent. In this setting, it is essential to come up with a general approach that can be used to determine whether the benefits of a certain combination outweigh the risks.
We will first consider the general principles of combining radiation with systemic therapies—including the risks and benefits and the potential for additive and synergistic local and distant effects, as well as the risk of increased toxicities—and discuss the general framework for thinking about the risk and benefits of concurrent therapy in a given case. We will then discuss specific combinations by focusing first on major cytotoxic chemotherapy drug classes and subsequently on targeted agents and immunotherapies.
Principles of combining radiation and systemic therapy
The theoretical framework for combining radiation with cytotoxic chemotherapy was first formulated by Steel and Peckham in 1979. They proposed two possible interactions—(1) spatial cooperation and (2) in-field cooperation. Spatial cooperation describes a scenario in which there is no interaction between the treatment modalities, with radiation acting exclusively locoregionally and cytotoxic chemotherapy agents acting to combat micrometastases at distant sites. Such interaction would result in independent and nonoverlapping toxicities and a lack of effect on the efficacy of either treatment modality. In reality, it is probably extremely rare for any agent to have purely spatial cooperation and no interaction between radiation and systemic therapy.
In-field cooperation, on the other hand, suggests that some interaction between the treatment modalities does occur on a cellular or subcellular level in both normal tissues and tumor. The interaction can be either supra-additive (synergistic), additive, or infra-additive (antagonistic). Synergistic or additive interaction can result in radiosensitization, which leads to improved locoregional control but has the potential for increased toxicities. Infra-additive interaction would have the opposite effect, resulting in radioprotection. Some examples of radiosensitization mechanisms include generating two or more DNA lesions in close proximity that together create a more complex break that is more difficult to repair, inhibition of DNA repair, cell cycle interference, elimination of hypoxic populations, induction of apoptosis, and others. Conversely, radiation has been proposed to enhance antitumor immunity and efficacy of immune checkpoint inhibitors through generation of neoantigens, stimulation of type I interferon response, and other mechanisms. We will discuss interaction between radiation and individual agents later in the chapter. The interactions are frequently too complex to fall into the original categories proposed by Steel. Bentzen et al. proposed a revision of the Steel hypothesis to account for the complexities of such interactions by including additional categories such as temporal modulation, biologic cooperation, cytotoxic enhancement, and normal tissue protection. , It is important to note that for many of the systemic agents, mechanisms of interaction are not fully understood.
The other important factor to consider is the relative effects of interaction on tumors and normal tissue and how this affects therapeutic gain. This is graphically represented by the schematic dose–response curves shown in Fig. 10.1 . Radiation as a monotherapy has a therapeutic gain represented by the offset between the tumor and normal tissue curves. Addition of systemic agents with additive or supra-additive cooperation will shift both curves to the left, but ideally the shift in the tumor curve is greater (as indicated by the longer arrow) compared to the normal tissue curve, thus enhancing treatment efficacy and therapeutic gain of the combined treatment. This forms the principle for combining radiation and systemic therapy in the definitive setting. However, in the palliative setting, one must carefully weigh the increased toxicities associated with concurrent treatment even when the addition of systemic agent may increase overall treatment efficacy.
A number of factors must be considered when making a decision about whether to hold or continue systemic therapy during radiation. Some factors are patient-specific, like a patient’s performance status and personal preferences and what role systemic therapy plays in the management of overall disease. For instance, some targeted systemic agents such as epidermal growth factor receptor (EGFR) inhibitors may not only play a critical role in controlling the patient’s extracranial metastatic disease but may also be essential in controlling central nervous system (CNS) metastases. It is unknown what effect holding EGFR inhibitors for the duration of radiation would have on the development of treatment resistance. Other factors are therapy specific. For instance, it is important to consider what is known about the safety profile of each drug when combined with radiation. The schedule of administration and half-life of the drug will determine how practical it is to hold the drug. The urgency of radiation treatment will determine if there is sufficient time to hold the drug to reduce levels low enough to avoid combined toxicity. If the patient is on a trial, there are frequently specific instructions about combining the agent with radiation that must be followed precisely. It is always a good idea to discuss this issue with the patient’s medical oncologist whenever possible.
For patients not on a trial, we recommend a systematic approach to evaluate all associated factors and come to an informed decision for each specific case. A flowchart describing one possible systematic approach is shown in Fig. 10.2 . We first ask what is known about the safety profile of combined radiation and a given systemic agent. If the safety profile is completely unknown, it is best to avoid using the drug concurrently whenever possible. We do not recommend using the mechanism of action as evidence for the presence or absence of interaction, as there have been surprises. For instance, CDK4/6 inhibitors, which were initially designed as mitigators of exposure to ionizing radiation due to their ability to arrest cells in G1—allowing for repair of DNA damage—have turned out to be potent radiosensitizers and were reported to induce severe toxicities in some instances. In order to get systemic therapy levels sufficiently low to minimize interaction with radiation, it is ideal to wait 3 to 4 elimination half-lives before starting RT, thus getting levels down to 6.25% to 12.5% of the therapeutic drug levels. Half-lives of many cytotoxic, targeted, and immunotherapy agents are listed in tables later in the chapter when these agents are discussed. However, if the radiation treatment must start urgently, such as in the case of cord compression or acute bleeding, it is not always possible to hold for 3 to 4 half-lives. In cases where the benefits of starting radiation urgently outweigh the risk of combined toxicity, it is important to start radiation immediately and ensure that no further systemic agent is administered until the radiation course is complete. Furthermore, for some agents—like many immune checkpoint blockade inhibitors—half-lives are too long to get drug levels below 12.5% in most cases. Fortunately, as discussed later in the chapter, it is feasible to administer these agents concurrently with RT in most cases. It should be noted that some agents, like paclitaxel, accumulate intracellularly at a much higher concentration than in the plasma, binding tightly to microtubules and thus preventing their elimination. For agents like this, a general rule of thumb of holding for 3 to 4 elimination half-lives does not hold. Even with a longer pause, it is not possible to entirely eliminate the possibility of increased combined toxicity. For agents such as anthracyclines and taxanes, instances of radiation recall—inflammatory reaction limited to previously irradiated tissues—can be triggered when systemic therapy is administered after completion of radiation.
Combining radiation with cytotoxic chemotherapy
Many conventional chemotherapy agents are radiosensitizing, resulting in increased toxicity when these drugs are combined with radiation. Agents with potent radiosensitizing activity include antimetabolites and nucleoside analogs, alkylating agents, platinum complexes, antimicrotubule agents (such as taxanes and vinca alkaloids), and anthracyclines, though other systemic agents can act as clinically significant radiosensitizers.
In the palliative setting where the goal of radiation treatment is to improve patients’ quality of life by relieving symptoms related to disease progression, it is particularly important to minimize treatment-related toxicity. For patients who are receiving systemic radiosensitizing drugs (or have recently been treated with radiosensitizers), we have historically carefully timed the delivery of radiation to minimize toxicity due to overlapping treatments without compromising disease control. For most chemotherapeutic drugs, it is safe to wait 3 to 4 half-lives (or at least 2 days for drugs with very short half-lives) after administration of the drug before starting radiation to allow for drug clearance. After completing radiation, it is reasonable to wait about 2 days before starting chemotherapy given the risk of a given drug interfering with the DNA damage repair process and cellular response to radiation in normal tissues. As discussed earlier, exceptions to this rule are agents with a higher risk of radiation recall or agents which accumulate and persist intracellularly for longer periods of time (e.g., taxanes), which may benefit from a longer hold.
Although the most conservative way to limit toxicity due to concurrent chemoradiation is to hold all systemic agents as described above, the goal of limiting toxicity must be balanced with the goal of controlling patients’ systemic disease. Thus, the timing of chemotherapy and RT must be considered a balance of risks and benefits, and we are learning that low doses of palliative RT and/or stereotactic body radiation therapy (SBRT) may be safe to give in conjunction with chemo/immunotherapy. Since patients on systemic chemotherapy regimens rely on timely delivery of these drugs to minimize their global disease burden, understanding the potential toxicities of concurrent radiation treatment allows us to more thoughtfully sequence radiation with chemotherapy. Studies of combination therapy in the definitive setting can offer insight into the specific risks of concurrent treatment.
The sections below summarize several key studies for different classes of frequently used systemic agents. These studies are not exhaustive but are representative of the types of studies that can guide our thinking about the risks of concurrent chemoradiation. When possible, we have included large phase III trials of radiation alone versus chemoradiation for each systemic agent; in the absence of this data, we turned to trials combining multiple drugs with radiation, or to smaller, early-phase studies of single agents in combination with radiation that were designed to assess toxicity and identify the maximum tolerated dose of these drugs. Although the data summarized below is difficult to apply directly to the palliative setting due to heterogeneity in trial design, radiation dose and fractionation, site of treatment (and therefore adjacent organs at risk [OARs]), and methods of toxicity reporting, these studies can be used to guide clinical assessments of risks versus benefits of radiation on a case-by-case basis.
Antimetabolites
Antimetabolites, which interfere with DNA and RNA synthesis, include 5-fluorouracil (5-FU), gemcitabine, and methotrexate. These agents are traditionally thought to be complementary to radiation because they are most toxic to cells undergoing active DNA synthesis, e.g., those in the relatively radioresistant S-phase. However, the interaction between antimetabolites and radiation is slightly more complicated since these agents also affect DNA damage repair rates in a non-cell-cycle-dependent manner. For example, 5-FU exerts its cytotoxic effect via inhibition of thymidylate synthase, leading to both misincorporation of fluoronucleotides into RNA and DNA as well as impaired DNA repair caused by deoxynucleotide pool imbalances.
5-FU has been used extensively as a radiosensitizer in the treatment of gastrointestinal (GI) malignancies and is well known to increase toxicity in this setting. Early trials on adjuvant RT for rectal cancer in the 1980s showed increased acute toxicity when adding 5-FU to radiation. For example, the GITSG adjuvant rectal study included randomization of patients to either adjuvant radiation alone or adjuvant chemoradiation with 5-FU (given during the first 3 days and last 3 days of radiation at 500 mg/m 2 ). In this small phase III trial with about 50 patients in each arm, the rate of severe toxicity in the combined modality arm was 61%, versus 18% in the radiation-only arm. Subsequently, the NCCTG 794751 trial, which also enrolled patients with high-risk rectal cancer, compared postoperative radiation alone (45 to 50.4 Gy) with postoperative chemoradiation (45 to 50.4 Gy with concurrent 5-FU at a dose of 500 mg/m 2 /day on days 1 to 3 and 21 to 23 of RT, preceded and followed by a 9-week cycle of 5-FU and methyl-CCNU). In this study, the chemoradiation arm showed an increase in acute toxicity, primarily hematologic (leukopenia: 78% vs. 21%; severe 18% vs. 0%) and GI (nausea: 38% vs. 6%; diarrhea: 59% vs. 42%; vomiting: 11% vs. 1%).
Following these early trials, subsequent studies have shown high rates of hematologic and GI toxicity in patients treated with RT+5-FU, though these trials were largely done without RT-only comparator arms. They are summarized in Table 10.1 . While most concurrent regimens with 5-FU and radiation limit delivery of 5-FU to the first and last weeks of RT, continuous infusion of 5-FU at lower doses has also been used concurrently throughout radiation in certain settings, e.g., as neoadjuvant therapy for patients with gastric cancer. In cases where patients getting 5-FU are being considered for palliative radiation, timing the delivery of radiation such that it does not overlap with 5-FU infusion (ideally with radiation starting 2 days after the last 5-FU infusion) would be advisable to limit toxicity.
TABLE 10.1
Summary of Antimetabolite Half-Life and Toxicity Data
| Drug | Half-Life | Study | Methods | Key Findings |
|---|---|---|---|---|
| 5-Fluorouracil Active metabolite FdUMP inhibits thymidylate synthase, resulting in decreased levels of dTTP and increased levels of dUMP (and consequently dUTP). Deoxynucleotide pool imbalances disrupt DNA synthesis and repair. dUTP and FdUTP are misincorporated into DNA, causing DNA damage. FUTP is misincorporated into RNA. |
Half-life following bolus infusion: 8–20 min (clearance can be faster when given via continuous infusion) | Phase III ( n = 227): post-op rectal , | Surgery followed by either adjuvant radiation alone or adjuvant chemoradiation with 5-FU (given during the first 3 days and last 3 days of radiation at 500 mg/m 2 /day) | Rate of severe toxicity in the combined modality arm was 61% versus 18% in the radiation only arm |
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Surgery followed by radiation alone (45–50.4 Gy) or 5FU+semustine -> RT+5FU -> 5FU+semustine. (5-FU dose w/RT: 500 mg/m 2 /day on days 1–3 and days 21–23 of RT.) |
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Surgery ± adjuvant CRT w/5FU/leucovorin: adjuvant treatment consisted of 5 days of daily 5-FU (425 mg/m 2 ) + leucovorin (20 mg/m 2 ), followed by 45 Gy in 25 fx w/400 mg/m 2 fluorouracil and 20 mg/m 2 leucovorin on the first 4 and the last 3 days of radiotherapy. |
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Randomized patients to either pre-op or post-op CRT (FU was given in a 120-hr continuous infusion at 1000 mg/m 2 /day during weeks 1 and 5 of radiotherapy); RT dose 50.4 Gy in 28 fx, with boost of 5.4 Gy in the post-op arm). |
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CRT either pre- or post-op, consisting of 5-FU + LV for 6 weeks followed by CRT w/50.4 Gy and concurrent chemotherapy weeks 1 and 5 of RT [FU (325 mg/m 2 for 5 days) w/ LV (20 mg/m 2 for 5 days)]. Both arms w/ subsequent adjuvant 5-FU/LV. |
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Patients w/resectable gastric cancer were treated w/ECF ± pre-op chemoradiation w/ 45 Gy in 25 fx plus CI 5-FU 200 mg/m 2 /day, 7 days per week throughout the entire period of radiotherapy (or capecitabine 825 mg/m 2 twice daily, days 1–5 each week of radiotherapy). | Similar toxicity in both arms—grade 3 or higher gastrointestinal toxicity occurred in 32% (ECF group) and 30% (chemoradiation group) of patients, while hematologic toxicity occurred in 50% and 52% of patients. | ||
| Gemcitabine Inhibits DNA synthesis via incorporation of dFdCTP. Radiosensitizes via inhibition of RNR and dATP depletion. |
Half-life (of gemcitabine triphosphate): 1.7–19.4 h |
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Patients underwent transurethral resection and induction CRT with either 5-FU + cisplatin + BID RT, or gemcitabine and once-daily RT to 40 Gy. Patients who achieved a complete response (CR) received consolidation CRT to 64 Gy and others underwent cystectomy. Gemcitabine dose: 27 mg/m 2 delivered twice a week. |
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| Phase I ( n = 32): post-op pancreatic cancer | Patients with resected pancreatic cancer were treated with between 24 and 42 Gy in 15 fractions to the pre-op tumor volume. Gemcitabine was given IV at full dose (1000 mg/m 2 weekly on days 1, 8, and 15), | Primary dose-limiting toxicity was grade 3 nausea/vomiting (2/2 at 42 Gy; 1/6 at 39 Gy). Max tolerated dose was 39 Gy in 15 fractions. | ||
| Retrospective review (n = 74): unresectable pancreatic cancer | Patients with locally advanced pancreatic cancer were treated with full-dose gemcitabine (1000 mg/m 2 weekly on days 1, 8, and 15) and concurrent radiotherapy to GTV w/1 cm expansion to PTV (36 Gy [median] in 15 daily fractions). |
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| Phase I (n = 29): locally advanced head and neck cancer | Patients with unresectable head and neck cancer received a course of radiation (70 Gy over 7 weeks, 5 days weekly) concurrent with weekly infusions of low-dose gemcitabine. | Severe acute and late mucosal and pharyngeal-related DLT required de-escalation of gemcitabine dose in successive patient cohorts receiving dose levels of 300 mg/m 2 /week, 150 mg/m 2 /week, and 50 mg/m 2 /week. No DLT was observed at 10 mg/m 2 /week. | ||
| Phase I (n = 27): stage III NSCLC | Patients w/stage III NSCLC received weekly gemcitabine during thoracic RT (3D-conformal) w/60 Gy in 30 fractions |
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| Methotrexate Binds to DHFR, inhibiting purine biosynthesis. Methotrexate-induced nucleotide depletion can indirectly affect DNA damage repair. |
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Single-arm prospective study of patients with leptomeningeal metastases (n = 59) | Intrathecal methotrexate once per week for 4 weeks (12.5–15 mg), with concurrent WBRT or partial spinal RT (86% received WBRT, 40 Gy in 20 fractions) | Severe neurotoxicity in 5% of patients ( n = 3); two deaths thought to be treatment-related |
| Concurrent CMF and RT for early-stage breast cancer ( n = 112) , | Six 4-week cycles of CMF (cyclophosphamide, 100 mg/m 2 /day PO, on days 1–14; methotrexate, 40 mg/m 2 IV on days 1 and 8; 5-FU 600 mg/m 2 IV on days 1 and 8) with concurrent RT (39.6 Gy in 22 fractions to the whole breast followed by boost to lumpectomy cavity of 16 Gy in 8 fractions; RT start on day 15–17 of cycle 1) | Moist desquamation in 54 patients (50%); 5 patients required treatment breaks due to acute desquamation |
Similar to 5-FU, gemcitabine acts as a potent radiosensitizer, even at low doses. It is intracellularly phosphorylated to gemcitabine triphosphate (dFdCTP), which directly interferes with DNA synthesis and is retained within cells for at least 72 hours (allowing for once- or twice-weekly dosing). The dose at which gemcitabine can be tolerated with concurrent radiation depends on the treatment site, radiation dose, and whether other systemic agents are being co-administered. Several phase I studies in different disease sites illustrating how the maximum tolerated dose of gemcitabine varies with both concurrent RT dose and treatment site are summarized in Table 10.1 . One study that looked at tolerance of concurrent gemcitabine with radiation for locally advanced head and neck cancer noted significant tumor and normal tissue radiosensitization by low-dose gemcitabine, with significant dose-limiting toxicity even at the relatively low dose of 50 mg/m 2 /week (in this cohort, confluent mucositis started between the fourth and sixth weeks of radiation, and five out of six patients receiving this dose experienced grade 3 acute toxicity). In contrast, no patients receiving gemcitabine at 10 mg/m 2 /week during radiation required a feeding tube or developed confluent mucositis. A separate phase I study investigating the maximum tolerated dose (MTD) in stage III non–small cell lung cancer (NSCLC) found that a dose of 300 mg/m 2 given weekly was well tolerated in patients receiving RT with 60 Gy in 30 fractions, while other trials of gemcitabine given with thoracic radiation have shown that the MTD of gemcitabine when given twice weekly is much lower (∼35 mg/m 2 given twice weekly). Finally, phase I studies in pancreatic cancer have shown that full-dose weekly gemcitabine (1000 mg/m 2 /week) has an acceptable toxicity profile when given concurrently with radiation to ∼36 to 39 Gy. ,
Methotrexate is another radiosensitizing antimetabolite that has been given concurrently with radiation. It inhibits dihydrofolate reductase and interferes with purine biosynthesis, and methotrexate-induced nucleotide depletion is thought to indirectly affect DNA damage repair. Overlapping toxicity profiles make concurrent treatment with radiation (particularly whole brain radiation therapy [WBRT]) and methotrexate particularly unsafe in the CNS, given the risk of neurotoxicity with high dose methotrexate (HD-MTX). In one study in which concurrent radiation and intrathecal methotrexate were given to poor-prognosis patients with leptomeningeal metastases from solid tumors, 51 out of 59 patients showed a partial or complete response to therapy, while only 8 patients had stable or progressive disease post-treatment. However, there was a risk of treatment-related death (2 out of 59 patients). Outside of the CNS, methotrexate has been given concurrently with dose-reduced radiation for early-stage breast cancer with acceptable levels of toxicity.
Generally, the radiosensitizing effects of antimetabolites tend to result in increased normal tissue toxicity when given concurrently with radiation. Outside of settings where these agents are being used specifically to enhance tumor control (and where there is data to guide the safe selection of both drug doses and radiation doses), it would be advisable to hold these agents for 3 to 4 half-lives prior to starting radiation and during radiation treatment. Fortunately, the short half-lives of most of these drugs makes this relatively easy to coordinate.
Alkylating agents
Alkylating agents, including cyclophosphamide, mitomycin C, temazolamide, and procarbazine, cause DNA damage through formation of adducts and DNA–DNA crosslinks. Many of these agents, like the antimetabolites discussed above, have relatively short half-lives, summarized in Table 10.2 . Of note, the nucleic acid adducts formed by these drugs can persist longer than the drugs themselves, and the persistence of these adducts is highly variable and dependent on cellular factors such as the rate of nucleotide excision repair. It is unclear how to account for the variable persistence of these adducts when timing radiation treatments, but we generally wait at least 2 days (if able) after drug delivery before starting radiation.
TABLE 10.2
Summary of Alkylating Agent Half-Life and Toxicity Data
| Drug | Half-Life | Study | Methods | Key Findings |
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| Cyclophosphamide Metabolized to phosphoramide mustard, a nitrogen mustard that cross-links DNA |
Half-life elimination: IV: 3–12 h |
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Concurrent vs. sequential CRT after conservative surgery for early-stage breast cancer. FNC chemo: Mitoxantrone (12 mg/m 2 ), fluorouracil (500 mg/m 2 ), and cyclophosphamide (500 mg/m 2 ) on day 1, repeated every 21 days for six courses. RT to breast ± LN; 50 Gy in 25 fx w/10–20 Gy boost to tumor bed. RT starting either C1D1 (concurrent) or 3–5 weeks after C6 (sequential) |
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| Mitomycin C Alkylates DNA |
Half-life elimination: 17 min (30 mg dose) |
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Greater toxicity in the MMC arm, predominantly hematologic (26% vs. 8% grade 4/5 toxicity, P < .001) |
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RT alone (45 Gy) vs. RT plus 5-FU (continuous infusion, 1000 mg/m 2 for 4 days or 750 mg/m 2 for 5 days during the first and last weeks of RT) and mitomycin C (12 mg/m 2 ) on day 1 of the first cycle of chemotherapy | More acute morbidities in CRT group (48% vs. 39%, P = .03), in all categories (hematologic, skin, GI, GU). | ||
| Phase III ( n = 103) | Similar to ACT-I—higher dose MMC (15 mg/m 2 ) on day 1 and 5-FU (750 mg/m 2 daily on days 1–5 and 29–33) w/RT 45 Gy over 5 weeks, followed by boost of 15–20 Gy 6 weeks after completion of initial RT. | Acute side effects (skin reactions and diarrhea) not significantly different between the RT and CRT arms. | ||
| Temozolomide | 1.8 h | Phase III: Glioblastoma | Patients with newly diagnosed GBM randomized to RT alone 60 Gy in 30 fractions vs. RT plus continuous daily temozolomide (75 mg/m 2 /day) followed by 6 cycles of adjuvant temozolomide (150–200 mg/m 2 for 5 days during each 28-day cycle). | RT+temozolomide resulted in grade 3–4 hematologic toxic effects in 7% of patients vs. 0% in RT-only group. |
| Procarbazine | ∼1 h | Radiation plus concurrent and adjuvant procarbazine, lomustine and vincristine in patients with malignant glioma | Patients with WHO grade III or IV glioma treated with IFRT concurrently with CCNU (75–110 mg/m 2 ), procarbazine (60 mg/m 2 ) and vincristine (1.4 mg/m 2 ) starting 2 weeks after surgery | Grades 3–4 hematologic toxicity 25% on higher dose of CCNU, 13% on lower dose of CCNU. Radiation necrosis in 10.3% of patients |
Mitomycin C is a short-lived alkylating agent that carries a high risk of hematologic toxicity. It has been delivered at doses of 10 to 15 mg/m 2 with concurrent 5-FU and radiation to the pelvis with acceptable levels of toxicity in the treatment of anal cancer. Radiation Therapy Oncology Group (RTOG) 87-04 was a phase III study of n = 291 patients with anal cancer who received 45 to 50.4 Gy of pelvic radiation + 5-FU with or without mitomycin C at 10 mg/m 2 per dose for two doses. This study found significantly higher rates of toxicity—predominantly hematologic—in patients who received mitomycin C (26% vs. 8% with grade 4/5 toxicity, P < .001). The Anal Cancer Trial (ACT I) compared pelvic radiation alone to chemoradiation with mitomycin C and 5-FU for the treatment of anal cancer and found that the additional toxicity due to 5-FU (1000 mg/m 2 /day for 4 days or 750 mg/m 2 /day for 5 days during the first and final weeks of radiotherapy) and mitomycin (12 mg/m 2 on day 1) was predominantly acute with a significant increase in early morbidity, including skin toxicity (27% -> 32%) and GI toxicity (14% -> 16%). In this trial, radiation consisted of 45 Gy in 20 to 25 fractions followed by a boost (of 15 Gy in 6 fractions or 25 Gy with Ir-192) that was delivered ∼6 to 7 weeks after completion of initial radiotherapy and was contingent on response to initial treatment. ,
Other alkylating agents with short half-lives include cyclophosphamide, temazolamide, and procarbazine. Cyclophosphamide, which is metabolized to a nitrogen mustard that cross-links DNA, has been given concurrently with radiation. In the ARCOSEIN trial studying concurrent versus sequential chemoradiation following surgery for early-stage breast cancer, concurrent delivery of breast radiation to 50 Gy in 25 fractions with FNC (fluorouracil, mitoxantrone, cyclophosphamide) chemotherapy (including cyclophosphamide given every 3 weeks at a dose of 500 mg/m 2 given every 3 weeks) yielded higher rates of esophagitis and anemia. CMF (cyclophosphamide, methotrexate, 5-fluorouracil) chemotherapy (including cyclophosphamide given daily on days 1 to 14 of each 4-week cycle at a dose of 100 mg/m 2 /day) has also been given concurrently with breast radiation in the adjuvant setting with acceptable levels of toxicity. Temozolomide and procarbazine provide examples of alkylating agents with very short half-lives (1 to 2 hours) that can be held for just 1 to 2 days prior to radiation and restarted within 1 to 2 days after completion of radiation.
Taxanes
Taxanes, including paclitaxel and docetaxel, are a class of drugs that bind to β-tubulin, promoting microtubule assembly and inhibiting depolymerization. Early studies suggested that taxanes lead to an arrest in the radiosensitive G2/M phases of the cell cycle; this taxane-mediated mitotic arrest is thought to lead to synergy between taxanes and radiation. More recently, studies have shown that paclitaxel causes only a very transient mitotic delay at clinically relevant doses of paclitaxel but results in highly abnormal chromosome missegregation, leading to radiosensitization. ,
Paclitaxel has been used as a radiosensitizer in conjunction with both breast and thoracic radiotherapy, and studies in both of these settings identified principal toxicities of pneumonitis and esophagitis with paclitaxel weekly doses between 45 and 60 mg/m 2 /week. A phase I dose-escalation study of n = 40 stage II or III breast cancer patients who received concurrent RT with paclitaxel after surgery and four cycles of AC found that dose-limiting toxicity—predominantly pneumonitis—was reached in 4 of 16 patients (25%) who received weekly paclitaxel at 60 mg/m 2 per week with concurrent radiation. A separate study of n = 51 patients with unresectable locoregionally recurrent breast cancer treated with radiation (60 Gy in 30 fractions) and concurrent weekly paclitaxel at 50 mg/m 2 found lower rates of pneumonitis. Another phase I/II study of n = 44 patients with locally advanced breast cancer found low rates of toxicity when paclitaxel was dosed twice weekly at 30 mg/m 2 with concurrent radiation; of note, this bi-weekly dosing schedule was chosen after weekly paclitaxel at 60 mg/m 2 led to skin and esophageal toxicity in 2 patients. For lung cancer, a phase I dose-escalation study of n = 27 patients with advanced NSCLC found that a dose of 70 mg/m 2 /week of paclitaxel in conjunction with radiation (60 Gy in 30 fractions) resulted in unacceptable levels of esophagitis, while a dose of 60 mg/m 2 /week had acceptable toxicity. In RTOG 0617, a phase III trial investigating both dose escalation from 60 to 74 Gy and the addition of cetuximab in the treatment of stage III NSCLC, both paclitaxel (45 mg/m 2 ) and carboplatin (AUC 2) were given weekly during radiation. This study found rates of pulmonary toxicity near 20% in both the 60 and 74 Gy arms, with higher rates of esophagitis and dysphagia in the high-dose arm (20.8% vs. 7.3%).
While nab-paclitaxel (Abraxane) has replaced paclitaxel in many systemic regimens, concerns about esophagitis and pneumonitis remain largely the same. Several recent studies of nab-paclitaxel with or without carboplatin in combination with thoracic radiation in NSCLC found this combination to be safe; others reported severe toxicity.
Docetaxel has also been given concurrently with radiation, with dose escalation trials generally finding that 15 to 30 mg/m 2 of docetaxel can be tolerated during radiation to the chest, head, and neck with acceptable toxicity. Two independent studies of docetaxel with concurrent RT for squamous cell carcinoma (SCC) of the head and neck used doses of 15 to 25 mg/m 2 weekly with good effect. , One phase I dose-escalation trial of docetaxel with concurrent chest radiotherapy (60 Gy in 1.8 to 2.0 Gy daily fractions) found a maximum-tolerated dose (MTD) of 20 mg/m 2 /week for docetaxel with esophagitis as a major dose-limiting toxicity. Another small phase I/II trial of patients with stage III/IV NSCLC treated with radiation (64 Gy) and weekly docetaxel found an MTD of 30 mg/m 2 /week. A subsequent phase III trial of patients with locally advanced NSCLC included a treatment regimen of docetaxel at a higher dose (40 mg/m 2 /week) with cisplatin (40 mg/m 2 /week) and concurrent thoracic radiation (60 Gy in 30 fractions). Of 99 patients treated with this regimen, 14% developed grades 3 and 4 esophagitis, and 10% developed grades 3 to 5 pneumonitis (including 2 patients with grade 5 pneumonitis).
In summary, taxanes are effective radiosentitizers of both tumors and normal tissue and thus can lead to increased toxicity including esophagitis and pneumonitis, especially for large radiation fields. Taxanes accumulate intracellularly at large concentrations by binding stably to microtubules; thus, waiting 3 to 4 elimination half-lives may be insufficient to eliminate increased toxicity risk. However, many trials described above and summarized in Table 10.3 show that concurrent or close sequential administration of taxanes can be tolerated, especially with smaller radiation fields that do not involve a large volume of the lung or esophagus.
TABLE 10.3
Summary of Taxane Half-Life and Toxicity Data
| Drug | Half-Life | Study | Methods | Key Findings |
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| Paclitaxel (Taxol) Stabilizes microtubules and inhibits their disassembly; interferes with late G2/M phase; induces tripolar mitoses and chromosome mis-segregation |
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Phase I ( n = 27): advanced NSCLC | Dose escalation study of paclitaxel with concurrent thoracic radiation (60 Gy in 30 fractions); paclitaxel was increased from 10 mg/m 2 /week for 6 weeks during radiation to 70 mg/m 2 /week. | DLT was esophagitis; MTD was 60 mg/m 2 /week. At 60 mg/m 2 /week, only one of seven patients had grade 3 esophagitis (none w/grade 4/5 esophagitis).Severe (grade 4) esophagitis in two of three patients treated w/paclitaxel at 70 mg/m 2 /week. |
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2 × 2 design = 60 Gy vs. 74 Gy, ± cetuximab. All patients received concurrent chemotherapy with 45 mg/m 2 paclitaxel and carboplatin once a week (AUC 2) | Toxicities (grade 3 or greater): esophagitis and/or dysphagia: 16 patients (7.3%) in the SD arm and 43 (20.8%) in the HD arm. Pulmonary toxicity: ∼20% in both arms. [No benefit to higher dose or cetuximab.] | ||
| Phase I dose–escalation study ( n = 40): Stage II/III breast cancer |
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Dose-limiting toxicity was reached in 4 of 16 patients (25%; 3 w/pneumonitis) who received weekly paclitaxel at 60 mg/m 2 per week with concurrent RT. No DLT in patients getting paclitaxel q3wk. | ||
| Single-center prospective study ( n = 51) of CRT for unresectable locoregionally recurrent breast cancer | Patients received RT (60 Gy in 30 fx) with weekly paclitaxel at 50 mg/m 2 for 5 weeks. | No grade 4 toxicity was observed. Grade 3 radiation dermatitis and leukocytopenia were observed in 10 (19.6%) and 12 (23.5%) pts., respectively. One patient experienced grade 2 pneumonitis. Normal tissue metrics: ipsilateral lung, mean <15 Gy, V20 <30%; contralateral lung, V5 <10%; spinal cord, max <45 Gy; humeral head, mean <25 Gy; heart, mean <8 Gy for left-sided lesions and <2 Gy for right-sided lesions. | ||
| Phase I/II ( n = 44): Stage IIB (T3N0) to III LABC patients | Primary chemoradiation consisted of paclitaxel (30 mg/m 2 twice weekly) for a total of 8–10 weeks, with concurrent RT (45 Gy at 1.8 Gy/fraction). [One reason for twice-weekly dosing of paclitaxel was that initial dose of 60 mg/m 2 weekly led to skin/esophageal toxicity] | Toxicity from paclitaxel+RT included grade 3 skin desquamation (7%), hypersensitivity (2%), and stomatitis (2%). | ||
| Docetaxel (Taxotere) Inhibits tubulin depolymerization, stabilizing microtubules; most active in M phase | ∼11 h | RTOG-0234Phase II ( n = 238): stage III to IV SCCHN s/p GTR | 60 Gy radiation with cetuximab once per week plus either cisplatin 30 mg/m 2 or docetaxel 15 mg/m 2 once per week. | 15 mg/m 2 docetaxel weekly was tolerated |
| Phase I/II ( n = 21): stage III-IV SCCHN | All patients treated w/2–3 cycles of induction chemo (cisplatin + 5-FU). Subsequent treatment consisted of docetaxel at either 20, 25, or 30 mg/m 2 weekly for 6 weeks with concurrent daily RT (68–74 Gy in 2-Gy fractions). |
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| Phase I ( n = 29): advanced NSCLC or esophageal cancer | Docetaxel was administered as two 21-day cycles at doses of 40, 60, and 75 mg/m 2 per cycle as follows: weekly (20 or 25 mg/m 2 on days 1, 8, and 15); twice per cycle (20 or 30 mg/m 2 on days 1 and 8); or once per cycle (40 or 60 mg/m 2 on day 1). Concurrent standard chest radiotherapy was given for 6 weeks (60 Gy in 1.8- to 2.0-Gy daily fractions). | MTD recommended for phase II study: 20 mg/m 2 weekly. Rates of grades 3–4 esophagitis: two out of six patients at 20 mg/m 2 /week; four out of six patients at 25 mg/m 2 /week | ||
| Nab-paclitaxel (Abraxane) Albumin-bound paclitaxel nanoparticle formulation |
13–27 h | Phase II ( n = 10): unresectable NSCLC | Patients received weekly nab-PTX (40 mg/m 2 ) plus carboplatin (AUC 2) and thoracic radiotherapy (60 Gy/30 fractions) for a total of 6 weeks. After concurrent chemoradiotherapy, patients received an additional two cycles of consolidation phase chemotherapy that consisted of 4-week cycles of nab-PTX (100 mg/m 2 on days 1, 8 and 15)/carboplatin (AUC 5 mg/ml/min on day 1). | Treatment-related death occurred in two patients. Grade 2 or worse severe radiation pneumonitis was observed in all three patients that had the volume of lung receiving at least 20 Gy (V20) >30%. |
| Phase I ( n = 10): unresectable stage III NCSLC | Weekly nab-paclitaxel w/ carboplatin (AUC 2) and concurrent RT 66 Gy in 33 fx, followed by 2 cycles consolidation chemo |
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| Phase I ( n = 30): neoadjuvant CRT in borderline resectable pancreatic cancer | Patients with BRPC received gemcitabine (1000 mg/m 2 )/ nab-paclitaxel (125 mg/m 2 ) on days 1, 8, and 15 during each 4-week cycle, which was repeated for 2 cycles as induction chemotherapy. After induction chemotherapy, patients received gemcitabine/nab-paclitaxel with concurrent radiation therapy. During CRT, the patients were scheduled to receive gemcitabine/nab-paclitaxel at 7 dose levels using a standard 3 + 3 dose escalation scheme. Radiation therapy was concurrently delivered at a total dose of 60 Gy | The recommended dose (RD) of gemcitabine/nab-paclitaxel was determined to be level 5 (gemcitabine, 800 mg/m 2 ; nab-paclitaxel, 100 mg/m 2 ). Primary toxicity: neutropenia | ||
| Phase I ( n = 9): Neoadjuvant CRT in locally advanced pancreatic cancer | Weekly nab-paclitaxel (100 mg/m 2 or 125 mg/m 2 ) w/RT (52.5 Gy in 25 fx) | No observed grade 3 gastrointestinal toxicities. One DLT (grade 3 neuropathy) was observed in a patient who received 125 mg/m 2 of nab-paclitaxel. |
Platinum compounds
Platinum complexes are effective radiosensitizers. Because of this, they are often administered concurrently with radiation in the definitive setting. Similarly to alkylating agents, they create DNA adducts and DNA–DNA crosslinks. In contrast with alkylating agents, most of the crosslinks are intrastrand, requiring nucleotide excision repair (NER) pathway for repair. There are multiple proposed mechanisms of interaction between platinum compounds and radiation. One simple model is that formation of cisplatin adducts in close proximity to radiation-induced DNA lesions may prevent repair of these lesions, leading to cell death. Alternative models propose that (1) radiation may increase cellular cisplatin uptake, (2) radiation and cisplatin may synergize due to cell cycle effects, and (3) cisplatin may inhibit the repair of radiation-induced DNA lesions. ,
Because of its radiosensitizing properties, cisplatin can increase radiation toxicity. For instance, RTOG 9410 compared sequential versus concurrent chemoradiation for stage III NSCLC and found that concurrent bolus cisplatin (100 mg/m 2 , weeks 1 and 5), vinblastine (5 mg/m 2 ), and radiation (63 Gy in 34 fractions) resulted in significantly more acute esophagitis than sequential cisplatin/vinblastine followed by RT, with 23% of patients experiencing grade 3 or 4 esophagitis in the concurrent arm versus 4% in the sequential arm. In a phase III study of patients with locally advanced laryngeal cancer who were randomized to either radiotherapy alone, chemotherapy (with cisplatin plus fluorouracil) followed by radiotherapy, or radiotherapy with concurrent cisplatin, both locoregional control and laryngeal preservation were significantly higher in the patients receiving concurrent chemoradiation compared with those receiving sequential treatment. However, acute and long-term toxicity with concurrent chemoradiation were higher than with sequential treatment. Rates of mucosal grade 3 or 4 toxicity were 43% in the concurrent arm versus 24% in the sequential arm, and the fraction of patients restricted to swallowing only soft foods and liquids at 1 year was higher in the concurrent arm (23% vs. 9%). Other studies combining platinum compounds and radiation are summarized in Table 10.4 .
TABLE 10.4
Summary of Platinum Compound Half-Life and Toxicity Data
| Drug | Half-Life | Study | Methods | Key Findings | |
|---|---|---|---|---|---|
| Cisplatin | Half-life: initial phase 20–30 min; terminal plasma elimination half-life for total platinum 5-10 days |
Intergroup 0099 : Phase III ( n = 147): chemoradiotherapy vs radiotherapy in patients with advanced nasopharyngeal cancer | 70 Gy in 35 to 39 fractions ± cisplatin 100 mg/m 2 on days 1, 22, and 43 during RT. Postradiotherapy, chemotherapy with cisplatin 80 mg/m 2 on day 1 and fluorouracil 1000 mg/m 2 /day on days 1–4 was administered every 4 weeks for 3 cycles. | 3-year OS 47% for RT group vs. 78% for CRT group ( P = .005). | Tox: grade 3 leukopenia, N/V, and hearing impairment higher in CRT arm. |
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| GOG 123 , : Phase III ( n = 369): RT vs. CRT for bulky stage IB cervical carcinoma | 369 evaluable patients; 186 were randomly allocated to receive RT alone and 183 to receive CT+RT. Radiation dosage was 45 Gy in 20 fractions followed by low dose-rate intracavitary application(s) of 30 Gy to Point A. Chemotherapy: intravenous cisplatin 40 mg/m 2 every week for up to 6 weekly cycles. Total extrafascial hysterectomy 6–8 weeks after the completion of RT. | 6-year OS: 78% CRT vs. 64% RT only | Grade 3 or 4 hematologic and GI toxicity: 35% CRT vs. 13% RT alone. No difference in late adverse events. | ||
| Carboplatin | Elimination half-life (normal renal function): 2.6–5.9 h; Platinum (from carboplatin): ≥5 days | CROSS trial : Phase III ( n = 366): resectable esophageal cancer |
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1% grade ≥3 esophagitis | |
| RTOG 0617 : Phase III ( n = 544): stage IIIA/IIIB NSCLC | 2 × 2 design = 60 Gy vs. 74 Gy, ± cetuximab. All patients received concurrent chemotherapy with 45 mg/m 2 paclitaxel and carboplatin once a week (AUC 2) | No benefit to higher dose (70 Gy) or cetuximab. | |||
| Oxaliplatin | Tri-exponential clearance with half-lives (successively) ∼0.28–0.43 h; ∼16–17 h, and 11–16 days. | NSABP R-04 : Phase III ( n = 1608) | 5FU (225 mg/m 2 /day continuous infusion 5 days/week during RT) or Capecitabine (825 mg/m 2 po bid 5 days/week during RT) ± oxaliplatin (50 mg/m 2 IV weekly ×5 during RT) in rectal cancer | More toxicity w/ addition of oxaliplatin | Overall grade 3+ toxicities were substantially greater in the oxaliplatin-containing arms. This was primarily the result of an increase in grades 3 and 4 diarrhea ( P < .0001) with the addition of this agent (grade >3 diarrhea: 6.9% w/5-FU -> 16.5% w/5-FU+ oxaliplatin; 6.9% w/capecitabine -> 16.5% w/capecitabine + oxaliplatin) |
| CALGB 89901 : Phase I/II ( n = 44) | Patients with clinical T3/T4 rectal adenocarcinoma and no evidence of metastases were treated with weekly oxaliplatin (for 6 weeks), continuous infusion FU 200 mg/m 2 intravenously, and RT (50.4 Gy in 28 fractions). In the phase I portion, oxaliplatin was escalated from 30 to 60 mg/m 2 | The maximum-tolerated dose (MTD) for oxaliplatin was 60 mg/m 2 . At the MTD, 12 out of 32 patients experienced grade 3 or 4 diarrhea. | |||
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